- The solvolysis of topotecan in alcohols and acetic anhydride
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Six derivatives of 10-hydroxycamptothecin were prepared via solvolysis of topotecan in corresponding alcohols and acetic anhydride. We attributed the specific reactivity of topotecan to the internal hydrogen-bonding between 10-hydroxy and the nitrogen atom in position 9. As a result the reaction underwent through an intermediate ortho-quionomethlide species to reach equilibrium. Bioactivity screening data showed all products could potentially inhibit the proliferation of several cancer cell lines in vitro and a bigger size group in 9-position would be favorable for the anti-tumor activities observably.
- Li, Jiajun,Wang, Guolin,Dong, Mengjie,Zhang, Qian
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scheme or table
p. 2324 - 2326
(2011/06/17)
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- Synthesis of water-soluble (aminoalkyl)camptothecin analogues: Inhibition of topoisomerase I and antitumor activity
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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.
- Kingsburgy,Boehm,Jakas,Holden,Hecht,Gallagher,Caranfa,McCabe,Faucette,Johnson,Hertzberg
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