DESIGN AND SYNTHESIS OF NATURAL COMPOUNDS ANALOGUES WITH CYTOTOXIC ACTIVITY

This Ph.D. work was carried out as a part of project focusing on the search of new naturally-derived topoisomerase I inhibitors as potential antitumor compounds. Topoisomerase I is the target of anticancer drug campthotecin (CPT). First generation analogues of CPT are already approved as anticancer agents in human therapy, and several second and third generation derivatives are well advanced in clinical trials. Nevertheless, identification of new campthotecins or alternative molecular scaffolds endowed with similar properties is highly desirable because CPT derivatives were shown to be worth of improvement, above all for the unstable -hydroxylactone moiety. First, new CPT derivatives were planned and synthesized, in an effort to decrease the toxicity and improve the E ring stability of the natural alkaloid. The study was undertaken to explore new structural changes at the E ring, while keeping a lactone moiety in this portion of the molecule. Thus, new analogues with an inverted lactone ring were designed and synthesized. The compounds retained a good cytotoxic activity on human non-small cancer cells H460. At the same time, the search of new scaffolds showing topoisomerase I inhibitory activity was developed. Attention focused on a new class of marine alkaloids called lamellarins that have been recently studied as Topo I inhibitors. In this Ph.D. work new lamellarin analogues were designed. Molecular models of the ternary complex formed between the DNA-Topo I ensemble and the new derivatives were built, and allowed to optimize the scaffold structure. Thus the synthesis of a number of new compounds endowed with cytotoxicity in the low micromolar range was accomplished.