The synthesis of camptothecin (CPT) analogs targeted against topoisomerase I is proposed. The rationale stems from several recent observations. These studies have shown: a) a significant increase of topo-I enzyme in human colon cancer cells during disease progression, b) evidence that the enzyme is an exquisite target for CPT and its analogs, and c) an unprecedented efficacy of several analogs against human colon, liver, and lung cancer xenografts. Although much of the previous data found in the course of this cooperative study stems from the utilization of racemic 20 (RS) CPT analogs, it is intended in this proposal to concentrate on the preparation of the pure enantiomer 20(S) CPT analogs. The compounds proposed for synthesis in our Program include the 20(S) analogs of 9-amino- 10, 11-methylenedioxy-CPT and certain easily hydrolyzable water soluble pro-drugs prepared from these compounds. Fore details, see Sections C and D. Specifically, we propose: 1) to synthesize the above CPT analogs in the pure nonracemic 20(S) form for both topoisomerase I and various other in vitro and in vivo studies by the other members of this consortium, 2) to conduct research on improved procedures for the preparation of 20(S) CPT analogs, 3) to conduct research on the preparation of water soluble analogs for which there is reasonable evidence that rapid hydrolysis to the parent drug will occur in plasma. particular emphasis will be placed on the 9- amino and 10,11-methylenedioxy-CPT analogs in water soluble form as 20(S) enantiomers, 4) in conjunction with Program 2, to conduct research on the preparation of new CPT analogs which may either increase the half life of the cleavable DNA-topo I-CPT complex or provide higher stability of the E(lactone) ring and more efficient inhibition of topo I, 5) to study the preparation of new, active CPT analogs with substituents at the 9 or 10,11- positions, 6) to conduct molecular modelling studies on CPT and its major analogs with emphasis on electron density patterns, 7) to conduct research on the preparation of 3H and 14C labelled 20(S) CPT analogs, 8) to conduct research on the in vitro and in vivo metabolism of CPT and major analogs, and to isolate and obtain the structure of major metabolites.
Showing the most recent 10 out of 17 publications
