Preparation and biological evaluation of 4-O-demethyldaunorubicin (carminomycin I) and of its 13-dihydro derivative.

Cassinelli, Guiseppe; Grein, A.; Masi, Paolo; Suarato, A.; Bernardi, L.; Arcamone, Federico; Marco, A. Di; Casazza, Anna Maria; Pratesi, Graziella; Soranzo, Carla

doi:10.7164/antibiotics.31.178

Cited by 36 publications

(7 citation statements)

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“…This has given an anthracycline complex whose glycosidic constituents represent a novel structural class within the family of doxorubicin related anthracyclines. In this communication we report the isolation and structure determination of the new, biologically active anthracyclines 1 l-deoxydaunorubicin (2), 11-deoxydoxorubicin (3), 11-deoxy-l 3-dihydrodaunorubicin (4), and 11-deoxy-13-deoxodaunorubicin (5). Purification of the anthracycline complex (6 g), isolated in the usual way,2 on a silica gel column6 gave 2 (0.4 g) (C27H29N09-HCI7, mp 175-176 °C dec, [a]23D +139°), 3 (0.6 g) (C77H29NOio-HC1, mp 171-173 °C dec, [a]23D + 11 ), 4 (0.2 g) (C27H3iN09-HC1, mp 163-164 °C dec,…”

Section: Sirmentioning

confidence: 98%

Structures of novel anthracycline antitumor antibiotics from Micromonospora peucetica

Arcamone¹,

Cassinelli²,

DiMatteo³

et al. 1980

J. Am. Chem. Soc.

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Section: Sirmentioning

confidence: 98%

Structures of novel anthracycline antitumor antibiotics from Micromonospora peucetica

Arcamone¹,

Cassinelli²,

DiMatteo³

et al. 1980

J. Am. Chem. Soc.

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“…Cultures were grown in production medium (8) as described above, and anthracycline metabolites were hydrolyzed with oxalic acid and extracted with chloroform as previously described (24 ,ug/ml in methanol) were used as external standards. The extracts were also subjected to thin-layer chromatography analysis on silica gel 60 F-254 (Merck & Co., Inc., Rahway, N.J.) by using a solvent system of chloroformmethanol (95:5) for aglycones and chloroform-methanolacetic acid-water (80:20:16:6) for glycosides (5). Plates were visualized under UV light (310 nm) with a TM-36 Chromato Vue Transilluminator (Ultra-Violet Products, Inc., Milwaukee, Wis.).…”

Section: Methodsmentioning

confidence: 99%

Cloning and expression of daunorubicin biosynthesis genes from Streptomyces peucetius and S. peucetius subsp. caesius

1990

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Genes for the biosynthesis of daunorubicin (daunomycin) and doxorubicin (adriamycin), important antitumor drugs, were cloned from Streptomycespeucetius (the daunorubicin producer) and S. peucetius subsp. caesius (the doxorubicin producer) by use of the actIltemla and actII polyketide synthase gene probes. Restriction Daunorubicin (daunomycin) and doxorubicin (adriamycin) are commercially important antibiotics with potent antitumor activity. Daunorubicin, first isolated in 1963 from Streptomyces peucetius (6, 7), was subsequently found in a number of other Streptomyces spp. (27). Doxorubicin was isolated in 1969 from S. peucetius subsp. caesius, a mutant of the wild-type strain (2), and has important clinical applications in cancer chemotherapy (1), even though both doxorubicin and daunorubicin cause cardiotoxic side effects that are dose limiting and irreversible. The production costs of these antibiotics are high because of low titers and formation of a complex mixture of products by the producing bacteria. Therefore, a genetic study of the biosynthesis of daunorubicin and doxorubicin was undertaken in our laboratory to elucidate the organization and regulation of the biosynthetic genes, with the hope that it may also lead to overproducing strains or strains with a simpler spectrum of secondary metabolites. This work has been facilitated by the recognition that the early genes involved in polyketide biosynthesis by other streptomycetes, such as the S. coelicolor actI and actIlI genes (9, 17) and the S. glaucescens tcmIa genes (20), hybridize to the analogous genes in other polyketide producers (16) and by the fact that antibiotic genes have been found to be clustered in all of the examples studied (14).A previous report (24) from this laboratory demonstrated that the daunorubicin producer S. peucetius (ATCC 29050) contains five nonoverlapping regions of DNA that hybridized to the actIl/tcmIa or actIII probe. The properties of S. peucetius and S. lividans strains transformed with clones from four of these regions supported the belief that many of the daunorubicin production (dnr) genes resided in region IV but also raised the possibility that bona fide dnr genes or genes that influence daunorubicin production and self-resistance were present in the three other regions (24). The latter idea is best tested by examining the effects of deletions in * Corresponding author.each of these four regions on daunorubicin production and resistance.Since our preliminary evidence (24) indicated that some portion of region II had been deleted from S. peucetius subsp. caesius (ATCC 27952), we made a detailed study of the properties of cosmid clones from three nonoverlapping regions of DNA in this strain. The effects of these clones and additional clones from the wild-type 29050 strain in homologous and heterologous hosts confirm that the genes required for formation of e-rhodomycinone, a key intermediate of daunorubicin biosynthesis, are present in region IV. In addition, we demonstrated that this region contains two daunorubi...

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“…Studies of the Streptomyces genes involved in the biosynthesis of daunorubicin (daunomycin) and doxorubicin (adriamycin), the two most widely employed agents in antitumor therapy, can be useful to produce specific intermediates for subsequent biotransformation into new analogs (3,5,11,17,21,24). Furthermore, a better understanding of the mechanism conferring resistance to the drugs in the producing organism may lead to the construction of improved strains.…”

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confidence: 99%

Expression of doxorubicin-daunorubicin resistance genes in different anthracycline-producing mutants of Streptomyces peucetius

Colombo¹,

Solinas²,

Perini³

et al. 1992

J Bacteriol

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Two DNA fragments, ric1 and ric2, were isolated from the Streptomyces peucetius 7600 mutant, which produces daunorubicin and doxorubicin, on the basis of their abilities to confer doxorubicin and daunorubicin resistance to Streptomyces lividans. These two fragments are unrelated by restriction mapping and do not show any homology by Southern analysis, yet both of them increase the level of resistance 10-fold in transformed S. lividans. Functional analysis revealed that ric1 also contains two genes of daunorubicin biosynthesis: one coding for the aklavinone C-11 hydroxylase and the other corresponding to the putative dnrR2 regulatory gene of wild-type S. peucetius ATCC 29050 (K. J. Stutzman-Engwall, S. L. Otten, and C. R. Hutchinson, J. Bacteriol. 174:144-154, 1992). Northern (RNA) blot experiments, performed with a ric1 fragment containing daunorubicin-doxorubicin resistance gene(s), revealed a transcript of about 2,100 nucleotides that is present only during the phase of anthracycline metabolite production. The amount of this transcript is higher in strain 7600 than in strain 7900, a mutant which produces 5-fold more daunorubicin and 10-fold less doxorubicin than 7600. Furthermore, two 7900-derived blocked mutants, 8600 and 9700, do not express the 2,100-nucleotide transcript in spite of the absence of gross rearrangements in the ric1 region such as occur with the 7900 parental strain.

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Preparation and biological evaluation of 4-O-demethyldaunorubicin (carminomycin I) and of its 13-dihydro derivative.

Cited by 36 publications

References 5 publications

Structures of novel anthracycline antitumor antibiotics from Micromonospora peucetica

Structures of novel anthracycline antitumor antibiotics from Micromonospora peucetica

Cloning and expression of daunorubicin biosynthesis genes from Streptomyces peucetius and S. peucetius subsp. caesius

Expression of doxorubicin-daunorubicin resistance genes in different anthracycline-producing mutants of Streptomyces peucetius

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