WO2013063468A1 - Amino acid derivates functionalized on the n- terminal capable of forming drug incapsulating microspheres - Google Patents
Amino acid derivates functionalized on the n- terminal capable of forming drug incapsulating microspheres Download PDFInfo
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- WO2013063468A1 WO2013063468A1 PCT/US2012/062222 US2012062222W WO2013063468A1 WO 2013063468 A1 WO2013063468 A1 WO 2013063468A1 US 2012062222 W US2012062222 W US 2012062222W WO 2013063468 A1 WO2013063468 A1 WO 2013063468A1
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- optionally substituted
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- certain embodiments
- alkyl
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Definitions
- RNAi RNA interference
- RNA-induced silencing complex (Whitehead supra).
- the RISC associates with and degrades complementary mRNA sequences, thereby preventing translation of the target mRNA into protein, i.e., "silencing" the gene.
- nucleotides have been complexed with a wide variety of delivery systems, including polymers, lipids, inorganic nanoparticles and viruses. See, e.g., Peer et al. Nature Nanotechnology, (2007) 2:751-760.
- delivery systems including polymers, lipids, inorganic nanoparticles and viruses.
- siRNA continues to require development of safer and more effective delivery systems.
- numerous lipid-like molecules have been developed including poly ⁇ -amino esters and amino alcohol lipids. See, e.g., PCT Application
- inventive compounds and compositions characterized, in certain embodiments, by conjugation of various groups, such as lipophilic groups, to an amino or amide group of an amino acid, a linear or cyclic peptide, a linear or cyclic polypeptide, or structural isomer thereof, to provide compounds of the present invention, collectively referred to herein as "APPLs".
- groups such as lipophilic groups
- Such APPLs are deemed useful for a variety of applications, such as, for example, improved nucleotide delivery.
- Exemplary APPLs include, but are not limited to, compounds of Formula (I),
- APPL comprises at least one instance of a group of formula (i), (ii), or (iii):
- each instance of R' is independently hydrogen or optionally substituted alkyl
- X is O, S, NR , wherein R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- Y is O, S, NR , wherein R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- R p is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; and
- R L is optionally substituted Ciso alkyl, optionally substituted C 2 -50 alkenyl, optionally substituted C 2 -50 alkynyl, optionally substituted heteroCi-so alkyl, optionally substituted heteroC2-5o alkenyl, optionally substituted heteroC2-so alkynyl, or a polymer.
- the group of formula (i) represents a group of formula
- the group of formula (i-a) is a group of formula (i-al) or a group of formula (i-a2):
- the group of formula (i-b) is a group of formula (i-bl) or a group of formula (i-b2):
- At least one instance of R 1 is a group of formula: wherein L is an optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene, and
- R 6 and R 7 are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group;
- R 6 and R 7 is a group of formula:
- each instance of R' is independently hydrogen or optionally substituted alkyl
- X is O, S, NR X , wherein R X is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- Y is O, S, NR Y , wherein R Y is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- R p is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; and
- R L is optionally substituted C 1-5 o alkyl, optionally substituted C 2 -50 alkenyl, optionally substituted C 2 -50 alkynyl, optionally substituted heteroCi-so alkyl, optionally substituted heteroC 2 -5o alkenyl, optionally substituted heteroC 2 -so alkynyl, or a polymer.
- each instance of R' is hydrogen.
- L is an optionally substituted alkylene.
- th rmula (iv) is of formula:
- q is an integer between 1 and 50, inclusive.
- each instance of R 1 is a group of formula (iv).
- An exemplary APPL of the present invention is compound (cKK-E12):
- compositions comprising an APPL or a salt thereof.
- composition comprising an
- the composition is a pharmaceutical composition, a cosmetic composition, a nutraceutical composition, or a composition with non-medical application.
- the composition with non-medical application is an emulsion or emulsifier useful as a food component, for extinguishing fires, for disinfecting surfaces, or for oil cleanup.
- the composition further comprises an agent.
- the agent is an organic molecule, inorganic molecule, nucleic acid, protein, peptide, polynucleotide, targeting agent, an isotopically labeled chemical compound, vaccine, an immunological agent, or an agent useful bioprocessing, e.g., in the intracellular
- the agent is a polynucleotide, and the polynucleotide is DNA or RNA.
- the RNA is RNAi, dsRNA, siRNA, shRNA, miRNA, or antisense RNA.
- the agent and the APPL are not covalently attached, e.g., for example, the agent and the APPL are non-covalently complexed to each other. However, in certain embodiments, the agent and the APPL are covalently attached.
- the composition is in the form of a particle.
- the particle is a nanoparticle or microparticle.
- the particle is a micelle, liposome, or lipoplex.
- the particle encapsulates an agent, e.g. , an agent to be delivered.
- a method of delivering a polynucleotide to a biological cell comprising providing a composition comprising an APPL, or salt thereof, and a polynucleotide, and exposing the composition to the biological cell under conditions sufficient to facilitate delivery of the polynucleotide into the interior of the biological cell; wherein the APPL is an amino acid, a linear or cyclic peptide, or a linear or cyclic polypeptide, or structural isomer thereof, wherein an amino or amide group of the APPL is conjugated to a group of formula (i), (ii), or (iii).
- the polynucleotide is DNA or RNA.
- the RNA is RNAi, dsRNA, siRNA, shRNA, miRNA, or antisense RNA.
- the RNA upon delivery of the RNA into the cell, the RNA is able to interfere with the expression of a specific gene in the biological cell.
- screening methods for example, in one embodiment, provided is a method of screening a compound library, the method comprising providing a plurality of different APPLs, or salts thereof, and performing at least one assay with the compound library to determine the presense or absence of a desired property;
- APPL is an amino acid, a linear or cyclic peptide, or a linear or cyclic polypeptide, or structural isomer thereof, wherein an amino or amide group of the APPL is conjugated to a group of formula (i), (ii), or (iii).
- the desired property is solubility in water, solubility at different pH, ability to bind polynucleotides, ability to bind heparin, ability to bind small molecules, ability to bind protein, ability to form microparticles, ability to increase tranfection efficiency, ability to support cell growth, ability to support cell attachment, ability to support tissue growth, and/or intracellular delivery of the APPL and/or an agent complexed or attached thereto to aid in bioprocessing.
- a method of treating a disease, disorder, or condition from which the subject suffers comprising administering to a subject in need thereof an effective amount of an APPL, or salt thereof, wherein the APPL is an amino acid, a linear or cyclic peptide, or a linear or cyclic polypeptide, or structural isomer thereof, wherein an amino or amide group of the APPL is conjugated to a group of formula (i), (ii), or (iii).
- Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
- the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
- Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
- HPLC high pressure liquid chromatography
- the invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
- alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 50 carbon atoms ("Ci-so alkyl"). In some embodiments, an alkyl group has 1 to 40 carbon atoms (“C ⁇ o alkyl”).
- an alkyl group has 1 to 30 carbon atoms ("C ⁇ o alkyl”). In some embodiments, an alkyl group has 1 to 20 carbon atoms ("C ⁇ o alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C ⁇ o alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("Ci-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C ⁇ alkyl”).
- an alkyl group has 1 to 5 carbon atoms ("Q-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“Ci_ 2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Q alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2 -6 alkyl”).
- Ci_6 alkyl groups include methyl (CO, ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ).
- alkyl groups include n-heptyl (C 7 ), n-octyl (Cg) and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents. In certain embodiments, the alkyl group is an unsubstituted Ciso alkyl. In certain embodiments, the alkyl group is a substituted Ciso alkyl.
- heteroalkyl refers to an alkyl group as defined herein which further includes at least one heteroatom (e.g., 1 to 25, e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, sulfur, nitrogen, boron, silicon, or phosphorus within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
- a heteroalkyl group refers to a saturated group having from 1 to 50 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-so alkyl").
- a heteroalkyl group refers to a saturated group having from 1 to 40 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroC ⁇ o alkyl"). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 30 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi ⁇ o alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC ⁇ o alkyl").
- a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-io alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-9 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-g alkyl").
- a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-7 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi ⁇ alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroCi-5 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain (“heteroC ⁇ alkyl").
- a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain ("heteroCi-3 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain
- heteroC ⁇ alkyl a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroC 2 -6 alkyl"). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-so alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-so alkyl.
- alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 50 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds) ("C 2 -50 alkenyl”). In some embodiments, an alkenyl group has 2 to 40 carbon atoms ("C 2 - 0 alkenyl”). In some embodiments, an alkenyl group has 2 to 30 carbon atoms (“C 2 -30 alkenyl”). In some embodiments, an alkenyl group has 2 to 20 carbon atoms (“C 2 - 20 alkenyl”).
- an alkenyl group has 2 to 10 carbon atoms ("C 2 - 10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2 -9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2 -8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2 _ 7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2 -6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2 _5 alkenyl”).
- an alkenyl group has 2 to 4 carbon atoms ("C 2 _4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2 -3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms ("C 2 alkenyl”).
- the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1- butenyl).
- Examples of C 2 - alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
- Examples of C 2 -6 alkenyl groups include the aforementioned C 2 - alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (Cg), octatrienyl (Cg), and the like.
- each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents.
- the alkenyl group is an unsubstituted C 2 -50 alkenyl.
- the alkenyl group is a substituted C 2 -50 alkenyl.
- heteroalkenyl refers to an alkenyl group as defined herein which further includes at least one heteroatom (e.g., 1 to 25, e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, sulfur, nitrogen, boron, silicon, or phosphorus within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
- a heteroalkenyl group refers to a group having from 2 to 50 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 -so alkenyl").
- a heteroalkenyl group refers to a group having from 2 to 40 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 ⁇ o alkenyl"). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 30 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 - 3 o alkenyl"). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 - 2 o alkenyl").
- a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -io alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -9 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 -g alkenyl").
- a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -7 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-6 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2
- heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms within the parent chain ("heteroC 2 ⁇ alkenyl”).
- a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain ("heteroC 2 -3 alkenyl”).
- a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2 -6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is
- the heteroalkenyl group is an unsubstituted heteroC 2 -so alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-so alkenyl.
- alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 50 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) and optionally one or more double bonds (e.g., 1, 2, 3, or 4 double bonds) ("C 2 -50 alkynyl").
- An alkynyl group that has one or more triple bonds and one or more double bonds is also referred to as an "ene-yene”.
- an alkynyl group has 2 to 40 carbon atoms ("C 2 - 0 alkynyl").
- an alkynyl group has 2 to 30 carbon atoms ("C 2 -30 alkynyl”). In some embodiments, an alkynyl group has 2 to 20 carbon atoms ("C 2 - 20 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2 - 10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2 -9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2 -8 alkynyl").
- an alkynyl group has 2 to 7 carbon atoms ("C 2 _ 7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2 -6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2 -5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2 ⁇ alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2 _ 3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms ("C 2 alkynyl”).
- the one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
- Examples of C 2 - alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
- Examples of C 2 -6 alkenyl groups include the aforementioned C 2 - alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like.
- alkynyl examples include heptynyl (C 7 ), octynyl (Cg), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C 2 _ 5 o alkynyl. In certain embodiments, the alkynyl group is a substituted C 2 _ 5 o alkynyl.
- heteroalkynyl refers to an alkynyl group as defined herein which further includes at least one heteroatom (e.g., 1 to 25, e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, sulfur, nitrogen, boron, silicon, or phosphorus within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
- a heteroalkynyl group refers to a group having from 2 to 50 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 _so alkynyl").
- a heteroalkynyl group refers to a group having from 2 to 40 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 ⁇ o alkynyl"). In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 30 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 _3o alkynyl"). In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 _ 2 o alkynyl").
- a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC ⁇ io alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 _9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 _g alkynyl").
- a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 _7 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 _6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2 _5 alkynyl").
- a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain ("heteroC 2 _ alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 2 _3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2 -6 alkynyl").
- each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents.
- the heteroalkynyl group is an unsubstituted heteroC 2 -5o alkynyl.
- the heteroalkynyl group is a substituted heteroC2-5o alkynyl.
- Carbocyclyl or “carbocyclic” refers to a radical of a non- aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ('3 ⁇ 4_ 10
- carbocyclyl and zero heteroatoms in the non-aromatic ring system.
- a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3 _g carbocyclyl").
- a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3 _7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3 _6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4 _6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“Cs_6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("Cs-io carbocyclyl”). Exemplary C 3 _6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ),
- cyclopropenyl C 3
- cyclobutyl C 4
- cyclobutenyl C 4
- cyclopentyl C 5
- cyclopentenyl C 5
- cyclohexyl C 6
- cyclohexenyl C 6
- cyclohexadienyl C 6
- Exemplary C 3 _g carbocyclyl groups include, without limitation, the aforementioned C 3 _ 6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (Cg), cyclooctenyl (Cg), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (Cg), and the like.
- Exemplary C 3 _ 10 carbocyclyl groups include, without limitation, the
- C 3 _g carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C 9 ), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (C 10 ), and the like.
- the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
- Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
- each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl”) with one or more substituents.
- the carbocyclyl group is an unsubstituted C 3 _ 10 carbocyclyl.
- the carbocyclyl group is a substituted C 3 _ 10 carbocyclyl.
- Carbocyclyl or “carbocyclic” is referred to as a
- cycloalkyl i.e., a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“Cs-io cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3 _ 8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3 _6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4 _6 cycloalkyl").
- a cycloalkyl group has 5 to 6 ring carbon atoms ("C5_6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("Cs-io cycloalkyl"). Examples of C 5 _6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ). Examples of C 3 _ 6 cycloalkyl groups include the aforementioned C 5 _6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
- C 3 _ 8 cycloalkyl groups include the aforementioned C 3 _6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
- each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl”) with one or more substituents.
- the cycloalkyl group is an unsubstituted C 3 _ 10 cycloalkyl.
- the cycloalkyl group is a substituted C 3 _ 10 cycloalkyl.
- heterocyclyl or “heterocyclic” refers to a radical of a 3- to
- 14-membered non-aromatic ring system having ring carbon atoms and 1 or more ⁇ e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, or phosphorus ("3-14 membered heterocyclyl").
- the point of attachment can be a carbon or nitrogen atom, as valency permits.
- a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic ⁇ e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds.
- Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
- Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
- each instance of heterocyclyl is independently unsubstituted (an
- heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
- a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, or phosphorus ("5-10 membered heterocyclyl").
- a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, or phosphorus ("5-8 membered heterocyclyl").
- a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, or phosphorus ("5-6 membered heterocyclyl").
- the 5-6 membered heterocyclyl has 1 or more (e.g., 1, 2, or 3) ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, or phosphorus.
- the 5-6 membered heterocyclyl has 1 or 2 ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, or phosphorus.
- the 5-6 membered heterocyclyl has 1 ring heteroatom selected from oxygen, sulfur, nitrogen, boron, silicon, or phosphorus.
- Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
- Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
- Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,
- Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
- Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
- Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
- Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl.
- heterocyclyl groups containing 2 heteroatoms include, without limitation, triazinanyl.
- Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
- Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
- Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl,
- decahydronaphthyridinyl decahydro-l,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e] [l,4]diazepinyl, l,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro- 5H-furo [3 ,2-b]pyranyl, 5 ,7-dihydro-4H-thieno [2,3-c]pyranyl, 2,3-dihydro- 1 H- pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5
- aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6 -i 4 aryl").
- an aryl group has 6 ring carbon atoms ("C 6 aryl”; e.g., phenyl).
- an aryl group has 10 ring carbon atoms ("Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
- Cio aryl e.g., naphthyl such as 1-naphthyl and 2-naphthyl.
- an aryl group has 14 ring carbon atoms ("C 14 aryl”; e.g., anthracyl).
- Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
- each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl”) with one or more substituents.
- the aryl group is an
- the aryl group is a substituted C 6 -i 4 aryl.
- heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4 ring heteroatoms) ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, or phosphorus ("5-14 membered heteroaryl").
- heteroaryl groups that contain one or more nitrogen atoms
- the point of attachment can be a carbon or nitrogen atom, as valency permits.
- Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
- Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
- Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
- Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
- the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
- a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, or phosphorus ("5-10 membered heteroaryl").
- a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, or phosphorus ("5-8 membered heteroaryl").
- a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, or phosphorus ("5-6 membered heteroaryl").
- the 5-6 membered heteroaryl has 1 or more (e.g., 1, 2, or 3) ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, or phosphorus. In some embodiments, the 5-6 membered heteroaryl has 1 or 2 ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, or phosphorus. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from oxygen, sulfur, nitrogen, boron, silicon, or phosphorus. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an
- heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
- Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
- Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
- Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
- 5- membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
- Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
- Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
- 6- membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
- Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
- Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,
- Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
- Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
- partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
- the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl moieties) as herein defined.
- saturated refers to a ring moiety that does not contain a double or triple bond, i.e., the ring contains all single bonds.
- alkylene is the divalent moiety of alkyl
- alkenylene is the divalent moiety of alkenyl
- alkynylene is the divalent moiety of alkynyl
- heteroalkylene is the divalent moiety of heteroalkyl
- heteroalkenylene is the divalent moiety of heteroalkenyl
- heteroalkynylene is the divalent moiety of heteroalkynyl
- carbocyclylene is the divalent moiety of carbocyclyl
- heterocyclylene is the divalent moiety of heterocyclyl
- arylene is the divalent moiety of aryl
- heteroarylene is the divalent moiety of heteroaryl.
- alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are, in certain embodiments, optionally substituted.
- Optionally substituted refers to a group which may be substituted or unsubstituted (e.g., "substituted” or "unsubstituted” alkyl, "substituted” or “unsubstituted” alkenyl, "substituted” or “unsubstituted” alkynyl, "substituted” or
- substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
- a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
- substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
- the present invention contemplates any and all such combinations in order to arrive at a stable compound.
- heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
- Exemplary carbon atom substituents include, but are not limited to, halogen, -
- R ⁇ is, independently, selected from Ciso alkyl, C 2 _ 5 o alkenyl, C 2 _ 5 o alkynyl, C 3 _ 10 carbocyclyl, 3-14 membered heterocyclyl, C 6 -i 4 aryl, and 5-14 membered heteroaryl, or two R ⁇ groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl
- each instance of R cc is, independently, selected from hydrogen, Ci_5o alkyl, C 2 _ 5 o alkenyl, C 2 _ 5 o alkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, C 6 -i 4 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
- each instance of R ee is, independently, selected from Ci_5o alkyl, C 2 _ 5 o alkenyl, C 2 _ 5 o alkynyl, C 3 _io carbocyclyl, C 6 -10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
- each instance of R is, independently, selected from hydrogen, Ci_5o alkyl, C 2 _ 5 o alkenyl, C 2 _ 5 o alkynyl, C 3 _io carbocyclyl, 3-10 membered heterocyclyl, C 6 -10 aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and
- halo refers to fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), or iodine (iodo, -I).
- a "counterion” is a negatively charged group associated with a positively charged quarternary amine in order to maintain electronic neutrality.
- exemplary counterions include halide ions (e.g., F , CI “ , Br “ , ⁇ ), N0 3 , C10 4 , OFT, H 2 P0 4 , HS0 4 , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid-5-sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate
- Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.
- Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.
- the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group).
- nitrogen protecting groups such as amide groups (e.g., -
- picolinamide 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p- phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, ( ⁇ '- dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o- (benzoyloxymethyl)benzamide.
- Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,- trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5, 6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7, 8-pentamethylchroman-6-sulfonamide (Pmc), methanes
- Ts p-toluenesulfonamide
- Mtr 2,
- nitrogen protecting groups include, but are not limited to,
- phenothiazinyl-(10)-acyl derivative N'-p-toluenesulfonylaminoacyl derivative, N'- phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N- 2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N- 1,1, 4,4- tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5- triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1- substituted 3,5-dinitro-4-pyridone, N
- the substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group).
- Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
- oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,
- DPMS diphenylmethylsilyl
- TMPS i-butylmethoxyphenylsilyl
- the substituent present on an sulfur atom is an sulfur protecting group (also referred to as a thiol protecting group).
- Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
- a "leaving group” is an art-understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502).
- Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and sulfonyl substituted hydroxyl groups (e.g., tosyl, mesyl, besyl).
- At least one instance refers to one instance, but also encompasses more than one instance, e.g., for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 instances, and up to 100 instances.
- amino acid refers to natural and unnatural D/L alpha-amino acids, as well as natural and unnatural beta- and gamma- amino acids.
- a “peptide” refers to two amino acids joined by a peptide bond.
- a “polypeptide” refers to three or more amino acids joined by peptide bonds.
- An “amino acid side chain” refers to the group(s) pended to the alpha carbon (if an alpha amino acid), alpha and beta carbon (if a beta amino acid), or the alpha, beta, and gamma carbon (if a gamma amino acid). Exemplary amino acid side chains are depicted herein; see, e.g., Table 1 of the Examples.
- a "polymer” refers to a compound comprised of at least 3 (e.g., at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, etc.) repeating covalently bound structural units.
- Conjugated and “attached” refer to the covalent attachment of a group, and are used interchangeably herein.
- lipophilic refers to the ability of a group to dissolve in fats, oils, lipids, and lipophilic non-polar solvents such as hexane or toluene.
- a lipophilic group refers to an unsubstituted n-alkyl or unsubstituted n-alkenyl group having 6 to 50 carbon atoms, e.g., 6 to 40, 6 to 30, 6 to 20, 8 to 20, 8 to 19, 8 to 18, 8 to 17, 8 to 16, or 8 to 15 carbon atoms.
- a "small organic molecule” or “small molecule” refers to an organic molecule with a molecular weight of 800 g/mol or less (e.g., less than 700 g/mol, less than 600 g/mol, less than 500 g/mol, less than 400 g/mol, less than 300 g/mol, less than 200 g/mol, less than 100 g/mol, between 50 to 800 g/mol, inclusive, between 100 to 800 g/mol, inclusive, or between 100 to 500 g/mol, inclusive).
- the small organic molecule is a therapeutically active agent such as a drug (e.g. , a small organic molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)).
- the small organic molecule may also be complexed with a metal. In this instance, the small organic molecule is also referred to as an "small organic molecule
- organometallic molecule
- a "large organic molecule” or “large molecule” refers to an organic compound with a molecular weight of greater than 800 g/mol (e.g. , greater than 800 g/mol, greater than 900 g/mol, greater than 1000 g/mol, greater than 2000 g/mol, between 801 to 2000 g/mol, inclusive, between 900 to 2000 g/mol, inclusive, between 1000 to 2000 g/mol, inclusive, or between 801 to 1000 g/mol, inclusive).
- the large organic molecule is a therapeutically active agent such as a drug (e.g. , a large organic molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)).
- the large organic molecule may also be complexed with a metal. In this instance, the large organic molecule is also referred to as an "large organometallic compound.”
- a "small inorganic molecule” refers to an inorganic compound with a molecular weight of 800 g/mol or less (e.g. , less than 700 g/mol, less than 600 g/mol, less than 500 g/mol, less than 400 g/mol, less than 300 g/mol, less than 200 g/mol, less than 100 g/mol, between 50 to 800 g/mol, inclusive, between 100 to 800 g/mol, inclusive, or between 100 to 500 g/mol, inclusive).
- the small inorganic molecule is a therapeutically active agent such as a drug (e.g. , a small inorganic molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations
- a "large inorganic molecule” refers to an inorganic compound with a molecular weight of greater than 800 g/mol (e.g. , greater than 800 g/mol, greater than 900 g/mol, greater than 1000 g/mol, greater than 2000 g/mol, between 801 to 2000 g/mol, inclusive, between 900 to 2000 g/mol, inclusive, between 1000 to 2000 g/mol, inclusive, or between 801 to 1000 g/mol, inclusive).
- the large inorganic molecule is a therapeutically active agent such as a drug (e.g. , a large inorganic molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations
- salt or “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et ah, describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
- Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
- Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
- Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate,
- ethanesulfonate formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
- Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1 ⁇ alkyl) 4 salts.
- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, sulfonate and aryl sulfonate.
- Further pharmaceutically acceptable salts include salts formed from the quarternization of an amine using an appropriate electrophile, e.g., an alkyl halide, to form a quarternized alkylated amino salt.
- Figure 1 depicts the structural design and optimization through in vivo evaluation in mice.
- Single amino acid-based lipid derivatives were tested at a dose of lmg/kg in mice, which indicated that lysine was a favorable amino acid.
- Lysine-based peptide and polypeptide-lipid derivatives were then investigated at the same dose.
- the hit rate was improved from 1.7% to 23% (including those compounds not screened due to particle instability or no entrapment of siRNA).
- the top hits and their analogs were explored at a lower dose of 0.1 mg/kg, which led to selection of cKK-E12 as the lead compound.
- cKK- E12; c cyclic; Control, phosphate-buffered saline.
- Figure 2 depicts the bio-distribution of free Cy5.5-labled siRNA and Cy5.5- labled siRNA-cKK-E12 formulation in mice at 1 hr and 24 hr.
- FIG. 3 depicts the silencing effects of apolipoproteins on cKK-E12 in HeLa cells.
- Apolipoproteins including ApoA-I (recombinant Human ApoA-I protein), ApoA-II (native Human ApoA-II protein), ApoB (native Human ApoB protein), ApoC-I (native Human ApoC-I protein), ApoC-II (native Human ApoC-II protein), ApoC-III (native Human ApoC-III protein), ApoE (native Human ApoE protein), ApoE2 (recombinant Human ApoE2 protein), ApoE3 (recombinant Human ApoE3 protein), ApoE4 (recombinant Human ApoE4 protein), ApoH (native Human ApoH protein).
- FIG. 4 depicts the effects of ApoE on gene silencing and cell uptake.
- B Cellular internalization of cKK-E12 with Alex-647 labeled siRNA after 3 hr of incubation is demonstrated by HT automated confocal microscopy. ApoE enhanced cell uptake and endosomal escape of cKK-E12; Scale bar: 20
- inventive compounds and compositions certain embodiments of which involve conjugation of various groups, such as lipophilic groups, to an amino or amide group of an amino acid, a linear or cyclic peptide, a linear or cyclic polypeptide, or structural isomer thereof, to provide compounds of the present invention, collectively referred to herein as "APPLs".
- APPLs Such APPLs are deemed useful for a variety of applications, such as, for example, improved nucleotide delivery.
- Exemplary APPLs include, but are not limited to, compounds of Formula (I),
- R L groups e.g., lipophilic groups
- a primary or secondary amino group or amide of the amino acid, peptide, or polypeptide precursor, or structural isomer thereof may be attached to the APPL via conjugation of a primary or secondary amino group or amide of the amino acid, peptide, or polypeptide precursor, or structural isomer thereof, with an epoxide, thiirane, or aziridine of formula (i-x), Michael addition to an ⁇ , ⁇ -unsaturated ester, thioester, or amide of formula (ii- x), or reductive amination to an aldehyde of formula (iii-x) (Scheme 1).
- the present invention provides APPLs, and in certain embodiments, compounds of Formula (I), (II), (III), (IV), (V), and (VI), comprising at least one instance of a group attached thereto of the formula:
- each instance of R' is independently hydrogen or optionally substituted alkyl
- X is O, S, NR X , wherein R X is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- Y is O, S, NR Y , wherein R Y is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- R p is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; and
- R L is optionally substituted Ciso alkyl, optionally substituted C 2 -50 alkenyl, optionally substituted C 2 -50 alkynyl, optionally substituted Ci-so heteroalkyl, optionally substituted C 2 -50 heteroalkenyl, optionally substituted C 2 -50 heteroalkynyl, or a polymer.
- Compounds of Formula (I) encompasses amino acids, linear peptides, and linear polypeptides which comprise one or more sites of conjugation, e.g., to the terminal amino group, to an amino substituent, and/or to an imino nitrogen, of a group of formula (i), (ii), or (iii).
- n is 0 or is an integer between 1 and 100,000, inclusive;
- each instance of m is independently 1, 2, or 3;
- each instance of Z is independently O, S, or NR z , wherein R z is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii), or (iii);
- each instance of R 1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, -OR A1 , -N(R A1 ) 2 , or -SR A1 ; wherein each occurrence of R A1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to an sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;
- R is a group of formula (i), (ii), or (iii);
- R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii), or (iii);
- R 3 and an R 1 group are joined to form an optionally substituted 5-6 membered heterocyclic ring;
- R 4 is -OR A4 , -N(R A4 ) 2 , or -SR A4 ; wherein each occurrence of R A4 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to an sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A4 groups are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;
- R 5 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- each instance of R' is independently hydrogen or optionally substituted alkyl
- X is O, S, NR X , wherein R X is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- Y is O, S, NR , wherein R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- R p is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; and
- R L is optionally substituted Ciso alkyl, optionally substituted C 2 -50 alkenyl, optionally substituted C 2 -50 alkynyl, optionally substituted heteroCi-so alkyl, optionally substituted heteroC2-5o alkenyl, optionally substituted heteroC2-so alkynyl, or a polymer.
- n when n is greater than 10, then neither R 2 nor R 3 is a group of the formula (iii). In certain embodiments, when n is greater than 9, then neither R nor R is a group of the formula (iii). In certain embodiments, when n is greater than 8, then
- n 0 and Z is O, one or more of the following compounds are excluded:
- R 2 is a group of the formula (i)
- R 3 and R 6 are independently hydrogen or a group of formula (i)
- Y is O.
- n is 0 or is an integer between 1 and 100,000, inclusive. It is thus understood that Formula (I) encompasses amino acids conjugated to a lipid group, as well as linear peptides and linear polypeptides conjugated to lipid groups.
- n is 0 or is an integer between 1 and 90,000, inclusive.
- n is 0 or is an integer between 1 and 80,000, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 70,000, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 50,000, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 40,000, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 30,000, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 20,000, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 10,000, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 9,000, inclusive.
- n is 0 or is an integer between 1 and 8,000, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 7,000, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 6,000, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 5,000, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 4,000, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 3,000, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 2,000, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 1,000, inclusive.
- n is 0 or is an integer between 1 and 900, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 800, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 700, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 600, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 500, inclusive. In certain embodiments, n is 0 or is an integer between 100 and 80,000, inclusive. In certain embodiments, n is 0 or is an integer between 200 and 80,000, inclusive. In certain embodiments, n is 0 or is an integer between 300 and 80,000, inclusive.
- n is 0 or is an integer between 400 and 80,000, inclusive. In certain embodiments, n is 0 or is an integer between 500 and 80,000, inclusive. In certain embodiments, n is 0 or is an integer between 500 and 40,000, inclusive. In certain embodiments, n is 0 or is an integer between 500 and 30,000, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 400, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 300, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 200, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 100, inclusive.
- n is 0 or is an integer between 1 and 75, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 50, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 25, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 15, inclusive. In certain embodiments, n is 0 or is an integer between 1 and 10, 1 nclusive. In certain embodiments, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
- the compound of Formula (I) is a compound of the
- the compound of Formula (I) is a compound of the Formula (I-b):
- the compound of Formula (I) is a compound of the Formula (I-c):
- the compound of Formula (I) is a compound of the Formula (I-d):
- the compound of Formula (I) is a compound of the Formula (I-e):
- each instance of m is independently 1, 2, or 3. In certain embodiments, at least one instance of m is 1. In certain embodiments, each instance of m is 1. In certain embodiments, at least one instance of m is 2. In certain embodiments, at least one instance of m is 3.
- each instance of R' is independently hydrogen or optionally substituted alkyl.
- at least one instance of R' is hydrogen.
- at least two instances of R' is hydrogen.
- each instance of R' is hydrogen.
- at least one instance of R' is optionally substituted alkyl, e.g., methyl.
- at least two instances of R' is optionally substituted alkyl, e.g., methyl.
- one instance of R' is optionally substituted alkyl, and the rest are hydrogen.
- each instance of Z is independently O, S, or NR Z , wherein R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii), or (iii).
- at least one instance of Z is O.
- each instance of Z is O.
- at least one instance of Z is S.
- each instance of Z is S.
- each instance of Z is NR .
- each instance of Z is NR z .
- each instance of R z is independently hydrogen or a group of the formula (i), (ii), or (iii). [0095] As generally defined above, each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, -OR A1 , -N(R A1 ) 2 , or -SR A1 .
- At least one instance of R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
- R 1 is optionally substituted alkyl; e.g., optionally substituted C 1-6 alkyl, optionally substituted C 2 _ 6 alkyl, optionally substituted C 3 _ 6 alkyl, optionally substituted C 4 _ 6 alkyl, optionally substituted C 4 _salkyl, or optionally substituted C 3 ⁇ alkyl.
- At least one instance of R 1 is optionally substituted alkenyl, e.g., optionally substituted C 2 _ 6 alkenyl, optionally substituted C 3 _ 6 alkenyl, optionally substituted C 4 _ 6 alkenyl, optionally substituted C 4 -salkenyl, or optionally substituted C 3 _ 4 alkenyl.
- At least one instance of R 1 is optionally substituted alkynyl, e.g., optionally substituted C 2 _ 6 alkynyl, optionally substituted C 3 _ 6 alkynyl, optionally substituted C 4 _ 6 alkynyl, optionally substituted C 4 _salkynyl, or optionally substituted C 3 _ 4 alkynyl.
- At least one instance of R 1 is optionally substituted carbocyclyl, e.g., optionally substituted C 3-1 o carbocyclyl, optionally substituted Cs-g carbocyclyl, optionally substituted C 5 - 6 carbocyclyl, optionally substituted C 5 carbocyclyl, or optionally substituted C 6 carbocyclyl.
- At least one instance of R 1 is optionally substituted heterocyclyl, e.g., optionally substituted 3-14 membered heterocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-8 membered heterocyclyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted 5 membered heterocyclyl, or optionally substituted 6 membered heterocyclyl.
- optionally substituted heterocyclyl e.g., optionally substituted 3-14 membered heterocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-8 membered heterocyclyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted 5 membered heterocyclyl, or optionally substituted 6 membered heterocyclyl.
- At least one instance of R 1 is optionally substituted aryl, e.g., optionally substituted phenyl.
- At least one instance of R 1 is optionally substituted heteroaryl, e.g., optionally substituted 5-14 membered heteroaryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5 membered heteroaryl, or optionally substituted 6 membered heteroaryl.
- R 1 alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group may be substituted, for example, with an optionally substituted amino group (e.g.
- R 6 and R 7 are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or a group of formula (i), (ii), or (iii).
- At least one instance of R 1 is an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group substituted with an amino group of the formula -N(R 6 )(R 7 ).
- at least one instance of R 1 is a group of formula:
- L is an optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted
- R 6 and R 7 are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group;
- R 6 and R 7 is a group of the formula (i), (ii), or (iii): wherein R', X, Y, R L , and R p are as defined herein.
- At least two instances of R 1 is a group of formula (iv). In certain embodiments, at least three instances of R 1 is a group of formula (iv). In certain embodiments, at least four instances of R 1 is a group of formula (iv). In certain embodiments, at least five instances of R 1 is a group of formula (iv). In certain embodiments, each instance of R 1 is a group of formula (iv).
- L is an optionally substituted alkylene; e.g. , optionally substituted Ci-soalkylene, optionally substituted Ci ⁇ oalkylene, optionally substituted Ci- 3 oalkylene, optionally substituted Ci ⁇ oalkylene, optionally substituted C 4 _ 2 oalkylene, optionally substituted C 6 - 2 oalkylene, optionally substituted Cg_ 2 oalkylene, optionally substituted Cio ⁇ oalkylene, optionally substituted Q-ealkylene, optionally substituted C 2 - 6 alkylene, optionally substituted C 3 _ 6 alkylene, optionally substituted C 4 _ 6 alkylene, optionally substituted C 4 _ 5 alkylene, or optionally substituted C 3 - 4 alkylene.
- L is an optionally substituted alkenylene, e.g. , optionally substituted C 2 - 5 oalkenylene, optionally substituted C 2 - 4 oalkenylene, optionally substituted C 2 - 3 oalkenylene, optionally substituted C 2 - 2 oalkenylene, optionally substituted C 4 - 2 oalkenylene, optionally substituted C 6 - 2 oalkenylene, optionally substituted C 8 - 2 oalkenylene, optionally substituted C 1 o- 2 oalkenylene, optionally substituted C 2 _ 6 alkenylene, optionally substituted C 3 _ 6 alkenylene, optionally substituted C 4 _ 6 alkenylene, optionally substituted C 4 _ 5 alkenylene, or optionally substituted C 3 _ 4 alkenylene.
- optionally substituted alkenylene e.g. , optionally substituted C 2 - 5 oalkenylene, optionally
- L is an optionally substituted alkynylene, e.g. , optionally substituted C 2 - 5 oalkynylene, optionally substituted C 2 - 4 oalkynylene, optionally substituted C 2 - 3 oalkynylene, optionally substituted C 2 - 2 oalkynylene, optionally substituted C 4 _ 2 oalkynylene, optionally substituted C 6 - 2 oalkynylene, optionally substituted C 8 - 2 oalkynylene, optionally substituted C 1 o- 2 oalkynylene, optionally substituted C 2 - 6 alkynylene, optionally substituted C 3 _ 6 alkynylene, optionally substituted C 4 _ 6 alkynylene, optionally substituted C 4 _ salkynylene, or optionally substituted C 3 _ 4 alkynylene.
- optionally substituted alkynylene e.g. , optionally substituted
- L is an optionally substituted heteroalkylene; e.g. , optionally substituted heteroCi-soalkylene, optionally substituted heteroCi ⁇ oalkylene, optionally substituted heteroCi-soalkylene, optionally substituted heteroC 1 _ 2 oalkylene, optionally substituted heteroC 4 _ 2 oalkylene, optionally substituted heteroC 6 - 2 oalkylene, optionally substituted heteroC 8 - 2 oalkylene, optionally substituted heteroCio ⁇ oalkylene, optionally substituted heteroCi-ealkylene, optionally substituted heteroCi ealkylene, optionally substituted heteroC 3 _ 6 alkylene, optionally substituted heteroC 4 _ 6 alkylene, optionally substituted heteroC 4 _ 5 alkylene, or optionally substituted heteroC 3 _ 4 alkylene.
- L is an optionally substituted heteroalkenylene, e.g. , optionally substituted heteroCi-soalkenylene, optionally substituted heteroC 2 - 4 oalkenylene, optionally substituted heteroC 2 - 3 oalkenylene, optionally substituted heteroC 2 - 2 oalkenylene, optionally substituted heteroC 4 _ 2 oalkenylene, optionally substituted heteroC 6 - 2 oalkenylene, optionally substituted heteroC 8 - 2 oalkenylene, optionally substituted heteroCio ⁇ oalkenylene, optionally substituted heteroC 2 - 6 alkenylene, optionally substituted heteroC 3 _ 6 alkenylene, optionally substituted heteroC 4 _ 6 alkenylene, optionally substituted heteroC 4 _ 5 alkenylene, or optionally substituted heteroC 3 _ 4 alkenylene.
- optionally substituted heteroalkenylene e.g. , optionally substituted heteroCi-
- L is an optionally substituted alkynylene, e.g. , optionally substituted heteroC 2 - 5 oalkynylene, optionally substituted heteroC 2 - 4 oalkynylene, optionally substituted heteroC 2 - 3 oalkynylene, optionally substituted heteroC 2 - 2 oalkynylene, optionally substituted heteroC 4 _ 2 oalkynylene, optionally substituted heteroC 6 - 2 oalkynylene, optionally substituted heteroC 8 - 2 oalkynylene, optionally substituted heteroCio ⁇ oalkynylene, optionally substituted heteroC 2 - 6 alkynylene, optionally substituted C 3 _ 6 alkynylene, optionally substituted heteroC 4 _ 6 alkynylene, optionally substituted heteroC 4 _ 5 alkynylene, or optionally sub stituted heteroC 3 _ 4 alkynylene
- L is an optionally substituted carbocyclylene, e.g. , optionally substituted C 3-1 o carbocyclylene, optionally substituted C 5 -8 carbocyclylene, optionally substituted C 5 _6 carbocyclylene, optionally substituted C 5 carbocyclylene, or optionally substituted C 6 carbocyclylene.
- L is an optionally substituted heterocyclylene, e.g. , optionally substituted 3- 14 membered heterocyclylene, optionally substituted 3-10 membered heterocyclylene, optionally substituted 5-8 membered heterocyclylene, optionally substituted 5-6 membered heterocyclylene, optionally substituted 5 membered heterocyclylene, or optionally substituted 6 membered heterocyclylene.
- optionally substituted heterocyclylene e.g. , optionally substituted 3- 14 membered heterocyclylene, optionally substituted 3-10 membered heterocyclylene, optionally substituted 5-8 membered heterocyclylene, optionally substituted 5-6 membered heterocyclylene, optionally substituted 5 membered heterocyclylene, or optionally substituted 6 membered heterocyclylene.
- L is an optionally substituted arylene, e.g. , optionally substituted phenylene.
- L is an optionally substituted heteroarylene, e.g., optionally substituted 5-14 membered heteroarylene, optionally substituted 5-10 membered heteroarylene, optionally substituted 5-6 membered heteroarylene, optionally substituted 5 membered heteroarylene, or optionally substituted 6 membered heteroarylene.
- the group of formula (iv) is a group of the formula:
- q is an integer between 1 and 50, inclusive.
- q is an integer between 1 and 40, inclusive. In certain embodiments, q is an integer between 1 and 30, inclusive. In certain embodiments, q is an integer between 1 and 20, inclusive. In certain embodiments, q is an integer between 4 and 20, inclusive. In certain embodiments, q is an integer between 6 and 20, inclusive. In certain embodiments, q is an integer between 8 and 20, inclusive. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 4. In certain embodiments, q is 5. In certain embodiments, q is 6. In certain embodiments, q is 7. In certain embodiments, q is 8. In certain embodiments, q is 9. In certain embodiments, q is 10.
- both R 6 and R 7 are hydrogen. In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (i), (ii), or (iii). In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (i). In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (ii). In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (iii). In certain embodiments, both R 6 and R 7 are independently a group of the formula (i), (ii), or (iii). In certain embodiments, both R 6 and R 7 are independently a group of the formula (i).
- both R 6 and R 7 are independently a group of the formula (ii). In certain embodiments, both R 6 and R 7 are independently a group of the formula (iii). In certain embodiments, both R 6 and R 7 are the same group, selected from a group of the formula (i), (ii), or (iii).
- R 1 encompasses amino acid side chains such as
- R 1 is a group selected from any one of the amino acid side chain groups listed therein.
- each instance of R 1 is the same.
- At least one R 1 group is different. In certain embodiments, each R 1 group is different. [00122] As ge , (ii), or (iii):
- R', X, Y, R L , and R p are as defined herein.
- R 2 is a group of the formula (i).
- R 2 is a group of the formula (ii). In certain embodiments, R 2 is a group of the formula (iii).
- R 3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii), or (iii); optionally wherein R 3 and an R 1 group are joined to form an optionally substituted 5-6 membered heterocyclic ring;
- R 3 is hydrogen. In certain embodiments, R 3 is optionally substituted alkyl; e.g., optionally substituted Ci- 6 alkyl, optionally substituted C 2 _ 6 alkyl, optionally substituted C 3 _ 6 alkyl, optionally substituted C 4 _ 6 alkyl, optionally substituted C 4 _ 5 alkyl, or optionally substituted C 3 ⁇ alkyl.
- R 3 is optionally substituted alkyl; e.g., optionally substituted Ci- 6 alkyl, optionally substituted C 2 _ 6 alkyl, optionally substituted C 3 _ 6 alkyl, optionally substituted C 4 _ 6 alkyl, optionally substituted C 4 _ 5 alkyl, or optionally substituted C 3 ⁇ alkyl.
- R 3 is optionally substituted alkenyl, e.g., optionally substituted C 2 _ 6 alkenyl, optionally substituted C 3 _ 6 alkenyl, optionally substituted C 4 _ 6 alkenyl, optionally substituted C 4 _salkenyl, or optionally substituted C 3 _ 4 alkenyl.
- R 3 is optionally substituted alkynyl, e.g., optionally substituted C 2 _ 6 alkynyl, optionally substituted C 3 _ 6 alkynyl, optionally substituted C 4 _ 6 alkynyl, optionally substituted C 4 _salkynyl, or optionally substituted C 3 _ 4 alkynyl.
- R 3 is optionally substituted carbocyclyl, e.g., optionally substituted C 3-1 o carbocyclyl, optionally substituted Cs-g carbocyclyl, optionally substituted C 5 - 6 carbocyclyl, optionally substituted C 5 carbocyclyl, or optionally substituted
- R 3 is optionally substituted heterocyclyl, e.g., optionally substituted 3- 14 membered heterocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-8 membered heterocyclyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted 5 membered heterocyclyl, or optionally substituted 6 membered heterocyclyl.
- R 3 is optionally substituted aryl, e.g., optionally substituted phenyl.
- R 3 is optionally substituted heteroaryl, e.g., optionally substituted 5-14 membered heteroaryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5 membered heteroaryl, or optionally substituted 6 membered heteroaryl.
- R 3 is a nitrogen protecting group.
- R 3 is group of the formula (i), (ii), or (iii). In certain embodiments, R 3 is group of the formula (i). In certain embodiments, R 3 is group of the formula (ii). In certain embodiments, R is group of the formula (iii).
- R 3 and an adjacent R 1 group are joined to form an optionally substituted 5-6 membered heterocyclic ring, e.g., a 5-membered heterocyclic ring, e.g., an optionally substituted pyrrolidinyl ring.
- R 3 is hydrogen and R 2 is a group of the formula (i),
- R 3 is hydrogen and R 2 is a group of the formula (i). In certain embodiments, R 3 is hydrogen and R 2 is a group of the formula (ii). In certain embodiments, R 3 is hydrogen and R 2 is a group of the formula (iii). In certain embodiments, both R 2 and R 3 are independently a group of the formula (i), (ii), or (iii). In certain embodiments, both R 2 and R 3 are independently a group of the formula (i). In certain embodiments, both R 2 and R 3 are independently a group of the formula (ii). In certain embodiments, both R 2 and R 3 are independently a group of the formula (ii). In certain embodiments, both R 2 and R 3 are independently a group of the formula (iii). In certain embodiments, both R 2 and R 3 are independently a group of the formula (iii). In certain embodiments, both R 2 and R 3 are the same group, selected from a group of the formula (i), (ii), or (iii).
- R 4 is -OR A4 , -N(R A4 ) 2 , or -SR A4 ; wherein each occurrence of R A4 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to an sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A4 groups are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.
- R 4 is -OR A4 , wherein R A4 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group. In certain embodiments, R A4 is hydrogen or optionally substituted alkyl. In certain embodiments, R A4 is hydrogen.
- R 4 is -N(R A4 ) 2 , wherein each occurrence of R A4 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or two R A4 groups are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.
- at least one instance of R A4 is hydrogen or optionally substituted alkyl.
- at least one instance of R A4 is hydrogen.
- R 4 is -SR A4 wherein R A4 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or sulfur protecting group.
- R A4 is hydrogen or optionally substituted alkyl. In certain embodiments, R A4 is hydrogen.
- R 5 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.
- at least one instance of R 5 is hydrogen.
- each instance of R 5 is hydrogen.
- the compound of Formula (I) is a compound of Formula (I-f):
- R 2 is a group of formula (iv).
- R 2 is a group of formula (i).
- R 2 is a group of formula (ii).
- R 2 is a group of formula (iii).
- R 3 is a group of formula (i).
- R is a group of formula (ii).
- R 3 is a group of formula (iii).
- R 4 is -OR A4 .
- R 5 is hydrogen.
- n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5.
- L is an optionally substituted alkylene.
- R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R is a group of formula (ii). In certain embodiments, R is a group of formula (iii).
- R is a group of formula (iv).
- R 3 is a group of formula (i).
- R 3 is a group of formula (ii).
- R 3 is a group of formula (iii).
- R 4 is - OR A4 .
- R 5 is hydrogen.
- n is 0.
- n is 1.
- n is 2.
- n is 3.
- n is 4.
- n is 5.
- L is an optionally substituted alkylene.
- R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R is a group of formula (ii). In certain embodiments, R is a group of formula (iii).
- At least one R is a group of formula (iv).
- R 4 is -OR A4 .
- R 5 is hydrogen.
- n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5.
- L is an optionally substituted alkylene.
- R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R is a group of formula (ii). In certain embodiments,
- R is a group of formula (iii). [00148] In certain embodiments of Formula (I-f), wherein R 2 is a group of formula (ii), the compound is of Formula (I-f 6):
- R is a group of formula (iv).
- R 3 is a group of formula (i).
- R 3 is a group of formula (ii).
- R 3 is a group of formula (iii).
- R 4 is - OR A4 .
- R 5 is hydrogen.
- n is 0.
- n is 1.
- n is 2.
- n is 3.
- n is 4.
- n is 5.
- each instance of R 1 is a group of th rmula (I-f7):
- L is an optionally substituted alkylene.
- R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R is a group of formula (ii). In certain embodiments, R is a group of formula (iii).
- R is a group of formula (iv).
- R 4 is -OR A4 .
- R 5 is hydrogen.
- n is 0.
- n is 1.
- n is 2.
- n is 3.
- n is 4.
- n is 5.
- L is an optionally substituted alkylene.
- R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R is a group of formula (ii). In certain embodiments, R is a group of formula (iii).
- R is a group of formula (iv).
- R 3 is a group of formula (i).
- R 3 is a group of formula (ii).
- R 3 is a group of formula (iii).
- R 4 is - OR A4 .
- R 5 is hydrogen.
- n is 0.
- n is 1.
- n is 2.
- n is 3.
- n is 4.
- n is 5.
- L is an optionally substituted alkylene.
- R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R is a group of formula (ii). In certain embodiments, R is a group of formula (iii).
- At least one R is a group of formula (iv).
- R 4 is -OR A4 .
- R 5 is hydrogen.
- n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5.
- L is an optionally substituted alkylene.
- R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R is a group of formula (ii). In certain embodiments,
- R is a group of formula (iii).
- Compounds of Formula (II) may be prepared via internal cyclization of the addition product of a primary or secondary amine or amide of an amino acid, peptide, or polypeptide, and an epoxide, thiirane, or aziridine of formula (i-x) (Scheme 2).
- Compounds of Formula (II) may encompass additional sites of conjugation, e.g., the secondary amino group, appended to a group attached to the secondary amino group, an amino substituent, and/or an imino nitrogen, to a group of formula (i), (ii), or (iii):
- each instance of R' is independently hydrogen or optionally substituted alkyl
- each instance of R 1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, -OR A1 , -N(R A1 ) 2 , or -SR A1 ; wherein each occurrence of R A1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to an sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R Al groups are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;
- R is hydrogen, a group of the formula (i), (ii), or (iii), or a group of the formula (v)
- R 8 and an R 1 group are joined to form an optionally substituted 5-6 membered heterocyclic ring;
- each instance of W is independently O, S, or NR W , wherein R w is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii), or (iii); and
- each instance of Y is independently O, S, or NR Y , wherein R Y is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- X is O, S, NR , wherein R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- Y is O, S, NR , wherein R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- R p is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; and
- R L is optionally substituted Ciso alkyl, optionally substituted C 2 -50 alkenyl, optionally substituted C 2 -50 alkynyl, optionally substituted heteroCi-so alkyl, optionally substituted heteroC2-5o alkenyl, optionally substituted heteroC2-so alkynyl, or a polymer.
- R 8 and R 6 are independently hydrogen or a group of formula (i), and salts thereof.
- At least one instance of R , R , R , R , R , or R is a group of the formula (i), (ii), or (iii).
- each instance of R' is independently hydrogen or optionally substituted alkyl.
- at least one instance of R' is hydrogen.
- at least two instances of R' is hydrogen.
- each instance of R' is hydrogen.
- at least one instance of R' is optionally substituted alkyl, e.g., methyl.
- at least two instances of R' is optionally substituted alkyl, e.g., methyl.
- one instance of R' is optionally substituted alkyl, and the rest are hydrogen.
- each instance of R 1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, -OR A1 , -N(R A1 ) 2 , or -SR A1 .
- At least one instance of R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
- R 1 is optionally substituted alkyl; e.g., optionally substituted C 1-6 alkyl, optionally substituted C 2 _ 6 alkyl, optionally substituted C 3 _ 6 alkyl, optionally substituted C 4 _ 6 alkyl, optionally substituted C 4 _salkyl, or optionally substituted C 3 ⁇ alkyl.
- At least one instance of R 1 is optionally substituted alkenyl, e.g., optionally substituted C 2 _ 6 alkenyl, optionally substituted C 3 _ 6 alkenyl, optionally substituted C 4 _ 6 alkenyl, optionally substituted C 4 _salkenyl, or optionally substituted C 3 _ 4 alkenyl.
- At least one instance of R 1 is optionally substituted alkynyl, e.g., optionally substituted C 2 _ 6 alkynyl, optionally substituted C 3 _ 6 alkynyl, optionally substituted C 4 _ 6 alkynyl, optionally substituted C 4 _salkynyl, or optionally substituted C 3 _ 4 alkynyl.
- At least one instance of R 1 is optionally substituted carbocyclyl, e.g., optionally substituted C 3-1 o carbocyclyl, optionally substituted C 5 -8 carbocyclyl, optionally substituted C 5 _ 6 carbocyclyl, optionally substituted C 5 carbocyclyl, or optionally substituted C 6 carbocyclyl.
- At least one instance of R 1 is optionally substituted heterocyclyl, e.g., optionally substituted 3- 14 membered heterocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-8 membered heterocyclyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted 5 membered heterocyclyl, or optionally substituted 6 membered heterocyclyl.
- optionally substituted heterocyclyl e.g., optionally substituted 3- 14 membered heterocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-8 membered heterocyclyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted 5 membered heterocyclyl, or optionally substituted 6 membered heterocyclyl.
- At least one instance of R 1 is optionally substituted aryl, e.g., optionally substituted phenyl.
- R 1 is optionally substituted heteroaryl, e.g., optionally substituted 5-14 membered heteroaryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5 membered heteroaryl, or optionally substituted 6 membered heteroaryl.
- R 1 alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group may be substituted, for example, with an optionally substituted amino group (e.g.
- R 6 and R 7 are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or a group of formula (i), (ii), or (iii).
- At least one instance of R 1 is an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group substituted with an amino group of the formula -N(R 6 )(R 7 ).
- at least one instance of R 1 is a group of formula:
- L is an optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted
- R 6 and R 7 are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group;
- R 6 and R 7 is a rou of the formula (i), (ii), or (iii):
- R', X, Y, R L , and R p are as defined herein.
- at least two instances of R 1 is a group of formula (iv).
- at least three instances of R 1 is a group of formula (iv).
- at least four instances of R 1 is a group of formula (iv).
- at least five instances of R 1 is a group of formula (iv).
- each instance of R 1 is a group of formula (iv).
- At least one instance of R provided in group R is a group of formula (iv). In certain embodiments, at least two instances of R 1 provided in group
- R is a group of formula (iv). In certain embodiments, at least three instances of R provided
- group R 8 1 in group R is a group of formula (iv). In certain embodiments, at least four instances of R provided in group R is a group of formula (iv). In certain embodiments, at least five
- instance of R provided in group R is a group of formula (iv).
- L is an optionally substituted alkylene; e.g. , optionally substituted Ci-soalkylene, optionally substituted C ⁇ oalkylene, optionally substituted Ci- 30 alkylene, optionally substituted C ⁇ oalkylene, optionally substituted C 4 _ 2 oalkylene, optionally substituted C 6 - 2 oalkylene, optionally substituted Cg_ 2 oalkylene, optionally substituted Cio ⁇ oalkylene, optionally substituted Ci ⁇ alkylene, optionally substituted Ci ⁇ alkylene, optionally substituted C 2 - 6 alkylene, optionally substituted C 3 _ 6 alkylene, optionally substituted C 4 _ 6 alkylene, optionally substituted C 4 _ 5 alkylene, or optionally substituted C 3 _ 4 alkylene.
- optionally substituted Ci-soalkylene optionally substituted C ⁇ oalkylene, optionally substituted Ci- 30 alkylene, optionally substituted C ⁇ oalkylene, optionally substitute
- L is an optionally substituted alkenylene, e.g. , optionally substituted C 2 - 5 oalkenylene, optionally substituted C 2 - 4 oalkenylene, optionally substituted C 2 - 3 oalkenylene, optionally substituted C 2 - 2 oalkenylene, optionally substituted C 4 _ 2 oalkenylene, optionally substituted C 6 - 2 oalkenylene, optionally substituted Cg_ 2 oalkenylene, optionally substituted C 1 o- 2 oalkenylene, optionally substituted C 2 _ 6 alkenylene, optionally substituted C 3 _ 6 alkenylene, optionally substituted C 4 _ 6 alkenylene, optionally substituted C 4 _ 5 alkenylene, or optionally substituted C3_ 4 alkenylene.
- optionally substituted alkenylene e.g. , optionally substituted C 2 - 5 oalkenylene, optionally substituted
- L is an optionally substituted alkynylene, e.g. , optionally substituted C 2 - 5 oalkynylene, optionally substituted C 2 - 4 oalkynylene, optionally substituted C 2 - 3 oalkynylene, optionally substituted C 2 - 2 oalkynylene, optionally substituted C 4 _ 2 oalkynylene, optionally substituted C 6 - 2 oalkynylene, optionally substituted C8- 2 oalkynylene, optionally substituted C 1 o- 2 oalkynylene, optionally substituted C 2 - 6 alkynylene, optionally substituted C 3 _ 6 alkynylene, optionally substituted C 4 _ 6 alkynylene, optionally substituted C 4 _ salkynylene, or optionally substituted C 3 _ 4 alkynylene.
- optionally substituted alkynylene e.g. , optionally substituted C
- L is an optionally substituted heteroalkylene; e.g. , optionally substituted heteroCi-soalkylene, optionally substituted heteroCi_ 4 oalkylene, optionally substituted heteroCi-soalkylene, optionally substituted heteroCi_ 2 oalkylene, optionally substituted heteroC 4 _ 2 oalkylene, optionally substituted heteroC 6 - 2 oalkylene, optionally substituted heteroC 8 - 2 oalkylene, optionally substituted heteroCio- 2 oalkylene, optionally substituted heteroCi_ 6 alkylene, optionally substituted heteroC 2 - 6 alkylene, optionally substituted heteroC 3 _ 6 alkylene, optionally substituted heteroC 4 _ 6 alkylene, optionally substituted heteroC 4 _ 5 alkylene, or optionally substituted heteroC 3 _ 4 alkylene.
- L is an optionally substituted heteroalkenylene, e.g. , optionally substituted heteroC 2 - 5 oalkenylene, optionally substituted heteroC 2 - 4 oalkenylene, optionally substituted heteroC 2 - 3 oalkenylene, optionally substituted heteroC 2 - 2 oalkenylene, optionally substituted heteroC 4 _ 2 oalkenylene, optionally substituted heteroC 6 - 2 oalkenylene, optionally substituted heteroC 8 - 2 oalkenylene, optionally substituted heteroCio- 2 oalkenylene, optionally substituted heteroC 2 - 6 alkenylene, optionally substituted heteroC 3 _ 6 alkenylene, optionally substituted heteroC 4 _ 6 alkenylene, optionally substituted heteroC 4 _ 5 alkenylene, or optionally substituted heteroC 3 _ 4 alkenylene.
- optionally substituted heteroalkenylene e.g. , optionally substituted
- L is an optionally substituted alkynylene, e.g. , optionally substituted heteroC 2 - 5 oalkynylene, optionally substituted heteroC 2 - 4 oalkynylene, optionally substituted heteroC 2 - 3 oalkynylene, optionally substituted heteroC 2 - 2 oalkynylene, optionally substituted heteroC 4 _ 2 oalkynylene, optionally substituted heteroC 6 - 2 oalkynylene, optionally substituted heteroC 8 - 2 oalkynylene, optionally substituted heteroCio- 2 oalkynylene, optionally substituted heteroC 2 - 6 alkynylene, optionally substituted C 3 _ 6 alkynylene, optionally substituted heteroC 4 _ 6 alkynylene, optionally substituted heteroC 4 _ 5 alkynylene, or optionally substituted heteroC 3 _ 4 alkynylene.
- alkynylene e.
- L is an optionally substituted carbocyclylene, e.g. , optionally substituted C 3-1 o carbocyclylene, optionally substituted C 5 -8 carbocyclylene, optionally substituted C 5 _ 6 carbocyclylene, optionally substituted C 5 carbocyclylene, or optionally substituted C 6 carbocyclylene.
- L is an optionally substituted heterocyclylene, e.g. , optionally substituted 3-14 membered heterocyclylene, optionally substituted 3-10 membered heterocyclylene, optionally substituted 5-8 membered heterocyclylene, optionally substituted 5-6 membered heterocyclylene, optionally substituted 5 membered heterocyclylene, or optionally substituted 6 membered heterocyclylene.
- optionally substituted heterocyclylene e.g. , optionally substituted 3-14 membered heterocyclylene, optionally substituted 3-10 membered heterocyclylene, optionally substituted 5-8 membered heterocyclylene, optionally substituted 5-6 membered heterocyclylene, optionally substituted 5 membered heterocyclylene, or optionally substituted 6 membered heterocyclylene.
- L is an optionally substituted arylene, e.g., optionally substituted phenylene.
- L is an optionally substituted heteroarylene, e.g., optionally substituted 5-14 membered heteroarylene, optionally substituted 5-10 membered heteroarylene, optionally substituted 5-6 membered heteroarylene, optionally substituted 5 membered heteroarylene, or optionally substituted 6 membered heteroarylene.
- the group of formula (iv) is a group of the formula:
- q is an integer between 1 and 50, inclusive.
- q is an integer between 1 and 40, inclusive. In certain embodiments, q is an integer between 1 and 30, inclusive. In certain embodiments, q is an integer between 1 and 20, inclusive. In certain embodiments, q is an integer between 4 and 20, inclusive. In certain embodiments, q is an integer between 6 and 20, inclusive. In certain embodiments, q is an integer between 8 and 20, inclusive. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 4. In certain embodiments, q is 5. In certain embodiments, q is 6. In certain embodiments, q is 7. In certain embodiments, q is 8. In certain embodiments, q is 9. In certain embodiments, q is 10.
- both R 6 and R 7 are hydrogen. In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (i), (ii), or (iii). In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (i). In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (ii). In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (iii). In certain embodiments, both R 6 and R 7 are independently a group of the formula (i), (ii), or (iii). In certain embodiments, both R 6 and R 7 are independently a group of the formula (i).
- both R 6 and R 7 are independently a group of the formula (ii). In certain embodiments, both R 6 and R 7 are independently a group of the formula (iii). In certain embodiments, both R 6 and R 7 are the same group, selected from a group of the formula (i), (ii), or (iii). [00189] It is understood that R 1 encompasses amino acid side chains such as exemplified in Table 1 of the Examples. In certain embodiments, R 1 is a group selected from any one of the amino acid side chain groups listed therein.
- each instance of R 1 is the same.
- At least one R 1 group is different. In certain embodiments, each R 1 group is different.
- each instance of W is independently O, S, or NR W , wherein R w is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii), or (iii).
- W is O.
- W is S.
- W is NR W .
- R w is hydrogen or a group of the formula (i), (ii), or (iii).
- each instance of Y is independently O, S, or NR Y , wherein R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.
- R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.
- Y is O.
- Y is S. In certain embodiments, Yis NR Y . In certain embodiments, R Y is hydrogen or a nitrogen protecting group.
- W is O and Y is O. In certain embodiments, W is O and Y is S. In certain embodiments, W is O and Y is NR . In certain embodiments, W is S and Y is O. In certain embodiments, W is S and Y is S. In certain embodiments, W is S and
- Y is NR Y .
- W is NR W and Y is O.
- W is NR W and Y is S.
- W is NR W and Y is NR Y .
- R 8 is hydrogen, a group of the formula (i), (ii), or (iii), or a group of the formu
- R 2 , R 3 , R 5 , Z, m, and n are as defined in Formula (I), p )rroovvided at least one instance of R w , R 2 , R 3 , R 8 , R 6 , R 7 , or R 8 is a group of the formula (i), (ii), or (iii). [00195] In certain embodiments, R is hydrogen.
- R 8 is a group of the formula (i), (ii), or (iii). In certain embodiments, R 8 is a group of the formula (i). In certain embodiments, R 8 is a group of the formula (ii). In certain embodiments, R is a group of the formula (iii).
- R 8 is a group of the formula (v).
- R 8 is a group of the formula (v) and R 2 is a group of the formula (i), (ii), or
- R 8 is a group of the formula (v) and R 3 is a group of the formula (i), (ii), or (iii).
- At least one R 1 is a group of formula (iv) and R 6 is a group of the formula (i), (ii), or (iii). In certain embodiments, at least one R 1 is a group of formula (iv) and R is a group of the formula (i), (ii), or (iii). In certain embodiments, at least one R 1 is a group of formula (iv), and both R 6 and R 7 are independently groups of the formula (i), (ii), or (iii).
- R 8 and the adjacent R 1 group are joined to form an optionally substituted 5-6 membered heterocyclic ring, e.g., a 5-membered heterocyclic ring, e.g., an optionally substituted pyrrolidinyl ring.
- R is a group of the formula (i), (ii), or (iii).
- R 8 is a group of the formula (v) and R 2 is a group of the formula (i),
- R 8 is a group of the formula (v) and R 3 is a group of the formula (i), (ii), or (iii).
- at least one R 1 is a group of formula (iv).
- R 1 is a group of formula (iv) and R 6 is a group of the formula (i), (ii), or
- R 1 is a group of formula (iv) and R 7 is a group of the formula (i), (ii), or (iii). In certain embodiments, both R 6 and R 7 are independently groups of the formula (i), (ii), or (iii).
- L is an optionally substituted alkylene.
- R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R is a group of formula (ii). In certain embodiments, R 7 is a group of formula (iii). In certain embodiments, both R 6 and R 7 are independently groups of the formula (i), (ii), or (iii).
- At least one R is a group of formula (iv).
- R 2 is a group of formula (i).
- R 2 is a group of formula
- R 2 is a group of formula (iii).
- R 3 is a group of formula (i).
- R is a group of formula (ii).
- R 3 is a group of formula (iii).
- R 5 is hydrogen.
- Z is O.
- n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, m is 1.
- L is an optionally substituted alkylene.
- R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R is a group of formula (ii). In certain embodiments, R 7 is a group of formula (iii). In certain embodiments, both R 6 and R 7 are independently groups of the formula (i), (ii), or (iii).
- L is an optionally substituted alkylene.
- R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R is a group of formula (ii). In certain embodiments, R 7 is a group of formula (iii). In certain embodiments, both R 6 and R 7 are independently groups of the formula (i), (ii), or (iii).
- R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R is a group of formula (ii). In certain embodiments, R 7 is a group of formula (iii). In certain embodiments, both R 6 and R 7 are independently groups of the formula (i), (ii), or (iii).
- R 1 is hydrogen. In certain embodiments, R 1 is a group of formula (iv). In certain embodiments, R 1 is a group of formula (iv) and R 6 is a group of the formula (i), (ii), or (iii). In certain embodiments, R 1 is a group of formula (iv) and both
- R 6 and R 7 are independently groups of the formula (i), (ii), or (iii).
- L is an optionally substituted alkylene.
- R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R is a group of formula (ii). In certain embodiments, R 7 is a group of formula (iii). In certain embodiments, both R 6 and R 7 are independently groups of the formula (i), (ii), or (iii).
- R 1 is hydrogen. In certain embodiments, R 1 is a group of formula (iv). In certain embodiments, R 1 is a group of formula (iv) and R 6 is a group of the formula (i), (ii), or (iii). In certain embodiments, R 1 is a group of formula (iv) and both
- R 6 and R 7 are independently groups of the formula (i), (ii), or (iii). [00210] In certain embodiments of Formula (Il-e), wherein R 1 alpha to the group
- L is an optionally substituted alkylene.
- R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula
- R 6 is a group of formula (iii).
- R 7 is a group of formula (i).
- R is a group of formula (ii).
- R 7 is a group of formula (iii).
- both R 6 and R 7 are independently groups of the formula (i), (ii), or (iii).
- R 1 is hydrogen. In certain embodiments, R 1 is a group of formula (iv). In certain embodiments, R 1 is a group of formula (iv) and R 6 is a group of the formula (i), (ii), or (iii). In certain embodiments, R 1 is a group of formula (iv) and both R 6 and R 7 are independently groups of the formula (i), (ii), or (iii).
- L is an optionally substituted alkylene.
- R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R is a group of formula (ii). In certain embodiments, R 7 is a group of formula (iii). In certain embodiments, both R 6 and R 7 are independently groups of the formula (i), (ii), or (iii). [00213] In certain embodiments of Formula (Il-a), wherein R 1 and R 8 are joined to form an optionally substituted 5-6 membered heterocyclic ring, provided is a compound of Formula (Il-g):
- L is an optionally substituted alkylene.
- Compounds of Formula (III) are the cyclic condensation product of the same or different two, three, four, five, six, seven, eight, nine, or ten amino acids, and which further comprise one or more sites of conjugation attached thereto, e.g., to an internal amide nitrogen, to an amino substituent, and/or to an imino nitrogen, of a group of formula (i), (iii), or (iii).
- groups may be conjugated before cyclization, i.e., to the amino acid precursors of the cyclization product, or after cyclization.
- p is an integer of between 1 and 9, inclusive;
- each instance of Q is independently O, S, or NR Q , wherein R Q is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii), (iii);
- each instance of R 1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, -OR A1 , -N(R A1 ) 2 , or -SR A1 ; wherein each occurrence of R A1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to an sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; and
- each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii), or (iii); and
- each instance of R' is independently hydrogen or optionally substituted alkyl
- X is O, S, NR X , wherein R X is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- R L is optionally substituted Ciso alkyl, optionally substituted C 2 -50 alkenyl, optionally substituted C 2 -50 alkynyl, optionally substituted heteroCi-so alkyl, optionally substituted heteroC2-5o alkenyl, optionally substituted heteroC2-so alkynyl, or a polymer;
- R Q , R 2 , R 6 , or R 7 is a group of the formula (i), (ii), or (iii).
- p is an integer of between 1 and 9, inclusive. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6. In certain embodiments, p is 7. In certain embodiments, p is 8. In certain embodiments, p is 9.
- the compound of Formula (III) is a compound of Formula (Ill-
- the compound of Formula (III) is a compound of Formula (Ill-b):
- the compound of Formula (III) is a compound of Formula (III-c):
- the compound of Formula (III) is a compound of Formula (Ill-d):
- the compound of Formula (III) is a compound of Formula (Ill-e):
- the compound of Formula (III) is a compound of Formula (Ill-f):
- the compound of Formula (III) is a compound of Formula (Ill-g):
- the compound of Formula (III) is a compound of Formula (Ill-h):
- the compound of Formula (III) is a compound of Formu -i):
- each instance of R' is independently hydrogen or optionally substituted alkyl.
- at least one instance of R' is hydrogen.
- at least two instances of R' is hydrogen.
- each instance of R' is hydrogen.
- at least one instance of R' is optionally substituted alkyl, e.g., methyl.
- at least two instances of R' is optionally substituted alkyl, e.g., methyl.
- one instance of R' is optionally substituted alkyl, and the rest are hydrogen.
- each instance of Q is independently O, S, or NR Q , wherein R Q is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii), or (iii).
- at least one instance of Q is O.
- each instance of Q is O.
- at least one instance of Q is S.
- each instance of Q is S.
- at least one instance of Q is NR .
- each instance of Q is NR .
- each instance of R v is independently hydrogen or a group of the formula (i), (ii), or (iii).
- each instance of R 1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, -OR A1 , -N(R A1 ) 2 , or -SR A1 .
- At least one instance of R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
- R 1 is optionally substituted alkyl; e.g. , optionally substituted C 1-6 alkyl, optionally substituted C 2 _ 6 alkyl, optionally substituted C 3 _ 6 alkyl, optionally substituted C 4 _ 6 alkyl, optionally substituted C 4 _ 5 alkyl, or optionally substituted C 3 ⁇ alkyl.
- At least one instance of R 1 is optionally substituted alkenyl, e.g. , optionally substituted C 2 _ 6 alkenyl, optionally substituted C 3 _ 6 alkenyl, optionally substituted C 4 _ 6 alkenyl, optionally substituted C 4 _ 5 alkenyl, or optionally substituted C 3 _ 4 alkenyl.
- At least one instance of R 1 is optionally substituted alkynyl, e.g. , optionally substituted C 2 _ 6 alkynyl, optionally substituted C 3 _ 6 alkynyl, optionally substituted C 4 _ 6 alkynyl, optionally substituted C 4 _ 5 alkynyl, or optionally substituted C 3 _ 4 alkynyl.
- At least one instance of R 1 is optionally substituted carbocyclyl, e.g. , optionally substituted C 3-1 o carbocyclyl, optionally substituted C 5 -8 carbocyclyl, optionally substituted C 5 _ 6 carbocyclyl, optionally substituted C 5 carbocyclyl, or optionally substituted C 6 carbocyclyl.
- At least one instance of R 1 is optionally substituted heterocyclyl, e.g. , optionally substituted 3- 14 membered heterocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-8 membered heterocyclyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted 5 membered heterocyclyl, or optionally substituted 6 membered heterocyclyl.
- At least one instance of R 1 is optionally substituted aryl, e.g. , optionally substituted phenyl.
- At least one instance of R 1 is optionally substituted heteroaryl, e.g. , optionally substituted 5-14 membered heteroaryl, optionally substituted 5- 10 membered heteroaryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5 membered heteroaryl, or optionally substituted 6 membered heteroaryl.
- R 1 alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group may be substituted, for example, with an optionally substituted amino group (e.g.
- R 6 and R 7 are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or a group of formula (i), (ii), or (iii).
- At least one instance of R 1 is an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group substituted with an amino group of the formula -N(R 6 )(R 7 ).
- at least one instance of R 1 is a group of formula:
- L is an optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted
- R 6 and R 7 are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group;
- R 6 and R 7 is a group of the formula (i), (ii), or (iii):
- R', X, Y, R L , and R p are as defined herein.
- At least two instances of R 1 is a group of formula (iv). In certain embodiments, at least three instances of R 1 is a group of formula (iv). In certain embodiments, at least four instances of R 1 is a group of formula (iv). In certain embodiments, at least five instances of R 1 is a group of formula (iv). In certain embodiments, at least six instances of R 1 is a group of formula (iv). In certain embodiments, at least seven instances of R 1 is a group of formula (iv). In certain embodiments, at least eight instances of R 1 is a group of formula (iv). In certain embodiments, at least nine instances of R is a group of formula (iv). In certain embodiments, each instance of R 1 is a group of formula (iv).
- L is an optionally substituted alkylene; e.g. , optionally substituted Ci-soalkylene, optionally substituted Ci ⁇ oalkylene, optionally substituted Ci- 30 alkylene, optionally substituted C ⁇ oalkylene, optionally substituted C 4 _ 2 oalkylene, optionally substituted C 6 - 2 oalkylene, optionally substituted Cg_ 2 oalkylene, optionally substituted Cio ⁇ oalkylene, optionally substituted Ci ⁇ alkylene, optionally substituted Ci ⁇ alkylene, optionally substituted C 2 - 6 alkylene, optionally substituted C 3 _ 6 alkylene, optionally substituted C 4 _ 6 alkylene, optionally substituted C 4 _ 5 alkylene, or optionally substituted C 3 _ 4 alkylene.
- optionally substituted Ci-soalkylene optionally substituted Ci ⁇ oalkylene, optionally substituted Ci ⁇ oalkylene, optionally substituted Ci ⁇ alkylene, optionally substituted
- L is an optionally substituted alkenylene, e.g. , optionally substituted C 2 - 5 oalkenylene, optionally substituted C 2 - 4 oalkenylene, optionally substituted C 2 - 3 oalkenylene, optionally substituted C 2 - 2 oalkenylene, optionally substituted C 4 - 2 oalkenylene, optionally substituted C 6 - 2 oalkenylene, optionally substituted Cg_ 2 oalkenylene, optionally substituted C 1 o- 2 oalkenylene, optionally substituted C 2 _ 6 alkenylene, optionally substituted C 3 _ 6 alkenylene, optionally substituted C 4 _ 6 alkenylene, optionally substituted C 4 - 5 alkenylene, or optionally substituted C 3 _ 4 alkenylene.
- optionally substituted alkenylene e.g. , optionally substituted C 2 - 5 oalkenylene, optionally substitute
- L is an optionally substituted alkynylene, e.g. , optionally substituted C 2 - 5 oalkynylene, optionally substituted C 2 - 4 oalkynylene, optionally substituted C 2 - 3 oalkynylene, optionally substituted C 2 - 2 oalkynylene, optionally substituted C 4 - 2 oalkynylene, optionally substituted C 6 - 2 oalkynylene, optionally substituted C 8 - 2 oalkynylene, optionally substituted C 1 o- 2 oalkynylene, optionally substituted C 2 - 6 alkynylene, optionally substituted C 3 _ 6 alkynylene, optionally substituted C 4 _ 6 alkynylene, optionally substituted C 4 _ 5 alkynylene, or optionally substituted C 3 _ 4 alkynylene.
- optionally substituted alkynylene e.g. , optionally substitute
- L is an optionally substituted heteroalkylene; e.g. , optionally substituted heteroCi-soalkylene, optionally substituted heteroC 1 _ 4 oalkylene, optionally substituted heteroCi-soalkylene, optionally substituted heteroC 1 _ 2 oalkylene, optionally substituted heteroC 4 _ 2 oalkylene, optionally substituted heteroC 6 - 2 oalkylene, optionally substituted heteroC 8 - 2 oalkylene, optionally substituted heteroC 1 o- 2 oalkylene, optionally substituted heteroCi-ealkylene, optionally substituted heteroC 2 - 6 alkylene, optionally substituted heteroC 3 _ 6 alkylene, optionally substituted heteroC 4 _ 6 alkylene, optionally substituted heteroC 4 _ 5 alkylene, or optionally substituted heteroC 3 _ 4 alkylene.
- optionally substituted heteroalkylene e.g., optionally substituted heteroCi-so
- L is an optionally substituted heteroalkenylene, e.g. , optionally substituted heteroC 2 - 5 oalkenylene, optionally substituted heteroC 2 - 4 oalkenylene, optionally substituted heteroC 2 - 3 oalkenylene, optionally substituted heteroC 2 - 2 oalkenylene, optionally substituted heteroC 4 _ 2 oalkenylene, optionally substituted heteroC 6 - 2 oalkenylene, optionally substituted heteroCg_ 2 oalkenylene, optionally substituted heteroCio ⁇ oalkenylene, optionally substituted heteroC 2 - 6 alkenylene, optionally substituted heteroC 3 _ 6 alkenylene, optionally substituted heteroC 4 _ 6 alkenylene, optionally substituted heteroC 4 _ 5 alkenylene, or optionally substituted heteroC 3 _ 4 alkenylene.
- optionally substituted heteroalkenylene e.g. , optionally substituted heteroC 2
- L is an optionally substituted heteroalkynylene, e.g. , optionally substituted heteroC 2 - 5 oalkynylene, optionally substituted heteroC 2 - 4 oalkynylene, optionally substituted heteroC 2 - 3 oalkynylene, optionally substituted heteroC 2 - 2 oalkynylene, optionally substituted heteroC 4 _ 2 oalkynylene, optionally substituted heteroC 6 - 2 oalkynylene, optionally substituted heteroCg_ 2 oalkynylene, optionally substituted heteroCio ⁇ oalkynylene, optionally substituted heteroC 2 - 6 alkynylene, optionally substituted heteroC 3 _ 6 alkynylene, optionally substituted heteroC 4 _ 6 alkynylene, optionally substituted heteroC 4 _ 5 alkynylene, or optionally substituted heteroC 3 _ 4 alkynylene.
- L is an optionally substituted carbocyclylene, e.g. , optionally substituted C 3-1 o carbocyclylene, optionally substituted C 5 -8 carbocyclylene, optionally substituted C 5 -6 carbocyclylene, optionally substituted C 5 carbocyclylene, or optionally substituted C 6 carbocyclylene.
- L is an optionally substituted heterocyclylene, e.g. , optionally substituted 3-14 membered heterocyclylene, optionally substituted 3-10 membered heterocyclylene, optionally substituted 5-8 membered heterocyclylene, optionally substituted 5-6 membered heterocyclylene, optionally substituted 5 membered heterocyclylene, or optionally substituted 6 membered heterocyclylene.
- optionally substituted heterocyclylene e.g. , optionally substituted 3-14 membered heterocyclylene, optionally substituted 3-10 membered heterocyclylene, optionally substituted 5-8 membered heterocyclylene, optionally substituted 5-6 membered heterocyclylene, optionally substituted 5 membered heterocyclylene, or optionally substituted 6 membered heterocyclylene.
- L is an optionally substituted arylene, e.g. , optionally substituted phenylene.
- L is an optionally substituted heteroarylene, e.g. , optionally substituted 5-14 membered heteroarylene, optionally substituted 5-10 membered heteroarylene, optionally substituted 5-6 membered heteroarylene, optionally substituted 5 membered heteroarylene, or optionally substituted 6 membered heteroarylene.
- the group of formula (iv) is a group of the formula:
- q is an integer between 1 and 50, inclusive.
- q is an integer between 1 and 40, inclusive. In certain embodiments, q is an integer between 1 and 30, inclusive. In certain embodiments, q is an integer between 1 and 20, inclusive. In certain embodiments, q is an integer between 4 and 20, inclusive. In certain embodiments, q is an integer between 6 and 20, inclusive. In certain embodiments, q is an integer between 8 and 20, inclusive. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 4. In certain embodiments, q is 5. In certain embodiments, q is 6. In certain embodiments, q is 7. In certain embodiments, q is 8. In certain embodiments, q is 9. In certain embodiments, q is 10.
- both R 6 and R 7 are hydrogen. In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (i), (ii), or (iii). In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (i). In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (ii). In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (iii). In certain embodiments, both R 6 and R 7 are independently a group of the formula (i), (ii), or (iii). In certain embodiments, both R 6 and R 7 are independently a group of the formula (i).
- both R 6 and R 7 are independently a group of the formula (ii). In certain embodiments, both R 6 and R 7 are independently a group of the formula (iii). In certain embodiments, both R 6 and R 7 are the same group, selected from a group of the formula (i), (ii), or (iii).
- R 1 encompasses amino acid side chains such as
- R 1 is a group selected from any one of the amino acid side chain groups listed therein.
- each instance of R 1 is the same.
- At least one R 1 group is different. In certain embodiments, each R 1 group is different.
- each instance of R 2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii), or (iii):
- R', X, Y, R L , and R p are as defined herein.
- R 2 is optionally substituted alkyl; e.g., optionally substituted C 1-6 alkyl, optionally substituted C 2 _ 6 alkyl, optionally substituted C 3 - 6 alkyl, optionally substituted C 4 _ 6 alkyl, optionally substituted C 4 _salkyl, or optionally substituted C 3 ⁇ alkyl.
- At least one instance of R 2 is optionally substituted alkenyl, e.g., optionally substituted C 2 _ 6 alkenyl, optionally substituted C 3 _ 6 alkenyl, optionally substituted C 4 _ 6 alkenyl, optionally substituted C 4 _ 5 alkenyl, or optionally substituted C 3 _ 4 alkenyl.
- R 2 is optionally substituted alkynyl, e.g., optionally substituted C 2 _ 6 alkynyl, optionally substituted C 3 _ 6 alkynyl, optionally substituted C 4 _ 6 alkynyl, optionally substituted C 4 _ 5 alkynyl, or optionally substituted C 3 _ 4 alkynyl.
- At least one instance of R 2 is optionally substituted carbocyclyl, e.g., optionally substituted C 3-1 o carbocyclyl, optionally substituted C 5 -8 carbocyclyl, optionally substituted C 5 - 6 carbocyclyl, optionally substituted C 5 carbocyclyl, or optionally substituted C 6 carbocyclyl.
- At least one instance of R 2 is optionally substituted heterocyclyl, e.g., optionally substituted 3- 14 membered heterocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-8 membered heterocyclyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted 5 membered heterocyclyl, or optionally substituted 6 membered heterocyclyl.
- optionally substituted heterocyclyl e.g., optionally substituted 3- 14 membered heterocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-8 membered heterocyclyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted 5 membered heterocyclyl, or optionally substituted 6 membered heterocyclyl.
- At least one instance of R 2 is optionally substituted aryl, e.g., optionally substituted phenyl.
- At least one instance of R 2 is optionally substituted heteroaryl, e.g., optionally substituted 5-14 membered heteroaryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 5-6 membered heteroaryl, optionally substituted
- At least one instance of R 2 is a nitrogen protecting group.
- At least one instance of R 2 is a group of the formula (i).
- At least one instance of R is a group of the formula (ii). In certain embodiments, at least one instance of R is a group of the formula (iii). [00265] In certain embodiments, each instance of R 2 is a group other than formula (i),
- both instances of R 2 are hydrogen, and thus at least one R O v is a group of the formula (i), (ii), or (iii), or at least one R 1 is a group of formula (iv), and at least one of R 6 or R 7 encompassed by R 1 is a group of the formula (i), (ii), or (iii).
- both instances of R 2 are hydrogen, and thus at least one R O v is a group of the formula (i), (ii), or (iii), or at least one R 1 is a group of formula (iv), and at least one of R 6 or R 7 encompassed by R 1 is a group of the formula (i), (ii), or (iii).
- At least one R 1 is a group of formula (iv). In certain embodiments, each instance of R 1 is a group of formula (iv). In certain embodiments, each instance of R 2 is hydrogen. In certain embodiments, at least one instance of R 2 is a group of formula (i). In certain embodiments, at least one instance of R is a group of formula (ii). In certain embodiments, at least one instance of R is a group of formula (iii). In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.
- each instance of R is a group of formula (iv).
- R 2 is hydrogen. In certain embodiments, each instance of R 2 is hydrogen. In certain embodiments, at least one instance of R is a group of formula (i). In certain embodiments, at least one instance of R is a group of formula (ii). In certain embodiments, at least one instance of R is a group of formula (iii). In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, L is an optionally substituted alkylene. In certain embodiments, R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii).
- R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R 7 is a group of formula (ii). In certain embodiments, R 7 is a group of formula (iii). In certain embodiments, both R 6 and R 7 are independently groups of formula (i), (ii), or (iii).
- each instance of R is hydrogen. In certain embodiments, at least one instance of R is a group of formula (i). In certain embodiments, at least one instance of R is a group of formula (ii). In certain embodiments, at least one instance of R is a group of formula (iii). In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, L is an optionally substituted alkylene. In certain embodiments, R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R is a group of formula (i). In certain embodiments,
- R 7 is a group of formula (ii). In certain embodiments, R 7 is a group of formula (iii). In certain embodiments, both R 6 and R 7 are independently groups of formula (i), (ii), or (iii).
- each instance of R is hydrogen. In certain embodiments, at least one instance of R is a group of formula (i). In certain embodiments, at least one instance of R is a group of formula (ii). In certain embodiments, at least one instance of R is a group of formula (iii). In certain embodiments, L is an optionally substituted alkylene. In certain embodiments, R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula
- R 7 is a group of formula (i). In certain embodiments, R 7 is a group of formula (ii). In certain embodiments, R is a group of formula (iii). In certain embodiments, both R 6 and R 7 are independently groups of formula (i), (ii), or (iii).
- L is an optionally substituted alkylene.
- R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R is a group of formula (ii). In certain embodiments, R 7 is a group of formula (iii). In certain embodiments, both R 6 and R 7 are groups of formula (i), (ii), or (iii).
- R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula (iii). In certain embodiments, R 7 is a group of formula (i). In certain embodiments, R 7 is a group of formula (ii). In certain embodiments, R 7 is a group of formula (iii). In certain embodiments, both R 6 and R 7 are independently groups of formula (i), (ii), or (iii).
- At least one R 1 is a group of formula (iv). In certain embodiments, each instance of R 1 is a group of formula (iv). In certain embodiments, each instance of R 2 is hydrogen. In certain embodiments, at least one instance of R 2 is a group of formula (i). In certain embodiments, at least one instance of R is a group of formula (ii). In certain embodiments, at least one instance of R is a group of formula (iii). In certain embodiments, R is a group of formula (iii). In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.
- At least one R is a group of formula (iv). In certain embodiments, each instance of R 1 is a group of formula (iv). In certain embodiments, each instance of R 2 is hydrogen. In certain embodiments, at least one instance of R 2 is a group of formula (i). In certain embodiments, at least one instance of R is a group of formula (ii). In certain embodiments, at least one instance of R is a group of formula (iii). In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. [00275] In certain embodiments of Formula (Ill-a), wherein at least one instance of R 2 is a group of formula (iii), provided is a compound of Formula (Ill-f):
- At least one R is a group of formula (iv). In certain embodiments, each instance of R 1 is a group of formula (iv). In certain embodiments, each instance of R 2 is hydrogen. In certain embodiments, at least one instance of R 2 is a group of formula (i). In certain embodiments, at least one instance of R is a group of formula (ii). In certain embodiments, at least one instance of R is a group of formula (iii). In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.
- each instance of Q is independently O, S, or NR Q , wherein R Q is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of formula (i), (ii), (iii);
- each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, -OR A1 , -N(R A1 ) 2 , or -SR A1 ; wherein each occurrence of R A1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to an sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;
- each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of formula (i), (ii), or (iii); and
- each instance of R' is independently hydrogen or optionally substituted alkyl
- X is O, S, NR X , wherein R X is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- R L is optionally substituted Ciso alkyl, optionally substituted C 2 -50 alkenyl, optionally substituted C 2 -50 alkynyl, optionally substituted heteroCi-so alkyl, optionally substituted heteroC2-5o alkenyl, optionally substituted heteroC2-so alkynyl, or a polymer;
- R Q , R 2 , R 6 , or R 7 is a group of the formula (i), (ii), or (iii).
- each instance of Q is independently O, S, or NR Q , wherein R Q is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii), or (iii).
- at least one instance of Q is O.
- each instance of Q is O.
- at least one instance of Q is S.
- each instance of Q is S.
- at least one instance of Q is NR .
- each instance of Q is NR .
- each instance of R v is independently hydrogen or a group of the formula (i), (ii), or (iii).
- each instance of R' is independently hydrogen or optionally substituted alkyl.
- at least one instance of R' is hydrogen.
- at least two instances of R' is hydrogen.
- each instance of R' is hydrogen.
- at least one instance of R' is optionally substituted alkyl, e.g., methyl.
- at least two instances of R' is optionally substituted alkyl, e.g., methyl.
- one instance of R' is optionally substituted alkyl, and the rest are hydrogen.
- each instance of R 1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, -OR A1 , -N(R A1 ) 2 , or -SR A1 .
- At least one instance of R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
- R 1 is optionally substituted alkyl; e.g. , optionally substituted C 1-6 alkyl, optionally substituted C 2 _ 6 alkyl, optionally substituted C 3 _ 6 alkyl, optionally substituted C 4 _ 6 alkyl, optionally substituted C 4 _ 5 alkyl, or optionally substituted C 3 ⁇ alkyl.
- At least one instance of R 1 is optionally substituted alkenyl, e.g. , optionally substituted C 2 _ 6 alkenyl, optionally substituted C 3 _ 6 alkenyl, optionally substituted C 4 _ 6 alkenyl, optionally substituted C 4 _ 5 alkenyl, or optionally substituted C 3 _ 4 alkenyl.
- At least one instance of R 1 is optionally substituted alkynyl, e.g. , optionally substituted C 2 _ 6 alkynyl, optionally substituted C 3 _ 6 alkynyl, optionally substituted C 4 _ 6 alkynyl, optionally substituted C 4 _ 5 alkynyl, or optionally substituted C 3 _ 4 alkynyl.
- At least one instance of R 1 is optionally substituted carbocyclyl, e.g. , optionally substituted C 3-1 o carbocyclyl, optionally substituted C 5 -8 carbocyclyl, optionally substituted C 5 _ 6 carbocyclyl, optionally substituted C 5 carbocyclyl, or optionally substituted C 6 carbocyclyl.
- At least one instance of R 1 is optionally substituted heterocyclyl, e.g. , optionally substituted 3- 14 membered heterocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-8 membered heterocyclyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted 5 membered heterocyclyl, or optionally substituted 6 membered heterocyclyl.
- At least one instance of R 1 is optionally substituted aryl, e.g. , optionally substituted phenyl.
- At least one instance of R 1 is optionally substituted heteroaryl, e.g. , optionally substituted 5-14 membered heteroaryl, optionally substituted 5- 10 membered heteroaryl, optionally substituted 5-6 membered heteroaryl, optionally substituted 5 membered heteroaryl, or optionally substituted 6 membered heteroaryl.
- R 1 alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group may be substituted, for example, with an optionally substituted amino group (e.g.
- R 6 and R 7 are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or a group of formula (i), (ii), or (iii).
- At least one instance of R 1 is an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group substituted with an amino group of the formula -N(R 6 )(R 7 ).
- at least one instance of R 1 is a group of formula:
- L is an optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted
- R 6 and R 7 are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group;
- R 6 and R 7 is a group of the formula (i), (ii), or (iii):
- R', X, Y, R L , and R p are as defined herein.
- both instances of R 1 are groups of formula (iv).
- L is an optionally substituted alkylene; e.g. , optionally substituted Ci-soalkylene, optionally substituted Ci ⁇ oalkylene, optionally substituted Ci- 30 alkylene, optionally substituted C ⁇ oalkylene, optionally substituted C4_ 2 oalkylene, optionally substituted C 6 - 2 oalkylene, optionally substituted Cg_ 2 oalkylene, optionally substituted Cio ⁇ oalkylene, optionally substituted Ci ⁇ alkylene, optionally substituted Ci ⁇ alkylene, optionally substituted C 2- 6 alkylene, optionally substituted C 3 _ 6 alkylene, optionally substituted C 4 _ 6 alkylene, optionally substituted C 4 _ 5 alkylene, or optionally substituted C 3 _ 4 alkylene.
- L is an optionally substituted alkenylene, e.g. , optionally substituted C 2 - 5 oalkenylene, optionally substituted C 2 - 4 oalkenylene, optionally substituted C 2 - 3 oalkenylene, optionally substituted C 2 - 2 oalkenylene, optionally substituted C 4 _ 2 oalkenylene, optionally substituted C 6 - 2 oalkenylene, optionally substituted Cg_ 2 oalkenylene, optionally substituted C 1 o- 2 oalkenylene, optionally substituted C 2 - 6 alkenylene, optionally substituted C 3 _ 6 alkenylene, optionally substituted C 4 _ 6 alkenylene, optionally substituted C 4- salkenylene, or optionally substituted C 3 _ 4 alkenylene.
- optionally substituted alkenylene e.g. , optionally substituted C 2 - 5 oalkenylene, optionally substituted C 2
- L is an optionally substituted alkynylene, e.g. , optionally substituted C 2 - 5 oalkynylene, optionally substituted C 2 - 4 oalkynylene, optionally substituted C 2 - 3 oalkynylene, optionally substituted C 2 - 2 oalkynylene, optionally substituted C 4 - 2 oalkynylene, optionally substituted C 6 - 2 oalkynylene, optionally substituted Cg_ 2 oalkynylene, optionally substituted C 1 o- 2 oalkynylene, optionally substituted C 2 - 6 alkynylene, optionally substituted C 3 _ 6 alkynylene, optionally substituted C 4 _ 6 alkynylene, optionally substituted C 4 - 5 alkynylene, or optionally substituted C 3 _ 4 alkynylene.
- optionally substituted alkynylene e.g. , optionally substituted
- L is an optionally substituted heteroalkylene; e.g. , optionally substituted heteroCi-soalkylene, optionally substituted heteroC 1 _ 4 oalkylene, optionally substituted heteroCi ⁇ oalkylene, optionally substituted heteroC 1 _ 2 oalkylene, optionally substituted heteroC 4 _ 2 oalkylene, optionally substituted heteroC 6 - 2 oalkylene, optionally substituted heteroCg_ 2 oalkylene, optionally substituted heteroC 1 o- 2 oalkylene, optionally substituted heteroCi-ealkylene, optionally substituted heteroC 2 - 6 alkylene, optionally substituted heteroC 3 _ 6 alkylene, optionally substituted heteroC 4 _ 6 alkylene, optionally substituted heteroC 4 _ 5 alkylene, or optionally substituted heteroC 3 _ 4 alkylene.
- optionally substituted heteroalkylene e.g., optionally substituted heteroCi-soalky
- L is an optionally substituted heteroalkenylene, e.g. , optionally substituted heteroC 2 - 5 oalkenylene, optionally substituted heteroC 2 - 4 oalkenylene, optionally substituted heteroC 2 - 3 oalkenylene, optionally substituted heteroC 2 - 2 oalkenylene, optionally substituted heteroC 4 _ 2 oalkenylene, optionally substituted heteroC 6 - 2 oalkenylene, optionally substituted heteroCg_ 2 oalkenylene, optionally substituted heteroCio ⁇ oalkenylene, optionally substituted heteroC 2 - 6 alkenylene, optionally substituted heteroC 3 _ 6 alkenylene, optionally substituted heteroC 4 _ 6 alkenylene, optionally substituted heteroC 4 _ 5 alkenylene, or optionally substituted heteroC 3 _ 4 alkenylene.
- optionally substituted heteroalkenylene e.g. , optionally substituted heteroC 2
- L is an optionally substituted heteroalkynylene, e.g. , optionally substituted heteroC 2 - 5 oalkynylene, optionally substituted heteroC 2 - 4 oalkynylene, optionally substituted heteroC 2 - 3 oalkynylene, optionally substituted heteroC 2 - 2 oalkynylene, optionally substituted heteroC 4 _ 2 oalkynylene, optionally substituted heteroC 6 - 2 oalkynylene, optionally substituted heteroC 8 - 2 oalkynylene, optionally substituted heteroCio ⁇ oalkynylene, optionally substituted heteroC 2 - 6 alkynylene, optionally substituted heteroC 3 _ 6 alkynylene, optionally substituted heteroC 4 _ 6 alkynylene, optionally substituted heteroC 4 _ 5 alkynylene, or optionally substituted heteroC 3 _ 4 alkynylene.
- L is an optionally substituted carbocyclylene, e.g. , optionally substituted C 3-1 o carbocyclylene, optionally substituted C 5 -8 carbocyclylene, optionally substituted C 5 _6 carbocyclylene, optionally substituted C 5 carbocyclylene, or optionally substituted C 6 carbocyclylene.
- L is an optionally substituted heterocyclylene, e.g. , optionally substituted 3- 14 membered heterocyclylene, optionally substituted 3-10 membered heterocyclylene, optionally substituted 5-8 membered heterocyclylene, optionally substituted 5-6 membered heterocyclylene, optionally substituted 5 membered heterocyclylene, or optionally substituted 6 membered heterocyclylene.
- optionally substituted heterocyclylene e.g. , optionally substituted 3- 14 membered heterocyclylene, optionally substituted 3-10 membered heterocyclylene, optionally substituted 5-8 membered heterocyclylene, optionally substituted 5-6 membered heterocyclylene, optionally substituted 5 membered heterocyclylene, or optionally substituted 6 membered heterocyclylene.
- L is an optionally substituted arylene, e.g. , optionally substituted phenylene.
- L is an optionally substituted heteroarylene, e.g. , optionally substituted 5- 14 membered heteroarylene, optionally substituted 5-10 membered heteroarylene, optionally substituted 5-6 membered heteroarylene, optionally substituted 5 membered heteroarylene, or optionally substituted 6 membered heteroarylene.
- optionally substituted heteroarylene e.g. , optionally substituted 5- 14 membered heteroarylene, optionally substituted 5-10 membered heteroarylene, optionally substituted 5-6 membered heteroarylene, optionally substituted 5 membered heteroarylene, or optionally substituted 6 membered heteroarylene.
- the group of formula (iv) is a group of the formula:
- q is an integer between 1 and 50, inclusive.
- q is an integer between 1 and 40, inclusive. In certain embodiments, q is an integer between 1 and 30, inclusive. In certain embodiments, q is an integer between 1 and 20, inclusive. In certain embodiments, q is an integer between 4 and 20, inclusive. In certain embodiments, q is an integer between 6 and 20, inclusive. In certain embodiments, q is an integer between 8 and 20, inclusive. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 4. In certain embodiments, q is 5. In certain embodiments, q is 6. In certain embodiments, q is 7. In certain embodiments, q is 8. In certain embodiments, q is 9. In certain embodiments, q is 10.
- both R 6 and R 7 are hydrogen. In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (i), (ii), or (iii). In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (i). In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (ii). In certain embodiments, R 6 is hydrogen and R 7 is a group of the formula (iii). In certain embodiments, both R 6 and R 7 are independently a group of the formula (i), (ii), or (iii). In certain embodiments, both R 6 and R 7 are independently a group of the formula (i).
- both R 6 and R 7 are independently a group of the formula (ii). In certain embodiments, both R 6 and R 7 are independently a group of the formula (iii). In certain embodiments, both R 6 and R 7 are the same group, selected from a group of the formula (i), (ii), or (iii).
- R 1 encompasses amino acid side chains such as
- R 1 is a group selected from any one of the amino acid side chain groups listed therein.
- each instance of R 1 is the same.
- At least one R 1 group is different. In certain embodiments, each R 1 group is different.
- each instance of R 2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or a group of the formula (i), (ii), or (iii):
- R', X, Y, R L , and R p are as defined herein.
- At least one instance of R 2 is optionally substituted alkyl; e.g., optionally substituted C 1-6 alkyl, optionally substituted C 2 _ 6 alkyl, optionally substituted C 3 _ 6 alkyl, optionally substituted C 4 _ 6 alkyl, optionally substituted C 4 _salkyl, or optionally substituted C 3 ⁇ alkyl.
- at least one instance of R 2 is optionally substituted alkenyl, e.g.
- At least one instance of R 2 is optionally substituted alkynyl, e.g. , optionally substituted C 2 _ 6 alkynyl, optionally substituted C 3 _ 6 alkynyl, optionally substituted C 4 _ 6 alkynyl, optionally substituted C 4 _ 5 alkynyl, or optionally substituted C 3 _
- At least one instance of R 2 is optionally substituted carbocyclyl, e.g. , optionally substituted C 3-1 o carbocyclyl, optionally substituted Cs-g
- carbocyclyl optionally substituted C 5 - 6 carbocyclyl, optionally substituted C 5 carbocyclyl, or optionally substituted C 6 carbocyclyl.
- At least one instance of R 2 is optionally substituted heterocyclyl, e.g. , optionally substituted 3- 14 membered heterocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-8 membered heterocyclyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted 5 membered heterocyclyl, or optionally substituted 6 membered heterocyclyl.
- At least one instance of R 2 is optionally substituted aryl, e.g. , optionally substituted phenyl.
- At least one instance of R 2 is optionally substituted heteroaryl, e.g. , optionally substituted 5-14 membered heteroaryl, optionally substituted 5- 10 membered heteroaryl, optionally substituted 5-6 membered heteroaryl, optionally substituted
- At least one instance of R 2 is a nitrogen protecting group.
- At least one instance of R 2 is a group of the formula (i).
- At least one instance of R is a group of the formula (ii). In certain embodiments, at least one instance of R is a group of the formula (iii).
- each instance of R 2 is a group other than formula (i),
- R 1 is a group of formula (iv)
- R 6 or R 7 encompassed by R 1 is a group of the formula (i), (ii), or (iii).
- R are hydrogen, and thus at least one R v is a group of the formula (i), (ii), or (iii), or at least one R 1 is a group of formula (iv), and at least one of R 6 or R 7 encompassed by R 1 is a group of the formula (i), (ii), or (iii).
- At least one instance of R 1 is a group of formula (iv).
- each instance of R 1 is a group of formula (iv).
- At least one instance of R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In certain embodiments, at least one instance of R is a group of formula (i). In certain embodiments, at least one instance of R is a group of formula (ii). In certain embodiments, at least one instance of R is a group of formula (iii).
- R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl.
- At least one instance of R is a group of formula (i). In certain embodiments, at least one instance of R is a group of formula (ii). In certain embodiments, at least one instance of R is a group of formula (iii). In certain embodiments, L is an optionally substituted alkylene. In certain embodiments, R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula
- R 7 is a group of formula (i). In certain embodiments, R 7 is a group of formula (ii). In certain embodiments, R is a group of formula (iii). In certain embodiments, both R 6 and R 7 are independently groups of formula (i), (ii), or (iii). [00320] In certain embodiments of Formula (IV-b), (V-b), or (Vl-b), wherein both R 1 groups are a group the formula (iv), provided is a compound of Formula (IV-c), (V-c), or (VI-c):
- At least one instance of R is a group of formula (i). In certain embodiments, at least one instance of R is a group of formula (ii). In certain embodiments, at least one instance of R is a group of formula (iii). In certain embodiments, L is an optionally substituted alkylene. In certain embodiments, R 6 is a group of formula (i). In certain embodiments, R 6 is a group of formula (ii). In certain embodiments, R 6 is a group of formula
- R 7 is a group of formula (i). In certain embodiments, R 7 is a group of formula (ii). In certain embodiments, R is a group of formula (iii). In certain embodiments, both R 6 and R 7 are independently groups of formula (i), (ii), or (iii).
- At least one instance of R 1 is a group of formula (iv).
- each instance of R 1 is a group of formula (iv).
- R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl.
- R is a group of formula (i).
- R is a group of formula (ii).
- R is a group of formula (iii).
- At least one instance of R 1 is a group of formula (iv).
- each instance of R 1 is a group of formula (iv).
- At least one instance of R 1 is a group of formula (iv).
- each instance of R 1 is a group of formula (iv).
- R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In certain embodiments, R is a group of formula (i). In certain embodiments, R is a group of formula (ii). In certain embodiments, R is a group of formula (iii).
- At least one instance of R 1 is a group of formula (iv).
- each instance of R 1 is a group of formula (iv).
- At least one instance of R 1 is a group of formula (iv).
- each instance of R 1 is a group of formula (iv).
- R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In certain embodiments, R is a group of formula (i). In certain embodiments, R is a group of formula (ii). In certain embodiments, R is a group of formula (iii).
- At least one instance of R 1 is a group of formula (iv).
- each instance of R 1 is a group of formula (iv).
- APPLs and in particular, APPL compounds of Formulae (I), (III), (IV), (V), and (VI), each include at least one instance of a group of the formula (i), (ii), or (iii):
- each instance of R' is independently hydrogen or optionally substituted alkyl
- X is O, S, NR , wherein R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- Y is O, S, NR , wherein R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- R p is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; and
- R L is optionally substituted C 1-5 o alkyl, optionally substituted C 2 -50 alkenyl, optionally substituted C 2 -50 alkynyl, optionally substituted heteroCi-so alkyl, optionally substituted heteroC 2 -5o alkenyl, optionally substituted heteroC 2 -so alkynyl, or a polymer.
- the at least one instance of group of formula (i) is incorporated as part of the scaffold, e.g., by monoaddition of a compound (i-x), followed by internal cyclization. See, e.g., Scheme 2.
- an APPL and in particular, a compound of Formulae (I), (II), (III), (IV), (V), or (VI), comprises at least one instance of a group of the formula (i) attached thereto:
- Y is O. In certain embodiments of formula (i), Y is S. In certain embodiments of formula (i), Y is NR , wherein R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group. In certain embodiments of formula (i), Y is O. In certain embodiments of formula (i), Y is S. In certain embodiments of formula (i), Y is NR , wherein R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group. In certain
- Y is NR , wherein R is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments of formula (i), each instance of R' is hydrogen.
- R L when the group R L is depicted as bisecting a carbon-carbon bond, e.g. , of the group of the formula (i), it is understood that R L may be substituted at either carbon.
- Nucleophilic attack of an amino or amide group at the least sterically hindered carbon of the epoxide, thiirane, or aziridine of formula (i-x) provides a group of the formula (i-al), (i-a2), or (i-a3) (route a), while nucleophilic attack at the more sterically hindered carbon of the epoxide, thiirane, or aziridine of formula (i-x) provides a group of the formula (i-bl), (i-b2), or (i-b3) (route b), wherein R p is hydrogen (Scheme 6).
- compounds of the present invention may comprise a mixture of products attached thereto arising from route (a) and route (b) depending on the preference, or lack thereof, of the mode of addition.
- the bisecting group R L depicted in the Formulae seeks to encompasses all contemplated modes of addition.
- the hydroxyl, thiol, or amino moiety - YR P may be reacted with an electrophile of the formula R p -X 2 wherein R P is a group other than hydrogen, and X 2 is a leaving group, to provide a substituted hydroxyl, thiol, and amino group in formula (i).
- R p is hydrogen. In certain embodiments of formula (i), R p is optionally substituted alkyl. In certain embodiments of formula (i), R p is optionally substituted alkenyl. In certain embodiments of formula (i), R p is optionally substituted alkynyl. In certain embodiments of formula (i), R p is optionally substituted carbocyclyl. In certain embodiments of formula (i), R p is optionally substituted heterocyclyl. In certain embodiments of formula (i), R p is optionally substituted aryl. In certain embodiments of formula (i), R p is hydrogen. In certain embodiments of formula (i), R p is optionally substituted alkyl. In certain embodiments of formula (i), R p is optionally substituted alkenyl. In certain embodiments of formula (i), R p is optionally substituted alkynyl. In certain embodiments of formula (i), R p is optionally substituted carbocyclyl. In certain embodiments of formula (i), R p
- R p is optionally substituted heteroaryl.
- R p is an oxygen protecting group when attached to an oxygen atom.
- R p is a sulfur protecting group when attached to a sulfur atom.
- R p is a nitrogen protecting group when attached to a nitrogen atom.
- group of formula (i) represents a group of formul -a) or a group of formula (i-b): (i-a) (i-b).
- the reaction mixture provides a mixture of APPLs comprising more APPLs conjugated to a group of formula (i-a) than formula (i-b), e.g., the reaction mixture comprises greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 99%, between about 60% to about 100%, between about 70% to about 100%, between about 80% to about 100%, between about 90% to about 100%, between about 95% to about 100%, or between about 99% to about 100%, of an APPL attached to formula (i-a).
- the epoxide, thiirane, or aziridine of formula (i-x) is chiral, i.e., having (R) or (S) stereochemistry.
- Chiral epoxides, thiiranes, and aziridines can be obtained from a variety of sources which are familiar to those skilled in the art of organic synthesis.
- the chiral epoxide, thiirane, or aziridine is obtained commercially.
- the chiral epoxide, thiirane, or aziridine is synthesized according to methods known to those of skill in the art, such as, but not limited to the Sharpless epoxidation of primary and secondary allylic alcohols into 2,3-epoxyalcohols (see, e.g., Katsuki et al, J. Am. Chem. Soc. 1980, 102, 5974; Hill et al, Org. Syn., Coll. Vol. 7, p.461 (1990); Vol. 63, p.66 (1985); Katsuki et al, Org. React. 1996, 48, 1-300).
- the chiral epoxide, thiirane, or aziridine is obtained from the resolution of a mixture ⁇ e.g., racemic mixture) of epoxides, thiiranes, or aziridines. In some embodiments, the chiral epoxide, thiirane, or aziridine is obtained by the separation of enantiomers or diastereoisomers using chiral chromatography.
- Chirality can be characterized in a variety of ways, e.g., obtaining a crystal structure of the compound containing a heavy atom attached thereto, obtaining the optical rotation of the compound, and/or NMR analysis after chemical modification of the optically active compound with a chiral derivatizing agent are some methods useful in evaluating chirality.
- the conjugation reaction is regioselective, and the reaction provides a chiral mixture of APPLs comprising more APPLs conjugated to a group of formula (i-al) than formula (i-bl), e.g., the reaction mixture comprises greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 99%, between about 60% to about 100%, between about 70% to about 100%, between about 80% to about 100%, between about 90% to about 100%, between about 95% to about 100%, or between about 99% to about 100%, of an APPL attached to formula (i-al).
- the conjugation reaction is regioselective, and the reaction provides a chiral mixture of APPLs comprising more APPLs conjugated to a group of formula (i-a2) than formula (i-b2), e.g., the reaction mixture comprises greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 99%, between about 60% to about 100%, between about 70% to about 100%, between about 80% to about 100%, between about 90% to about 100%, between about 95% to about 100%, or between about 99% to about 100%, of an APPL attached to formula (i-a2).
- an APPL and in particular, a compound of Formulae (I), (II), (III), (IV), (V), or (VI), comprises at least one instance of a group of the formula (ii) attached thereto:
- X is O. In certain embodiments of formula (ii), X is S. In certain embodiments of formula (ii), X is NR X , wherein R X is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group. In certain embodiments of formula (ii), X is NR X , wherein R X is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments of formula (i), each instance of R' is hydrogen.
- an APPL and in particular, a compound of Formulae (I), (II), (III), (IV), (V), or (VI), comprises at least one instance of a group of the formula (ii) attached thereto:
- R L is optionally substituted C 1-5 o alkyl, optionally substituted C 2 -50 alkenyl, optionally substituted C 2 -50 alkynyl, optionally substituted Q-50 heteroalkyl, optionally substituted C 2 -50 heteroalkenyl, optionally substituted C 2 -50 heteroalkynyl, or a polymer.
- the group R L seeks to encompass lipophilic, hydrophobic, and/or non-polar groups, but such terms should not limit the scope of R L .
- R L is an optionally substituted Ci-so alkyl. In certain embodiments, R L is an optionally substituted C 6 - 5 oalkyl. In certain embodiments, R L is an optionally substituted C 6 - 4 oalkyl. In certain embodiments, R L is an optionally substituted C 6 - 3 oalkyl. In certain embodiments, R L is an optionally substituted C 6 - 2 oalkyl. In certain embodiments, R L is an optionally substituted C8- 2 oalkyl. In certain embodiments, R L is an optionally substituted Csalkyl. In certain embodiments, R L is an optionally substituted Cgalkyl.
- R L is an optionally substituted Cioalkyl. In certain embodiments, R L is an optionally substituted Cnalkyl. In certain embodiments, R L is an optionally substituted Cnalkyl. In certain embodiments, R L is an optionally substituted C 13 alkyl. In certain embodiments, R L is an optionally substituted
- R L is an optionally substituted Cnalkyl. In certain embodiments, R L is an optionally substituted Cnalkyl. In certain embodiments, R L is an optionally substituted Cnalkyl. In certain embodiments, R L is an optionally substituted Cnalkyl. In certain embodiments, R L is an optionally substituted C 2 oalkyl. In any of the above embodiments, the group R L is an unsubstituted alkyl group.
- R L is an unsubstituted alkyl.
- exemplary unsubstituted alkyl groups include, but are not limited to, -CH 3 , -C 2 H 5 , -C 3 H7, - C 4 H 9 , -CsHn, -C 6 H 1 , -CjHis, -CgH 17 , -CgF! ⁇ , -C 10 H 21 , -CnH 23 , -Q 2 H 25 , -C 13 H 27 , -C 14 H 2 9, - Ci 5 H 1 , -C 2 oH 41 , -C 2 iH 4 , -C 22 H 15 , -C 23 FI 47 , -C 24 H 49 , and
- At least one instance of R L is a substituted alkyl.
- at least one instance of R L is an alkyl substituted with one or more fluorine substituents.
- exemplary fluorinated alkyl groups include, but are not limited to:
- R L is an optionally substituted C 2 -50 alkenyl. In certain embodiments, R L is an optionally substituted C 6 - 5 oalkenyl. In certain embodiments, R L is an optionally substituted C 6 - 4 oalkenyl. In certain embodiments, R L is an optionally substituted C 6 - 3 oalkenyl. In certain embodiments, R L is an optionally substituted C 6 - 2 oalkenyl. In certain embodiments, R L is an optionally substituted C8- 2 oalkenyl. In certain embodiments, R L is an optionally substituted Csalkenyl.
- R L is an optionally substituted Cgalkenyl. In certain embodiments, R L is an optionally substituted Cioalkenyl. In certain embodiments, R L is an optionally substituted Cnalkenyl. In certain embodiments, R L is an optionally substituted Cnalkenyl. In certain embodiments, R L is an optionally substituted Cnalkenyl. In certain embodiments, R L is an optionally substituted C 14 alkenyl. In certain embodiments, R L is an optionally substituted Cnalkenyl. In certain embodiments, R L is an optionally substituted Cnalkenyl. In certain embodiments, R L is an optionally substituted Cnalkenyl. In certain embodiments, R L is an optionally substituted Cnalkenyl. In certain embodiments, R L is an optionally substituted Cnalkenyl. In certain embodiments, R L is an optionally substituted Cnalkenyl.
- R L is an optionally substituted Cnalkenyl. In certain embodiments, R L is an optionally substituted Cnalkenyl. In certain embodiments, R L is an optionally substituted Cioalkenyl. In any of the above embodiments, the group R L is an unsubstituted alkenyl group. [00347] Exemplary unsubstituted alkenyl groups include, but are not limited to:
- Myristoleic -(CH 2 ) 7 CH CH(CH 2 ) 3 CH 3 ,
- Palmitoliec -(CH 2 ) 7 CH CH(CH 2 ) 5 CH 3 ,
- Oleic -(CH 2 ) 7 CH CH(CH 2 ) 7 CH 3 ,
- R L is defined as a C 6 -soalkyl or C 6 -soalkenyl groups
- such groups are meant to encompass lipophilic groups (also referred to as a "lipid tail").
- Lipophilic groups comprise a group of molecules that include fats, waxes, oils, fatty acids, and the like. Lipid tails present in these lipid groups can be saturated and unsaturated, depending on whether or not the lipid tail comprises double bonds.
- the lipid tail can also comprise different lengths, often categorized as medium (i.e. , with tails between 7-12 carbons, e.g. , C 7-12 alkyl or C 7-12 alkenyl), long (i.e. , with tails greater than 12 carbons and up to 22 carbons, e.g. , C 13 _ 22 alkyl or C 13 _ 2 2 alkenyl), or very long (i.e. , with tails greater than 22 carbons, e.g. , C 23 - 3 o alkyl or C 23 - 3 o alkenyl).
- R L is an optionally substituted C 2 -so alkynyl. In certain embodiments, R L is an optionally substituted C 6 - 5 oalkynyl. In certain embodiments, R L is an optionally substituted C 6 ⁇ oalkynyl. In certain embodiments, R L is an optionally substituted C 6 - 3 oalkynyl. In certain embodiments, R L is an optionally substituted C 6 - 2 oalkynyl. In certain embodiments, R L is an optionally substituted C8- 2 oalkynyl. In certain embodiments, R L is an optionally substituted Csalkynyl.
- R L is an optionally substituted Cgalkynyl. In certain embodiments, R L is an optionally substituted Cioalkynyl. In certain embodiments, R L is an optionally substituted Cnalkynyl. In certain embodiments, R L is an optionally substituted C 12 alkynyl. In certain embodiments, R L is an optionally substituted C 13 alkynyl. In certain embodiments, R L is an optionally substituted C 14 alkynyl. In certain embodiments, R L is an optionally substituted Cisalkynyl. In certain embodiments, R L is an optionally substituted Cnalkynyl. In certain embodiments, R L is an optionally substituted Cnalkynyl.
- R L is an optionally substituted Cnalkynyl. In certain embodiments, R L is an optionally substituted Cnalkynyl. In certain embodiments, R L is an optionally substituted C 2 oalkynyl. In any of the above embodiments, the group R L is an unsubstituted alkynyl group.
- R L is an optionally substituted heteroCi-50 alkyl.
- R L is an optionally substituted heteroC 6 -so alkyl.
- R L is an optionally substituted heteroC 6 - 4 o alkyl.
- R L is an optionally substituted heteroC 6 - 3 oalkyl.
- R L is an optionally substituted heteroC 6 - 2 oalkyl.
- R L is an optionally substituted heteroCio ⁇ oalkyl.
- R L is an optionally substituted heteroCgalkyl.
- R L is an optionally substituted heteroCgalkyl.
- R L is an optionally substituted heteroCioalkyl. In certain embodiments, R L is an optionally substituted heteroCnalkyl. In certain embodiments, R L is an optionally substituted heteroC 12 alkyl. In certain embodiments, R L is an optionally substituted heteroC 13 alkyl. In certain embodiments, R L is an optionally substituted heteroC 14 alkyl. In certain embodiments, R L is an optionally substituted heteroCisalkyl. In certain embodiments, R L is an optionally substituted heteroCiealkyl. In certain embodiments, R L is an optionally substituted heteroCnalkyl. In certain embodiments, R L is an optionally substituted heteroCigalkyl.
- R L is an optionally substituted heteroCigalkyl. In certain embodiments, R L is an optionally substituted heteroC 2 oalkyl. In any of the above embodiments, the group R L is an unsubstituted heteroalkyl group.
- Exemplary unsubstituted heteroalkyl groups include, but are not limited to,
- R L is an optionally substituted heteroC 2 - 5 oalkenyl. In certain embodiments, R L is an optionally substituted heteroC 6 - 5 0 alkenyl. In certain embodiments, R L is an optionally substituted heteroC 6 - 4 oalkenyl. In certain embodiments, R L is an optionally substituted heteroC 6 - 3 oalkenyl. In certain embodiments, R L is an optionally substituted heteroC 6 - 2 oalkenyl. In certain embodiments, R L is an optionally substituted heteroCg_ 2 oalkenyl. In certain embodiments, R L is an optionally substituted heteroCgalkenyl.
- R L is an optionally substituted heteroCgalkenyl. In certain embodiments, R L is an optionally substituted heteroCioalkenyl. In certain embodiments, R L is an optionally substituted heteroCnalkenyl. In certain embodiments, R L is an optionally substituted heteroCgalkenyl. In certain embodiments, R L is an optionally substituted heteroCgalkenyl. In certain embodiments, R L is an optionally substituted heteroC 14 alkenyl. In certain embodiments, R L is an optionally substituted heteroCisalkenyl. In certain embodiments, R L is an optionally substituted heteroCiealkenyl. In certain embodiments, R L is an optionally substituted heteroCnalkenyl.
- R L is an optionally substituted heteroCigalkenyl. In certain embodiments, R L is an optionally substituted heteroCigalkenyl. In certain embodiments, R L is an optionally substituted heteroC 2 oalkenyl. In any of the above embodiments, the group R L is an unsubstituted heteroalkenyl group.
- R L is an optionally substituted heteroC 2 -soalkynyl. In certain embodiments, R L is an optionally substituted heteroC 6 -soalkynyl. In certain embodiments, R L is an optionally substituted heteroC 6 - 4 oalkynyl. In certain embodiments, R L is an optionally substituted heteroC 6 - 3 oalkynyl. In certain embodiments, R L is an optionally substituted heteroC 6 - 2 oalkynyl. In certain embodiments, R L is an optionally substituted heteroC 8 - 2 oalkynyl. In certain embodiments, R L is an optionally substituted heteroCsalkynyl.
- R L is an optionally substituted heteroCgalkynyl. In certain embodiments, R L is an optionally substituted heteroCnalkynyl. In certain embodiments, R L is an optionally substituted heteroCnalkynyl. In certain embodiments, R L is an optionally substituted heteroCnalkynyl. In certain embodiments, R L is an optionally substituted heteroCnalkynyl. In certain embodiments, R L is an optionally substituted heteroCnalkynyl. In certain embodiments, R L is an optionally substituted heteroCnalkynyl. In certain embodiments, R L is an optionally substituted heteroCnalkynyl. In certain embodiments, R L is an optionally substituted heteroCnalkynyl. In certain embodiments, R L is an optionally substituted heteroCnalkynyl. In certain embodiments, R L is an optionally substituted heteroCnalkynyl. In certain embodiments, R L is an optionally substituted heteroCnalky
- R L is an optionally substituted heteroCnalkynyl. In certain embodiments, R L is an optionally substituted heteroCnalkynyl. In certain embodiments, R L is an optionally substituted heteroCnalkynyl. In certain embodiments, R L is an optionally substituted heteroC 2 oalkynyl. In any of the above embodiments, the group R L is an unsubstituted heteroalkynyl group.
- At least one instance of R L is a polymer.
- a polymer refers to a compound comprised of at least 3 (e.g. , at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, etc.) repeating covalently bound structural units.
- the polymer is in certain embodiments biocompatible (i.e. , non-toxic).
- Exemplary polymers include, but are not limited to, cellulose polymers (e.g. , hydroxyethylcellulose, ethylcellulose,
- carboxymethylcellulose methylc cellulose, hydroxypropylmethylcellulose (HPMC)
- dextran polymers polymaleic acid polymers, poly(acrylic acid) polymers, poly(vinylalcohol) polymers, polyvinylpyrrolidone (PVP) polymers, and polyethyleneglycol (PEG) polymers, and combinations thereof.
- an APPL precursor is treated with one or more conjugating reagents, e.g., selected from an epoxide, thiirane, or aziridine of formula (i-x), an ⁇ , ⁇ -unsaturated ester, thioester, or amide of formula (ii-x), or an an aldehyde of formula (iii-x), to provide the APPL.
- conjugating reagents e.g., selected from an epoxide, thiirane, or aziridine of formula (i-x), an ⁇ , ⁇ -unsaturated ester, thioester, or amide of formula (ii-x), or an an aldehyde of formula (iii-x)
- a method of preparing an APPL functionalized with a group of formula (i) comprising heating the precursor in an organic solvent (e.g. , EtOH) with one or more conjugating reagents of formula (i-x) to provide the desired APPL.
- an organic solvent e.g. , EtOH
- conjugating reagents of formula (i-x) to provide the desired APPL.
- the mixture is heated between about 100 to about 200 °C, inclusive, e.g., about 150 °C.
- a method of preparing an APPL functionalized with a group of formula (ii) comprising heating the precursor in an organic solvent (e.g. , EtOH) with one or more conjugating reagents of formula (ii-x) to provide the desired APPL.
- an organic solvent e.g. , EtOH
- conjugating reagents of formula (ii-x) to provide the desired APPL.
- the mixture is heated between about 50 to about 100 °C, inclusive, e.g., about 90°C.
- a method of preparing an APPL functionalized with a group of formula (iii) comprising mixing the precursor in an organic solvent (e.g. , THF) with one or more conjugating reagents of formula (iii-x) and a reducing agent (e.g., NaBH(OAc) 3 ) to provide the desired APPL.
- an organic solvent e.g. , THF
- conjugating reagents of formula (iii-x) and a reducing agent e.g., NaBH(OAc) 3
- the temperature of the reaction mixture is room temperature mixture.
- each instance of R L is the same in the APPL.
- each instance of R L is the same wherein R L is an optionally substituted alkyl.
- each instance of R L is the same wherein R L is an unsubstituted alkyl.
- each instance of R L is the same wherein R L is selected from the group consisting of -CH 3 , - C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -CsHn, -C 6 H 1 , -CjHis, -CgH 17 , -CgF! ⁇ , -C 10 H 21 , -CnH 23 , -C 12 H 2 5, - C 13 H 27 , -Q 4 H 29 , -3 ⁇ 4 ⁇ 1 , ⁇ 16 ⁇ , -C 17 H 5, -CigFLj, -C ⁇ H ⁇ , and -C 2 oH 41 .
- each instance of R L is the same wherein R L is an n-alkyl group selected from - CsHn, -C 9 FL 9 , -Q0H21, -CnH 23 , -C 12 H 2 5, -C 13 H 27 , -C 14 H 2 9, - ⁇ 5 ⁇ 31 , and -C ⁇ H ⁇ .
- the APPL may comprise two or more (e.g. , two, three, four, five, six, seven, eight, nine, or ten) different groups of the formula (i), (ii), and/or (iii) attached thereto.
- the APPL comprises two different R L groups.
- the APPL comprises a mixture of two different R L groups, wherein the first R L group is an optionally substituted alkyl, and the second R L group is a polymer.
- the degree of conjugation may be controlled by the reaction conditions (e.g. , temperature, starting materials,
- the synthesized APPL may be purified by any technique known in the art including, but not limited to, precipitation, crystallization, chromatography, distillation, etc.
- the APPL is isolated as a salt.
- the APPL is reacted with an acid (e.g. , an organic acid or inorganic acid) to form the corresponding salt.
- tertiary amines are alkylated to form a quaternary ammonium salt of the APPL.
- the tertiary amines may be alkylated with any alkylating agent, for example, alkyl halides such as methyl iodide may be used to from the quaternary amino groups.
- the anion associated with the quaternary amine may be any organic or inorganic anion. In certain embodiments, the anion is a pharmaceutically acceptable anion.
- the invention also provides libraries of APPLs prepared by the inventive methods.
- a method of screening a compound library the method comprising providing a plurality of different APPLs, or salts thereof; and performing at least one assay with the compound library to determine the presense or absence of a desired property.
- These APPLs may be prepared and/or screened using high-throughput techniques involving liquid handlers, robots, microtiter plates, computers, etc.
- the APPLs are screened for their ability to transfect polynucleotides or other agents (e.g. , proteins, peptides, small molecules) into the cell.
- a method of screening a compound library the method comprising providing a plurality of two or more different APPLs and screening the compound library for a desired property.
- a library of different APPLs is prepared in parallel.
- a different precursor and/or conjugating reagent is added to each vial in a set of vials or to each well of a multi-well plate used to prepare the library.
- the array of reaction mixtures is incubated at a temperature and length of time sufficient to allow formation of the APPL.
- the APPL may then be isolated and purified using techniques known in the art.
- the APPL may then be screened using high-throughput techniques to identify APPLs with a desired property, e.g.
- the desired property is solubility in water, solubility at different pH, ability to bind polynucleotides, ability to bind heparin, ability to bind small molecules, ability to bind protein, ability to form microparticles, ability to increase tranfection efficiency, ability to support cell growth, ability to support cell attachment, ability to support tissue growth, and/or intracellular delivery of the APPL and/or an agent complexed or attached thereto to aid in bioprocessing, e.g., for the purpose of manufacturing proteins.
- the APPLs may be screened for properties or characteristics useful as coatings, additives, materials, and excipients in biotechnology and biomedical applications such as the coating of medical devices or implants with films or multilayer films, as non-biofouling agents, micropatterning agents, and cellular encapsulation agents.
- the APPL may be screened for properties or characteristics useful in gene therapy (e.g. , the ability to bind polynucleotides and/or increase in transfection efficiency), bioprocessing (e.g., aiding in the intracellular manufacturing of proteins), or the administration and/or delivery of a therapeutic agent (e.g. , polynucleotide, small molecule, antigen, drug, protein, peptide, etc.) to a subject, tissue, organ, or cell.
- a therapeutic agent e.g. , polynucleotide, small molecule, antigen, drug, protein, peptide, etc.
- R 1 of such compounds is an amino acid side chain as defined in Table 1 of the Examples.
- Exemplary amino acid, peptide, and polypeptide compounds of Formula (I) include, but are not limited to:
- Exemplary cyclized compounds of Formula (II), include, but are not limited to:
- Exemplary cyclic dipeptide and cyclic polypeptide compounds of Formula (III) include, but are not limited to:
- compositions [00369] The present invention contemplates an APPL as a component of a composition.
- a composition comprising an APPL, or salt thereof, and an excipient, wherein the APPL is an amino acid, a linear or cyclic peptide, or a linear or cyclic polypeptide, or structural isomer thereof, and wherein an amino or amide group of the APPL is conjugated to a group of formula (i), (ii), or (iii).
- a composition comprising an APPL, or salt thereof, and an excipient, wherein the APPL is an amino acid, a linear or cyclic peptide, or a linear or cyclic polypeptide, or structural isomer thereof, and wherein an amino or amide group of the APPL is conjugated to a group of formula (i), (ii), or (iii).
- the group of formula (i), (ii), or (iii) is attached to an amino group present on the APPL scaffold.
- compositions comprising an APPL and an excipient of some sort may be useful in a variety of medical and non-medical applications.
- pharmaceutical compositions comprising an APPL and an excipient may be useful in the delivery of an effective amount of an agent to a subject in need thereof.
- Nutraceutical compositions comprising an APPL and an excipient may be useful in the delivery of an effective amount of a nutraceutical, e.g., a dietary supplement, to a subject in need thereof.
- Cosmetic compositions comprising an APPL and an excipient may be formulated as a cream, ointment, balm, paste, film, or liquid, etc., and may be useful in the application of make-up, hair products, and materials useful for personal hygiene, etc.
- Compositions comprising an APPL and an excipient may be useful for non-medical applications, e.g., such as an emulsion or emulsifier, useful, for example, as a food component, for extinguishing fires, for disinfecting surfaces, for oil cleanup, etc.
- compositions comprising an APPL and an excipient may further be useful in bioprocessing, such as a cell's bioprocessing of a commercially useful chemical or fuel.
- bioprocessing such as a cell's bioprocessing of a commercially useful chemical or fuel.
- intracellular delivery of the APPL or an agent complexed thereto may be useful in bioprocessing by maintaining the cell's health and/or growth, e.g., in the manufacturing of proteins.
- the composition may comprise one type of APPL but may also comprise any number of different types of APPLs, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more different types of APPLs.
- the composition further comprises an agent, as described herein.
- the agent is a small molecule, organometallic compound, nucleic acid, protein, peptide, polynucleotide, metal, targeting agent, an isotopically labeled chemical compound, drug, vaccine, immunological agent, or an agent useful in bioprocessing.
- the agent is a polynucleotide.
- the polynucleotide is DNA or RNA.
- the RNA is RNAi, dsRNA, siRNA, shRNA, miRNA, or antisense RNA.
- the polynucleotide and the one or more APPLs are not covalently attached.
- the one or more APPLs are in the form of a particle.
- the particle is a nanoparticle or microparticle.
- the one or more APPLs are in the form of liposomes or micelles. It is understood that, in certain embodiments, these APPLs self-assemble to provide a particle, micelle, or liposome.
- the particle, micelle, or liposome encapsulates an agent.
- the agent to be delivered by the particle, micelle, or liposome may be in the form of a gas, liquid, or solid.
- the APPLs may be combined with polymers (synthetic or natural), surfactants, cholesterol, carbohydrates, proteins, lipids etc. to form the particles. These particles may be further combined with an excipient to form the composition.
- Excipients include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or
- excipients include, but are not limited to, any non-toxic, inert solid, semi- solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
- materials which can serve as excipients include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; detergents such as Tween 80; buffering agents such as magnesium
- Ringer's solution ethyl alcohol; and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
- the excipients may be chosen based on what the composition is useful for.
- the choice of the excipient will depend on the route of administration, the agent being delivered, time course of delivery of the agent, etc., and can be administered to humans and/or to animals, orally, rectally, parenterally, intracisternally, intravaginally, intranasally, intraperitoneally, topically (as by powders, creams, ointments, or drops), bucally, or as an oral or nasal spray.
- Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof.
- Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc. , and combinations thereof.
- Exemplary surface active agents and/or emulsifiers include natural emulsifiers ⁇ e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays ⁇ e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols ⁇ e.g.
- natural emulsifiers ⁇ e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin
- colloidal clays ⁇ e.g. bentonite [aluminum silicate] and Ve
- stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers ⁇ e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives ⁇ e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters ⁇ e.g. polyoxyethylene sorbitan monolaurate [Tween 20],
- polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
- Exemplary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
- starch e.g. cornstarch and starch paste
- gelatin e.g. cornstarch and starch paste
- sugars e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.
- natural and synthetic gums e.g. acacia
- methylcellulose methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc. , and/or combinations thereof.
- Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
- antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
- Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g. , sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g. , citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
- EDTA ethylenediaminetetraacetic acid
- salts and hydrates thereof e.g. , sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
- citric acid and salts and hydrates thereof e.g. ,
- antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
- Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
- Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
- Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
- preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.
- the preservative is an anti-oxidant.
- the preservative is a chelating agent.
- Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic s
- Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc. , and combinations thereof.
- Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury,
- Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.
- the composition may comprise a phospholipid.
- exemplary phospholipids include, but are not limited to, disteroylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), Dipalmitoylphosphatidylcholine (DPPC), and dioleoyl-sn-glycero-3-phosphocholine (DOPC), l,2-Dilauroyl-sn-Glycero-3-Phosphocholine (dilauroylphosphatidylcholine, DLPC), 1 ,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (dimyristoylphosphatidylcholine, DMPC), 1 ,2-Dipentadecanoyl-sn-Glycero-3- Phosphocholine (dipentadecanoylphosphatidylcholine, DPDPC), 1,2-dipalmitoyl-sn-Glycero
- composition may further comprise a polymer.
- exemplary polymers contemplated herein include, but are not limited to, cellulosic polymers and copolymers, for example, cellulose ethers such as methylcellulose (MC),
- HEC hydroxyethylcellulose
- HPC hydroxypropyl cellulose
- HPMC hydroxypropyl methyl cellulose
- MHEC methylhydroxyethylcellulose
- MHPC carboxymethyl cellulose
- CMC carboxymethyl cellulose and its various salts, including, e.g., the sodium salt, hydroxyethylcarboxymethylcellulose (HECMC) and its various salts,
- CMVEC carboxymethylhydroxyethylcellulose
- other polysaccharides and polysaccharide derivatives such as starch, dextran, dextran derivatives, chitosan, and alginic acid and its various salts, carageenan, varoius gums, including xanthan gum, guar gum, gum arabic, gum karaya, gum ghatti, konjac and gum tragacanth, glycosaminoglycans and proteoglycans such as hyaluronic acid and its salts, proteins such as gelatin, collagen, albumin, and fibrin, other polymers, for example, polyhydroxyacids such as polylactide, polyglycolide, polyl(lactide-co-glycolide) and poly(.epsilon.-caprolactone-co-glycolide)-, carboxyvinyl polymers and their salts (e.g.
- polystyrene resin polystyrene resin
- PVP polyvinylpyrrolidone
- polyacrylic acid and its salts polyacrylamide
- polyacilic acid/acrylamide copolymer polyalkylene oxides such as polyethylene oxide, polypropylene oxide, poly(ethylene oxide- propylene oxide), and a Pluronic polymer, polyoxyethylene (polyethylene glycol), polyanhydrides, polyvinylalchol, polyethyleneamine and polypyrridine, polyethylene glycol (PEG) polymers, such as PEGylated lipids (e.g.
- the composition may further comprise an emulsifying agent.
- emulsifying agents include, but are not limited to, a polyethylene glycol (PEG), a polypropylene glycol, a polyvinyl alcohol, a poly-N- vinyl pyrrolidone and copolymers thereof, poloxamer nonionic surfactants, neutral water-soluble polysaccharides (e.g., dextran, Ficoll, celluloses), non-cationic poly(meth)acrylates, non-cationic polyacrylates, such as poly(meth)acrylic acid, and esters amide and hydroxyalkyl amides thereof, natural emulsifiers (e.g.
- acacia agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl
- colloidal clays e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]
- long chain amino acid derivatives e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl
- carboxy polymethylene polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer
- carrageenan cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate
- polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
- the emulsifying agent is cholesterol.
- the composition may further comprise an apolipoprotein.
- Apolipoprotein E Apolipoprotein E
- the apolipoprotein is ApoA, ApoB, ApoC, ApoE, or ApoH, or an isoform thereof.
- Liquid compositions include emulsions, microemulsions, solutions,
- the liquid composition may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- injectable compositions for example, injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- acceptable vehicles and solvents for pharmaceutical or cosmetic compositions that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil can be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid are used in the preparation of injectables.
- the particles are suspended in a carrier fluid comprising 1% (w/v) sodium carboxymethyl cellulose and 0.1% (v/v) Tween 80.
- the injectable composition can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- compositions for rectal or vaginal administration may be in the form of suppositories which can be prepared by mixing the particles with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the particles.
- suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the particles.
- Solid compositions include capsules, tablets, pills, powders, and granules.
- the particles are mixed with at least one excipient and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and be
- the dosage form may also comprise buffering agents.
- Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- Tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
- compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- compositions for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches.
- the APPL is admixed with an excipient and any needed preservatives or buffers as may be required.
- Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
- the ointments, pastes, creams, and gels may contain, in addition to the APPL, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.
- Powders and sprays can contain, in addition to the APPL, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances.
- Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons .
- Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
- dosage forms can be made by dissolving or dispensing the microparticles or nanoparticles in a proper medium.
- Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the particles in a polymer matrix or gel.
- Agents to be delivered by the systems described herein may be therapeutic, diagnostic, or prophylactic agents. Any chemical compound to be administered to a subject may be delivered using the complexes, picoparticles, nanoparticles, microparticles, micelles, or liposomes, described herein.
- the agent may be an organic molecule (e.g. , a therapeutic agent, a drug), inorganic molecule, nucleic acid, protein, amino acid, peptide, polypeptide, polynucleotide, targeting agent, isotopically labeled organic or inorganic molecule, vaccine, immunological agent, etc.
- the agents are organic molecules with pharmaceutical activity, e.g. , a drug.
- the drug is an antibiotic, anti-viral agent, anesthetic, steroidal agent, anti-inflammatory agent, anti-neoplastic agent, anti-cancer agent, antigen, vaccine, antibody, decongestant, antihypertensive, sedative, birth control agent, progestational agent, anti-cholinergic, analgesic, anti-depressant, anti-psychotic, ⁇ -adrenergic blocking agent, diuretic, cardiovascular active agent, vasoactive agent, non-steroidal antiinflammatory agent, nutritional agent, etc.
- the agent to be delivered may be a mixture of agents.
- Diagnostic agents include gases; metals; commercially available imaging agents used in positron emissions tomography (PET), computer assisted tomography (CAT), single photon emission computerized tomography, x-ray, fluoroscopy, and magnetic resonance imaging (MRI); and contrast agents.
- PET positron emissions tomography
- CAT computer assisted tomography
- MRI magnetic resonance imaging
- suitable materials for use as contrast agents in MRI include gadolinium chelates, as well as iron, magnesium, manganese, copper, and chromium.
- Examples of materials useful for CAT and x-ray imaging include iodine- based materials.
- Therapeutic and prophylactic agents include, but are not limited to, antibiotics, nutritional supplements, and vaccines.
- Vaccines may comprise isolated proteins or peptides, inactivated organisms and viruses, dead organisms and viruses, genetically altered organisms or viruses, and cell extracts.
- Therapeutic and prophylactic agents may be combined with interleukins, interferon, cytokines, and adjuvants such as cholera toxin, alum, Freund's adjuvant, etc.
- Prophylactic agents include antigens of such bacterial organisms as
- Streptococccus pneumoniae Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyrogenes, Corynebacterium diphtheriae, Listeria monocytogenes, Bacillus anthracis, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Neisseria meningitidis, Neisseria gonorrhoeae, Streptococcus mutans, Pseudomonas aeruginosa, Salmonella typhi, Haemophilus parainfluenzae, Bordetella pertussis, Francisella tularensis, Yersinia pestis, Vibrio cholerae, Legionella pneumophila, Mycobacterium tuberculosis, Mycobacterium leprae, Treponema pallidum, Leptospirosis interrogans, Borrelia burgdorferi,
- antigens of such viruses as smallpox, influenza A and B, respiratory syncytial virus, parainfluenza, measles, HIV, varicella-zoster, herpes simplex 1 and 2, cytomegalovirus, Epstein-Barr virus, rotavirus, rhinovirus, adenovirus, papillomavirus, poliovirus, mumps, rabies, rubella, coxsackieviruses, equine encephalitis, Japanese encephalitis, yellow fever, Rift Valley fever, hepatitis A, B, C, D, and E virus, and the like; antigens of fungal, protozoan, and parasitic organisms such as Cryptococcus neoformans, Histoplasma capsulatum, Candida albicans, Candida tropicalis, Nocardia asteroides, Rickettsia ricketsii, Rickettsia ty
- Chlamydial trachomatis Plasmodium falciparum, Trypanosoma brucei, Entamoeba histolytica, Toxoplasma gondii, Trichomonas vaginalis, Schistosoma mansoni, and the like.
- These antigens may be in the form of whole killed organisms, peptides, proteins,
- an APPL and the complexes, liposomes, micelles, microparticles, picoparticles and nanoparticles, prepared therefrom, may be modified to include targeting agents or targeting regions.
- the APPL scaffold may include a targeting region.
- agents or regions that target particular cells are known in the art. See, e.g., Cotten et ah, Methods Enzym. 217:618, 1993.
- the targeting agents may be included throughout the particle or may be only on the surface.
- the targeting agent may be a protein, peptide, carbohydrate, glycoprotein, lipid, small molecule, nucleic acids, etc.
- the targeting agent may be used to target specific cells or tissues or may be used to promote endocytosis or phagocytosis of the particle.
- targeting agents include, but are not limited to, antibodies, fragments of antibodies, low-density lipoproteins (LDLs), transferrin, asialycoproteins, gpl20 envelope protein of the human immunodeficiency virus (HIV), carbohydrates, receptor ligands, sialic acid, aptamers, etc.
- LDLs low-density lipoproteins
- transferrin asialycoproteins
- carbohydrates receptor ligands
- sialic acid aptamers, etc.
- the targeting agent may be included in the mixture that is used to form the particles.
- the targeting agent may be associated with ⁇ i.e., by covalent, hydrophobic, hydrogen bonding, van der Waals, or other interactions) the formed particles using standard chemical techniques.
- APPLs are particularly useful in the administration of polynucleotides.
- APPLs comprise secondary or tertiary amines, and, although these amines are hindered, they are available to non-covalently interact with a polynucleotide (e.g., DNA, RNA, synthetic analogs of DNA and/or RNA, DNA/RNA hydrids, etc.).
- Polynucleotides or derivatives thereof are contacted with an APPL under conditions suitable to form a polynucleotide/ APPL non-covalent complex.
- the interaction of the APPL with the polynucleotide is thought to at least partially prevent the degradation of the polynucleotide.
- the neutral or slightly-positively-charged complex is also able to more easily pass through the hydrophobic membranes (e.g., cytoplasmic, lysosomal, endosomal, nuclear) of the cell.
- the complex is slightly positively charged.
- the complex has a positive ⁇ -potential. In certain embodiments the ⁇ -potential is between 0 and +30.
- a method of delivering a polynucleotide to a biological cell comprising providing a composition comprising an APPL, or salt thereof, and a polynucleotide; and exposing the composition to the biological cell under conditions sufficient to facilitate delivery of the polynucleotide into the interior of the biological cell; wherein the APPL is an amino acid, a linear or cyclic peptide, or a linear or cyclic polypeptide, or structural isomer thereof, wherein an amino or amide group of the APPL is conjugated to a group of formula (i), (ii), or (iii).
- the method is an in vivo method.
- the method is an in vitro method.
- An APPL may be at least partially provided as a salt (e.g., is protonated) so as to form a complex with the negatively charged polynucleotide.
- the polynucleotide/ APPL complex form particles that are useful in the delivery of
- polynucleotides to cells may be associated with more than one APPL may be associated with a polynucleotide molecule.
- the complex may include 1-100 APPLs, 1- 1000 APPLs, 10-1000 APPLs, or 100-10,000 APPLs associated with a polynucleotide molecule.
- the nitrogen:phosphate ratio (i.e., the ratio between the amino groups present in the APPL, and the phosphate groups present in the polynucleotide) is between about 10: 1 to about 50: 1, inclusive. In certain embodiments, the nitrogen phosphate ratio is between about 10: 1 to about 45: 1, between about 15: 1 to about 45: 1, or between about 20: 1 to about 40: 1, inclusive. In certain embodiments, the APPL:polynucleotide mass ratio is between about 10: 1 to about 20: 1, inclusive. In certain embodiments, the
- APPL:polynucleotide mass ratio is about 15: 1. In certain embodiments, the
- APPL:polynucleotide molar ratio is between about 10: 1 to about 400: 1, inclusive. In certain embodiments, the APPL:polynucleotide molar ratio is between about 10: 1 to about 350: 1, between about 15: 1 to about 300: 1, or between about 20: 1 to about 250: 1, inclusive.
- the complex may form a particle.
- the diameter of the particles ranges from 10-500 micrometers. In certain embodiments, the diameter of the particles ranges from 10-1200 micrometers. In certain embodiments, the diameter of the particles ranges from 50-150 micrometers. In certain embodiments, the diameter of the particles ranges from 10-500 nm, in certain embodiments the diameter of the particles ranges from 10-1200 nm, and in certain embodimentsfrom 50- 150 nm.
- the particles may be associated with a targeting agent as described below. In certain embodiments, the diameter of the particles ranges from 10-500 pm, in certain embodimentsthe diameter of the particles ranges from 10-1200 pm, and in certain
- the particles may be associated with a targeting agent as described below.
- the film architecture is precisely designed and can be controlled to 1 nm precision with a range from 1 to 150000 nm and with a definite knowledge of its molecular composition.
- the polynucleotide may be complexed, encapsulated by an APPL, or included in a composition comprising an APPL.
- the polynucleotide may be any nucleic acid including, but not limited to, RNA and DNA.
- the polynucleotide is DNA.
- the polynucleotide is RNA.
- the RNA upon delivery of the RNA into a cell, the RNA is able to interfere with the expression of a specific gene in the biological cell.
- the polynucleotide is an RNA that carries out RNA interference (RNAi).
- RNAi RNA interference
- the polynucleotide is a dsRNA (double- stranded RNA). In certain embodiments, the polynucleotide is an siRNA (short interfering RNA). In certain embodiments, the polynucleotide is an shRNA (short hairpin RNA). In certain embodiments, the polynucleotide is an miRNA (micro RNA). Micro RNAs (miRNAs) are genomically encoded non-coding RNAs of about 21 - 23 nucleotides in length that help regulate gene expression, particularly during development. See, e.g., Bartel, 2004, Cell, 116:281; Novina and Sharp, 2004, Nature, 430: 161; and U.S.
- miRNAs are genomically encoded non-coding RNAs of about 21 - 23 nucleotides in length that help regulate gene expression, particularly during development. See, e.g., Bartel, 2004, Cell, 116:281; Novina and Sharp, 2004, Nature, 430: 16
- Patent Publication 2005/0059005 also reviewed in Wang and Li, 2007, Front. Bioscl, 12:3975; and Zhao, 2007, Trends Biochem. Set, 32: 189.
- the polynucleotide is an antisense RNA.
- the polynucleotide may be provided as an antisense agent or RNA interference (RNAi). See, e.g., Fire et al, Nature 391:806-811, 1998.
- RNAi RNA interference
- Antisense therapy is meant to include, e.g., administration or in situ provision of single- or double- stranded oligonucleotides or their derivatives which specifically hybridize, e.g., bind, under cellular conditions, with cellular mRNA and/or genomic DNA, or mutants thereof, so as to inhibit expression of the encoded protein, e.g., by inhibiting transcription and/or translation.
- oligonucleotides or their derivatives which specifically hybridize, e.g., bind, under cellular conditions, with cellular mRNA and/or genomic DNA, or mutants thereof, so as to inhibit expression of the encoded protein, e.g., by inhibiting transcription and/or translation.
- the binding may be by conventional base pair complementarity, or, for example, in the case of binding to DNA duplexes, through specific interactions in the major groove of the double helix ⁇ i.e., triple helix formation). See, e.g., Chan et al, J. Mol. Med. 75(4):267-282, 1997.
- dsRNA, siRNA, shRNA, miRNA, antisense RNA, and/or RNAi can be designed and/or predicted using one or more of a large number of available algorithms.
- the following resources can be utilized to design and/or predict polynucleotides: algorithms found at Alnylum Online, Dharmacon Online, OligoEngine Online, Molecula Online, Ambion Online, BioPredsi Online, RNAi Web Online, Chang Bioscience Online, Invitrogen Online, LentiWeb Online GenScript Online, Protocol Online; Reynolds et al., 2004, Nat.
- the polynucleotides may be of any size or sequence, and they may be single- or double-stranded. In certain embodiments, the polynucleotide is greater than 100 base pairs long. In certain embodiments, the polynucleotide is greater than 1000 base pairs long and may be greater than 10,000 base pairs long. The polynucleotide is optionally purified and substantially pure. In certain embodiments, the polynucleotide is greater than 50% pure, in certain embodiments greater than 75% pure, and in certain embodimentsgreater than 95% pure. The polynucleotide may be provided by any means known in the art. In certain embodiments, the polynucleotide has been engineered using recombinant techniques.
- the polynucleotide may also be obtained from natural sources and purified from contaminating components found normally in nature.
- the polynucleotide may also be chemically synthesized in a laboratory. In certain embodiments, the polynucleotide is synthesized using standard solid phase chemistry.
- the polynucleotide may be modified by chemical or biological means. In certain embodiments, these modifications lead to increased stability of the polynucleotide. Modifications include methylation, phosphorylation, end-capping, etc. [00422] Derivatives of polynucleotides may also be used in the present invention.
- Modified bases include, but are not limited to, those found in the following nucleoside analogs: 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3- methyl adenosine, 5-methylcytidine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 7-deazaadenosine,
- Modified sugars include, but are not limited to, 2'-fluororibose, ribose, 2'-deoxyribose, 3'- azido-2',3'-dideoxyribose, 2',3'-dideoxyribose, arabinose (the 2'-epimer of ribose), acyclic sugars, and hexoses.
- the nucleosides may be strung together by linkages other than the phosphodiester linkage found in naturally occurring DNA and RNA.
- Modified linkages include, but are not limited to, phosphorothioate and 5'-N-phosphoramidite linkages.
- modified polynucleotides may be provided by any means known in the art; however, as will be appreciated by those of skill in this art, the modified polynucleotides may be prepared using synthetic chemistry in vitro.
- the polynucleotides to be delivered may be in any form.
- the polynucleotide may be a circular plasmid, a linearized plasmid, a cosmid, a viral genome, a modified viral genome, an artificial chromosome, etc.
- the polynucleotide may be of any sequence.
- the polynucleotide encodes a protein or peptide.
- the encoded proteins may be enzymes, structural proteins, receptors, soluble receptors, ion channels, pharmaceutically active proteins, cytokines, interleukins, antibodies, antibody fragments, antigens, coagulation factors, albumin, growth factors, hormones, insulin, etc.
- the polynucleotide may also comprise regulatory regions to control the expression of a gene. These regulatory regions may include, but are not limited to, promoters, enhancer elements, repressor elements, TATA box, ribosomal binding sites, stop site for transcription, etc.
- the polynucleotide is not intended to encode a protein.
- the polynucleotide may be used to fix an error in the genome of the cell being transfected.
- the polynucleotide to be delivered comprises a sequence encoding an antigenic peptide or protein.
- Nanoparticles containing these polynucleotides can be delivered to an individual to induce an immunologic response sufficient to decrease the chance of a subsequent infection and/or lessen the symptoms associated with such an infection.
- the polynucleotide of these vaccines may be combined with interleukins, interferon, cytokines, and adjuvants such as cholera toxin, alum, Freund's adjuvant, etc.
- a large number of adjuvant compounds are known; a useful compendium of many such compounds is prepared by the National Institutes of Health. See, e.g., Allison Dev. Biol. Stand. 92:3-11, 1998; Unkeless et ah, Annu. Rev. Immunol. 6:251-281, 1998; and Phillips et al, Vaccine 10: 151-158, 1992.
- the antigenic protein or peptides encoded by the polynucleotide may be derived from such bacterial organisms as Streptococccus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyrogenes, Corynebacterium diphtheriae, Listeria monocytogenes, Bacillus anthracis, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Neisseria meningitidis, Neisseria gonorrhoeae, Streptococcus mutans,
- the present invention also contemplates APPLs useful as a delivery device.
- APPLs have several properties that make them particularly suitable for delivery, including: 1) the ability of an APPL to complex and "protect” labile agents; 2) the ability to buffer the pH in the endosome; 3) the ability to act as a "proton sponge” and cause endosomolysis; and 4) the ability to neutralize the charge on negatively charged agents.
- an APPL is used to form particles containing the agent to be delivered.
- An APPL may be used to encapsulate agents including, but not limited to, organic molecules (e.g., cholesterol, drugs), inorganic molecules, nucleic acids, proteins, peptides, polynucleotides, targeting agents, isotopically labeled organic or inorganic molecules, vaccines, immunological agents, etc. Other exemplary agents are described in greater detail herein.
- These particles may include other materials such as polymers (e.g. , synthetic polymers (e.g. , PEG, PLGA), natural polymers (e.g. , phospholipids)).
- the APPL is mixed with one or more agents (e.g. , cholesterol) and/or one or more other materials (e.g., polymers).
- the diameter of the particles range from between 1 micrometer to 1,000 micrometers. In certain embodiments, the diameter of the particles range from between from 1 micrometer to 100 micrometers. In certain embodiments, the diameter of the particles range from between from 1 micrometer to 10 micrometers. In certain embodiments, the diameter of the particles range from between from 10 micrometer to 100 micrometers. In certain embodiments, the diameter of the particles range from between from 100 micrometer to 1,000 micrometers. In certain embodiments, the particles range from 1-5 micrometers. In certain embodiments, the diameter of the particles range from between 1 nm to 1,000 nm. In certain embodiments, the diameter of the particles range from between from 1 nm to 100 nm.
- the diameter of the particles range from between from 1 nm to 10 nm. In certain embodiments, the diameter of the particles range from between from 10 nm to 100 nm. In certain embodiments, the diameter of the particles range from between from 100 nm to 1,000 nm. In certain embodiments, the particles range from 1-5 nm. In certain embodiments, the diameter of the particles range from between 1 pm to 1,000 pm. In certain embodiments, the diameter of the particles range from between from 1 pm to 100 pm. In certain embodiments, the diameter of the particles range from between from 1 pm to 10 pm. In certain embodiments, the diameter of the particles range from between from 10 pm to 100 pm. In certain embodiments, the diameter of the particles range from between from 100 pm to 1,000 pm. In certain embodiments, the particles range from 1- 5 pm.
- the particles may be prepared using any method known in this art. These include, but are not limited to, spray drying, single and double emulsion solvent evaporation, solvent extraction, phase separation, simple and complex coacervation, and other methods well known to those of ordinary skill in the art.
- methods of preparing the particles are the double emulsion process and spray drying.
- the conditions used in preparing the particles may be altered to yield particles of a desired size or property (e.g. , hydrophobicity, hydrophilicity, external morphology, "stickiness", shape, etc.).
- the method of preparing the particle and the conditions (e.g. , solvent, temperature, concentration, air flow rate, etc.) used may also depend on the agent being encapsulated and/or the composition of the matrix.
- the particles prepared by any of the above methods have a size range outside of the desired range, the particles can be sized, for example, using a sieve.
- the particle may also be coated.
- the particles are coated with a targeting agent.
- the particles are coated to achieve desirable surface properties ⁇ e.g., a particular charge).
- the present invention further contemplates use of APPLs in the preparation of micelles or liposomes.
- Any agent may be further included in a micelle or liposome.
- Micelles and liposomes are particularly useful in delivering hydrophobic agents such as hydrophobic small molecules.
- a polynucleotide it is also referred to as a "lipoplex.”
- lipoplex a polynucleotide
- Many techniques for preparing micelle and liposomes are known in the art, and any such method may be used with an APPL to make micelles and liposomes.
- liposomes are formed through spontaneous assembly.
- liposomes are formed when thin lipid films or lipid cakes are hydrated and stacks of lipid crystalline bilayers become fluid and swell.
- the hydrated lipid sheets detach during agitation and self-close to form large, multilamellar vesicles (LMV). This prevents interaction of water with the hydrocarbon core of the bilayers at the edges.
- LMV multilamellar vesicles
- APPLs are first dissolved in an organic solvent to assure a homogeneous mixture of the APPL. The solvent is then removed to form a polymer-derived film. This polymer-derived film is thoroughly dried to remove residual organic solvent by placing the vial or flask on a vaccuum pump overnight. Hydration of the polymer-derived film is accomplished by adding an aqueous medium and agitating the mixture. Disruption of LMV suspensions using sonic energy typically produces small unilamellar vesicles (SUV) with diameters in the range of 15-50 nm.
- SUV small unilamellar vesicles
- Lipid extrusion is a technique in which a lipid/polymer suspension is forced through a polycarbonate filter with a defined pore size to yield particles having a diameter near the pore size of the filter used. Extrusion through filters with 100 nm pores typically yields large, unilamellar polymer-derived vesicles (LUV) with a mean diameter of 120-140 nm.
- LUV unilamellar polymer-derived vesicles
- the amount of APPL in the liposome ranges from 30-80 mol , in certain embodiments40-70 mol , and in certain embodiments 60-70 mol .
- the APPL employed further complexes an agent, such as DNA and RNA.
- the application of the liposome is the delivery of polynucleotides.
- siRNAs for dominant genetic skin disorders including pachyonychia congenita. J Dermatol Sci, 2008. 51(3): p. 151-7. Many of these diseases are fatal, such as cancer, severe hypercholesterolemia, and familial amyloidotic polyneuropathy. See, e.g., Frank- Kamenetsky, M., et al., Therapeutic RNAi targeting PCSK9 acutely lowers plasma
- RNA interference RNA interference
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IL232158A IL232158A (en) | 2011-10-27 | 2014-04-22 | Piperazine-2,5-dione derivatives, pharmaceutical compositions comprising them and use thereof in the preparation of medicaments |
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