Synthesis and antitumor activity of 2-deamino- and N2-(gamma-hydroxypropyl)actinomycin D.

2-Deamino- and N2-(gamma-hydroxypropyl)actinomycin D were synthesized by modification of the parent actinomycin D molecule at the 2 position of the phenoxazinone moiety. The common intermediate was 2-deamino-2-chloroactinomycin D. Catalytic hydrogenation of this material afforded the 2-deamino derivative while treatment with gamma-hydroxypropylamine yielded the N2-(gamma-hydroxypropyl) derivative. These 2-substituted actinomycin D derivatives were less potent in microbiological assays than the parent compound. Evaluation of activity in vivo against three murine tumor systems indicated that optimal dose levels of 2-deaminoactinomydin D were 50 times greater than toxic dose levels of actinomycin D. N2-(gamma-hydroxyporpyl)actinomycin D exhibited antitumor activity similar to the parent compound.