Synthesis and biological assays of 9-(acylamino) homocamptothecins as DNA topoisomerase I inhibitors

Abstract

In an effort to improve the stability of homocamptothecin and reduce the toxicity, novel homocamptothecin analogs with acylamino groups at C(9) were designed and synthesized. The cytotoxic activities of all the synthetic compounds against three cancer cell lines were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, and irinotecan was used as reference compound. Compound 7c with a piperidinylacetamido group and 10a with phenylacetamido group at C(9) showed potent activities both in vitro and in vivo. In addition, they also revealed remarkable topoisomerase I inhibitions which were exhibited with well-established bonds with amino acid residues Arg364 and Asp533 in the active pocket. On the basis of the biological activities, 7c and 10a would be potential candidates for further studies.

Keywords: Antitumor activity; Cytotoxic activity; Friedländer condensation; Homocamptothecin; Inhibitors; Structureactivity relationship (SAR); Topoisomerase I.