WO2019050564A1 - CXCR4 SELECTIVE BINDING CONJUGATE WITH HIGH AFFINITY AND METHOD OF USING THE SAME - Google Patents

CXCR4 SELECTIVE BINDING CONJUGATE WITH HIGH AFFINITY AND METHOD OF USING THE SAME Download PDF

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Publication number
WO2019050564A1
WO2019050564A1 PCT/US2018/018530 US2018018530W WO2019050564A1 WO 2019050564 A1 WO2019050564 A1 WO 2019050564A1 US 2018018530 W US2018018530 W US 2018018530W WO 2019050564 A1 WO2019050564 A1 WO 2019050564A1
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ipr
high affinity
selective binding
binding ligand
peptide conjugate
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PCT/US2018/018530
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English (en)
French (fr)
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Junge ZHANG
Liang Zeng Yan
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Mainline Biosciences
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Priority to CA3065086A priority Critical patent/CA3065086A1/en
Priority to EP18852912.7A priority patent/EP3679053A4/en
Priority to JP2020504380A priority patent/JP2020532496A/ja
Priority to KR1020207000227A priority patent/KR20200043970A/ko
Priority to KR1020237034343A priority patent/KR20230145543A/ko
Priority to CN201880049498.7A priority patent/CN111183146A/zh
Publication of WO2019050564A1 publication Critical patent/WO2019050564A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0056—Peptides, proteins, polyamino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7158—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for chemokines

Definitions

  • the present invention relates to a high affinity CXCR4 selective binding ligand peptide conjugate ("PC") of the Formula: P-(L-A) n (I) or a pharmaceutically acceptable salt thereof, and a method for using and producing the same.
  • the high affinity CXCR4 selective binding ligand peptide conjugate of the invention are useful in diagnosing, treating or imaging a patient.
  • each A is independently a diagnostic agent, a therapeutic agent, or an imaging agent;
  • L is a linker or absent;
  • P is a high affinity CXCR4 selective binding peptidyl ligand.
  • the invention relates to a targeted drug delivery or imaging a patient or diagnosing a patient for a disease of which overexpression and/or upregulation of CXCR4 is implicated, such as cancers, HIV infection, and immune disorders.
  • a targeted drug delivery or imaging a patient or diagnosing a patient for a disease of which overexpression and/or upregulation of CXCR4 is implicated such as cancers, HIV infection, and immune disorders.
  • Compositions, kits and methods are disclosed herein for such uses.
  • CXCL12 also called stromal cell-derived factor-1 or SDF-1
  • CXCR4 a chemokine and chemokine receptor pair play important roles in hematopoiesis, multiple stages of tumorigenesis, and embryonic development
  • CXCR4 activation of CXCR4 by CXCL12 has shown to direct leukocyte chemotaxis in the immune system in response to inflammation and progenitor cell migration during embryologic development.
  • CXCR4 Activation of CXCR4 by CXCL12 has also been shown to mediate signaling pathway that is involved in breast cancer metastasis and memory T cell migration (Orimo, A., et al., Cell 2005, 121, 335-348).
  • CXCR4 a G-protein-coupled receptor also known as fusin or CD 184 (cluster of differentiation 184), is constitutively- or over-expressed in a wide variety of human cancers, promoting local tumor cell proliferation, survival and angiogenesis (Huang, E.H., et al., J. Surg. Res. 2009, 155, 231-236). It has also been reported that CXCR4 is a co-receptor for HIV entry and infection of host cells and has been evaluated as a potential HIV therapy (Tamamura, H., et al., Biochem. Biophys. Res. Commun. 1998, 253, 877-882; Oberlin, E. et al., Nature, 1996, 382, 833-835).
  • CXCR4 is overexpressed in numerous human cancers.
  • CXCR4 antagonism has been shown to disrupt tumor-stromal interactions, sensitize cancer cells to cytotoxic drugs, and reduce tumor growth and metastatic burden.
  • CXCR4 is a target not only for potential therapeutic intervention of cancer treatment, but also for noninvasive monitoring of disease progression, therapeutic guidance, and other diagnostic purposes (Chatterjee, S. et al., Adv Cancer Res. 2014; 124:31-82). Binding and Interacting with CXCR4 have been suggested as a potential way of targeted drug delivery (Wang, Y. et al., Curr PharmcolRep (2016) 2: 1-10).
  • CXCR4 i.e., CXCR4 selective binding conjugate
  • CXCR4 selective binding conjugate can have a wide variety uses including, but not limited to, in treating a wide array of clinical conditions associated with activation or over- expression of CXCR4, diagnosing a patient, and in mediacl imaging.
  • the high affinity CXCR4 selective binding ligand peptide conjugate comprises a peptidyl moiety that has a high affinity for selectively binding to CXCR4 which is linked or attached to (optionally via a linker) to an active component.
  • the active component can be a diagnostic agent, a therapeutic agent, or an imaging agent. In this manner, the peptidyl moiety selectively binds to CXCR4 receptor and delivers the active component.
  • the high affinity CXCR4 selective binding ligand peptide conjugate is a compound of the Formula:
  • n is an integer from 1 to the total number of amino acid residue within P that have a side-chain functional group;
  • P is a high affinity CXCR4 selective binding peptide moiety;
  • each L is independently an optional linker (i.e., it can be absent or be a linker such as polyethylene glycol moiety or other linkers known to one skilled in the art);
  • each A is independently an active component such as a diagnostic agent, a therapeutic agent, or an imaging agent. While it is readily apparent to those skilled in the art, it should be noted that when L is absent, A is attached directly to P, e.g., through a chemical bond, such as an amide bond or an ester bond.
  • compound of Formula I is used in diagnosis of or treatment of a clinical condition associated with overexpression or upregulation of CXCR4, i.e., A is a diagnostic agent or a drug.
  • compound of Formula I includes (i) a peptidyl ligand (i.e., a peptide moiety) that has a high affinity to CXCR4, (2) optionally a linker, and (3) an active component, e.g., a diagnostic agent, a therapeutic agent (e.g., a drug), or an imaging agent (e.g., a radioactive moiety, a fluorescent moiety, etc.).
  • moiety P i.e., a high affinity CXCR4 selective bindign petide moiety
  • a is 0 or 1
  • AA 1 along with the sulfur atom that is attached thereto is 3-mercaptopropionic acid, optionally substituted cysteine, or optionally substituted
  • Ar 1 is an optionally substituted aryl
  • X 1 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), or Lys(iPr);
  • X 2 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), Lys(iPr), D-Arg, D-
  • X 3 is Lys, Gly or absent;
  • X 4 is Lys, Phe, 2Nal, INal, the D -isomer thereof, Gly, or absent;
  • X 5 is Lys, Gly or absent
  • R 2 is -OR 4 or - HR 5 , wherein R 4 and R 5 are H, alkyl, optionally substituted aryl or optionally substituted aralkyl.
  • optional linker and moiety A i.e., -L-A moiety
  • Formula I can be attached to any of the amino acids via a functional group that is present in the side-chain thereof.
  • a is 0 or 1
  • AA 1 along with the sulfur atom that is attached thereto is 3-mercaptopropionic acid, optionally substituted cysteine, or optionally substituted homocysteine;
  • AA 2 along with the sulfur atom that is attached thereto is cysteine or homocysteine;
  • Ar 1 is an optionally substituted aryl;
  • X 1 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), or Lys(iPr);
  • X 2 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), Lys(iPr), D-Arg, D-Dap, D-
  • Another aspect of the invention provides a diagnostic kit comprising a high affinity CXCR4 selective binding ligand peptide conjugate disclosed herein, e.g., a compound of Formula I where A is a diagnostic agent.
  • Yet another aspect of the invention provides a composition comprising (i) a high affinity CXCR4 selective binding ligand peptide conjugate disclosed herein and (ii) a pharmaceutically acceptable carrier, diluent, excipient or a combination thereof.
  • Still another aspect of the invention provides a method for imaging cancer cells in a patient. Such a method generally includes administering to a patient an imaging effective amount of a high affinity CXCR4 selective binding ligand peptide conjugate of the invention, e.g., compound of Formula I where A is an imaging agent; and imaging cancer cells in said patient using an imaging apparatus.
  • Yet other aspects of the invention provide a method for treating cancer in a patient by administering a therapeutically effective amount of a pharmaceutical composition that includes a compound of Formula I, where A is a therapeutic agent for cancer (i.e., a cancer or oncology drug).
  • A is a therapeutic agent for cancer (i.e., a cancer or oncology drug).
  • a of compound of Formula I is a diagnostic agent or an imaging agent
  • compounds of the invention can be used in a diagnostic or an imaging kit, respectively.
  • compound of Formula I is used in treating a patient suffering from rheumatoid arthritis, pulmonary fibrosis, HIV infection, or a cancer.
  • the method includes administering a therapeutically effective amount of a compound of Formula I (where A is a therapeutic agent for treating rheumatoid arthritis, pulmonary fibrosis, HIV infection, or a cancer, respectively) to a patient in need of such a treatment.
  • Typical cancer that is treated with a compound of Formula I includes, but are not limited to, breast cancer, pancreatic cancer, melanoma, prostate cancer, kidney cancer, neuroblastoma, non-Hodgkin's lymphoma, lung cancer, ovarian cancer, colorectal cancer, multiple myeloma, glioblastoma multiforme, and chronic lymphocytic leukemia.
  • Another aspect of the invention provides a method for targeted drug delivery for a clinical condition associated with overexpression and/or upregulation of CXCR4.
  • exemplary clinical conditions include, but are not limited to, rheumatoid arthritis, pulmonary fibrosis, HIV infection, and cancer.
  • Specific examples of cancers include breast cancer, pancreatic cancer, melanoma, prostate cancer, kidney cancer, neuroblastoma, non-Hodgkin's lymphoma, lung cancer, ovarian cancer, colorectal cancer, multiple myeloma, glioblastoma multiforme, and chronic lymphocytic leukemia.
  • Another aspect of the invention provides a method for disease diagnosis and monitoring for a clinical condition associated with overexpression and/or upregulation of CXCR4.
  • exemplary clinical conditions include, but are not limited to, rheumatoid arthritis, pulmonary fibrosis, HIV infection, and cancer.
  • Specific examples of cancers include breast cancer, pancreatic cancer, melanoma, prostate cancer, kidney cancer, neuroblastoma, non- Hodgkin's lymphoma, lung cancer, ovarian cancer, colorectal cancer, multiple myeloma, glioblastoma multiforme, and chronic lymphocytic leukemia.
  • exemplary clinical conditions include, but are not limited to, rheumatoid arthritis, pulmonary fibrosis, HIV infection, and cancer.
  • Specific examples of cancers include breast cancer, pancreatic cancer, melanoma, prostate cancer, kidney cancer, neuroblastoma, non- Hodgkin's lymphoma, lung cancer, ovarian cancer, colorectal cancer, multiple myeloma, glioblastoma multiforme, and chronic lymphocytic leukemia.
  • CXCR4 plays an important role in immune and inflammatory responses in various diseases and disorders, including cancer, viral infections, as well as autoimmune pathologies such as rheumatoid arthritis.
  • the present invention is based at least in part on reducing or preventing overexpression or activation of CXCR4 to treat, diagnose or image a clinical condition associated with CXCR4 overexpression and/or activation.
  • overexpression and/or activation refers to expression of a gene above its normal (i.e., control) or baseline level and/or activation of CXCR4 above its normal, control or baseline level, respectively.
  • normal baseline level
  • control level refers to expression and/or activity level of CXCR4 in subject(s) that do not have a disease or a clinical condition associated with overexpression and/or activation of CXCR4, such as those disclosed herein.
  • the baseline level can be a normal level, meaning the level in a sample from a normal subject that do not have a clinical condition associated with overexpression and/or activation (or activity) of CXCR4.
  • the overexpression and/or activation of CXCR4 can also be determined by comparing the sample result with a positive control.
  • the term "positive control” as used herein refers to a level of CXCR4 expression and/or activation (or activity) established in a sample from a subject or from a population of individuals, where the sample was believed, based on data from that sample, to have a disease or a clinical condition associated with overexpression and/or activation of CXCR4 (e.g., cancer, autoimmune disease such as rheumatoid arthritis and viral infection, such as HIV infection).
  • a disease or a clinical condition associated with overexpression and/or activation of CXCR4 e.g., cancer, autoimmune disease such as rheumatoid arthritis and viral infection, such as HIV infection.
  • the baseline level can be established from a previous sample from the subject being tested, so that the disease progression or regression of the subject can be monitored over time and/or the efficacy of treatment can be evaluated.
  • Some aspects of the invention provide compounds that have a high affinity toward
  • CXCR4 that is attached to a diagnostic agent, a therapeutic agent or an imaging agent, optionally through a linker.
  • Such compounds include a CXCR4 binding moiety and an active component.
  • the invention also provides methods for using the same, e.g., in targeted delivery of therapeutics to treat clinical conditions manifested by or associated with overexpression and/or activation of CXCR4.
  • the term "high affinity" means the compound or the moiety that binds to CXCR4 has a binding constant (3 ⁇ 4) of about 10 nM or less, typically about 3 nM or less, and often 1 nM or less.
  • high affinity means the compound or the moiety that binds to CXCR4 has 50% binding inhibition concentration (IC 50 ) of about 30 nM or less, typically about 10 nM or less and often about 3 nM or less.
  • IC 50 binding inhibition concentration
  • a high affinity CXCR4 selective binding ligand peptide conjugate is of the Formula:
  • n is an integer from 1 to the sum of (the total number of amino acids in P and the total number of side-chain functional group), typically n is 1 to the number of amino acids in P, or n is 1 to the number of amino acids in P that have a side-chain with a functional group, often n is an integer of 1 to 5, more often n is an integer from 1 to 3;
  • A is one or more diagnostic agents, a therapeutic agents, or imaging agents
  • each L is independently a bifunctional linker or absent;
  • A is attached to P, e.g., through a chemical bond, such as an amide bond or an ester bond; and
  • P is a high affinity CXCR4 selective binding peptidyl ligand (i.e., a peptide moiety that selectively binds to CXCR4).
  • n is an integer from 1 to the sum of (the total number of amino acids in P and the total number of side-chain functional group).
  • n is an integer from 1 to 7, often from 1 to 5, more often from 1 to 3 and most often 1 or 2.
  • n can be an integer from 1 to 9 (7 amino acid residue of P + 2 side-chain functional groups). In this manner, all of the functional groups of P can be attached to -L-A moiety.
  • the moiety A in compound of Formula I can be attached to any portion of the P moiety. Typically, A moiety is attached to the N-terminal end or the C-terminal end of said peptide (the P moiety), or to a function group that is present on the side-chain of the amino acid residue of said peptide, or a combination of any one of the positions thereof. In some embodiments, compound of Formula I has a plurality of A moieties.
  • P is a high affinity CXCR4 binding peptidyl of the
  • a is 0 or 1 ;
  • AA 1 along with the sulfur atom that is attached thereto is 3-mercaptopropionic acid, optionally substituted cysteine, or optionally substituted
  • Ar 1 is an optionally substituted aryl
  • X 1 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), or Lys(iPr);
  • X 2 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), Lys(iPr), D-Arg, D-
  • X 3 is Lys, Gly or absent
  • X 4 is Lys, Phe, 2Nal, INal, the D -isomer thereof, Gly, or absent;
  • X 5 is Lys, Gly or absent
  • R 2 is -OR 4 or - HR 5 , wherein R 4 and R 5 are H, alkyl, optionally substituted aryl, or optionally substituted aralkyl.
  • Moiety -L-A of Compound of Formula I can be attached to AA 1 (e.g., to a-amino group of cysteine or homocysteine) and/or R 4 and/or R 5 , or R 4 and R 5 can be -L-A, where L is optionally a linker and A is a therapeutic agent, a diagnostic agent, or an imaging agent. Still further the moiety -L-A can be attached to the a-amino group of the N-terminal amino acid or a functional group of the side-chain of any of the amino acids of the peptidyl moiety.
  • A is an imaging agent.
  • 45 ⁇ useful imaging agent of the invention includes a positron-emitting radioisotope such CI, "Ti 51 Mn, 61 Cu, 6 Zn, 68 Ga, U C, 1 N, 15 0, and 18 F.
  • a positron-emitting radioisotope such as, "Ti 51 Mn, 61 Cu, 6 Zn, 68 Ga, U C, 1 N, 15 0, and 18 F.
  • the positron-emitting radioisotope is attached to the linker or as a part of the linker (L moiety).
  • a useful imaging agent includes a radioactive metal isotope that is coordinated (i.e., chelated) to a chelating group.
  • Particularly useful radioactive metal isotope include technetium, rhenium, gallium, gadolinium, indium, copper and a combination thereof.
  • Appropriate chelating groups for a particular radioactive metal isotope are well known to one skilled in the art. For example, ferrocene and its derivatives, ethylenediaminetetraacetic acid (“EDTA”), its derivatives, a peptidyl moiety Dap-Asp-Cys and its derivatives (see U.S. Pat. No. 7, 128,893), and others known in the art.
  • Yet another example of a useful imaging agent includes a contrasting agent.
  • Contrasting agents are widely used, for example, in magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • contrasting agents are known to one skilled in the art including gadobenate, gadobutrol, gadodiamide, gadofosveset, gadopentetate, gadoterate, gadoteridol,
  • gadoversetamide gadoxetate, and iron oxide.
  • Still another example of a useful imaging agent includes a fluorescent dye, such as fluorenylmethyloxycarbonyl (FMOC) and its derivatives, an AlexaFluor dye, an Oregon Green dye, a fluoresceins, a BODIPY (boron-dipyrromethene) dye, a cyanine dye, a rhodamine dye, a DyLight dye, and Texas Red.
  • a fluorescent dye such as fluorenylmethyloxycarbonyl (FMOC) and its derivatives, an AlexaFluor dye, an Oregon Green dye, a fluoresceins, a BODIPY (boron-dipyrromethene) dye, a cyanine dye, a rhodamine dye, a DyLight dye, and Texas Red.
  • A is a diagnostic agent.
  • diagnostic agents that can be used in compound of the invention include an imaging agent, an isotopic agent, or a radioactive agent.
  • linker L comprises a functional group that is capable of releasing A in vivo.
  • Suitable functional groups that is capable of releasing A depends on the nature of the function group on moiety A that is linked to the linker.
  • the functional group on L can be a carboxylate such that an ester bond or an amide bond, respectively, is formed between A and L.
  • the corresponding functional group on L can be a hydroxyl group or an amino group to form an ester bond or an amide bond, respectively.
  • Other suitable functional groups on L that is capable releasing A in vivo are well known to one skilled in the art including a disulfide bond linkage, an ester linkage, a thiol-maleimide linkage, and the like.
  • A is a therapeutic agent.
  • Suitable therapeutic agents include those that are known to one skilled in the art for treatment of cancer, autoimmune disease (e.g., rheumatoid arthritis), viral infection (e.g., HIV infection), etc.
  • Exemplary therapeutic agents that are useful in compounds of the invention include, but are not limited to, bleomycin, daunorubicin, doxorubicin, docetaxel, irinotecan, monomethyl auristatin E, mertansine, paclitaxel, SN-38, tesirine, tubulysin, vinca alkaloids, and an analog or derivative thereof, HIV protease inhibitors, HIV fusion inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV entry inhibitors, and therapeutics for autoimmune diseases.
  • High affinity CXCR4 selective binding ligand peptide conjugates of the invention include, but are not limited to:
  • R a is acetyl-, acetyl-Cys(S-paclitaxel)-, or acetyl-Cys(S-paclitaxel)-(mini-PEG6)-; and R b is glycyl-amide, glycyl-Cys(S-paclitaxel)-amide, or (mini-PEG6)-Cys(S-paclitaxel)- amide,
  • R a or R b comprises S-paclitaxel.
  • compounds of the invention are of the Formula:
  • a is 0 or 1
  • AA 1 along with the sulfur atom that is attached thereto is 3-mercaptopropionic acid, optionally substituted cysteine, or optionally substituted homocysteine, wherein A is optionally attached to a-amino group of said cysteine or homocysteine;
  • Ar 1 is an optionally substituted aryl
  • X 1 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), or Lys(iPr);
  • X 2 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), Lys(iPr), D-Arg, D-Dap, D-
  • L is optionally a linker
  • A is a therapeutic agent, a diagnostic agent or an imaging agent.
  • a is 0. Still in other instances, a is
  • AA 1 together with the sulfur atom that is attached thereto is 3- mercaptopropionic acid. Still yet in other instances, AA 1 together with the sulfur atom that is attached thereto is cysteine. In other instances, AA 1 together with the sulfur atom that is attached thereto is homocysteine.
  • AA 2 together with the sulfur atom that is attached thereto is cysteine. In yet other embodiments, AA 2 together with the sulfur atom that is attached thereto is homocysteine.
  • a in compounds of Formula III is an imaging agent.
  • a in compounds of Formula III is a therapeutic agent.
  • Exemplary therapeutic agents within compounds of Formula III include, but are not limited to, bleomycin, calicheamicin, daunorubicin, docetaxel, doxorubicin, irinotecan, mertansine, monomethyl auristatin E, paclitaxel, SN-38, tesirine, topotecan, tubulysin, vinca alkaloids, and an analog or derivative thereof, and a combination thereof.
  • L can be any biocompatible bifunctional linker such as polyethylene glycol
  • PEG polyamino acid
  • m is an integer from 0 to 100, typically 1 to 50, often 1 to 25, and more often 1 to 10.
  • L is a polymer (e.g., PEG, PAA)
  • the total number of monomer within the chain is from about 1 (i.e., a monomer) to about 20, typically from about 1 to about 10, and often from about 1 to 6.
  • a in compounds of Formula III is a diagnostic agent, such as a radioactive agent, fluorescent agent, etc.
  • imaging agents are well known to one skilled in the art.
  • contrast agents for magnetic resonance imaging agents, ultrasound contrast agents, and radio contrast agents See, for example, en.wikipedia.org/wiki/ Contrast agent.
  • Another aspect of the invention provides a diagnostic kit comprising a high affinity CXCR4 selective binding ligand peptide conjugate described herein where A of compound of Formula I is a diagnostic agent.
  • compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carrier can include a diluent, an excipient, a flavoring agent, an adjuvant, a binder, a stabilizer, coloring agent, or a combination thereof.
  • pharmaceutically acceptable carrier refers to any excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • the present invention includes pharmaceutical compositions comprising at least one compound of the invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.
  • the compounds of the invention are administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • Suitable dosage ranges are typically 1-500 mg daily, typically 1-100 mg daily, and often 1-30 mg daily, depending on numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved.
  • One of ordinary skill in the art of treating such diseases is typically able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compounds of the invention.
  • compounds of the invention are administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • Typical manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
  • a compound or compounds of the invention, together with one or more conventional adjuvants, carriers, or diluents, can be placed into the form of pharmaceutical compositions and unit dosages.
  • the pharmaceutical compositions and unit dosage forms can be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms can contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • compositions can be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use.
  • Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
  • the compounds of the invention can be formulated in a wide variety of oral administration dosage forms.
  • the pharmaceutical compositions and dosage forms can comprise a compound or compounds of the invention or pharmaceutically acceptable salts thereof as the active component.
  • the pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
  • the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be as solid forms suitable for oral administration.
  • liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations.
  • Emulsions can be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia.
  • Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents.
  • Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
  • Solid form preparations include solutions, suspensions, and emulsions, and can contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the compounds of the invention can also be formulated for parenteral
  • compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
  • oily or nonaqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and can contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
  • the active ingredient can be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
  • a suitable vehicle e.g., sterile, pyrogen-free water.
  • the compounds of the invention can be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams can, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions can be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the compounds of the invention can be formulated for administration as suppositories.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
  • the compounds of the invention can also be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the compounds of the invention can be formulated for nasal administration.
  • the solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray.
  • the formulations can be provided in a single or multidose form. In the latter case of a dropper or pipette, this can be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this can be achieved for example by means of a metering atomizing spray pump.
  • the compounds of the invention can be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
  • the compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size can be obtained by means known in the art, for example by micronization.
  • the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol can conveniently also contain a surfactant such as lecithin.
  • the dose of drug can be controlled by a metered valve.
  • the active ingredients can be provided in a form of a dry powder, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • the powder carrier typically forms a gel in the nasal cavity.
  • the powder composition can be presented in unit dose form, for example, in capsules or cartridges of e.g., gelatine or blister packs from which the powder can be administered by means of an inhaler.
  • formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
  • the compounds of the invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary or desired and when patient compliance with a treatment regimen is crucial.
  • Compounds in transdermal delivery systems are frequently attached to a skin-adhesive solid support.
  • the compound of interest can also be combined with a penetration enhancer, e.g., Azone (l-dodecylazacycloheptan-2-one).
  • Azone l-dodecylazacycloheptan-2-one
  • Sustained release delivery systems can be inserted subcutaneously into the subdermal layer by surgery or injection.
  • the subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.
  • the pharmaceutical preparations are typically in unit dosage forms.
  • the preparation is often subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • compositions which include therapeutically effective mounts of compounds of Formula I or pharmaceutically acceptable salts thereof or a prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously.
  • the compounds of Formula I and pharmaceutically acceptable salts thereof are as described above.
  • the carrier(s), diluent(s), or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of Formula I, or a pharmaceutically acceptable salt thereof or a prodrug thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • compositions of this disclosure comprise a combination of a compound of the present disclosure and one or more additional therapeutic or prophylactic agent
  • both the compound and the additional agent are usually present at dosage levels of between about 10 to 150%, and more typically between about 10 and 80% of the dosage normally administered in a monotherapy regimen.
  • Still another aspect of the invention provides a method for imaging cancer cells in a patient comprising administering to a patient an imaging effective amount of a high affinity CXCR4 selective binding ligand peptide conjugate of Formula I, where A is an imaging agent, and imaging cancer cells in said patient using an imaging apparatus.
  • the imaging apparatus used depends on the nature of imaging agent A of compound of Formula I. For example, if A is a positron-emitting radioisotope, then the imaging apparatus used is a PET scan, and when A is a contrasting agent, then the imaging apparatus can be a computed topography apparatus or an MRI apparatus. When A is a radioactive isotope, the imaging apparatus can be an x-ray machine or other similar device.
  • One particular aspect of the invention provides a method for treating cancer in a patient.
  • the method comprises administering a therapeutically effective amount of a compound of Formula I (where A is a cancer drug) or a pharmaceutical composition comprising a compound of Formula I (where A is a cancer drug) to a cancer patient.
  • Another particular aspect of the invention provides a diagnostic or an imaging kit comprising a high affinity CXCR4 selective binding ligand peptide conjugate (PC) of Formula I, where A is a diagnostic agent or an imaging agent, respectively.
  • PC selective binding ligand peptide conjugate
  • Still another particular aspect of the invention provides a method for treating a patient suffering from rheumatoid arthritis, pulmonary fibrosis, HIV infection, or a cancer.
  • the method includes administering a therapeutically effective amount of a compound of Formula I to a patient in need of treatment thereof.
  • a of compound of Formula I is a therapeutic agent that can be used to treat the particular clinical condition to be treated.
  • BOP (benzotriazol-l-yloxy)-tris(dimethylamino) phosphonium hexafluorophosphate
  • Bz (benzotriazol-l-yloxy)-tris(dimethylamino) phosphonium hexafluorophosphate
  • hydroxybenzotriazole hCys: homocysteine; iPr: isopropyl; IPA: isopropyl alcohol; Me: methyl; Mmt: 4-mthoxytrityl; Mpa: 3-mercaptopropionic acid; 2Nal: 2-naphthylalanine; INal: 1- naphthylalanine; NMM: N-methylmorpholine; NMP: N-methyl-pyrrolidone; Orn: ornithine; Pbf: 2,2,4,6,7-pentamethyl-dihydrobenzofurane-5-sulfonyl; PBS: phosphate buffered saline; PyBOP: (benzotriazol-l-yloxy)-tris(pyrrolidino)-phosphonium hexafluoro-phosphate; PyBrOP: bromotris(pyrrolidino)phosphonium hexafluorophosphate; tBu: ter
  • Peptides were synthesized using solid phase peptide synthesis chemistry known in the art.
  • the cyclic structure of those peptides was established, for a disulfide, by using air oxidation, or iodine oxidation in the presence of acidic acid, or for a bisthioether ring, by nucleophilic substitution using a bis(halomethyl) aryl compound, typically using 1.3 equivalents of a bis(bromom ethyl) aryl compound, in the presence of a base, such as 15 mM ammonium bicarbonate solution.
  • a base such as 15 mM ammonium bicarbonate solution.
  • Isotopic or radioactive labeled acetones are commercially available from various vendors. If there is a need for custom preparation of isotopic or radioactive labeled acetones, methods can be found in known arts, for example Rolf Voges, et al., Preparation of Compounds Labeled with Tritium and Carbon-14 (John Wiley & Sons (2009).
  • Paclitaxel Activation Preparation of 2'-maleimide-paclitaxel: Dissolving one gram of paclitaxel (1.2 mmoles) in 160 mL of DCM, adding 0.12 mmole of DMAP and cooling the reaction mixture to 0 °C. To the cooled reaction mixture, was added 2.4 mmoles of 3- maleimidopropionic acid, and followed by 1.2 mmoles of DIC under stirring. The reaction mixture was then slowly warmed up to room temperature and the coupling reaction was allowed to proceed at room temperature for 18 h under continuous stirring.
  • Strong anion exchange resin (chloride form, substitution 3 mmole/g, water content 50%, using 2 grams of resin per gram of peptide) was first washed three times with milli Q water, then three times with 1 N NaOH solution three times, 5 min/time, and then five times with milli Q water, 5 min/time. The resin was further washed with 75% ethanol water until the pH reaches about 7.4. This resin was treated with 10% acetic acid solution three times, five minutes each time. The resin was then washed with 1% acetic acid solution three times, five minutes each time. The resin was ready for the salt conversion of the purified peptide.
  • the purified, lyophilized peptide was dissolved in 1% acetic acid solution and added to the prepared resin described above. The mixture was agitated or magnetically stirred at room temperature for 1 h. The supernatant was separated. The resin was washed three times with 1%) acetic acid solution. The supernatant and the washing solution were combined, filtered through a 0.22mm membrane and lyophilized, to afford a peptide in acetate salt.
  • Peptide chain assembly The peptide chain of Cys(Mmt)-Tyr(tBu)-Lys(iPr,Boc)-
  • N-terminal acetylation was carried out with 5 mL of a mixture of acetic anhydride/DIEA/DMF (1 : 1 :4, v/v/v) for 30 min at room temperature. The resin was then washed with DMF three time and then with DCM twice, dried under vacuum.
  • H 4 HCO 3 was used to adjust the reaction mixture to pH 7.5.
  • the conjugation reaction was completed in about half an hour as confirmed by MS.
  • the final product was purified using a reverse-phased preparative column Daisogel (50x250mm, 8mm); mobile phases - Solvent A: 0.1%) TFA water; Solvent B: 0.1%> TFA acetonitrile. Fractions containing the target product were combined and lyophilized (a TFA salt).
  • Peptide chain assembly The peptide chain of Cys(Trt)-Cys(Mmt)-Tyr(tBu)-
  • Lys(iPr,Boc)-(D-Arg(Pbf))-2Nal-Gly-Cys(Mmt)-Lys(iPr,Boc)-Gly was assembled by standard Fmoc chemistry using Rink AM resin. Briefly, 3.6 g of Rink AM resin was swollen in DCM for 14 h and then washed four times with DMF. Removal of Fmoc was carried out in 20% piperidine in DMF for 20 min at room temperature and washed several times with DMF. Ninhydrin test was negative. Stepwise chain assembly started with Fmoc-Gly-OH from the C-terminal end of the linear peptide.
  • Fmoc protection was removed again using 20% piperidine in DMF for 20 min.
  • N-terminal acetylation was carried out with 20 mL of a mixture of acetic anhydride/DIEA/DMF (1 : 1 :4, v/v/v) for 30 min at room temperature. The resin was then washed with DMF three time and then with DCM twice, dried under vacuum.
  • Peptide chain assembly The peptide chain of Cys(Trt)-Cys(Mmt)-Tyr(tBu)-
  • Lys(iPr,Boc)-(D-Arg(Pbf))-2Nal-Gly-Cys(Mmt)-Lys(iPr,Boc)-Gly was assembled by standard Fmoc chemistry using Rink AM resin. Briefly, 3.6 g of Rink AM resin was swollen in DCM for 14 h and then washed four times with DMF. Removal of Fmoc was carried out in 20% piperidine in DMF for 20 min at room temperature and washed several times with DMF. Ninhydrin test was negative. Stepwise chain assembly started with Fmoc-Gly-OH from the C-terminal end of the linear peptide.
  • Fmoc protection was removed again using 20% piperidine in DMF for 20 min.
  • N-terminal acetylation was carried out with 20 mL of a mixture of acetic anhydride/DIEA/DMF (1 : 1 :4, v/v/v) for 30 min at room temperature. The resin was then washed with DMF three time and then with DCM twice, dried under vacuum.
  • H 4 HCO 3 was used to adjust the reaction mixture to pH 7.5.
  • the conjugation reaction was completed in about half an hour as confirmed by MS.
  • the final product was purified using a reverse-phased preparative column Daisogel (50x250mm, 8mm); mobile phases - Solvent A: 0.1% TFA water; Solvent B: 0.1% TFA acetonitrile. Fractions containing the target product were combined and lyophilized (a TFA salt).
  • Peptide chain assembly The peptide chain of Cys(Trt)-(mini-PEG6)-Cys(Mmt)-
  • Tyr(tBu)-Lys(iPr,Boc)-(D-Arg(Pbf))-2Nal-Gly-Cys(Mmt)-Lys(iPr,Boc)-Gly (SEQ ID NO: 10) was assembled by standard Fmoc chemistry using Rink AM resin. Briefly, 3.6 g of Rink AM resin was swollen in DCM for 14 h and then washed four times with DMF. Removal of Fmoc was carried out in 20% piperidine in DMF for 20 min at room temperature and washed several times with DMF. Ninhydrin test was negative. Stepwise chain assembly started with Fmoc-Gly- OH from the C-terminal end of the linear peptide.
  • Fmoc protection was removed again using 20% piperidine in DMF for 20 min.
  • N-terminal acetylation was carried out with 20 mL of a mixture of acetic anhydride/DIEA/DMF (1 : 1 :4, v/v/v) for 30 min at room temperature. The resin was then washed with DMF three time and then with DCM twice, dried under vacuum.
  • H 4 HCO 3 was used to adjust the reaction mixture to pH 7.5.
  • the conjugation reaction was completed in about half an hour as confirmed by MS.
  • the final product was purified using a reverse-phased preparative column Daisogel (50x250mm, 8mm); mobile phases - Solvent A: 0.1%) TFA water; Solvent B: 0.1%> TFA acetonitrile. Fractions containing the target product were combined and lyophilized (a TFA salt).
  • Peptide chain assembly The peptide chain of Phe-Tyr(tBu)-Lys(iPr,Boc)-(D-
  • Arg(Pbf))-2Nal-Gly-(D-Glu(OAll)-Lys(iPr,Boc)-(mini-PEG6)-Cys(Trt)-Gly was assembled by standard Fmoc chemistry using Rink AM resin. Briefly, 1.0 g of Rink AM resin was swollen in DCM for 14 h and then washed four times with DMF. Removal of Fmoc was carried out in 20% piperidine in DMF for 20 min at room temperature and washed several times with DMF. Ninhydrin test was negative. Stepwise chain assembly started with Fmoc-Gly- OH from the C-terminal end of the linear peptide.
  • the deprotected side chain carboxylic acid of D-Glu was then activated with PyBOP ((benzotriazol- l-yloxy)-tris(pyrrolidino)-phosphonium hexafluorophosphate)/DIEA and cyclized to the alpha amino group of Phe residue on resin.
  • PyBOP (benzotriazol- l-yloxy)-tris(pyrrolidino)-phosphonium hexafluorophosphate)/DIEA
  • the cyclization was completed within 2 h, as confirmed by MS after a test cleavage.
  • H 4 HC0 was used to adjust the reaction mixture to pH 7.5.
  • the conjugation reaction was completed in about half an hour as confirmed by MS.
  • the final product was purified using a reverse-phased preparative column Daisogel (50x250mm, 8mm); mobile phases - Solvent A: 0.1%) TFA water; Solvent B : 0.1%> TFA acetonitrile. Fractions containing the target product were combined and lyophilized (a TFA salt).
  • Peptide chain assembly The peptide chain of Cys(Mmt)-Tyr(tBu)-Lys(iPr,Boc)-
  • Fmoc protection was removed again using 20% piperidine in DMF for 20 min.
  • N-terminal acetylation was carried out with 5 mL of a mixture of acetic anhydride/DIEA/DMF (1 : 1 :4, v/v/v) for 30 min at room temperature. The resin was then washed with DMF three time and then with DCM twice, dried under vacuum.
  • NH 4 HCO 3 was used to adjust the reaction mixture to pH 7.5.
  • the conjugation reaction was completed in about half an hour as confirmed by MS.
  • the final product was purified using a reverse-phased preparative column Daisogel (50x250mm, 8mm); mobile phases - Solvent A: 0.1% TFA water; Solvent B: 0.1% TFA acetonitrile. Fractions containing the target product were combined and lyophilized (a TFA salt).
  • Isotopic or radioactive labeled acetones are commercially available from various vendors. If there is a need for custom preparation of isotopic or radioactive labeled acetones, methods can be found in known arts, for example Rolf Voges, et al., Preparation of Compounds Labeled with Tritium and Carbon-14 (John Wiley & Sons (2009).

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