Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity

S. Dallavalle, A. Ferrari, B. Biasotti, L. Merlini, S. Penco, G. Gallo, M. Marzi, M. O. Tinti, R. Martinelli, C. Pisano, P. Carminati, N. Carenini, G. Beretta, P. Perego, M. De Cesare, G. Pratesi, F. Zunino

Research output: Contribution to journalArticle

Abstract

In an attempt to synthesize potential anticancer agents acting by inhibition of topoisomerase I (Topo I) a new series of oxyiminomethyl derivatives in position 7 of camptothecin (CPT) was prepared. The synthesis relied on the condensation of 20S-CPT-7-aldehyde or 20S-CPT-7-ketones with alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl O-substituted hydroxylamines. The compounds were tested for their cytotoxic activity in vitro against H460 non-small lung carcinoma cell line, the activity being for 24 out of 37 compounds in the 0.01-0.3 μM range. A QSAR analysis indicated that lipophilicity is the main parameter correlated with cytotoxicity. Investigation of the DNA - Topo I - drug cleavable complex showed a rough parallelism between cytotoxicity and inhibition of Topo I. Persistence of the DNA cleavage after NaCl-mediated disruption of the ternary complex suggests that for the most potent compounds, e.g., 15, the cytotoxicity was at least in part related to stabilization of the complex, as also supported by the persistence of the DNA - enzyme complex in drug-treated cells. The in vivo antitumor efficacy of the most potent analogue (15) was evaluated in direct comparison with topotecan using human lung tumor xenograft models. In the range of optimal doses (2-3 mg/kg), the improved efficacy of 15 was documented in terms of inhibition of tumor growth and rate of complete response.

Original languageEnglish
Pages (from-to)3264-3274
Number of pages11
JournalJournal of Medicinal Chemistry
Volume44
Issue number20
DOIs
Publication statusPublished - Sep 27 2001

ASJC Scopus subject areas

  • Organic Chemistry

Fingerprint Dive into the research topics of 'Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity'. Together they form a unique fingerprint.

  • Cite this

    Dallavalle, S., Ferrari, A., Biasotti, B., Merlini, L., Penco, S., Gallo, G., Marzi, M., Tinti, M. O., Martinelli, R., Pisano, C., Carminati, P., Carenini, N., Beretta, G., Perego, P., De Cesare, M., Pratesi, G., & Zunino, F. (2001). Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity. Journal of Medicinal Chemistry, 44(20), 3264-3274. https://doi.org/10.1021/jm0108092