Studies related to antitumor antibiotics: X. Reactions of maytansine and its analogs with DNA in vitro

Abstract

The antileukemic agent maytansine and certain synthetic carbinolamide analogs which also show antineoplastic activity rapidly alkylate nucleic acids in a reaction which is promoted by acidic conditions. Alkylation is evidenced by the heat-induced strand scission of alkylated covalently closed circular DNA detected by ethidium fluorescence assay. Alkylation of poly ( d[ 14C]G) · poly( d[ 3H]C) by carbinolamide at 37°C is accompanied by neither depurination nor depyrimidation. The reaction of maytansine with DNA is interpreted as acid-induced dehydration of the carbinolamide moiety to an azomethie lactone and subsequent attack on this species by nucleophiles on the bases of DNA. The observed lack of reactivity and the low alkylating ability of two different analogs, both of which undergo dehydration very slowly, and a third analog, where loss of the alcohol is resisted, are in accord with this interpretation and the known loss of antileukemic activity of maytansine upon conversion to the 9-ether derivative. Certain carbinolamides at a concentration of 9 × 10 −5 M have no effect on the rate of Escherichia coli DNA polymerase I catalyzed synthesis of duplex DNA on denatured calf thymus DNA template.