123948-88-9Relevant articles and documents
PROCESS FOR PREPARING TOPOTECAN
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Page/Page column title page; 7, (2008/06/13)
A process for preparing topotecan.
Synthesis of water-soluble (aminoalkyl)camptothecin analogues: Inhibition of topoisomerase I and antitumor activity
Kingsburgy,Boehm,Jakas,Holden,Hecht,Gallagher,Caranfa,McCabe,Faucette,Johnson,Hertzberg
, p. 98 - 107 (2007/10/02)
Water-soluble analogues of the antitumor alkaloid camptothecin (1) were prepared in which aminoalkyl groups were introduced into ring A or B. Most of the analogues were prepared by oxidation of camptothecin to 10-hydroxy-camptothecin (2) followed by a Mannich reaction to give N-substituted 9-(aminomethyl)-10-hydroxycamptothecins (4-12) or by subsequent modification of Mannich product 4 (13, 15, 17, 19, 21). Others were obtained by modification of the hydroxyl group of 2 (25, 26) or by total synthesis (35, 42, 43). These analogues, as well as some of their synthetic precursors, were evaluated for inhibition of topoisomerase I, cytotoxicity, and antitumor activity. Although there was not a quantitative correlation between these assays, compounds that inhibited topoisomerase I were also cytotoxic and demonstrated antitumor activity in vivo. Further evaluation of the most active water-soluble analogue led to the selection of 9-[(dimethylamino)methyl]-10-hydroxycamptothecin (4, SK and F 104864) for development as an antitumor agent. In addition to its water solubility, ease of synthesis from natural camptothecin, and high potency, 4 demonstrated broad-spectrum activity in preclinical tumor models and is currently undergoing Phase I clinical trials in cancer patients.
