Production of new anthracycline antibiotics 1-hydroxyoxaunomycin and 6-deoxyoxaunomycine by limited biosynthetic conversion using a daunorubicin-negative mutant.

Abstract

A limited biosynthetic conversion of some known anthracyclinones using a specific daunorubicin-nonproducing mutant provided four new anthracycline antibiotics: l-Hydroxy-10-methoxycarbonyl-1 3-deoxocarminomycin; 1 -hydroxy-1 3-deoxocarminomycin; 1 -hydroxyoxaunomycin and 6-deoxyoxaunomycin. Their isolation and purification from bioconversion broth, structural determination and antitumor activities against leukemic L1210cells are described. 1609Microbial conversion with anthracycline-nonproducing mutants is a useful means for obtaining new hybrid anthracyclines. Wehave obtained a number of new hybrid anthracyclines by bioconversion of natural anthracyclinones using biosynthetically blocked mutants of aclarubicin-producing Streptomyces galilaeus MA144 Ml and daunorubicin-producing Streptomyces coeruleorubidus ME-130 A4.r~6) Recently we have found an intensely potent anthracycline antibiotic oxaunomycin (1-0-daunosaminyl /?-rhodomycinone) in the culture broth ,of a blocked mutant of a new baumycin-producing Streptomyces sp. D788.7) Since it was 30-fold more cytotoxic against L1210 cell culture than its TV-dimethyl derivative betaclamycin T (7-0-rhodosaminyl /?-rhodomycinone), our attention was directed to the 7-0-daunosaminyl derivatives of other rhodomycinone aglycones such as /?-isorhodomycinone (/?-isoRMN) and a-citromycinone (a-CTN). Their corresponding 7-O-rhodosaminyl derivatives such as obelmycin A8) and yellamycin A9) have been isolated and evaluated biologically by us, but their 7-O-daunosaminyl derivatives have not been yet obtained.In this paper we describe production of the target 7-0-daunosaminyl hybrid anthracyclines 1-hydroxyoxaunomycin and 6-deoxyoxaunomycin by bioconversion of /MsoRMNand a-CTNusing a specific daunorubicin (DRN)-nonproducing mutant. Materials and Methods Microbial StrainA bioconversion strain used for 7-O-daunosaminylation was a DRN-nonproducing mutant strain * Present address:

A comprehensive review of glycosylated bacterial natural products

“…Sub-class I contains 365 anthracycline O-glycosides (and a few C-glycosides) bearing variant carbohydrate substitution ranging from mono-to pentasaccharides. C7-and/or C10-Oglycosylation predominates (358 compounds) within sub-class I anthracyclines including D-788, [189][190][191][192][193] oxaunomycins, 193 doxorubicins, 194,195 spartanamicins, 196 daunorubicins, 194,195 daunomycins, 185,197,198 aclacinomycins (aklavins), [199][200][201][202][203][204][205] rhodomycins, 184,[206][207][208][209][210] betaclamycins (and CG-21-C, CG1-C, CG21-B analogs), [211][212][213] auramycins, [214][215][216][217][218][219] MA-144-U and G analogs, [220][221][222] steffimycins, [223][224][225][226] baumycins, 227,228 pyrrocyclines,…”

“…In both subclasses I and II, the core sugar moiety is further modified via differential acylation of the 2 0 -OH and/or 3 0 -OH with a carbamoyl, 5-methyl-pyrrole-2carboxyl or pyrrole-2-carboxyl moiety (Fig. 26,193). In addition, 4 0 -OH methylation was observed among some members.…”

“…Sub-class I contains 365 anthracycline O -glycosides (and a few C -glycosides) bearing variant carbohydrate substitution ranging from mono- to pentasaccharides. C7- and/or C10- O -glycosylation predominates (358 compounds) within sub-class I anthracyclines including D-788, 189–193 oxaunomycins, 193 doxorubicins, 194,195 spartanamicins, 196 daunorubicins, 194,195 daunomycins, 185,197,198 aclacinomycins (aklavins), 199–205 rhodomycins, 184,206–210 betaclamycins (and CG-21-C, CG1-C, CG21-B analogs), 211–213 auramycins, 214–219 MA-144-U and G analogs, 220–222 steffimycins, 223–226 baumycins, 227,228 pyrrocyclines, 222 rubeomycins, 229,230 pyrromycins, 231 oblemycins (cytorhodins), 232,233 sulfurmycins, 214–219 cinerubins, 188,234–236 mutactimycins, 237–239 alldimycins, 233,240 nocardicyclins, 241 violamycins, 242 ditrisarubicins, 243 aranciamycins, 244–247 A447A∼D1, 248 ciclamycins, 249 isoquinocycline A, 188,250 kosinostatin (quinocycline B), 251,252 isoquinocycline B, 252,253 micromonomycin 254 and other representative anthracyclines. 100,188,201,202,211,229,255–263 Less common sub-class I O -glycoside regioselectivity was observed at C-1 (mutactimycin PR 237,238 ), C-4 [histomodulin, 264 komodoquinone A 265,266 and 4- O -(β- d -glucopyranosyl)-ε-rhodomycinone 267 ], and C-9 (cytorhodins X and Y).…”

Cloning and characterization of a glycosyltransferase gene involved in the biosynthesis of anthracycline antibiotic β-rhodomycin from Streptomyces violaceus

“…Therefore, the possibilities for producing new components or derivatives by biological or genetical means are large. In fact, we have obtained many L-RM metabolites by mutagenesis of a L-RM producer, and hybrid anthracyclines by a technique of microbial conversion using some other anthracycline producers [1,2]. More recently, we have succeeded in the production of hybrid anthracycline by a heterologous dnrK-carrying L-RM producer [3].…”

Cloning and characterization of a glycosyltransferase gene involved in the biosynthesis of anthracycline antibiotic β-rhodomycin fromStreptomyces violaceus

“…Therefore, the possibilities for producing new components or derivatives by biological or genetical means are large. In fact, we have obtained many β‐RM metabolites by mutagenesis of a β‐RM producer, and hybrid anthracyclines by a technique of microbial conversion using some other anthracycline producers [1,2]. More recently, we have succeeded in the production of hybrid anthracycline by a heterologous dnrK ‐carrying β‐RM producer [3].…”