Sulfurmycin D

Following the discovery of new anthracycline antibiotics, auramycins A and B and sulfurmycins A and B, we found 10 minor analogues of auramycins and sulfurmycins, C, D, E, F and G, from the culture broth of a mutant strain of Streptomyces galilaeus OBB-111 and prepared 2 analogues as the chemical derivatives from auramycin G and sulfurmycin G. All analogues have a sugar moiety at C-7 position of the aglycones. These analogues exhibit activities against Gram-positive bacteria and P388 leukemia.

Anthracyclines possessing either a 9-alkyl modification in the A-ring of the tetracyclic aglycone and/or specific changes to the amino sugar moiety retain effective cytotoxic activity against multidrug resistant (MDR) cell lines. To obtain a better understanding of the structural features responsible for this potentially valuable behaviour, we used the MTT tetrazolium dye reduction assay to calculate resistance factors (RF = the ratio of ID50 for the drug-resistant line to that for the parental line) for the EMT6/P mouse mammary tumour and its MDR variant EMT6/AR1.0, and the H69/P human small cell lung cancer line and its MDR counterpart H69/LX4. Both MDR lines exhibit marked resistance to doxorubicin, MDR 1 gene amplification, hyperexpression of the membrane P-glycoprotein and reduced drug accumulation. RF values for doxorubicin were 34 and 131 in the EMT6 and H69 cell line pairs, respectively. The 9-alkyl-substituted anthracyclines were confirmed as having RF values 9- to 15-fold lower than those for doxorubicin.