US20220412963A1 - Fluorescence tagging of glycans and other biomolecules through reductive amination for enhanced ms signals - Google Patents
Fluorescence tagging of glycans and other biomolecules through reductive amination for enhanced ms signals Download PDFInfo
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- US20220412963A1 US20220412963A1 US17/338,022 US202117338022A US2022412963A1 US 20220412963 A1 US20220412963 A1 US 20220412963A1 US 202117338022 A US202117338022 A US 202117338022A US 2022412963 A1 US2022412963 A1 US 2022412963A1
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- 238000006268 reductive amination reaction Methods 0.000 title description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 231
- 238000002372 labelling Methods 0.000 claims abstract description 31
- -1 hydroxy, amino Chemical group 0.000 claims description 102
- 239000001257 hydrogen Substances 0.000 claims description 82
- 229910052739 hydrogen Inorganic materials 0.000 claims description 82
- 150000003839 salts Chemical class 0.000 claims description 78
- 125000000217 alkyl group Chemical group 0.000 claims description 71
- 239000012453 solvate Substances 0.000 claims description 65
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 59
- 125000001188 haloalkyl group Chemical group 0.000 claims description 58
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 57
- 229910052736 halogen Inorganic materials 0.000 claims description 57
- 150000002367 halogens Chemical group 0.000 claims description 57
- 150000002431 hydrogen Chemical group 0.000 claims description 57
- 125000003282 alkyl amino group Chemical group 0.000 claims description 56
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 55
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 55
- 125000004423 acyloxy group Chemical group 0.000 claims description 55
- 125000003342 alkenyl group Chemical group 0.000 claims description 55
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 55
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 55
- 125000004414 alkyl thio group Chemical group 0.000 claims description 55
- 125000000304 alkynyl group Chemical group 0.000 claims description 55
- 125000003368 amide group Chemical group 0.000 claims description 55
- 125000000262 haloalkenyl group Chemical group 0.000 claims description 55
- 125000000232 haloalkynyl group Chemical group 0.000 claims description 55
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 55
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 55
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- 238000000926 separation method Methods 0.000 claims description 18
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 18
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- 150000001412 amines Chemical class 0.000 claims description 15
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- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 229940117953 phenylisothiocyanate Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 150000003346 selenoethers Chemical class 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003883 substance clean up Methods 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 239000003491 tear gas Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/531—Production of immunochemical test materials
- G01N33/532—Production of labelled immunochemicals
- G01N33/533—Production of labelled immunochemicals with fluorescent label
Definitions
- glycans are used for protein research and can be important to clinical chemists and pharmaceutical manufacturers, especially where glycosylation profiling of proteins is monitored to ensure consistency of a therapeutic product.
- fluorescent labeling of glycans is beneficial because the sensitivity and selectivity of glycan detection can be improved as well as the chromatographic behavior.
- MS Mass spectrometry
- MS active compounds useful in fluorescence labeling of glycans such as oligosaccharides, N-linked glycans, O-linked glycans and other biomolecules including, but not limited to, proteins and peptides that contain an aldehyde group or a ketone group.
- These MS active, fluorescent compounds have three functional components: (a) a tertiary or quaternary amino group or other MS active atom; (b) a highly fluorescent moiety, and (c) an amine group that can react with a ketone or aldehyde group of the glycan or other biomolecule.
- the amine group provides effective labeling of glycans through reductive amination.
- the fluorescent moiety provides the fluorescent signal.
- the tertiary amino group (otherwise sometimes referred to herein as the MS active atom) provides a strong MS signal.
- each compound can be a reagent for fluorescence labeling and enhanced MS signaling of glycans and other biomolecules.
- labeling and “tagging” are used interchangeably through this specification.
- the MS active, fluorescence tagging compounds can be of the structural Formula I:
- FL is a fluorophore, such as a phenyl, quinoline, naphthalene, coumarin, quinolinones or rhodamine compound;
- R 3a is selected from ester, amide, amine, oxygen, urea, carbamate, carbonate, sulfur, thiourea, thiocarbamate, alkyl or carbonyl;
- the compound of Formula I is selected from:
- R 1 and R 2 are independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- R 3a is selected from ester, amide, amine, oxygen, urea, carbamate, carbonate, sulfur, thiourea, thiocarbamate, alkyl or carbonyl;
- R a is selected from
- R b is oxo, or
- R c , R d , R e , R f and Rg are independently selected from hydrogen and optionally substituted alkyl.
- the compounds described herein can have optical centers and therefore can occur in different enantiomeric and disastereomeric configurations.
- the present compounds further include enantiomers, diastereomers and other stereoisomers of such compounds of each formula, as well as racemic compounds and racemic mixtures and other mixtures of stereoisomers thereof.
- Biopolymers such as glycans, play significant roles in physiological and pathological processes. Labeling (otherwise referred to herein as “tagging”) glycans with fluorescent reagent compounds can improve detection of the glycan. Quantitative analysis of glycans from normal and disease specimens can provide insight into disease onset and progression. Relative glycan quantification can be accomplished through modification of the glycans with either chromogenic or fluorogenic tags for optical measurement or isotopic tags for mass spectrometric analysis. Yang et. al., Glycan Analysis by Isobaric Aldehyde Reactive Tags and Mass Spectrometry, 85 ANAL CHEM. 8188 (2013).
- ESI MS electrospray ionization mass spectrometry
- ESI MS electrospray ionization mass spectrometry
- novel compounds useful in the fluorescence tagging of glycans and with enhanced MS signaling such as N-linked glycans O-linked glycans and other bio-molecules including, but not limited to, proteins, peptides and amino acids. These compounds are useful to analyze glycans and/or other biomolecules in a sample.
- the glycan can be labeled with one of the compounds described herein and then subjected to liquid chromatography, and mass spectrometry and fluorescence detection.
- alkoxy refers to an alkyl ether radical, wherein the term alkyl is as defined below.
- suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
- alkyl refers to a straight-chain or branched-chain alkyl radical containing from 1 to and including 20, preferably 1 to 10, and more preferably 1 to 6, carbon atoms. Alkyl groups can be optionally substituted as defined herein without changing or effecting the fluorescent or mass spec properties of the molecule. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl and the like.
- alkylene refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (—CH 2 —).
- alkylamino can be a mono- or dialkylated groups (also referred to “dialkylamino”) such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino and the like and combination, refers to —NRR′, wherein R is independently selected from the group consisting of hydrogen and alkyl, and R′ is alkyl, any of which can themselves be optionally substituted and the dialkyamino group can further comprise a spacer (sometimes referred to as a linker or linker group).
- a molecular spacer or simply a “spacer” in chemistry is any part of a molecule that provides a connection between two other functional parts of a molecule, for example, the rapid reacting portion, the MS active portion and the fluorescent portion.
- parent molecular moiety means and includes a phenyl, quinoline, naphthalene, coumarin, quinolinones or rhodamine
- amino refers to —NRR′, wherein R and R′ are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which can themselves be optionally substituted.
- aryl as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings can be attached together in a pendent manner or can be fused.
- aryl embraces aromatic radicals such as benzyl, phenyl, naphthyl, anthracenyl, phenanthryl, indanyl, indenyl, annulenyl, azulenyl, tetrahydronaphthyl, heteroaryl (e.g., pyridine) and biphenyl.
- benzo and “benz,” as used herein, alone or in combination, refer to the divalent radical C 6 H 4 ⁇ derived from benzene. Examples include benzothiophene and benzimidazole.
- carbamate refers to an ester of carbamic acid (—NHCOO—) which can be attached to the parent molecular moiety from either the nitrogen or acid end, and which can be optionally substituted as defined herein.
- O-carbamyl as used herein, alone or in combination, refers to a —OC(O)NRR′, group-with R and R′ as defined herein.
- N-carbamyl as used herein, alone or in combination, refers to a ROC(O)NR′— group, with R and R′ as defined herein.
- carbonyl when alone includes formyl [—C(O)H] and in combination is a —C(O)— group.
- carboxy refers to —C(O)OH or the corresponding “carboxylate” anion, such as is in a carboxylic acid salt.
- An “O-carboxy” group refers to a RC(O)O— group, where R is as defined herein.
- a “C-carboxy” group refers to a —C(O)OR groups where R is as defined herein.
- cycloalkyl refers to a carbocyclic substituent obtained by removing a hydrogen from a saturated carbocyclic molecule and having three to fourteen carbon atoms. In one embodiment, a cycloalkyl substituent has three to ten carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- halo or halogen, as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.
- haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
- haloalkyl refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
- a monohaloalkyl radical for one example, can have an iodo, bromo, chloro or fluoro atom within the radical.
- Dihalo and polyhaloalkyl radicals can have two or more of the same halo atoms or a combination of different halo radicals.
- haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
- Haloalkylene refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (—CFH—), difluoromethylene (—CF 2 —), chloromethylene (—CHCl—) and the like.
- heteroalkyl refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized.
- the heteroatom(s) O, N and S can be placed at any interior position of the heteroalkyl group. Up to two heteroatoms can be consecutive, such as, for example, —CH 2 —NH—OCH 3 .
- heterocycloalkyl and, interchangeably, “heterocycle,” as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic radical containing at least one, preferably 1 to 4, and more preferably 1 to 2 heteroatoms as ring members, wherein each said heteroatom can be independently selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein there are preferably 3 to 8 ring members in each ring, more preferably 3 to 7 ring members in each ring, and most preferably 5 to 6 ring members in each ring.
- Heterocycloalkyl and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group.
- Heterocycle groups of the compounds are exemplified by aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like.
- the heterocycle groups can be optionally substituted unless specifically prohibited.
- the term “optionally substituted” means the anteceding group can be substituted or unsubstituted.
- the substituents of an “optionally substituted” group can include, without limitation, one or more substituents independently selected from the following groups or a specific designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino
- Two substituents can be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy.
- An optionally substituted group can be unsubstituted (e.g., —CH 2 CH 3 ), fully substituted (e.g., —CF 2 CF 3 ), monosubstituted (e.g., —CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., —CH 2 CF 3 ).
- R or the term R′ refers to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which can be optionally substituted.
- aryl, heterocycle, R, etc. occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence.
- certain groups can be attached to a parent molecular moiety or can occupy a position in a chain of elements from either end as written.
- an unsymmetrical group such as —C(O)N(R)— can be attached to the parent molecular moiety at either the carbon or the nitrogen.
- bond refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
- a bond can be single, double, or triple unless otherwise specified.
- a dashed line between two atoms in a drawing of a molecule indicates that an additional bond can be present or absent at that position.
- PTMs Post Translational Modifications
- urea means and includes a compound having the chemical formula CO(NH 2 ) 2 where the molecule has two —NH 2 groups joined by a carbonyl (C ⁇ O) functional group
- a hydrogen bond is an electromagnetic attractive interaction between polar molecules, where hydrogen is bonded to an electronegative atom such as nitrogen or oxygen.
- the hydrogen bond represents a strong dipole-dipole attraction. These hydrogen-bond attractions can occur between molecules (intermolecular) or within different parts of a single molecule (intramolecular).
- a hydrogen atom is attached to an electronegative atom, it is considered a hydrogen bond donor.
- the electronegative atom is considered a hydrogen bond acceptor, whether it is bonded to a hydrogen atom or not.
- the compounds described herein can also be in the form of a salt or solvate, or acid addition salts.
- a salt for example, in acid-base neutralization, an acid and a base react to form water and a salt. Basically, to react together, there must be the transfer of protons between acids and bases.
- different acids can produce different ions. For example, an Arrhenius acid produces hydronium ions when it dissociates in water.
- a Bronsted-Lowry acid is a proton donor that donates hydrogen ions to the base.
- proton acceptors and proton donors are the basis for the reaction and are referred to sometimes as a conjugate base or a conjugate acid.
- a conjugate pair refers to acids and bases with common features, where there is an equal loss/gain of protons between the pairs.
- NH 4 + is the conjugate acid to the base NH 3 because NH 3 gains a hydrogen ion to form NH 4 + as H 2 O donates a hydrogen ion to form OH ⁇ , the conjugate base.
- a Lewis acid accepts an electron pair and a Lewis base donates an electron pair donor.
- the proton H + can be an electron pair acceptor.
- a compound can be both, a Lewis acid and a Lewis base, depending on the reaction.
- methyl iodide can behave as both, a Lewis acid and a Lewis base, where the methyl group is donated to form a salt.
- the compounds of the formulas described herein can have one or more quaternary nitrogen.
- the quaternary nitrogen has a positive charge on the nitrogen and can be associated with a counterion and include all quaternary amine-counterion complexes of compounds when a compound includes a quaternary amine group.
- tagging, conjugating and derivatizing when referred to in the context of an association between a compound of Formula I through Formula X refers to the bond formation of one of the compounds with an aldehyde containing compound.
- oxo indicates that the chemical compound contains oxygen linked to another atom by a double bond and can denote that the compound is derived from a specified compound by replacement of a methylene group with a carbonyl group.
- oxo is sometimes used as a prefix (i.e., in IUPAC nomenclature) for the functional group ⁇ O, a substituent oxygen atom connected to another atom by a double bond.
- acids which can be employed to form a salt of any of the compounds provided herein include inorganic acids and organic acids as well known to those skilled in the art such as, but not limited to, N-hydroxysuccinimide, hydrochloric, hydrofluoric, hydroiodic, hydrobromic, sulfuric, hydrosulfuric, thiosulfuric, hydrocyanic, phosphoric, phosphorous, hydrochlorous, chlorous, nitrous, nitric, chloric, perchloric, sulfurous, oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion.
- acids can form a salt including, but not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+),camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gent
- the counterion can be the conjugate base formed after reacting a compound or groups of compounds with an acid. In other words, counterion holds the opposite charge to that of the compound or compounds it is associated with.
- the counterion represents the anionic part of the salt.
- counterions of a salt compound described herein can include, but are not limited to, any of the following common anions and oxoanions: N-hydroxysuccinimidyl, hydride (H ⁇ ), fluoride (F ⁇ ), chloride (Cl ⁇ ), bromide (Br ⁇ ), iodide (I ⁇ ), oxide (O 2 ⁇ ), hydroxide (OH ⁇ ), peroxide (O 2 2 ⁇ ), sulfide (S 2 ⁇ ), hydrogen sulfide (HS ⁇ ), selenide (Se 2 ⁇ ), nitride (N 3 ⁇ ), azide (N 3 ⁇ ), phosphide (P 3 ⁇ ), arsinide (As 3 ⁇ ), carbide (C 4 ⁇ ), cyanide (CN ⁇ ), hypochlorite (ClO 1 ⁇ ), chlorite (ClO 2 ⁇ ), chlorate (ClO 3 ⁇ ), perchlorate
- a biomolecule such as a glycan
- a biomolecule are tagged, derivatized or conjugated through an aldehyde or ketone with an amine of one or more of the compounds provided herein containing fluorescent, MS active properties through reductive amination.
- a carbonyl functionality e.g. ketone, aldehyde
- reaction can be conducted in the presence reducing agents such as sodium cyanoborohydride or sodium triacetoxyborohydride.
- the reaction can be conducted in a mixture of citric acid and/or acetic acid with an organic solvent such as dimethylsulfoxide.
- the reaction can also be conducted in a solvent selected from tetrahydrofuran, dichloromethane, 1,2-dichloroethane, ethanol, methanol or isopropanol, toluene and xylene, and mixtures thereof.
- MS active, fluorescence tagging compounds can be a quinoline derivative of the structural Formula II:
- each R 1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- R 3a is selected from ester, amide, amine, oxygen, urea, carbamate, carbonate, sulfur, thiourea, thiocarbamate, alkyl or carbonyl;
- the compound of Formula II with the proviso that when y is zero, R 3a is amine, oxygen or sulfur and z is two, R 3b is other than
- the compound of Formula II with the proviso that when y is one and R 3a is an amide, and z is two or three, R 3b is other than
- compounds of Formula IIA are provided as follows:
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- the compound of Formula IIA is other than 6-amino-N-[2-(diethylamino)ethyl]-2-quinolinecarboxamide.
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- the compound of Formula IIC is provided with the proviso that when z is two, R 3b is other than
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- a compound of Formula IID is provided with the proviso that when z is two, R 3b is other than
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- compounds of Formula IIE are provided with the proviso that when z is two, R 3b is other than
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- exemplary compounds (Table A) of the structural Formulas II, IIA, IIB, IIC, IID, IIE, IIF or IIG which can be useful for fluorescent labeling of glycans and subsequent analysis by means of liquid chromatography and mass spectrometry.
- the compounds of structural Formulas II, IIA, IIB, IIC, IID, IIE, IIF or IIG can be optionally substituted with any group that does not substantially reduce the fluorescence of the compound.
- compounds of Formula II, IIA, IIB, IIC, IID, IIE, IIF or IIG wherein R 1 is hydrogen.
- the compounds of Formula II, IIA, IIB, IIC, IID, IIE, IIF or IIG include compounds wherein R 2 is hydrogen.
- the compounds of Formula II, IIA, IIB, IIC, IID, IIE, IIF or IIG are also provided wherein R 1 and R 2 are hydrogen.
- Methods for tagging, derivatizing or conjugating biomolecules containing at least one ketone group or aldehyde group with a compound of Formula II, IIA, IIB, IIC, IID, IIE, IIF or IIG, or a compound of Table A by reductive amination reaction are further provided.
- the reaction between a compound of Formula II and an aldehyde containing biomolecule, such as a glycan can be conducted under conditions that facilitate reductive amination in the presence of a reducing agent, such as from sodium cyanoborohydride or sodium triacetoxyborohydride.
- the reaction can be carried out in a solution or suspension of a compound of Formula II, IIA, IIB, IIC, IID, IIE, IIF or IIG, or a compound of Table A in an acidic media, for example in citric acid or acetic acid, and mixing with a solution or suspension of a reducing agent such as cyanoborohydride or sodium triacetoxyborohydride in an organic solvent, for example, tetrohydrofuran or dimethylsulfoxide.
- a reducing agent such as cyanoborohydride or sodium triacetoxyborohydride in an organic solvent, for example, tetrohydrofuran or dimethylsulfoxide.
- Methods for analyzing a biomolecule containing an aldehyde group, such as a glycan, in a sample containing at least one biomolecule by means of liquid chromatography and mass spectrometry comprise the step of labeling the biomolecule in the sample by reacting with a compound of Formula II, IIA, IIB, IIC, IID, IIE, IIF or IIG, or a compound of Table A for a time and under conditions suitable to facilitate the labeling through reductive amination; and subjecting the labeled conjugate to liquid chromatography and mass spectrometry.
- Analytical kits for assaying glycans and other biomolecules comprise (i) a labeling module comprising a compound of Formula II and salts and solvate thereof; and optionally one or more of the following:
- Solid phase extraction is a sample preparation technology that utilizes solid particle, chromatographic packing material, usually contained in a cartridge type device, to chemically separate the different components of a sample.
- the SPE device having a chromatographic bed can perform four critical functions to make the analysis of the sample more successful including: (1) simplification of complex sample matrix along with compound purification; (2) reduction in ion suppression or enhancement in MS applications; (3) capability to fractionate sample matrix to analyze compounds by class; and (4) trace concentration enrichment of very low level compounds.
- samples are typically in the liquid state although specialty applications may be run with some samples in the gas phase.
- the separation device of the kit described herein can include, but is not limited to, devices using reversed phase chromatography, ion exchange chromatography and hydrophilic interaction chromatography (“HILIC”) and include devices which utilize graphitic stationary phases such as porous graphitized carbon and mobile phases acidified by formic acid or are separated by capillary electrophoresis.
- HILIC hydrophilic interaction chromatography
- desalting, buffer exchanges or diafiltration are methodologies associated with removing salts or solvents in solutions containing biomolecules.
- the removal of salts or the exchange of buffers can be accomplished in a centrifugal device such as the Amicon Ultra-0.5 device by concentrating the sample, then reconstituting the concentrate to the original sample volume with any desired solvent.
- glycoproteins can be chemically deglycosylated through alkaline beta-elimination or hydrazinolysis as well as by endoglycosidases.
- Glycans and other biomolecules can be conjugated to MS active fluorescent compounds of Formula II and salts or solvates thereof.
- the following schematic shows the tagging of a glycan using a compound of Formula II through reductive amination:
- biomolecules also referred to herein sometimes as biomolecules
- MS active fluorescent compounds of Formula II conjugates resulting therefrom are provided.
- the MS active, fluorescence tagging compounds can be a coumarin derivative of Formula III:
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- R 3a is selected from ester, amide, amine, oxygen, urea, carbamate, carbonate, sulfur, thiourea, thiocarbamate, alkyl or carbonyl;
- the compounds of the structural Formula IIIA are:
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- compounds are provided of the structural Formula IIIG, with the proviso that when y is zero, and z is two, R 3b is other than
- exemplary compounds (Table B) of the structural Formulas III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF or IIIG which can be useful for fluorescent labeling of glycans and subsequent analysis by means of liquid chromatography and mass spectrometry.
- the compounds of structural Formulas III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF or IIIG could be optionally substituted with any group that does not substantially reduce the fluorescence of the compound.
- provided herein are compounds of Formula III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF or IIIG wherein R 1 is hydrogen. In an embodiment, provided herein are compounds of Formula III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF or IIIG wherein R 2 is hydrogen.
- provided herein are compounds of Formula III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF or IIIG wherein R 1 and R 2 are hydrogen.
- Methods for tagging, derivatizing or conjugating glycans and other biomolecules containing at least one ketone group or an aldehyde group with a compound of Formula III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF or IIIG or a compound of Table B by reductive amination reaction are also provided.
- the reaction between a compound of Formula III and an aldehyde containing biomolecule, such as a glycan can be conducted under conditions that facilitate reductive amination in the presence of a reducing agent selected from sodium cyanoborohydride or sodium triacetoxyborohydride.
- the reaction can be carried out in a solution or suspension of a compound of Formula III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF or IIIG or a compound of Table B in an acidic media, for example in citric acid or acetic acid, and mixing with a solution or suspension of a reducing agent such as cyanoborohydride or sodium triacetoxyborohydride in an organic solvent, for example, tetrohydrofuran or dimethylsulfoxide.
- a reducing agent such as cyanoborohydride or sodium triacetoxyborohydride
- organic solvent for example, tetrohydrofuran or dimethylsulfoxide.
- the analytical method comprises the steps of labeling the biomolecule, such as a glycan, in the sample by reacting with a compound of Formula III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF or IIIG or a compound of Table B for a time and under conditions suitable to facilitate the labeling through reductive amination; and subjecting the labeled conjugate to liquid chromatography and mass spectrometry.
- kits for assaying biomolecules such as glycans
- the kits comprise (i) a labeling module comprising a compound of Formula III and salts and solvate thereof; and optionally one or more of the following:
- Biomolecules such as glycans, can be conjugated to MS active fluorescent compounds of Formula III and salts or solvates thereof.
- the following schematic shows the tagging of a glycan using a compound of Formula III through reductive amination:
- the MS active, fluorescence tagging compounds can be a naphthalene derivative of Formula IV:
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- R 3a is selected from ester, amide, amine, oxygen, urea, carbamate, carbonate, sulfur, thiourea, thiocarbamate, alkyl or carbonyl;
- provided herein are compounds of Formula IV, with the proviso that when y is zero and R 3a is oxygen or amine, and z is three, R 3b is other than —S(O) 3 H.
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- exemplary compounds (Table C) of the structural Formulas IV, IVA, IVB, IVC, IVD, IVE, IVF or IVG which can be useful for fluorescent labeling of glycans and subsequent analysis by means of liquid chromatography and mass spectrometry.
- the compounds of structural formulas IV, IVA, IVB, IVC, IVD, IVE, IVF or IVG can be optionally substituted with any group that does not substantially reduce the fluorescence of the compound.
- provided herein are compounds of Formula IV, IVA, IVB, IVC, IVD, IVE, IVF or IVG wherein R 1 is hydrogen. In an embodiment, provided herein are compounds of Formula IV, IVA, IVB, IVC, IVD, IVE, IVF or IVG wherein R 2 is hydrogen. In an embodiment, provided herein are compounds of Formula IV, IVA, IVB, IVC, IVD, IVE, IVF or IVG wherein R 1 and R 2 are hydrogen.
- the methods for tagging, derivatizing or conjugating glycans and other biomolecules containing at least one ketone group or an aldehyde group are also provided with a compound of Formula IV, IVA, IVB, IVC, IVD, IVE, IVF or IVG by reductive amination reaction are also provided.
- the reaction between a compound of Formula IV and an aldehyde containing biomolecule, such as a glycan can be conducted under conditions that facilitate reductive amination in the presence of a reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride.
- the reaction can be carried out in a solution or suspension of a compound of Formula IV, IVA, IVB, IVC, IVD, IVE, IVF or IVG in an acidic media, for example in citric acid or acetic acid, and mixing with a solution or suspension of a reducing agent such as cyanoborohydride or sodium triacetoxyborohydride in an organic solvent, for example, tetrohydrofuran or dimethylsulfoxide.
- a reducing agent such as cyanoborohydride or sodium triacetoxyborohydride in an organic solvent, for example, tetrohydrofuran or dimethylsulfoxide.
- the analytical methods comprise the steps of labeling the biomolecule, such as a glycan, in the sample by reacting with a compound of Formula IV, IVA, IVB, IVC, IVD, IVE, IVF or IVG for a time and under conditions suitable to facilitate the labeling through reductive amination; and subjecting the labeled conjugate to liquid chromatography and mass spectrometry.
- Analytical kits for assaying biomolecules can include (i) a labeling module comprising a compound of Formula IV and salts and solvate thereof; and optionally one or more of the following:
- Glycans can be conjugated to MS active fluorescent compounds of Formula IV and salts or solvates thereof.
- the following schematic shows the tagging of a glycan using a compound of Formula IV through reductive amination:
- the MS active, fluorescence tagging compounds can be a rhodamine derivative of Formula V, VI, VII, VIII or IX:
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- R 3a is selected from ester, amide, amine, oxygen, urea, carbamate, carbonate, sulfur, thiourea, thiocarbamate, alkyl or carbonyl;
- R a is selected from
- R b is oxo or
- R c , R d , R e , R f and Rg are independently selected from hydrogen and optionally substituted alkyl; and salts or solvates thereof.
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- R a is selected from
- R b is oxo or
- R c , R d , R e , R f and Rg are independently selected from hydrogen and optionally substituted alkyl; and salts or solvates thereof.
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- R a is selected from
- R b is oxo or
- R c , R d , R e , R f and Rg are independently selected from hydrogen and optionally substituted alkyl; and salts or solvates thereof.
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- each R 1 and R 2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- R 1 is hydrogen.
- R 2 is hydrogen.
- R 1 and R 2 are hydrogen.
- Methods for tagging, derivatizing or conjugating glycans and other biomolecules containing at least one ketone group or an aldehyde group with a compound of Formula V, VI, VII, VIII or IX or a compound of Table D by reductive amination reaction are provided.
- the reaction between a compound of Formula V, VI, VII, VIII or IX or a compound of Table D and an aldehyde containing biomolecule, such as a glycan can be conducted under conditions that facilitate reductive amination in the presence of a reducing agent, such as from sodium cyanoborohydride or sodium triacetoxyborohydride.
- the reaction can be carried out in a solution or suspension of a compound of Formula V, VI, VII, VIII or IX or a compound of Table D in an acidic media, for example in citric acid or acetic acid, and mixing with a solution or suspension of a reducing agent such as cyanoborohydride or sodium triacetoxyborohydride in an organic solvent, for example, tetrohydrofuran or dimethylsulfoxide.
- a reducing agent such as cyanoborohydride or sodium triacetoxyborohydride in an organic solvent, for example, tetrohydrofuran or dimethylsulfoxide.
- the analytical method comprises the steps of labeling the biomolecule, such as a glycan, in the sample by reacting with a compound of Formula V, VI, VII, VIII or IX or a compound of Table D for a time and under conditions suitable to facilitate the labeling through reductive amination; and subjecting the labeled conjugate to liquid chromatography and mass spectrometry.
- Analytical kits for assaying biomolecules can include (i) a labeling module comprising a compound of Formula VI, VII, VIII, IX or a compound of Table D, and salts and solvate thereof; and optionally one or more of the following:
- Glycans conjugated to MS active fluorescent compounds of Formula V, VI, VII, VIII or IX, and salts or solvates thereof are also provided.
- analytical kits for assaying glycans and other biomolecules include (i) a labeling module comprising a compound of Formula X, XA, XB, XC, XD, XE, XF or XG and salts and solvate thereof; and optionally one or more of the following is provided:
- Kits comprising MS active, fluorescence tagging compounds can contain a phenyl derivative of Formula X:
- R 1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- R 3a is selected from ester, amide, amine, oxygen, urea, carbamate, carbonate, sulfur, thiourea, thiocarbamate, alkyl or carbonyl;
- Kits comprising MS active, fluorescence tagging compounds can contain a phenyl derivative of Formula XA:
- R 1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- Kits comprising MS active, fluorescence tagging compounds can contain a phenyl derivative of Formula XB:
- R 1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- Kits comprising MS active, fluorescence tagging compounds can contain a phenyl derivative of Formula XC:
- R 1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- Kits comprising MS active, fluorescence tagging compounds can contain a phenyl derivative of Formula XD:
- R 1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- Kits comprising MS active, fluorescence tagging compounds can contain a phenyl derivative of Formula XE:
- R 1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- Kits comprising MS active, fluorescence tagging compounds can contain a phenyl derivative of Formula XF:
- R 1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- Kits comprising MS active, fluorescence tagging compounds can contain a phenyl derivative of Formula XG:
- R 1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N 3 , SH, SCH 3 , C(O)CH 3 , CO 2 CH 3 and CO 2 H;
- kits containing exemplary compounds (Table E) of the structural Formulas X, XA, XB, XC, XD, XE, XF or XG which can be useful for fluorescent labeling of glycans and subsequent analysis by means of liquid chromatography and mass spectrometry.
- the compounds of structural formulas X, XA, XB, XC, XD, XE, XF or XG can be optionally substituted with any group that does not substantially reduce the fluorescence of the compound.
- Methods for tagging, derivatizing or conjugating glycans and other biomolecules containing at least one ketone group or an aldehyde group with a compound of Formula XIV, XIVA, XIVB, XIVC, XIVD, XIVE, XIVF or XIVG by reductive amination reaction are provided.
- the reaction between the compound of Formula X and an aldehyde containing biomolecule, such as a glycan can be conducted under conditions that facilitate reductive amination in the presence of a reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride.
- the reaction can be carried out in a solution or suspension of a compound of Formula X, XA, XB, XC, XD, XE, XF or XG in an acidic media, for example in citric acid or acetic acid, and mixing with a solution or suspension of a reducing agent such as cyanoborohydride or sodium triacetoxyborohydride in an organic solvent, for example, tetrohydrofuran or dimethylsulfoxide.
- a reducing agent such as cyanoborohydride or sodium triacetoxyborohydride in an organic solvent, for example, tetrohydrofuran or dimethylsulfoxide.
- Methods for analyzing glycans and other biomolecules containing an aldehyde group in a sample containing at least one biomolecule, such as a glycan by means of liquid chromatography and mass spectrometry.
- These analytical methods include the step of labeling the biomolecule, such as a glycan, in the sample by reacting with a compound of Formula X, XA, XB, XC, XD, XE, XF or XG for a time and under conditions suitable to facilitate the labeling through reductive amination; and subjecting the labeled conjugate to liquid chromatography and mass spectrometry.
- glycans can be conjugated to MS active fluorescent compounds of Formula X and salts or solvates thereof.
- the following schematic shows the tagging of a glycan using a compound of Formula X through reductive amination:
- the organic layer was separated and the aqueous layer was extracted with 2 mL of dichloromethane.
- the organic phases were combined, dried, and then evaporated to dryness to provide the crude material. This was subjected to standard organic chemistry purification techniques to provide the desired material C in >95% purity.
- OPA o-phthalaldehyde
- mercaptan The o-phthalaldehyde procedure can detect amino acids with a typical detectable level in the order of about 100 femtomole (fmol).
- an adduct can be unstable and, therefore, should be prepared shortly before the detection step.
- the reagent may not form a derivative with secondary amino acids.
- FMOC 9-fluorenylmethylchloroformate
- PITC phenylisothiocyanate
- the dansyl chloride method provides stable derivatives with a minimum detectability in the order of about 1.5 pmol. It is able to detect secondary amines and cysteine, but it results in multiple derivatives.
- Fluorescent succinimidocarbamates are useful as derivatizing agents for amines, amino acids, peptides, phosphates and other classes of compounds.
- succinimidocarbamate reagent When the succinimidocarbamate reagent is used to tag a compound with a fluorescent group, a detection limit of about 1 pmol can be achieved.
- These reagents can be used in conjunction with modern separation techniques such as high performance liquid chromatography, thin layer chromatography or capillary electrophoresis.
- the following determinations can be performed separately: (1) the glycosylated sites; (2) the glycosylated site occupancy; (3) the structure and amount of each glycan at each site: and (4) the number of glycoforms.
- Harvey, D. J. Identification of Protein-Bound Carbohydrates by Mass Spectrometry, 1 PROTEOMICS 311-319 (2001) at 312, incorporated herein by reference.
- MS can provide the answers to each of these steps. Hence the need for enhanced MS signals. Because of the branched nature of the glycan, however, structural determination of the glycan is complicated.
- the monosaccharide unit, the anomericity and ring size of each monosaccharide, the monosaccharide sequence and ring conformation together with identification of other groups must be determined.
- MS can be used directly or indirectly to make these determinations using MALDI and/or ESI as the preferred MS technique. Id. at 313-316, incorporated herein by reference.
- Compounds described herein are useful for derivatizing glycans because they can form stable, highly fluorescent MS derivative compounds and conjugate glycans.
- the general methodology for an analysis of a glycan or amino acid derivatized by these compounds include three closely related processes: (1) formation of derivatives in the sample; (2) separation of the derivatives; and (3) detection of the separated derivatives.
- the first step is generally performed by reacting a mixture with one of the present compounds as a reagent to yield a derivatized compound.
- the derivatives provide a fluorescent signal which can then be detected in the detection stage of the analysis.
- the separation step is based upon the differences in the chemical structure of the derivatives.
- the derivatized compounds can differ from each other in the same way that the chemical structures of the precursor compounds differ.
- the derivatives must be separated so that the detector signal can be correctly related to the concentration of each derivative.
- the derivatized glycans can be separated and detected by chromatography, e.g., by high performance liquid chromatography (“HPLC”) or capillary zone electrophoresis (“CZE”).
- the detection step is generally carried out using either an absorbance or fluorescence detector. As each derivative is eluted from the chromatographic column after separation, its presence and quantity is detected by a mass spectrometer and/or by the aborbance or emission of light. The sensitivity of the assay depends upon the strength of the signal produced.
- LC liquid chromatography
- Fluorescent measurements are sensitive and quantitative; the low detection limit is in the low femtomoles.
- mass spectrometry instrumentation With recent advancements in mass spectrometry instrumentation, the combination of liquid chromatography, fluorescence and MS has gained more popularity as an analytical instrument platform for routine characterization of fluorescently labeled N-linked glycans. Therefore, relative quantitation and molecular weight measurements can be done in a single analysis. Shigeo Suzuki et al., Comparison of the Sensitivities of Various Derivatives of Oligosaccharides in LC/MS with Fast Atom Bombardment and Electrospray Ionization Interfaces, 1006 A NAL C HEM 2073 (1996). However, a challenge has been that glycans do not ionize efficiently via electro-spray-ionization (“ESI”).
- EI electro-spray-ionization
- Absorbance detection is generally used in protein mapping work. Two different detection processes which are often used for this purpose are: a) detection at 210-215 nm using a single wavelength detector; and b) broadband spectral detection using a photodiode array (PDA) detector.
- PDA photodiode array
- all peptides absorb at that wavelength, thus the user can ensure that all peptides eluted from the column are detected.
- One difficulty with this technique is that a wide variety of compounds absorb in this region of the spectrum, and extreme care must be taken to ensure that all reagents, eluents, glassware, etc. are scrupulously clean to ensure that the observed signal is solely from the peptides.
- the PDA detector collects the spectra of the eluent at specific time intervals (e.g. a spectrum between 200 and 350 nm is collected every second). This provides more information than a single wavelength and thus can assist in distinguishing between peptides which can elute with similar retention times.
- the condition of the sample is important.
- Compounds other than analyte will generally have an adverse effect on ion yield and are preferably removed.
- carbohydrates are particularly susceptible to the effects of salts.
- many carbohydrates occur as mixtures. Therefore, it is important to ensure that isolation and purification techniques do not cause fractionation of the sample with a loss of quantitative information.
Abstract
Novel reagents comprising MS active, fluorescent compounds having an activated functionality for reaction with aldehydes and useful in labeling biomolecules such as glycans and methods of making the same are taught and described.
Description
- This application is a continuation application of U.S. patent application Ser. No. 16/312,826, filed Dec. 21, 2018, which is the U.S. National Phase of International Application No. PCT/US2017/038070, filed Jun. 19, 2017, which claims priority to U.S. Provisional Patent Application No. 62/352,724, filed Jun. 21, 2016. The entire contents of these applications are incorporated herein by reference.
- Analysis of glycans is used for protein research and can be important to clinical chemists and pharmaceutical manufacturers, especially where glycosylation profiling of proteins is monitored to ensure consistency of a therapeutic product. As such, fluorescent labeling of glycans is beneficial because the sensitivity and selectivity of glycan detection can be improved as well as the chromatographic behavior. However, upon derivation with a reagent having the fluorescent moiety, the functional group of the compound is estimated. Mass spectrometry (“MS”) is then required to identify the specific compound. Furthermore, certain tagging reagents have good fluorescence signal, but a poor MS signal.
- There is a need, therefore, for compounds which can react with glycans and other biomolecules to provide a derivative compound (or one that is tagged or labeled by the reagent), and/or a conjugate glycan, that produces reliable mass spectrometry and fluorescence signals.
- Provided herein are MS active compounds useful in fluorescence labeling of glycans such as oligosaccharides, N-linked glycans, O-linked glycans and other biomolecules including, but not limited to, proteins and peptides that contain an aldehyde group or a ketone group. These MS active, fluorescent compounds have three functional components: (a) a tertiary or quaternary amino group or other MS active atom; (b) a highly fluorescent moiety, and (c) an amine group that can react with a ketone or aldehyde group of the glycan or other biomolecule. The amine group provides effective labeling of glycans through reductive amination. The fluorescent moiety provides the fluorescent signal. The tertiary amino group (otherwise sometimes referred to herein as the MS active atom) provides a strong MS signal.
- In particular, compounds of the various formulas are described herein. Each compound can be a reagent for fluorescence labeling and enhanced MS signaling of glycans and other biomolecules. The terms “labeling” and “tagging” are used interchangeably through this specification.
- The MS active, fluorescence tagging compounds can be of the structural Formula I:
- and salts or solutes thereof,
- wherein
- FL is a fluorophore, such as a phenyl, quinoline, naphthalene, coumarin, quinolinones or rhodamine compound;
- R3 is
- R3a is selected from ester, amide, amine, oxygen, urea, carbamate, carbonate, sulfur, thiourea, thiocarbamate, alkyl or carbonyl;
- R3b is
- y=0-12; and
- z=1-12.
- In an embodiment, the compound of Formula I is selected from
- and salts or solvates thereof, wherein
- R1 and R2 are independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3 is
- R3a is selected from ester, amide, amine, oxygen, urea, carbamate, carbonate, sulfur, thiourea, thiocarbamate, alkyl or carbonyl;
- R3b is
- y=0-12;
- z=1-12;
- Ra is selected from
- Rb is oxo, or
- and
- Rc, Rd, Re, Rf and Rg are independently selected from hydrogen and optionally substituted alkyl.
- The compounds described herein can have optical centers and therefore can occur in different enantiomeric and disastereomeric configurations. The present compounds further include enantiomers, diastereomers and other stereoisomers of such compounds of each formula, as well as racemic compounds and racemic mixtures and other mixtures of stereoisomers thereof.
- Biopolymers, such as glycans, play significant roles in physiological and pathological processes. Labeling (otherwise referred to herein as “tagging”) glycans with fluorescent reagent compounds can improve detection of the glycan. Quantitative analysis of glycans from normal and disease specimens can provide insight into disease onset and progression. Relative glycan quantification can be accomplished through modification of the glycans with either chromogenic or fluorogenic tags for optical measurement or isotopic tags for mass spectrometric analysis. Yang et. al., Glycan Analysis by Isobaric Aldehyde Reactive Tags and Mass Spectrometry, 85 ANAL CHEM. 8188 (2013). The ion abundance of N-linked glycans in electrospray ionization mass spectrometry (“ESI MS”) can be increased by derivatizing the glycans with neutral, hydrophobic reagents. Walker et. al., Hydrophobic Derivatization of N-linked Glycans for Increased Ion Abundance in Electrospray Ionization Mass Spectrometry, 22 J. AM. SOC. MASS SPECTROM. 1309 (2011). In other words, hydrophobic derivatization of glycans can increase ion abundance in ESI MS. In addition, we have uncovered that by using a reagent or tagging compound having a high pKa, MS signaling of the derivatized or tagged glycan is further enhanced.
- Hence, provided herein are novel compounds useful in the fluorescence tagging of glycans and with enhanced MS signaling such as N-linked glycans O-linked glycans and other bio-molecules including, but not limited to, proteins, peptides and amino acids. These compounds are useful to analyze glycans and/or other biomolecules in a sample. To analyze a glycan or other biomolecule, the glycan can be labeled with one of the compounds described herein and then subjected to liquid chromatography, and mass spectrometry and fluorescence detection.
- The term “alkoxy,” as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
- The term “alkyl,” as used herein, alone or in combination, refers to a straight-chain or branched-chain alkyl radical containing from 1 to and including 20, preferably 1 to 10, and more preferably 1 to 6, carbon atoms. Alkyl groups can be optionally substituted as defined herein without changing or effecting the fluorescent or mass spec properties of the molecule. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl and the like. The term “alkylene,” as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (—CH2—).
- The term “alkylamino,” as used herein can be a mono- or dialkylated groups (also referred to “dialkylamino”) such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino and the like and combination, refers to —NRR′, wherein R is independently selected from the group consisting of hydrogen and alkyl, and R′ is alkyl, any of which can themselves be optionally substituted and the dialkyamino group can further comprise a spacer (sometimes referred to as a linker or linker group). A molecular spacer or simply a “spacer” in chemistry is any part of a molecule that provides a connection between two other functional parts of a molecule, for example, the rapid reacting portion, the MS active portion and the fluorescent portion.
- The term “parent molecular moiety” as used herein means and includes a phenyl, quinoline, naphthalene, coumarin, quinolinones or rhodamine
- The term “amino,” as used herein, alone or in combination, refers to —NRR′, wherein R and R′ are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which can themselves be optionally substituted.
- The term “aryl,” as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings can be attached together in a pendent manner or can be fused. The term “aryl” embraces aromatic radicals such as benzyl, phenyl, naphthyl, anthracenyl, phenanthryl, indanyl, indenyl, annulenyl, azulenyl, tetrahydronaphthyl, heteroaryl (e.g., pyridine) and biphenyl.
- The terms “benzo” and “benz,” as used herein, alone or in combination, refer to the divalent radical C6H4═ derived from benzene. Examples include benzothiophene and benzimidazole.
- The term “carbamate,” as used herein, alone or in combination, refers to an ester of carbamic acid (—NHCOO—) which can be attached to the parent molecular moiety from either the nitrogen or acid end, and which can be optionally substituted as defined herein.
- The term “O-carbamyl” as used herein, alone or in combination, refers to a —OC(O)NRR′, group-with R and R′ as defined herein.
- The term “N-carbamyl” as used herein, alone or in combination, refers to a ROC(O)NR′— group, with R and R′ as defined herein.
- The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H] and in combination is a —C(O)— group.
- The term “carboxy,” as used herein, refers to —C(O)OH or the corresponding “carboxylate” anion, such as is in a carboxylic acid salt. An “O-carboxy” group refers to a RC(O)O— group, where R is as defined herein. A “C-carboxy” group refers to a —C(O)OR groups where R is as defined herein.
- The term “cycloalkyl” refers to a carbocyclic substituent obtained by removing a hydrogen from a saturated carbocyclic molecule and having three to fourteen carbon atoms. In one embodiment, a cycloalkyl substituent has three to ten carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- The term “halo,” or “halogen,” as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.
- The term “haloalkoxy,” as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
- The term “haloalkyl,” as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, can have an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals can have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Haloalkylene” refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (—CFH—), difluoromethylene (—CF2—), chloromethylene (—CHCl—) and the like.
- The term “heteroalkyl,” as used herein, alone or in combination, refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The heteroatom(s) O, N and S can be placed at any interior position of the heteroalkyl group. Up to two heteroatoms can be consecutive, such as, for example, —CH2—NH—OCH3.
- The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic radical containing at least one, preferably 1 to 4, and more preferably 1 to 2 heteroatoms as ring members, wherein each said heteroatom can be independently selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein there are preferably 3 to 8 ring members in each ring, more preferably 3 to 7 ring members in each ring, and most preferably 5 to 6 ring members in each ring. “Heterocycloalkyl” and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Heterocycle groups of the compounds are exemplified by aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocycle groups can be optionally substituted unless specifically prohibited.
- The term “optionally substituted” means the anteceding group can be substituted or unsubstituted. When substituted, the substituents of an “optionally substituted” group can include, without limitation, one or more substituents independently selected from the following groups or a specific designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, arylthio, lower alkylsulfinyl, lower alkylsulfonyl, arylsulfinyl, arylsulfonyl, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Two substituents can be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group can be unsubstituted (e.g., —CH2CH3), fully substituted (e.g., —CF2CF3), monosubstituted (e.g., —CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., —CH2CF3). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as “substituted,” the substituted form is specifically intended. Additionally, different sets of optional substituents to a moiety can be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, “optionally substituted with.”
- The term R or the term R′, appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which can be optionally substituted. Such R and R′ groups should be understood to be optionally substituted as defined herein. Whether an R group has a number designation or not, every R group, including R, R′ and Rn where n=(1, 2, 3, . . . n), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. Those of skill in the art will further recognize that certain groups can be attached to a parent molecular moiety or can occupy a position in a chain of elements from either end as written. Thus, by way of example only, an unsymmetrical group such as —C(O)N(R)— can be attached to the parent molecular moiety at either the carbon or the nitrogen.
- The term “bond” refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond can be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond can be present or absent at that position. The development and production of therapeutic proteins is becoming the fastest-growing segment of the pharmaceutical industry. The efficacy, stability and protein secretion of these large molecule drugs depend on their Post Translational Modifications (“PTMs”). Glycosylation is the most complex and common PTM and plays a vital role in the safety and efficacy of many therapeutic proteins such as recombinant antibodies. Several studies have shown the correlation between glycosylation variations caused by cell line selection and changes in culture medium parameters. Patrick Hossler et al., Optimal and Consistent Protein Glycosylation in Mammalian Cell Culture, 19 G
LYCOBIOLOGY 926 (2009). These variations can have a profound effect on the biological activities of the mAb drugs, which leads to changes in drug potency in the final product. Regulatory agencies require monitoring of batch-to-batch recombinant antibody drug production quality and mandate detailed assessment of the protein glycosylation micro-heterogeneity and consistency. - The term “urea” means and includes a compound having the chemical formula CO(NH2)2 where the molecule has two —NH2 groups joined by a carbonyl (C═O) functional group
- The compounds described herein can also form hydrogen bonds with other compounds. A hydrogen bond is an electromagnetic attractive interaction between polar molecules, where hydrogen is bonded to an electronegative atom such as nitrogen or oxygen. The hydrogen bond represents a strong dipole-dipole attraction. These hydrogen-bond attractions can occur between molecules (intermolecular) or within different parts of a single molecule (intramolecular). When a hydrogen atom is attached to an electronegative atom, it is considered a hydrogen bond donor. The electronegative atom is considered a hydrogen bond acceptor, whether it is bonded to a hydrogen atom or not.
- Asymmetric centers exist in the compounds presented herein. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the compounds encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1-isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of certain stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds described can exist as geometric isomers and includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds can exist as tautomers. All tautomeric isomers are provided. Additionally, the present compounds can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.
- Hence, the compounds described herein can also be in the form of a salt or solvate, or acid addition salts. Through a reaction with either organic or inorganic acids, compounds presented herein or groups of compounds can form a salt. For example, in acid-base neutralization, an acid and a base react to form water and a salt. Basically, to react together, there must be the transfer of protons between acids and bases. Also, different acids can produce different ions. For example, an Arrhenius acid produces hydronium ions when it dissociates in water. Similarly, a Bronsted-Lowry acid is a proton donor that donates hydrogen ions to the base. Hence, proton acceptors and proton donors are the basis for the reaction and are referred to sometimes as a conjugate base or a conjugate acid. A conjugate pair refers to acids and bases with common features, where there is an equal loss/gain of protons between the pairs. For example NH4 + is the conjugate acid to the base NH3 because NH3 gains a hydrogen ion to form NH4 + as H2O donates a hydrogen ion to form OH−, the conjugate base. On the other hand, under a different theory, a Lewis acid accepts an electron pair and a Lewis base donates an electron pair donor. Accordingly, the proton H+ can be an electron pair acceptor. Moreover, a compound can be both, a Lewis acid and a Lewis base, depending on the reaction. For example, methyl iodide can behave as both, a Lewis acid and a Lewis base, where the methyl group is donated to form a salt.
- The compounds of the formulas described herein can have one or more quaternary nitrogen. The quaternary nitrogen has a positive charge on the nitrogen and can be associated with a counterion and include all quaternary amine-counterion complexes of compounds when a compound includes a quaternary amine group.
- The terms tagging, conjugating and derivatizing when referred to in the context of an association between a compound of Formula I through Formula X refers to the bond formation of one of the compounds with an aldehyde containing compound.
- The term “oxo” indicates that the chemical compound contains oxygen linked to another atom by a double bond and can denote that the compound is derived from a specified compound by replacement of a methylene group with a carbonyl group. In addition, oxo is sometimes used as a prefix (i.e., in IUPAC nomenclature) for the functional group ═O, a substituent oxygen atom connected to another atom by a double bond.
- Examples of acids which can be employed to form a salt of any of the compounds provided herein include inorganic acids and organic acids as well known to those skilled in the art such as, but not limited to, N-hydroxysuccinimide, hydrochloric, hydrofluoric, hydroiodic, hydrobromic, sulfuric, hydrosulfuric, thiosulfuric, hydrocyanic, phosphoric, phosphorous, hydrochlorous, chlorous, nitrous, nitric, chloric, perchloric, sulfurous, oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. In addition, other acids can form a salt including, but not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+),camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (−L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5, disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid (−L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), undecylenic acid.
- For the compounds described herein, the counterion can be the conjugate base formed after reacting a compound or groups of compounds with an acid. In other words, counterion holds the opposite charge to that of the compound or compounds it is associated with. Thus, with respect to possible salts of the compounds herein having a conjugate acid of NH4 +, the counterion represents the anionic part of the salt. In addition, it can be possible to have four organic substituents on the nitrogen. These species are not amines but are quaternary ammonium cations having a charged nitrogen center. Quaternary ammonium salts can exist with many kinds of anions.
- Hence, counterions of a salt compound described herein can include, but are not limited to, any of the following common anions and oxoanions: N-hydroxysuccinimidyl, hydride (H−), fluoride (F−), chloride (Cl−), bromide (Br−), iodide (I−), oxide (O2−), hydroxide (OH−), peroxide (O2 2−), sulfide (S2−), hydrogen sulfide (HS−), selenide (Se2−), nitride (N3−), azide (N3 −), phosphide (P3−), arsinide (As3−), carbide (C4−), cyanide (CN−), hypochlorite (ClO1 −), chlorite (ClO2 −), chlorate (ClO3 −), perchlorate (ClO4 −), sulfite (SO3 2−), sulfate (SO4 2−), hydrogen sulfate (HSO4 −), thiosulfate (S2O3 2−), nitrite (NO2 −), nitrate (NO3 −), phosphite (PO3 2−), phosphate (PO4 3−), (mono)hydrogen phosphate (HPO4 2−), dihydrogen phosphate (H2PO4 −), carbonate (CO3 2−), hydrogen carbonate (HCO3 −), oxalate (C2O4 2−), cyanate (NCO−), isocyanate (OCN−), thiocyanate (SCN−), chromate (CrO4 2−), dichromate (Cr2O7 2−), permanganate (MnO4 −).
- Compounds for labeling biomolecules such as N and O glycans, with MS active fluorescent compounds of Formula I, as well as conjugates resulting therefrom are provided. In an embodiment, a biomolecule (such as a glycan) are tagged, derivatized or conjugated through an aldehyde or ketone with an amine of one or more of the compounds provided herein containing fluorescent, MS active properties through reductive amination. If a carbonyl functionality (e.g. ketone, aldehyde) is present on the reagent, it is possible that the reagent could self-react and/or form linear polymers under the conditions of reductive amination. Therefore, considerations must be made towards the same.
- General conditions for the reductive amination reaction can be applied for tagging. For example, the reaction can be conducted in the presence reducing agents such as sodium cyanoborohydride or sodium triacetoxyborohydride. The reaction can be conducted in a mixture of citric acid and/or acetic acid with an organic solvent such as dimethylsulfoxide. The reaction can also be conducted in a solvent selected from tetrahydrofuran, dichloromethane, 1,2-dichloroethane, ethanol, methanol or isopropanol, toluene and xylene, and mixtures thereof.
- The following schematic depicting labeling (tagging) a glycan using a compound of Formula I through reductive amination:
- wherein FL and R3 are as described above.
- The following schematic shows the tagging of an amine containing glycan through reductive amination:
- wherein FL and R3 are as described above.
- MS active, fluorescence tagging compounds can be a quinoline derivative of the structural Formula II:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3 is
- R3a is selected from ester, amide, amine, oxygen, urea, carbamate, carbonate, sulfur, thiourea, thiocarbamate, alkyl or carbonyl;
- R3b is
- y=0-12;
- z=1-12;
- and salts or solvates thereof.
- Compounds of structural Formula II are provided, with the proviso that said compound of Formula II is other than 6-amino-N-[2-(diethylamino)ethyl]-2-quinolinecarboxamide, and with the proviso that when y is one, R3a is amide, R3b is other than
- In an embodiment, the compound of Formula II, with the proviso that when y is zero, R3a is amine, oxygen or sulfur and z is two, R3b is other than
- In an embodiment, the compound of Formula II, with the proviso that when y is one and R3a is an amide, and z is two or three, R3b is other than
- In yet another embodiment, compounds of Formula IIA are provided as follows:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, the compound of Formula IIA is other than 6-amino-N-[2-(diethylamino)ethyl]-2-quinolinecarboxamide.
- Compounds of the structural Formula IIB are provided as follows:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- Compounds of the structural Formula IIC are provided as follows:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, the compound of Formula IIC is provided with the proviso that when z is two, R3b is other than
- Compound of Formula IID are provided as followed:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, a compound of Formula IID is provided with the proviso that when z is two, R3b is other than
- Also provided are compounds of the structural Formula IIE:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, compounds of Formula IIE are provided with the proviso that when z is two, R3b is other than
- Compounds of Formula IIF are further provided as follows:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- Further provided herein are compounds of Formula IIG:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In addition, provided below are exemplary compounds (Table A) of the structural Formulas II, IIA, IIB, IIC, IID, IIE, IIF or IIG which can be useful for fluorescent labeling of glycans and subsequent analysis by means of liquid chromatography and mass spectrometry. The compounds of structural Formulas II, IIA, IIB, IIC, IID, IIE, IIF or IIG can be optionally substituted with any group that does not substantially reduce the fluorescence of the compound.
- Provided herein are compounds of Formula II, IIA, IIB, IIC, IID, IIE, IIF or IIG wherein R1 is hydrogen. In an embodiment, the compounds of Formula II, IIA, IIB, IIC, IID, IIE, IIF or IIG include compounds wherein R2 is hydrogen. The compounds of Formula II, IIA, IIB, IIC, IID, IIE, IIF or IIG are also provided wherein R1 and R2 are hydrogen.
- Methods for tagging, derivatizing or conjugating biomolecules containing at least one ketone group or aldehyde group with a compound of Formula II, IIA, IIB, IIC, IID, IIE, IIF or IIG, or a compound of Table A by reductive amination reaction are further provided. The reaction between a compound of Formula II and an aldehyde containing biomolecule, such as a glycan can be conducted under conditions that facilitate reductive amination in the presence of a reducing agent, such as from sodium cyanoborohydride or sodium triacetoxyborohydride. The reaction can be carried out in a solution or suspension of a compound of Formula II, IIA, IIB, IIC, IID, IIE, IIF or IIG, or a compound of Table A in an acidic media, for example in citric acid or acetic acid, and mixing with a solution or suspension of a reducing agent such as cyanoborohydride or sodium triacetoxyborohydride in an organic solvent, for example, tetrohydrofuran or dimethylsulfoxide.
- Methods for analyzing a biomolecule containing an aldehyde group, such as a glycan, in a sample containing at least one biomolecule by means of liquid chromatography and mass spectrometry are provided. These methods comprise the step of labeling the biomolecule in the sample by reacting with a compound of Formula II, IIA, IIB, IIC, IID, IIE, IIF or IIG, or a compound of Table A for a time and under conditions suitable to facilitate the labeling through reductive amination; and subjecting the labeled conjugate to liquid chromatography and mass spectrometry.
- Analytical kits for assaying glycans and other biomolecules comprise (i) a labeling module comprising a compound of Formula II and salts and solvate thereof; and optionally one or more of the following:
-
- (i) a deglycosylation module comprising one or more endoglycosidases, a buffer, and one or more surfactants, or one or more compounds that can perform a chemical release of glycoprotein; and
- (ii) a separation device for clean-up such as a solid phase extraction device, or a centrifugal filtration device or the like.
- Solid phase extraction (“SPE”) is a sample preparation technology that utilizes solid particle, chromatographic packing material, usually contained in a cartridge type device, to chemically separate the different components of a sample. The SPE device having a chromatographic bed can perform four critical functions to make the analysis of the sample more successful including: (1) simplification of complex sample matrix along with compound purification; (2) reduction in ion suppression or enhancement in MS applications; (3) capability to fractionate sample matrix to analyze compounds by class; and (4) trace concentration enrichment of very low level compounds. In SPE, samples are typically in the liquid state although specialty applications may be run with some samples in the gas phase.
- The separation device of the kit described herein, however, can include, but is not limited to, devices using reversed phase chromatography, ion exchange chromatography and hydrophilic interaction chromatography (“HILIC”) and include devices which utilize graphitic stationary phases such as porous graphitized carbon and mobile phases acidified by formic acid or are separated by capillary electrophoresis. In addition, desalting, buffer exchanges or diafiltration are methodologies associated with removing salts or solvents in solutions containing biomolecules. The removal of salts or the exchange of buffers can be accomplished in a centrifugal device such as the Amicon Ultra-0.5 device by concentrating the sample, then reconstituting the concentrate to the original sample volume with any desired solvent. The process of “washing out” can be repeated until the concentration of the contaminating microsolute has been sufficiently reduced. Noteworthy, as part of the kit, glycoproteins can be chemically deglycosylated through alkaline beta-elimination or hydrazinolysis as well as by endoglycosidases.
- Glycans and other biomolecules can be conjugated to MS active fluorescent compounds of Formula II and salts or solvates thereof. The following schematic shows the tagging of a glycan using a compound of Formula II through reductive amination:
- where FL R1, R2 and R3 are as described herein.
- Therefore, methods of tagging biomolecules (also referred to herein sometimes as biomolecules), such as glycans, with the MS active fluorescent compounds of Formula II, as well as conjugates resulting therefrom are provided.
- The MS active, fluorescence tagging compounds can be a coumarin derivative of Formula III:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3 is
- R3a is selected from ester, amide, amine, oxygen, urea, carbamate, carbonate, sulfur, thiourea, thiocarbamate, alkyl or carbonyl;
- R3b is
- y=0-12;
- z=1-12;
- and salts or solvates thereof.
- Provided herein are compounds of Formula III, with the proviso that when y is zero, R3a is ester and z is two, R3b is other than
- In an embodiment, the compounds of the structural Formula IIIA are:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, provided herein are compounds of Formula IIIB:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, provided herein are compounds of Formula IIIC:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In yet another embodiment, provided herein are compounds of the structural Formula IIID:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, provided herein are compounds of the structural Formula IIIE:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, provided herein are compounds of structural Formula IIIF:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, provided are compounds of Formula IIIG:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, compounds are provided of the structural Formula IIIG, with the proviso that when y is zero, and z is two, R3b is other than
- In addition, provided below are exemplary compounds (Table B) of the structural Formulas III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF or IIIG which can be useful for fluorescent labeling of glycans and subsequent analysis by means of liquid chromatography and mass spectrometry. The compounds of structural Formulas III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF or IIIG could be optionally substituted with any group that does not substantially reduce the fluorescence of the compound.
- In an embodiment, provided herein are compounds of Formula III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF or IIIG wherein R1 is hydrogen. In an embodiment, provided herein are compounds of Formula III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF or IIIG wherein R2 is hydrogen.
- In an embodiment, provided herein are compounds of Formula III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF or IIIG wherein R1 and R2 are hydrogen.
- Methods for tagging, derivatizing or conjugating glycans and other biomolecules containing at least one ketone group or an aldehyde group with a compound of Formula III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF or IIIG or a compound of Table B by reductive amination reaction are also provided. The reaction between a compound of Formula III and an aldehyde containing biomolecule, such as a glycan can be conducted under conditions that facilitate reductive amination in the presence of a reducing agent selected from sodium cyanoborohydride or sodium triacetoxyborohydride. The reaction can be carried out in a solution or suspension of a compound of Formula III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF or IIIG or a compound of Table B in an acidic media, for example in citric acid or acetic acid, and mixing with a solution or suspension of a reducing agent such as cyanoborohydride or sodium triacetoxyborohydride in an organic solvent, for example, tetrohydrofuran or dimethylsulfoxide.
- Further provided are methods for analyzing a biomolecule containing an aldehyde group, such as a glycan, in a sample containing at least one biomolecule, such as a glycan, by means of liquid chromatography and mass spectrometry. The analytical method comprises the steps of labeling the biomolecule, such as a glycan, in the sample by reacting with a compound of Formula III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF or IIIG or a compound of Table B for a time and under conditions suitable to facilitate the labeling through reductive amination; and subjecting the labeled conjugate to liquid chromatography and mass spectrometry.
- Analytical kits for assaying biomolecules, such as glycans, are provided where the kits comprise (i) a labeling module comprising a compound of Formula III and salts and solvate thereof; and optionally one or more of the following:
-
- (i) a deglycosylation module comprising one or more endoglycosidases, a buffer, and one or more surfactants, or one or more compounds that can perform a chemical release of glycoprotein; and
- (ii) a separation device for clean-up such as a solid phase extraction device or a centrifugal filtration device or the like.
- Biomolecules, such as glycans, can be conjugated to MS active fluorescent compounds of Formula III and salts or solvates thereof. The following schematic shows the tagging of a glycan using a compound of Formula III through reductive amination:
- wherein FL R1, R2 and R3 are as described above.
- Hence, the methods of tagging glycans, with MS active fluorescent compounds of Formula III, as well as conjugates resulting therefrom are provided.
- The MS active, fluorescence tagging compounds can be a naphthalene derivative of Formula IV:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3 is
- R3a is selected from ester, amide, amine, oxygen, urea, carbamate, carbonate, sulfur, thiourea, thiocarbamate, alkyl or carbonyl;
- R3b is
- y=0-12;
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, provided herein are compounds of Formula IV, with the proviso that when y is two, R3a is other than ester.
- In an embodiment, provided herein are compounds of Formula IV, with the proviso that when y is zero, R3a is oxygen, amide or ester, and z is two or three, R3b is other than
- In an embodiment, provided herein are compounds of Formula IV, with the proviso that when y is zero and R3a is oxygen or amine, and z is three, R3b is other than —S(O)3H.
- In an embodiment, provided herein are compounds of Formula IVA:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, provided herein are compounds of Formula IVB:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, provided are compounds of Formula IVC:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, provided are compounds of Formula IVC with the proviso that when z is two, R3b is other than
- In an embodiment, provided are compounds of Formula IVD:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, provided are compounds of Formula IVD with the proviso that when z is two, R3b is other than
- In an embodiment, provided are compounds of Formula IVE:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, provided are compounds of structural Formula IVE with the proviso that when z is two, R3b is other than
- In an embodiment, provided are compounds of Formula IVF:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, provided are compounds of Formula IVG:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In addition, provided below are exemplary compounds (Table C) of the structural Formulas IV, IVA, IVB, IVC, IVD, IVE, IVF or IVG which can be useful for fluorescent labeling of glycans and subsequent analysis by means of liquid chromatography and mass spectrometry. The compounds of structural formulas IV, IVA, IVB, IVC, IVD, IVE, IVF or IVG can be optionally substituted with any group that does not substantially reduce the fluorescence of the compound.
- In an embodiment, provided herein are compounds of Formula IV, IVA, IVB, IVC, IVD, IVE, IVF or IVG wherein R1 is hydrogen. In an embodiment, provided herein are compounds of Formula IV, IVA, IVB, IVC, IVD, IVE, IVF or IVG wherein R2 is hydrogen. In an embodiment, provided herein are compounds of Formula IV, IVA, IVB, IVC, IVD, IVE, IVF or IVG wherein R1 and R2 are hydrogen.
- The methods for tagging, derivatizing or conjugating glycans and other biomolecules containing at least one ketone group or an aldehyde group are also provided with a compound of Formula IV, IVA, IVB, IVC, IVD, IVE, IVF or IVG by reductive amination reaction are also provided. The reaction between a compound of Formula IV and an aldehyde containing biomolecule, such as a glycan can be conducted under conditions that facilitate reductive amination in the presence of a reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride. The reaction can be carried out in a solution or suspension of a compound of Formula IV, IVA, IVB, IVC, IVD, IVE, IVF or IVG in an acidic media, for example in citric acid or acetic acid, and mixing with a solution or suspension of a reducing agent such as cyanoborohydride or sodium triacetoxyborohydride in an organic solvent, for example, tetrohydrofuran or dimethylsulfoxide.
- Methods for analyzing a biomolecule containing an aldehyde group, such as a glycan, in a sample containing at least one biomolecule, such as a glycan, by means of liquid chromatography and mass spectrometry are also provided. The analytical methods comprise the steps of labeling the biomolecule, such as a glycan, in the sample by reacting with a compound of Formula IV, IVA, IVB, IVC, IVD, IVE, IVF or IVG for a time and under conditions suitable to facilitate the labeling through reductive amination; and subjecting the labeled conjugate to liquid chromatography and mass spectrometry.
- Analytical kits for assaying biomolecules, such as glycans, can include (i) a labeling module comprising a compound of Formula IV and salts and solvate thereof; and optionally one or more of the following:
-
- (i) a deglycosylation module comprising one or more endoglycosidases, a buffer, and one or more surfactants, or one or more compounds that can perform a chemical release of glycoprotein; and
- (ii) a separation device for clean-up such as a solid phase extraction device or a centrifugal filtration device or the like.
- Glycans can be conjugated to MS active fluorescent compounds of Formula IV and salts or solvates thereof. The following schematic shows the tagging of a glycan using a compound of Formula IV through reductive amination:
- Wherein FL R1, R2 and R3 are as described above.
- Therefore, methods of tagging glycans with MS active fluorescent compounds of Formula IV, as well as conjugates resulting therefrom are provided herein.
- The MS active, fluorescence tagging compounds can be a rhodamine derivative of Formula V, VI, VII, VIII or IX:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3 is
- R3a is selected from ester, amide, amine, oxygen, urea, carbamate, carbonate, sulfur, thiourea, thiocarbamate, alkyl or carbonyl;
- R3b is
- y=0-12;
- z=1-12;
- Ra is selected from
- Rb is oxo or;
- Rc, Rd, Re, Rf and Rg are independently selected from hydrogen and optionally substituted alkyl; and salts or solvates thereof.
- In an embodiment, provided herein are compounds of Formula VA, VIA, VIIA, VIIIA or IXA:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- Ra is selected from
- Rb is oxo or
- Rc, Rd, Re, Rf and Rg are independently selected from hydrogen and optionally substituted alkyl; and salts or solvates thereof.
- In an embodiment, provided herein are compounds of Formula VB, VIB, VIIB, VIIIB or IXB:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- Ra is selected from
- Rb is oxo or
- Rc, Rd, Re, Rf and Rg are independently selected from hydrogen and optionally substituted alkyl; and salts or solvates thereof.
- In yet another embodiment, provided are compounds of Formula VC, VIC, VIIC, VIIIC or IXC:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In an embodiment, provided herein are compounds of Formula VD, VID, VIID, VIIID or IXD:
- In an embodiment, provided herein are compounds of Formula VE, VIE, VIIE, VIIIE or IXE:
- wherein each R1 and R2 is independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In addition, provided below are exemplary compounds (Table D) of the structural Formulas V, VI, VII, VIII and IX which can be useful for fluorescent labeling of glycans and subsequent analysis by means of liquid chromatography and mass spectrometry. The compounds of structural Formulas V, VI, VII, VIII and IX can be optionally substituted with any group that does not substantially reduce the fluorescence of the compound.
- The compounds of Formula V, VI, VII, VIII or IX are provided wherein R1 is hydrogen. In an embodiment, provided herein are compounds of Formula V, VI, VII, VIII or IX wherein R2 is hydrogen. In an embodiment, provided herein are compounds of Formula V, VI, VII, VIII or IX wherein R1 and R2 are hydrogen.
- Methods for tagging, derivatizing or conjugating glycans and other biomolecules containing at least one ketone group or an aldehyde group with a compound of Formula V, VI, VII, VIII or IX or a compound of Table D by reductive amination reaction are provided. The reaction between a compound of Formula V, VI, VII, VIII or IX or a compound of Table D and an aldehyde containing biomolecule, such as a glycan can be conducted under conditions that facilitate reductive amination in the presence of a reducing agent, such as from sodium cyanoborohydride or sodium triacetoxyborohydride. The reaction can be carried out in a solution or suspension of a compound of Formula V, VI, VII, VIII or IX or a compound of Table D in an acidic media, for example in citric acid or acetic acid, and mixing with a solution or suspension of a reducing agent such as cyanoborohydride or sodium triacetoxyborohydride in an organic solvent, for example, tetrohydrofuran or dimethylsulfoxide.
- Methods are provided for analyzing a biomolecule containing an aldehyde group, such as a glycan, in a sample containing at least one biomolecule, such as a glycan, by means of liquid chromatography and mass spectrometry. The analytical method comprises the steps of labeling the biomolecule, such as a glycan, in the sample by reacting with a compound of Formula V, VI, VII, VIII or IX or a compound of Table D for a time and under conditions suitable to facilitate the labeling through reductive amination; and subjecting the labeled conjugate to liquid chromatography and mass spectrometry.
- Analytical kits for assaying biomolecules, such as glycans, can include (i) a labeling module comprising a compound of Formula VI, VII, VIII, IX or a compound of Table D, and salts and solvate thereof; and optionally one or more of the following:
-
- (i) a deglycosylation module comprising one or more endoglycosidases, a buffer, and one or more surfactants, or one or more compounds that can perform a chemical release of glycoprotein; and
- (ii) a separation device for clean-up such as a solid phase extraction device or a centrifugal filtration device or the like.
- Glycans conjugated to MS active fluorescent compounds of Formula V, VI, VII, VIII or IX, and salts or solvates thereof are also provided.
- In another embodiment, analytical kits for assaying glycans and other biomolecules include (i) a labeling module comprising a compound of Formula X, XA, XB, XC, XD, XE, XF or XG and salts and solvate thereof; and optionally one or more of the following is provided:
-
- (i) a deglycosylation module comprising one or more endoglycosidases, a buffer, and one or more surfactants, or one or more compounds that can perform a chemical release of glycoprotein; and
- (ii) a separation device for clean-up such as a solid phase extraction device or a centrifugal filtration device or the like.
- Kits comprising MS active, fluorescence tagging compounds can contain a phenyl derivative of Formula X:
- wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3 is
- R3a is selected from ester, amide, amine, oxygen, urea, carbamate, carbonate, sulfur, thiourea, thiocarbamate, alkyl or carbonyl;
- R3b is
- y=0-12;
- z=1-12;
- and salts or solvates thereof.
- Kits comprising MS active, fluorescence tagging compounds can contain a phenyl derivative of Formula XA:
- wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- Kits comprising MS active, fluorescence tagging compounds can contain a phenyl derivative of Formula XB:
- wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- Kits comprising MS active, fluorescence tagging compounds can contain a phenyl derivative of Formula XC:
- wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- Kits comprising MS active, fluorescence tagging compounds can contain a phenyl derivative of Formula XD:
- wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- Kits comprising MS active, fluorescence tagging compounds can contain a phenyl derivative of Formula XE:
- wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- Kits comprising MS active, fluorescence tagging compounds can contain a phenyl derivative of Formula XF:
- wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- Kits comprising MS active, fluorescence tagging compounds can contain a phenyl derivative of Formula XG:
- wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
- R3b is
- z=1-12;
- and salts or solvates thereof.
- In addition, provided below are kits containing exemplary compounds (Table E) of the structural Formulas X, XA, XB, XC, XD, XE, XF or XG which can be useful for fluorescent labeling of glycans and subsequent analysis by means of liquid chromatography and mass spectrometry. The compounds of structural formulas X, XA, XB, XC, XD, XE, XF or XG can be optionally substituted with any group that does not substantially reduce the fluorescence of the compound.
- Methods for tagging, derivatizing or conjugating glycans and other biomolecules containing at least one ketone group or an aldehyde group with a compound of Formula XIV, XIVA, XIVB, XIVC, XIVD, XIVE, XIVF or XIVG by reductive amination reaction are provided. The reaction between the compound of Formula X and an aldehyde containing biomolecule, such as a glycan can be conducted under conditions that facilitate reductive amination in the presence of a reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride. The reaction can be carried out in a solution or suspension of a compound of Formula X, XA, XB, XC, XD, XE, XF or XG in an acidic media, for example in citric acid or acetic acid, and mixing with a solution or suspension of a reducing agent such as cyanoborohydride or sodium triacetoxyborohydride in an organic solvent, for example, tetrohydrofuran or dimethylsulfoxide.
- Methods for analyzing glycans and other biomolecules containing an aldehyde group in a sample containing at least one biomolecule, such as a glycan, by means of liquid chromatography and mass spectrometry. These analytical methods include the step of labeling the biomolecule, such as a glycan, in the sample by reacting with a compound of Formula X, XA, XB, XC, XD, XE, XF or XG for a time and under conditions suitable to facilitate the labeling through reductive amination; and subjecting the labeled conjugate to liquid chromatography and mass spectrometry.
- As provided herein, glycans can be conjugated to MS active fluorescent compounds of Formula X and salts or solvates thereof. The following schematic shows the tagging of a glycan using a compound of Formula X through reductive amination:
- wherein FL R1, R2 and R3 are as described above.
- Methods of labeling the glycans with MS active fluorescent compounds of Formula X, as well as conjugates resulting therefrom are provided.
- The following Scheme I and Scheme II can be used to make the compounds described herein.
- 40 mg of B was dissolved in 2.5 mL of a 1:4 mixture of dimethylformamide:dichloromethane in a 10 mL flask equipped with a stir bar and purged with N2. 1.7 mg of dimethylaminopyridine and 181 μL of dicyclohexylcarbodiimide were then added to the flask. After stirring for 10 min, 2-(diethylamino)ethylamine (57 mg) in 3 mL of dichloromethane was added to the flask. This was then stirred at room temperature for 20 hours. After this time, 3 mL of water was added to the reaction flask. The organic layer was separated and the aqueous layer was extracted with 2 mL of dichloromethane. The organic phases were combined, dried, and then evaporated to dryness to provide the crude material. This was subjected to standard organic chemistry purification techniques to provide the desired material C in >95% purity.
- 1.8 g of C was dissolved in a mixture of 5.3 g of trifluoracetic acid in 30 mL of dichloromethane. The reaction mixture was stirred at room temperature for 48 hours. After removal of the solvent under reduced pressure, the crude material was dissolved in 30 mL of 0.5 N HCl. This mixture was then extracted with 50 mL aliquots of ethyl acetate. The organic phases were combined, dried, and then evaporated to dryness to yield 1.2 gram of the crude product. This was subjected to standard organic chemistry purification techniques to provide the desired material D in >98% purity.
- The method used for Scheme I is applicable to Scheme II for making the compounds presented herein.
- A number of alternative derivatization procedures have been developed to permit the assay of glycans by high performance liquid chromatographic and electrophoretic separations. Under certain conditions, the compounds presented herein can be subject to rapid tagging processes where reagent solution is added to released glycans at room temperature for four or five minutes, and then lyophilized and subsequently reconstituted in acetonitrile/water solution. Other possible derivatization methods that might be utilized to tag glycans with the reagents described herein include:
- (1) The o-phthalaldehyde (“OPA”)/mercaptan method. The OPA procedure can detect amino acids with a typical detectable level in the order of about 100 femtomole (fmol). Here, an adduct can be unstable and, therefore, should be prepared shortly before the detection step. Also, the reagent may not form a derivative with secondary amino acids.
- (2) The 9-fluorenylmethylchloroformate (“FMOC”) method. The FMOC procedure provides for stable derivatives having a minimum detectable level in the order of a few hundred fmol. Free tryptophan and cystine are sometimes difficult to quantitate. The derivatizing reagent is preferably removed from the reaction mixture by an extraction step because it is itself fluorescent. The reagent has also been reported to form multiple derivatives with histidine. The reagent can be hazardous to work with, because it is corrosive and is a lachrymator.
- (3) The phenylisothiocyanate (“PITC”) method. The PITC procedure yields stable derivatives which are formed rapidly. It can be used for both primary and secondary amino acids, as well as cystine. The method uses absorbance as the detection procedure, and can provide a minimum detection limit of 1 pmol. However, the derivatives are not fluorescent and detection must be performed at 254 nm, which does not allow for good detection selectivity.
- (4) The dansyl chloride method. The dansyl chloride method provides stable derivatives with a minimum detectability in the order of about 1.5 pmol. It is able to detect secondary amines and cysteine, but it results in multiple derivatives.
- (5) Fluorescent succinimidocarbamates are useful as derivatizing agents for amines, amino acids, peptides, phosphates and other classes of compounds. When the succinimidocarbamate reagent is used to tag a compound with a fluorescent group, a detection limit of about 1 pmol can be achieved. These reagents can be used in conjunction with modern separation techniques such as high performance liquid chromatography, thin layer chromatography or capillary electrophoresis.
- Most amino acids and/or glycans are not readily detectable in the absence of a strong chromophore or fluorophore or MS active moiety. The absorbance and fluorescence response are quite weak. One tactic used to maximize the sensitivity of an assay is to convert the compound of interest into a derivative that exhibits a better response for the detection method being utilized. The selection of a derivatizing agent is an important choice in the development of an analytical procedure. The derivatizing agent affects the ultimate sensitivity and accuracy of the analysis by maximizing the sensitivity, yield and stability of the derivatized molecules.
- Basically, the following determinations can be performed separately: (1) the glycosylated sites; (2) the glycosylated site occupancy; (3) the structure and amount of each glycan at each site: and (4) the number of glycoforms. Harvey, D. J., Identification of Protein-Bound Carbohydrates by Mass Spectrometry, 1 PROTEOMICS 311-319 (2001) at 312, incorporated herein by reference. In most situations, MS can provide the answers to each of these steps. Hence the need for enhanced MS signals. Because of the branched nature of the glycan, however, structural determination of the glycan is complicated. Here, the monosaccharide unit, the anomericity and ring size of each monosaccharide, the monosaccharide sequence and ring conformation together with identification of other groups must be determined. With the exception of ring conformation, MS can be used directly or indirectly to make these determinations using MALDI and/or ESI as the preferred MS technique. Id. at 313-316, incorporated herein by reference.
- Compounds described herein are useful for derivatizing glycans because they can form stable, highly fluorescent MS derivative compounds and conjugate glycans. The general methodology for an analysis of a glycan or amino acid derivatized by these compounds include three closely related processes: (1) formation of derivatives in the sample; (2) separation of the derivatives; and (3) detection of the separated derivatives. The first step is generally performed by reacting a mixture with one of the present compounds as a reagent to yield a derivatized compound. The derivatives provide a fluorescent signal which can then be detected in the detection stage of the analysis.
- The separation step is based upon the differences in the chemical structure of the derivatives. The derivatized compounds can differ from each other in the same way that the chemical structures of the precursor compounds differ. The derivatives must be separated so that the detector signal can be correctly related to the concentration of each derivative. The derivatized glycans can be separated and detected by chromatography, e.g., by high performance liquid chromatography (“HPLC”) or capillary zone electrophoresis (“CZE”).
- The detection step is generally carried out using either an absorbance or fluorescence detector. As each derivative is eluted from the chromatographic column after separation, its presence and quantity is detected by a mass spectrometer and/or by the aborbance or emission of light. The sensitivity of the assay depends upon the strength of the signal produced.
- Analytical methods of analyzing glycans have become considerably sophisticated. Exemplary analytical instrumentation includes CE-, HPAEC-PAD, HILIC-LC/FLR, RPLC/MS, and MALDI-MS. Liquid chromatography (“LC”) separation with fluorescence detection is widely used in the pharmaceutical industry for the characterization of enzymatically/chemically released glycan, typically tagged with a fluorescent dye at the reducing end of a glycan. Kalyan R. Anumula & Shirish T. Dhume, High Resolution and High Sensitivity Methods for Oligosaccharide Mapping and Characterization by Normal Phase High Performance Liquid Chromatography Following Derivatization with Highly Fluorescent Anthranilic Acid, 8 G
LYCOBIOLOGY 685 (1998); Karina Mariňo et al., A Systematic Approach to Protein Glycosylation Analysis: A Path Through the Maze, 6 NATURE CHEMICAL BIOLOGY 713 (2010). - Fluorescent measurements are sensitive and quantitative; the low detection limit is in the low femtomoles. With recent advancements in mass spectrometry instrumentation, the combination of liquid chromatography, fluorescence and MS has gained more popularity as an analytical instrument platform for routine characterization of fluorescently labeled N-linked glycans. Therefore, relative quantitation and molecular weight measurements can be done in a single analysis. Shigeo Suzuki et al., Comparison of the Sensitivities of Various Derivatives of Oligosaccharides in LC/MS with Fast Atom Bombardment and Electrospray Ionization Interfaces, 1006 A
NAL CHEM 2073 (1996). However, a challenge has been that glycans do not ionize efficiently via electro-spray-ionization (“ESI”). - Absorbance detection is generally used in protein mapping work. Two different detection processes which are often used for this purpose are: a) detection at 210-215 nm using a single wavelength detector; and b) broadband spectral detection using a photodiode array (PDA) detector. In the first method, all peptides absorb at that wavelength, thus the user can ensure that all peptides eluted from the column are detected. One difficulty with this technique is that a wide variety of compounds absorb in this region of the spectrum, and extreme care must be taken to ensure that all reagents, eluents, glassware, etc. are scrupulously clean to ensure that the observed signal is solely from the peptides. In the second method, the PDA detector collects the spectra of the eluent at specific time intervals (e.g. a spectrum between 200 and 350 nm is collected every second). This provides more information than a single wavelength and thus can assist in distinguishing between peptides which can elute with similar retention times.
- To obtain high quality mass spectra, the condition of the sample is important. Compounds other than analyte will generally have an adverse effect on ion yield and are preferably removed. Indeed, while small amounts of sodium are essential for ionization by MALDI, carbohydrates are particularly susceptible to the effects of salts. Moreover, many carbohydrates occur as mixtures. Therefore, it is important to ensure that isolation and purification techniques do not cause fractionation of the sample with a loss of quantitative information.
Claims (17)
1-16. (canceled)
17. A kit for assaying biomolecules comprising a labeling compound selected from
(a) a compound of Formula X,
wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
R3 is
R3a is selected from ester, amide, amine, oxygen, urea, carbamate, carbonate, sulfur, thiourea, thiocarbamate, alkyl or carbonyl;
R3b is
wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
R3b is
wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
R3b is
wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
R3b is
wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
R3b is
wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
R3b is
wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
R3b is
wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
R3b is
18. The kit of claim 17 , further comprising one or more endoglycosidases.
19. The kit of claim 18 , further comprising a buffer.
20. The kit of claim 18 , further comprising one or more surfactants.
21. The kit of claim 18 , further comprising one or more compounds that can perform a chemical release of a glycoprotein.
22. The kit of claim 17 , further comprising a separation device.
23. The kit of claim 22 , wherein the separation device is a solid phase extraction device.
24. The kit of claim 22 , wherein the separation device is a centrifugal filtration device.
25. The kit of claim 17 , wherein the labeling compound is a compound of Formula X,
wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
R3 is
R3a is selected from ester, amide, amine, oxygen, urea, carbamate, carbonate, sulfur, thiourea, thiocarbamate, alkyl or carbonyl;
R3b is
26. The kit of claim 17 , wherein the labeling compound is a compound of XA,
wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
R3b is
27. The kit of claim 17 , wherein the labeling compound is a compound of XB:
wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
R3b is
28. The kit of claim 17 , wherein the labeling compound is a compound of XC:
wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
R3b is
29. The kit of claim 17 , wherein the labeling compound is a compound of XD:
wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
R3b is
30. The kit of claim 17 , wherein the labeling compound is a compound of XE:
wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
R3b is
31. The kit of claim 17 , wherein the labeling compound is a compound of XF:
wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
R3b is
32. The kit of claim 17 , wherein the labeling compound is a compound of XC:
wherein R1 is selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower cycloalkyl, lower acyloxy, hydroxy, amino, lower alkylamino, amido, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfonate, sulfonic acid, N3, SH, SCH3, C(O)CH3, CO2CH3 and CO2H;
R3b is
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EP3472132A1 (en) | 2019-04-24 |
US20190331669A1 (en) | 2019-10-31 |
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US11061023B2 (en) | 2021-07-13 |
WO2017222954A1 (en) | 2017-12-28 |
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