The growing need of highly potent anticancer agents has stimulated the investigation of streptomycetes producing daunomycin-type anthracyclines. This review compares the features of production strains and their mutants and emphasizes the necessity of application of biochemical and biophysical analytical methods for better understanding these microorganisms and, above all, their further improving and practical usage.

• MeSH
• Biotransformation MeSH
• Daunorubicin biosynthesis   history   MeSH
• History, 20th Century MeSH
• Mutation MeSH
• Antibiotics, Antineoplastic biosynthesis   history   MeSH
• Streptomyces genetics   metabolism   MeSH
• Check Tag
• History, 20th Century MeSH
• Publication type
• Journal Article MeSH
• Historical Article MeSH
• Review MeSH
• Comparative Study MeSH
• Names of Substances
• Daunorubicin MeSH
• Antibiotics, Antineoplastic MeSH

Semisynthetic derivatives of daunomycinone with 7,9-isopropylacetal, 7-O-methyl, 7-O-(4-penten-2-yl), and 7-O-(2-hydroxyethyl) substituents were converted by Streptomyces peucetius var. caesius (an adriamycin-blocked mutant) into 7-deoxy-13-dihydrodaunomycinone, while daunomycinone was transformed into 13-dihydrodaunomycinone (predominantly) and 7-deoxy-13-dihydrodaunomycinone. S. coeruleorubidus mutants 24-74 (accumulating aclavinone derivatives instead of daunomycin and related compounds) and 96-85 (producing no anthracycline substances), and S. aureofaciens B-96 (a tetracycline-blocked mutant) transformed the above substrates into the corresponding 13-dihydro derivatives, with the exception of 7,9-isopropylacetal daunomycinone which remained intact. 7-O-Propyn-1-yl daunomycinone was not transformed by any of the strains used under the conditions.

• MeSH
• Naphthacenes metabolism   MeSH
• Streptomycetaceae metabolism   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• daunomycinone MeSH Browser
• Naphthacenes MeSH

Substances studied at this department in 1954-1983 are reviewed; a total of 226 compounds are characterized in a tabular form. They include natural compounds as well as those prepared by biotransformation, by semisynthetic and synthetic methods.

• MeSH
• Anti-Bacterial Agents isolation & purification   MeSH
• Microbiology MeSH
• Chemistry, Organic * MeSH
• Organic Chemistry Phenomena MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH

Cosynthesis of anthracycline compounds was followed in five phenotypic groups of mutants of Streptomyces coeruleorubidus (A--E), blocked in the biosynthesis of the daunomycine complex, and in two mutant types of Streptomyces galilaeus (F, G) blocked in the biosynthesis of glycosides of epsilon-pyrromycinone and aklavinone. Glycosides of daunomycinone and 13-dihydrodaunomycinone were produced in combinations A+B, A+C, A+D, A+E and A+F, epsilon-rhodomycinone was synthesized in combinations A+E, A+F, B+E and B+F. During the cultivation of types B--E with type G or F non-anthracycline compounds, typical of S. galilaeus, were cosynthesized. No cosynthesis could be observed in other combinations of the mutant types. Negative results were also obtained with combinations of mutants of the same group and during cultivation of all mutant types with streptomycetes not producing anthracyclines. A scheme illustrating metabolic pathways leading to the biosynthesis of daunomycinone, aklavinone, epsilon-rhodomycinone in S. coeruleorubidus and S. galilaeus was constructed.

• MeSH
• Daunorubicin analogs & derivatives   biosynthesis   MeSH
• Mutation MeSH
• Streptomyces metabolism   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Daunorubicin MeSH

The ability to transorm biologically exogenous daunomycinone, 13-dihydrodaunomycinone, aklavinone, 7-deoxyaklavinone, epsilon-rhodomycinone, epsilon-isorhodomycinone and epsilon-pyrromycinone was studied in submerged cultures of the following strains: wild Streptomyces coeruleorubidus JA 10092 (W1) and its improved variants 39-146 and 84-17 (type P1) producing glycosides of daunomycinone and of 13-dihydrodaunomycinone, together with epsilon-rhodomycinone, 13-dihydrodaunomycinone and 7-deoxy-13-dihydrodaunomycinone; in five mutant types of S. coeruleorubidus (A, B, C, D, E) blocked in the biosynthesis of glycosides and differing in the production of free anthracyclinones; in the wild Streptomyces galilaeus JA 3043 (W2) and its improved variant G-167 (P2) producing glycosides of epsilon-pyrromycinone and of aklavinone together with 7-deoxy and bisanhydro derivatives of both aglycones; in two mutant types S. galilaeus (F and G) blocked in biosynthesis of glycosides and differing in the occurrence of anthracyclinones. The following bioconversions were observed: daunomycinone leads to 13-dihydrodaunomycinone and 7-deoxy-13-dihydrodaunomycinone (all strains); 13-dihydrodaunomycinone leads to 7-deoxy-13-dihydrodaunomycinone (all strains); daunomycinone or 13-dihydrodaunomycinone leads to glycosides of daunomycinone and of 13-dihydrodaunomycinone, identical with metabolites W1 and P1 (type A), or only a single glycoside of daunomycinone (type E); aklavinone leads to epsilon-rhodomycinone (types A and B); aklaviinone leads to 7-deoxyaklavinone and bisanhydroaklavinone (type C); epsilon-rhodomycinone leads to zeta-rhodomycinone (types C, E); epsilon-rhodomycinone leads to glycosides of epsilon-rhodomycinone (types W2, P2); epsilon-isorhodomycinone leads to glycosides of epsilon-isorhodomycinone (types W2, P2); epsilon-pyrromycinone leads to a glycoside of epsilon-pyrromycinone (types W1, P1). 7-Deoxyaklavinone remained intact in all tests. Exogenous daunomycinone suppressed the biosynthesis of its own glycosides in W1 and P1; it simultaneously increased the production of epsilon-rhodomycinone in P1.

• MeSH
• Biotransformation MeSH
• Daunorubicin analogs & derivatives   metabolism   MeSH
• Streptomyces metabolism   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Daunorubicin MeSH

When improving Streptomyces coeruleorubidus JA 10092, a producer of antibiotics of the daunomycinone complex, the most active variants were found among isolates of morphological types bld-1 (with a suppressed production of the aerial mycelium on organic media containing glucose) and whi (with an asporogenic aerial mycelium on glucose media and with the bald phenotype on media containing starch). Submerged cultures of the whi mutants produced increased quantities of daunomycinone glycosides in the antibiotic complex, the amount of free anthracyclinones being simultaneously decreased. The whi strains differed from the wild type also in higher demands for aeration, concentration of glucose and in an increased production capacity in starch media. The overall antibiotic activity increased more than 40 times after a six-step selection (application of UV light, gamma-radiation, nitrous acid and natural spreads) combined with an altered fermentation technology.

• MeSH
• Daunorubicin biosynthesis   MeSH
• Culture Media MeSH
• Mutation MeSH
• Streptomyces cytology   genetics   metabolism   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Daunorubicin MeSH
• Culture Media MeSH

The wild strain Streptomyces coeruleorubidus JA 10092 was found to segregate into two spontaneous morphological variants (spo-1 and bld-1) with a different ability to form aerial mycelium in media with glucose as the main carbon source. Six new types of developmental mutants were obtained from the bald variant bld-1 after treatment with mutagens (UV light, gamma radiation, nitrous acid) and after natural selection. Formation of the aerial mycelium was fully suppressed in the bld-2 type growing on media both with glucose and with starch. The other types were bald only on starch media, forming the aerial mycelium on media with glucose; types spo-2, spo-3, spo-4 and spo-5 differed in size, shape and surface structure of spores, the type whi formed asporogenous aerial hyphae.

• MeSH
• Aminoglycosides biosynthesis   MeSH
• Glucose metabolism   MeSH
• Mutation * MeSH
• Selection, Genetic MeSH
• Starch metabolism   MeSH
• Spores, Bacterial growth & development   MeSH
• Streptomyces genetics   growth & development   metabolism   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Aminoglycosides MeSH
• Glucose MeSH
• Starch MeSH