INTERCONVERSION AND STABILITY OF DUOCARMYCINS, A NEW FAMILY OF ANTITUMOR ANTIBIOTICS - CORRELATION TO THEIR CYTOTOXIC AND ANTIMICROBIAL ACTIVITIES IN-VITRO

Stability and interconversion of duocarmycins were studied in relation to their cytotoxicities and antimicrobial activities. The compounds s tudied included duocarmycin A and SA, which have a spirocyclopropylhex adienone moiety, and four halogenated seco-compounds of duocarmycin A: duocarmycin BI, B2, C1 and C2, from which the cyclopropane ring struc ture is absent. Duocarmycins were potent cytotoxic compounds to cells. The cytotoxic activity seen on Balb 3T3/H-ras cells after 72 h drug e xposure was in the following order (IC50 (nM): concentration for 50% g rowth inhibition); SA (0.05) > A (0.3) > B2 (1.5) > B1 (3.0) > C2 (20) > C1 (40). Average minimum inhibitory concentrations (MICs) of duocar mycins against microorganisms showed essentially the same ranking orde r as that of cytotoxicity. There was a large difference between SA and A in their stability in aqueous solvents. For halogenated seco-compou nds, a good correlation was found between their cytotoxicities in vitr o and their conversion rate to duocarmycin A, suggesting that halogena ted seco-compounds undergo closure to the spirocyclopropylhexadienone structure, the pertinent active form, in cells.