Characterization and chemical structures of new antitumor antibiotics and hybrid anthracyclines produced bystreptomyces

Abstract

The Streptomyces sp. MCH79 was selected from the cytotoxicity assay against tumor cells to search for novel antitumor compound from microbial metabolites. This strain was identified as Streptomyces ostreogriseus on the basis of its cultural, morphological and physiological properties. The active compounds, MCH-14 (40.1 mg), MCH-15 (26.9 mg), MCH-16 (20.1 mg), MCH-17 (91.7 mg), MCH-18 (21.6 mg), MCH-22 (135.2 mg), MCH-31 (52.2 mg), MCH-23 (25.4 mg), MCH-32 (19.6 mg), MCH-Vi (9600 mg) and MCH-Vj (143.4 mg), were recovered from the mycelium of fermentation broth (120ℓ)with acetone extraction followed by purification on a silica gel column chromatography and reverse-phase HPLC chromatography. The structure of MCH compounds were determined by spectroscopic methods of UV, FT-IR, $^1H$-NMR, $^{13}C$-NMR, DEPT, $^1H-^1H$ COSY, $^{13}C-^1H$ COSY, HMBC and FAB-MS as well as physicochemical data such as melting point and optical rotation. Structural studies revealed that there were seven novel oligomycin analogues, 41-demethyl-29 -hydroxy-homooligomycin A, 41-demethyl-oligomycin E, 41-demethyl-44-hydroxy-homooligomycin A, 41-demethyl-homooligomycin E, 41-demethyl-homooligomycin B, homooligomycin E, 41-demethyl-homooligomycin A and four known oligomycins, 44-homooligomycin B, 44-homooligomycin A, oligomycin A, 44-homooligomycin C. The MCH compounds showed selective growth inhibition against cell lines such as RHEK-1 (human epidermal keratinocyte cell line), RHEK-1/pSV2 ras (cell line transformed with $pSV_2$ras), NIH-3T3 (NIH Swiss mouse embryo fibrolast), F25 (oncogene ras transformed NIH-3T3) and human tumor cell lines, SNU-1 (human stomach cancer) and SNU-354 (human liver cancer), with the $IC_{50}$ values range of 0.073-19.0, 0.025-6.50, 1.17-159.75, 0.22-0.75, 0.17-0.63, 0.19-1.05㎍/ml, respectively. The MCH compounds showed stronger cytotoxic effect on RHEK-1/pSVras and F25 than on their parent cells, RHEK-1 and NIH-3T3, indicating that the compounds conferred differe...