Lipodepsipeptide antibiotics and methods of preparation
AssigneeBioSource Pharm, Inc.
InventorsRichard A. Leese, William V. Curran, Donald B. Borders
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Abstract
Novel cyclodepsipeptide intermediates have been prepared from the A21978 complex and used to synthesize new lipodepsipeptide antibiotics. The three intermediates can be readily derivatized to give new families of antibiotics that have potent antibacterial activity against gram positive bacteria.
Claims9
A method for preparing an intermediate for use in the synthesis of a lipodepsipeptide antibiotic, including the steps of:
- (a) Obtaining an A21978 complex having a cyclic depsipeptide unit by fermentation of Streptomyces roseosporus;
- (b) Protecting the orinithine amino group of the A21978 antibiotic complex by FMOC, the protective function 9-fluorenylmethoxycarbonyl;
- (c) Treating the product from the reaction of step (b) with a deacylase enzyme to provide a single protected peptide;
- and
- (d) Using a modified Edman degradation method or peptidase enzymatic reactions to obtain a protected intermediate in the form of a cdpeptide chosen from the group consisting of FMOC-cdpeptide-2, FMOC-cdpeptide-1, or FMOC-cdpeptide, by reducing in size by one to three amino acids in the exocyclic tripeptide side chain of the cyclic depsipeptide unit of said complex.
An antibacterial compound prepared from a chemically derivatized protected form of cdpeptide, having the following structure, where Y equals FMOC or H:
- said compound is selected from a group consisting of the following or their corresponding salts:
- Cmp A X1 X2 X3 Y 1P CH3(CH2)11NHCO — — Asp FMOC 1 CH3(CH2)11NHCO — — Asp H 2 CH3(CH2)11NHCO — Asn Asp FMOC 3 CH3(CH2)11NHCO — Asn Asp H 4 CH3(CH2)8CO — Asn Asp H 4P CH3(CH2)8CO — Asn Asp FMOC 5 CH3(CH2)8CO L-Phe Asn Asp H 5P CH3(CH2)8CO L-Phe Asn Asp FMOC 6 CH3(CH2)8CO D-Phe Asn Asp H 6P CH3(CH2)8CO D-Phe Asn Asp FMOC 7 CH3(CH2)9SO2 L-Phe Asn Asp H 8 CH3(CH2)9SO2 L-Phe Asn Asp FMOC 9 CH3(CH2)8CO L-Kyn Asn Asp H 9P CH3(CH2)8CO L-Kyn Asn Asp FMOC 10 CH3(CH2)8CO D-Kyn Asn Asp H 10P CH3(CH2)8CO D-Kyn Asn Asp FMOC 11 CH3(CH2)8CO L-1-Naph Asn Asp H 11P CH3(CH2)8CO L-1-Naph Asn Asp FMOC 12 CH3(CH2)8CO L-Bthio Asn Asp H 12P CH3(CH2)8CO L-Bthio Asn Asp FMOC 13 CH3(CH2)8CO L-Harm Asn Asp H 13P CH3(CH2)8CO L-Harm Asn Asp FMOC 14 CH3(CH2)8CO D-Harm Asn Asp H 14P CH3(CH2)8CO D-Harm Asn Asp FMOC 15 CH3(CH2)15NHCO — Asn Asp H 15P CH3(CH2)15NHCO — Asn Asp FMOC 16 CH3(CH2)11NHCO L-2-Naph Asn Asp H 16P CH3(CH2)11NHCO L-2-Naph Asn Asp FMOC 17 CH3(CH2)8CO L-2-Naph Asn Asp H 17P CH3(CH2)8CO L-2-Naph Asn Asp FMOC *Standard amino acid abbreviations with L-configuration except L-β-(3-benzothienyl)-alanine(L-Bthio);
- L-1,2,3,4-tetrahydronorharman-3-carboxylic acid (L-Harm);
- L-β-(1-naphthyl)-alanine (L-1-Naph);
- L-β-(2-naphthyl)-alanine (L-2-Naph) and where noted for D-configuration.
A protected cdpeptide intermediate designated protected cdpeptide, as represented in the following embodiment, and which can be used to synthesize a lipodepsipeptide antibiotic:
- H-protected cdpeptide;
- H-(X3)-protected cdpeptide;
- H-(X2)(X3)-protected cdpeptide, where, for all three cases H is hydrogen, X2 is asparaginyl, X3 is aspartyl and the protecting group is 9-fluorenylmethoxycarbonyl, designated FMOC;
- wherein the protected 9-fluorenylmethoxycarbonyl-cdpeptide, designated FMOC-cdpeptide, C58H72N12O21, has the structure:
A protected cdpeptide intermediate designated protected cdpeptide-1, as represented in the following embodiment, and which can be used to synthesize a lipodepsipeptide antibiotic:
- H-protected cdpeptide H-(X3)-protected cdpeptide;
- H-(X2)(X3)-protected cdpeptide, where, for all three cases H is hydrogen, X2 is asparaginyl, X3 is aspartyl and the protecting group is 9-fluorenylmethoxycarbonyl, designated FMOC;
- wherein the protected 9-fluorenylmethoxycarbonyl-cdpeptide-1, designated FMOC-cdpeptide-1, C62H77N13O24, has the structure:
A protected cdpeptide intermediate designated protected cdpeptide-2, as represented in the following embodiment, and which can be used to synthesize a lipodepsipeptide antibiotic:
- H-protected cdpeptide H-(X3)-protected cdpeptide;
- H-(X2)(X3)-protected cdpeptide, where, for all three cases H is hydrogen, X2 is asparaginyl, X3 is aspartyl and the protecting group is 9-fluorenylmethoxycarbonyl, designated FMOC;
- wherein the protected 9-fluorenylmethoxycarbonyl-cdpeptide-2 designated FMOC-cdpeptide-2, C66H83N15O26, has the structure:
A protected cdpeptide intermediate designated protected cdpeptide, as represented in the following embodiment, and which can be used to synthesize a lipodepsipeptide antibiotic, the protecting group being a solid phase support;
- and the protected solid phase support-cdpeptide has the structure:
Dependencies are inferred from the claim text.