Plant antitumor agents. 29. Synthesis and biological activity of ring D and ring E modified analogues of camptothecin
Nicholas, A., Wani, M., Manikumar, G., Wall, M., Kohn, K. W., & Pommier, Y. (1990). Plant antitumor agents. 29. Synthesis and biological activity of ring D and ring E modified analogues of camptothecin. Journal of Medicinal Chemistry, 33(3), 972-978.
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