WO2008151306A1 - Synthèse de composés cyclodepsipeptide ayant une activité antinéoplasique et/ou antimicrobienne - Google Patents

Synthèse de composés cyclodepsipeptide ayant une activité antinéoplasique et/ou antimicrobienne Download PDF

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Publication number
WO2008151306A1
WO2008151306A1 PCT/US2008/065991 US2008065991W WO2008151306A1 WO 2008151306 A1 WO2008151306 A1 WO 2008151306A1 US 2008065991 W US2008065991 W US 2008065991W WO 2008151306 A1 WO2008151306 A1 WO 2008151306A1
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compound
mmol
etoac
nmr
hexane
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PCT/US2008/065991
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English (en)
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George R. Pettit
Thomas H. Smith
Song Feng
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Arizona Board Of Regents, A Body Corporate Of The State Of Arizona, Acting For And On Behalf Of Arizona State University
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Publication of WO2008151306A1 publication Critical patent/WO2008151306A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C07D273/01—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having one nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/675—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids of saturated hydroxy-carboxylic acids
    • C07C69/68—Lactic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the present invention is directed to effective methods of synthesizing cyclodepsipeptide compounds having antineoplastic and/or antimicrobial activity.
  • the methods are directed to synthesis of kitastatin 1 (1a), respirantin (1b) or a valeryl modification (Ic).
  • the present invention is further directed to important intermediates used in the disclosed methods.
  • FDA United States Food, Drug and Cosmetic Administration
  • kitastatin 1 (1a) respirantin (1b) or a valeryl modification (Ic) in sufficient quantities to meet the public demand. It is toward the fulfillment of that need that the present invention is directed.
  • the present invention is directed to methods of synthesis of potentially useful cyclodepsipeptide compounds having antineoplastic and/or antimicrobial activity.
  • the methods of synthesis are directed to production of three exceptional cancer cell growth inhibitory cyclodepsipeptides from the bacteria Kitasatospora spp. found on the Beaufort Sea coast of the Alaska North Slope 1a , including newly discovered kitastatin 1 (1a) ( Figure 1), and two other cyclodepsipeptides, namely respirantin (1b) and a valeryl modification (1c). 1b
  • One preferred method of preparing a cyclodepsipeptide comprises coupling a compound having the structure
  • R is H or CHO
  • R 1 is CH 2 CH(CH 3 ) 2 or CH(CH 3 ) 2 ;
  • X is CHO or Cbz.
  • the intermediate compound having the structure is prepared according to the following scheme:
  • the ⁇ -keto ester alcohol intermediate compound having the structure of: is preferably prepared by coupling a compound having the structure and the fragment having the structure
  • the preferred method of synthesizing a cyclodepsipeptide compound having antineoplastic and/or antimicrobial activity comprises the steps set forth in the following scheme:
  • R is R is H or CHO; and X is CHO or Cbz.
  • the present invention is further directed to the important intermediates used in the synthesis of these cyclodepsipeptide having antineoplastic and/or antimicrobial activity.
  • the intermediate are selected from the group consisting of:
  • the intermediate compound is in a substantially pure form.
  • the invention further encompasses methods of preparing the intermediates.
  • Preferred methods of preparing intermediates include for example, coupling the compounds below:
  • Another example includes selective carboxyl deprotection by treatment of a £-butyl ester compound having the following structure:
  • the catalytic salt is CuSO 4 and the reaction is carried out in refluxing toluene.
  • FIG. 1 shows cyclodepsipeptides, specifically, kitastatin (1a), respirantin (1b) and valeryl modification (1c); (+)-Antimycin A 3b (2).
  • salts of the compounds of the invention may be formed, for example, by reacting the compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Formation salts is well within the ability of one skilled in the art. Examples of specific salts of the compound of the invention are provided herein, but are not intended to be limiting.
  • Preferred compounds synthesized by the methods disclosed herein inhibit the growth of cancer cells and/or parasitic microbial growth.
  • the compounds synthesized can be used to inhibit cancer cell growth and microbial activity.
  • kitastatin 1 (1a) and respirantin (1b) macrocycle reveals that these compounds are composed of common amino acids, or ⁇ -hydroxycarboxylic acids derived from them, along with the ⁇ -ketoester unit.
  • Ia and 1b Since the absolute stereochemistry of Ia and 1b was undetermined at the onset of this study, our initial target Ib was selected by assuming the most common S-configuration for the constituent amino acids and their presumed ⁇ -hydroxy derivatives. Fortunately, that proved to be the correct choice among the 256 possible optical isomers.
  • a retrosynthetic analysis of the ultimately successful route to respirantin (1b) is presented in Scheme 1. Antimycin syntheses 2 techniques were used for appending the protected benzoic acid 3 to amino substituted macrocycles.
  • aReagents and conditions (a) K 2 CO 3 , MeI, DMSO, 23°C, 48 h, 65%. (b) KOH, aq CH 3 OH,
  • aReagents and conditions (a) (i) Oxalyl chloride, catalytic DMF, DCM, 0-23°C, 2h. (ii) 19, pyridine, 23°C, 16 h, 75%. (b) LiI, pyridine, H0°C, 40 h, 89%. (c) (i) 7, 1:1 TFA-DCM, 0.5 h. (ii) PyBroP, DIPEA, DCM, product from (i), 4 h, 65%. (d) BF 3 .Et 2 O, DCM, 0.5 h, 87% for 23, 83% for 27-28. (e) 25, MNBA, DMAP, TEA, DCM, 23°C, 16 h, 77%.
  • the diester 20 was obtained via reaction of the acid chloride derived from silyl ester 18 under neutral conditions 11,12 with alcohol 19. 5 Selective hydrolytic cleavage of methyl ester 20 could not be achieved as extensive cleavage of the internal ester linkage occurred.
  • the desired carboxylic acid 21 was obtained via nucleophilic alkyl cleavage with LiI in pyridine. 13 Formation of the amide linkage leading to amide 22 proved to be problematic. Reaction of carboxylic acid 21 with the amine derived from TFA deprotection of Boc protected 7 under a variety of peptide coupling procedures (BOP 14 , PyBroP 15 , DEPC 16 ) afforded at best low yields of amide 22 along with the pyrazine 24.
  • aReagents and conditions (a) TBAF, THF, 0°C, 1 h, 85%. (b) 25, MNBA, DMAP, TEA, DCM, 23°C, 16 h, 75%. (c) BF 3 -Et 2 O, DCM, 23°C, 1.5 h, 92%.
  • aReagents and conditions (a) (i) Oxalyl chloride, catalytic DMF, DCM, 0-23°C, 2h. (ii) 33, pyridine, 23°C, 16 h, 55%. (b) BF 3 -Et 2 O, DCM, 23°C, 1 h, 51%. (c) K 2 CO 3 , aqueous CH 3 OH or TBAF.
  • aReagents and conditions (a) (i) Oxalyl chloride, catalytic DMF, DCM, 0-23°C, 2h. (ii) 37, pyridine, 23°C, 16 h, 81%. (b) TBAF, THF, 23°C, 1 h, 100%. (c) 25, MNBA, DMAP, TEA, DCM, 23°C, 16 h, 87%. (d) TBAF, THF, 23°C, 1 h, 100%. (e) (i) TBDPSCl or TBDMSCl, imidazole, DMF, 23°C, 16 h.
  • amide 45 was inert to BF 3 .Et 2 O at ambient temperature, as well as several other acidic reagents, and TBAF caused the expected elimination of the leucic acid residue. Consequently, we chose to proceed with a MNBA promoted coupling of alcohol 9 with carboxylic acid 41 to provide ester 43. To achieve good results with this esterfication, it was necessary to use freshly prepared acid 41. Apparently the acidity of 41 is sufficient to cause decomposition to the corresponding ⁇ -hydroxyacid. As anticipated, cleavage of the t- butyl ester in the presence of the TBDMS group proved to be problematic.
  • aReagents and conditions (a) MeI, K 2 CO 3 , DMSO, 23°C, 3 h, 28%. (b) H 2 , Pd/C, EtOAc, 23°C, 2 h, 73%. (c) 3, EDCI, HOBt, NMM, DMF, 23°C, 11 h, 61%. (d) H 2 , Pd/C, EtOAc,
  • aReagents and conditions (a) CbzNHS, DMF, 100°C, 6 h. (b) (i) BzIBr, K 2 CO 3 , DMF, 120°C, 3 h. (ii) LiOH, aq THF/CH 3 OH, 23°C, 18 h. (c) 4, EDCI, HOBt, NMM, DMF, 23°C, 11 h. (d) H2, Pd/C, EtOAc, 23°C, 2 h.
  • Kitastatin 1 (1a), respirantin (1b), and the valeryl analog Ic were evaluated as inhibitors of cancer cell growth versus the murine P388 leukemia cell line 30 and a panel of human cancer cell lines. 31 The data are reported in Table 1. Table 1. Comparison of the Cancer Cell Growth Inhibition (GI 50 , ⁇ g/ml) of Kitastatin 1 (1a), Respirantin (1b), and the Valeryl Analog Ic against a Panel of Murine (P388, Lymphocytic Leukemia) and Human Cancer Cell Lines.
  • pancreatic cancer is one of the most deadly types and is notoriously refractory to current modes of treatment.
  • Solvents were redistilled prior to use. Reagents were used as received. MNBA was obtained from TCI America. Thin layer chromatography (tic) was carried out with Analtech 250 ⁇ thick silica gel GHLF plates and visualized with H 2 SO 4 , phosphomolybdic acid, iodine, or UV. Organic extracts were dried over anhydrous NaSO 4 and evaporated under reduced pressure using a rotary evaporator. The crude products were separated by flash column chromatography on flash (230-400 mesh ASTM) silica from E. Merck.
  • Silyl ether 18 (3.23 g, 10.16 mmol) was dissolved in CH 2 Cl 2 (10 mL) containing DMF (280 ⁇ L, 0.26 g, 3.62 mmol) under N 2 and cooled to 0°C.
  • Oxalyl chloride (5.6 mL of 2M solution in CH 2 Cl 2 , 11.2 mmol) was added dropwise over 5 min. The solution was stirred at 0°C for 1.5 h and at ambient temperature for 0.5 h. The solvent was evaporated. To the residue was added dropwise a solution of alcohol 19 (1.27 g, 8.71 mmol) in pyridine (5 mL).
  • Methyl (3,6-diisobutyl-5-methoxycarbonylmethyl-pyrazin-2-yl)acetate (24).
  • Ketone 7 (0.28g, 0.97 mmol) was placed in 1:1 TFA-DCM (4.0 mL) under N 2 and stirred at ambient for 45 min. The solvent was evaporated and the residue coevaporated with toluene (2 x 10 mL). The residue was dissolved in DCM (3.0 mL) and cooled to 0°C.
  • TEA (0.41 mL, 293.3 mg, 2.91 mmol) was added dropwise and the solution stirred at 0°C for 4 h.
  • reaction mixture was diluted with EtOAc (50 mL), washed with 5% citric acid (2 x 10 mL), H 2 O (10 mL), 6% NaHCO 3 (2 x 10 mL), H 2 O (10 mL), 5 M NaCl (10 mL), dried and evaporated.
  • Methyl 4-(2- ⁇ 2-[2-benyloxycarbonylamino-3-(t-butyldimethylsilyloxy) butyryloxy]propionyloxy ⁇ -3-methylpentanoylamino)6-methyl-3-oxoheptanoate (26).
  • Carboxylic acid 25 (0.26g, 0.72 mmol)
  • alcohol 23 241.2 mg, 0.65 mmol
  • MNBA (0.25g, 0.73 mmol)
  • DMAP (20.0 mg, 0.16 mmol) and TEA (0.30 mL, 0.22 g, 2.13 mmol) were placed in DCM (3.5 mL) under N 2 and stirred at ambient for 16 h.
  • reaction mixture was diluted with EtOAc (50 mL), washed with H 2 O (10 mL), 6% NaHCO 3 (2 x 10 mL), H 2 O (10 mL), 5% citric acid (2 x 10 mL), H 2 O (10 mL), 5 M NaCl (10 mL), dried, and evaporated.
  • Methyl 2-hydroxy 3-formylaminobenzoate 50.
  • Benzoic acid derivative 49 (1.37 g, 7.57 mmol) and NaHCO 3 (1.40 g, 16.65 mmol) were placed in DMF (20 mL) under N 2 .
  • MeI (5.37 g, 2.36 mL, 37.85 mmol) in DMF (20 mL) was added and the mixture stirred at ambient temperature for 15 h.
  • Methyl 2-benzyloxy-3-formylaminobenzoate (51). To methyl ester 50 (1.01 g, 5.20 mmol) and benzyl bromide (1.44 g, 1 mL, 8.42 mmol) in DMF (20 mL under N 2 ) was added K 2 CO 3 (1.44 g, 10.40 mmol) and the mixture stirred at 60°C for 15 h. The mixture was diluted with EtOAc (100 mL), washed with H 2 O (2 x 20 mL), 5 M NaCl (10 mL), dried, solvent evaporated and the residue coevaporated with toluene (20 mL).
  • Benzoic acid 3 (14.0 mg, 0.051 mmol), 1-hydroxybenzotriazole (7.0 mg, 0.051 mmol), EDCI (7.4 mg, 0.038 mmol), and N-methylmorpholine (20 ⁇ L, 0.18 mmol) were added successively to a solution of amine 4 (15.0 mg, 0.026 mmol) in DMF (1.5 mL) under N 2 .
  • the reaction mixture was stirred at ambient temperature for H h, the reaction was terminated by addition of saturated NaHSO 4 (20 mL), and extracted with EtOAc (30 mL).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des procédés efficaces de synthèse de composés cyclodepsipeptide ayant une activité antinéoplasique et/ou antimicrobienne. Les synthèses totales des cyclodepsipeptides cycliques à dix-huit chaînons kitastatine (1a) et respirantine (1b) sont apprises. Une étape importante de la synthèse est une transestérification intramoléculaire de l'alcool cétoester 6 pour permettre le macrocycle protégé 5. Les produits de synthèse se sont avérés être identiques aux produits naturels et la stéréochimie absolue de 6 des 7 centres asymétriques de cyclodepsipeptide 1b a été établie de manière univoque. La kitatastine (1a) et la respirantine (1b) se sont avérées être des inhibiteurs remarquables de la croissance de cellules cancérigènes et sont liées à la famille antimycine d'antibiotiques.
PCT/US2008/065991 2007-06-05 2008-06-05 Synthèse de composés cyclodepsipeptide ayant une activité antinéoplasique et/ou antimicrobienne WO2008151306A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11174291B2 (en) 2015-02-13 2021-11-16 Arizona Board Of Regents On Behalf Of Arizona State University Silstatin compounds
US11629167B2 (en) 2017-11-09 2023-04-18 Arizona Board Of Regents On Behalf Of Arizona State University Betulastatin compounds

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4789757A (en) * 1987-07-17 1988-12-06 W. R. Grace & Co.-Conn. N-formylation of amino carboxylic compounds with formamide
US5026872A (en) * 1984-02-01 1991-06-25 American Cyanamid Aromatic ether-ketone polyamines, intermediates and products, and methods for preparing same
US5514773A (en) * 1992-01-15 1996-05-07 Fujisawa Pharmaceutical Co., Ltd. Depsipeptide derivatives, production thereof and use thereof
US6403555B1 (en) * 1999-12-08 2002-06-11 Xcyte Therapies, Inc. Depsipeptide and congeners thereof for use as immunosuppressants
US6734165B2 (en) * 2001-08-23 2004-05-11 The Trustees Of Columbia University In The City Of New York Method for re-sensitizing vancomycin resistant bacteria which selectively cleave a cell wall depsipeptide
US6900192B2 (en) * 2000-10-06 2005-05-31 Xenoport, Inc. Bile-acid conjugates for providing sustained systemic concentrations of drugs
US20050239804A1 (en) * 1999-06-30 2005-10-27 The Regents Of The University Of California Method for improved chemical synthesis of guanidinium alkaloids
US7122519B2 (en) * 2000-04-07 2006-10-17 The Trustees Of The University Of Pennsylvania Didemnin analogs and fragments and methods of making and using them
US20070010489A1 (en) * 2002-04-26 2007-01-11 Arimilli Murty N Cellular accumulation of phosphonate analogs of hiv protease inhibitor compounds

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5026872A (en) * 1984-02-01 1991-06-25 American Cyanamid Aromatic ether-ketone polyamines, intermediates and products, and methods for preparing same
US4789757A (en) * 1987-07-17 1988-12-06 W. R. Grace & Co.-Conn. N-formylation of amino carboxylic compounds with formamide
US5514773A (en) * 1992-01-15 1996-05-07 Fujisawa Pharmaceutical Co., Ltd. Depsipeptide derivatives, production thereof and use thereof
US20050239804A1 (en) * 1999-06-30 2005-10-27 The Regents Of The University Of California Method for improved chemical synthesis of guanidinium alkaloids
US6403555B1 (en) * 1999-12-08 2002-06-11 Xcyte Therapies, Inc. Depsipeptide and congeners thereof for use as immunosuppressants
US7122519B2 (en) * 2000-04-07 2006-10-17 The Trustees Of The University Of Pennsylvania Didemnin analogs and fragments and methods of making and using them
US6900192B2 (en) * 2000-10-06 2005-05-31 Xenoport, Inc. Bile-acid conjugates for providing sustained systemic concentrations of drugs
US6734165B2 (en) * 2001-08-23 2004-05-11 The Trustees Of Columbia University In The City Of New York Method for re-sensitizing vancomycin resistant bacteria which selectively cleave a cell wall depsipeptide
US20070010489A1 (en) * 2002-04-26 2007-01-11 Arimilli Murty N Cellular accumulation of phosphonate analogs of hiv protease inhibitor compounds

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KOLOTOVA ET AL.: "The Reactions of Aroylp<ruvic Acids and their Derivatives with o-aminophenyldiphenytmethanol", RUSS CHEM BUL., vol. 47, 1998, pages 2246 - 2248 *
KONG ET AL.: "Colubricidin A, a Novel Macrolide Antibiotic from a Streptomyces sp. Tetrahedron", LETT., vol. 40, 1999, pages 9219 - 9223 *
URUSHIBATA ET AL.: "Respirantin, A Novel Insecticidal Cyclodepsipeptide from Streptomyces", J ANTIBIOT., vol. 46, 1993, pages 701 - 703 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11174291B2 (en) 2015-02-13 2021-11-16 Arizona Board Of Regents On Behalf Of Arizona State University Silstatin compounds
US11629167B2 (en) 2017-11-09 2023-04-18 Arizona Board Of Regents On Behalf Of Arizona State University Betulastatin compounds

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