Syntheses and biological activities of rebeccamycin analogues. Introduction of a halogenoacetyl substituent

In the course of structure-activity relationships on rebeccamycin analogues , a series of compounds bearing a halogenoacetyl substituent were synthesiz ed with the expectation of increasing the interaction with DNA, possibly vi a covalent reaction with the double helix. Two rebeccamycin analogues beari ng an acetyl instead of a bromoacetyl substituent were prepared to gain an insight into the role of the halogen atom. The new compounds show very litt le effect on protein kinase C and no covalent reaction with DNA was detecte d. However, the drugs behave as typical topoisomerase I poisons, and they a re significantly more toxic toward P388 leukemia cells than to P388/CPT5 ce lls resistant to camptothecin. The introduction of a bromo- or chloro-acety l substituent does not affect the capacity of the drug to interfere with to poisomerase I either in vitro or in cells. One of the bromoacetyl derivativ es, compound 8, is the most cytotoxic rebeccamycin derivative among the hun dred of derivatives we have synthesized to date. In addition, we determined the antimicrobial activities against two Grampositive bacteria, Bacillus c ereus and Streptomyces chartreusis, and against the Gram-negative bacterium Escherichia coli. The effect of the drugs on Candida albicans yeast growth and their anti-HTV-1 activities were also measured.