Synthesis and Antitumor Activity of Camptothecin Analogues

Abstract

Several compounds related to the antitumor alkaloid camptothecin (CPT), a known inhibitor of mammalian topoisomerase I, have been synthesized by total synthesis and evaluated for in vitro cytotoxic activity and in vivo antileukemic activity against P 388 mouse leukemia. Modifications of the A, B, C, and E rings of CPT were carried out to investigate new derivatives with potent antitumor activity, but almost all of these compounds proved to be less active than the parent compound in vitro. Interestingly, 20-amino-CPT showed strong antitumor activity in in vivo assays, because the structure-activity relationship studies revealed that the α-hydroxy lactone ring of CPT is critical for antitumor activity. On the basis of these studies, we also found some important new hexacyclic CPT derivatives, which showed marked antitumor activities both in vitro and in vivo. © 1991, The Society of Synthetic Organic Chemistry, Japan. All rights reserved.