Ferrocenyl Quinone Methide–Thiol Adducts as New Antiproliferative Agents: Synthesis,Metabolic Formation from Ferrociphenols,and Oxidative Transformation |
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| Authors: | Dr Yong Wang Dr Marie‐Aude Richard Dr Siden Top Dr Patrick M Dansette Dr Pascal Pigeon Dr Anne Vessières Dr Daniel Mansuy Prof Gérard Jaouen |
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| Institution: | 1. Sorbonne Universités, UPMC Univ Paris 06, Paris, France;2. PSL, Chimie ParisTech, Paris, France;3. Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université Paris Descartes, PRES Paris Cité Sorbonne, Paris Cedex 06, France |
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| Abstract: | Ferrociphenols ( FCs ) and their oxidized, electrophilic quinone methide metabolites ( FC‐QMs ) are organometallic compounds related to tamoxifen that exhibit strong antiproliferative properties. To evaluate the reactivity of FC‐QMs toward cellular nucleophiles, we studied their reaction with selected thiols. A series of new compounds resulting from the addition of these nucleophiles, the FC‐SR adducts, were thus synthesized and completely characterized. Such conjugates are formed upon metabolism of FCs by liver microsomes in the presence of NADPH and thiols. Some of the FC‐SR adducts exhibit antiproliferative properties comparable to those of their FC precursors. Under oxidizing conditions they either revert to their FC‐QM precursors or transform into new quinone methides (QMs) containing the SR moiety, FC‐SR‐QM . These results provide interesting data about the reactivity and mechanism of antiproliferative effects of FCs , and also open the way to a new series of organometallic antitumor compounds. |
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| Keywords: | antitumor agents glutathione liver microsomes Michael addition organometallic compounds |
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