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Semisynthesis, Biological Activity, and Molecular Modeling Studies of C-Ring-Modified Camptothecins

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Istituto CNR per la Sintesi Organica e Fotoreattività “I.S.O.F.”, Area della Ricerca di Bologna, Via P. Gobetti 101, 40129 Bologna, Italy, Indena SPA, Viale Ortles 12, 20139 Milano, Italy, Diparitmento di Oncologia Sperimentale e Laboratori, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milano, Italy, and Molecular Modelling Section (MMS), Dipartimento di Scienze Farmaceutiche, Università di Padova, Via Marzolo 5, I-35131 Padova, Italy
†Dedicated to the memory of Dr. Arturo Battaglia. He committed his life to the organic synthesis of biologically active molecules and to teaching his alumni the great importance of chemistry for life.
* To whom correspondence should be addressed. Phone: (+39) 0516398283. Fax: (+39) 051 6398349. E-mail: [email protected]
‡Istituto CNR per la Sintesi Organica e Fotoreattività “I.S.O.F.”.
§Indena SPA.
∥Fondazione IRCCS Istituto Nazionale Tumori.
⊥Università di Padova.
Cite this: J. Med. Chem. 2009, 52, 4, 1029–1039
Publication Date (Web):February 3, 2009
Copyright © 2009 American Chemical Society

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    Abstract Image

    The synthesis, biological activity, and molecular modeling studies of C-ring-modified camptothecins are reported. A general synthetic protocol, based on “C-5 camptothecin (C-5-CPT) enolate chemistry”, allows one to obtain various C5-substituted analogues. All new compounds, obtained as 1:1 epimeric mixtures, were tested for their antiproliferative activity. Experimental data showed that all novel derivatives are less active than the reference compounds and that one of the two epimers is more active than the other. Molecular docking simulations were performed to achieve more insight into the interactions between the new C5-modified CPTs and Topo I. A good correlation was observed when the data of cytotoxicity and the values calculated for the free binding energy were combined.

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    Elemental analysis data for all new and enantiomeric pure compounds. This material is available free of charge via the Internet at

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