Section 8
Chapter 7,660

Plant antitumor agents. 29. Synthesis and biological activity of ring D and ring e modified analogues of camptothecin

Nicholas, A.W.; Wani, M.C.; Manikumar, G.; Wall, M.E.; Kohn, K.W.; Pommier, Y.

Journal of Medicinal Chemistry 33(3): 972-978


ISSN/ISBN: 0022-2623
PMID: 2155323
DOI: 10.1021/jm00165a014
Accession: 007659697

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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.

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