title: Plant antitumor agents. 29. Synthesis and biological activity of ring D and ring E modified analogues of camptothecin.
abstract: The total synthesis of the pentacyclic camptothecin analogues 3 and 4 in 11 steps from p-tolualdehyde is described. The overall shape of compound 3 is the same as that of potent, naturally occurring camptothecin (1a). Despite the near spatial identity of 3 and 1b (racemic, (20RS)-camptothecin) from a three-dimensional standpoint, the 9KB and 9PS cytotoxicity assays indicate at least a 40-60-fold decrease in activity of 3 compared to that of 1b, and the isomer 4 was inactive. Similarly, studies of the inhibition of topoisomerase I activity indicated only slight activity for 3 and no activity for 4. It is evident that the pyridone ring D is essential for antitumor activity. Three E ring modified analogues of camptothecin, 2d-f, are described in which the net change is replacement of O by N in ring E. Compared to (20S)-camptothecin (1a) or (20RS)-camptothecin (1b), the ring E modified analogues 2d-f display little or no cytotoxic activity, greatly reduced effect on the inhibition of topoisomerase I, and total loss of life prolongation in the in vivo L-1210 mouse leukemia assay, indicative of the highly restricted structural and electronic requirements of ring E for biological activity in camptothecin.
authors.affiliation: Research Triangle Institute, Research Triangle Park, North Carolina 27709.
authors.forename: A W
authors.initials: AW
authors.lastname: Nicholas
authors.forename: M C
authors.initials: MC
authors.lastname: Wani
authors.forename: G
authors.initials: G
authors.lastname: Manikumar
authors.forename: M E
authors.initials: ME
authors.lastname: Wall
authors.forename: K W
authors.initials: KW
authors.lastname: Kohn
authors.forename: Y
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
chemical_list: D059004:Topoisomerase I Inhibitors; D002166:Camptothecin