PRODRUG ANALOGS OF THE ANTI-TUMOR ALKALOID CAMPTOTHECIN

Two classes of (+)-camptothecin (1) derivatives are prepared by acylation of camptothecin-21-isopropylamide (5a). The 17-acetyl (5b) 17-hexanoyl (5c), and 17-acryloyl (5d) derivatives represent lipophilic substances with the potential for reconversion to 1 in vivo. A 17-pyrrolidinyl derivative 5e is prepared from 5b by a nucleophilic substitution reaction and represents a hydrophilic derivative of 1, which may not be able to be converted to 1 in vivo. It is reported also that 5b undergoes C-17 substitution by other nucleophiles (isopropylamine, imidazole, cyanide, and ethanethiol). The ester amide derivatives 5b-d are shown to have an antitumor activity in vivo (L1210, P388) less than 1 or its sodium salt 2a, and the amine amide derivative 5e is shown to be inactive in these assay systems. Both 5b and 5c exhibit apparent activity in vivo in the Lewis lung LL32 antitumor assay but no activity in the melanocytic melanoma B-16 assay. All of these derivatives have low or moderate in vitro biological activity (9KB, L1210, P388) relative to 1. In one preliminary in vitro assay, 5c appeared to be nearly as active as 2a in causing the fragmentation of DNA and inhibiting thymidine's incorporation into DNA in intact HeLa cells. Consequently, the intact α-hydroxy-5-lactone ring of 1 may not be absolutely necessary for antitumor activity. © 1979, American Chemical Society. All rights reserved.