Synthesis, Cytotoxicity, and COMPARE Analysis of Ferrocene and [3]Ferrocenophane Tetrasubstituted Olefin Derivatives against Human Cancer Cells

• Published in: ChemMedChem 2010-12, Vol.5 (12), p.2039-2050
• Main Authors: Görmen, Meral, Pigeon, Pascal, Top, Siden, Hillard, Elizabeth A., Huché, Michel, Hartinger, Christian G., de Montigny, Frédéric, Plamont, Marie-Aude, Vessières, Anne, Jaouen, Gérard
• Format: Article
• Language: English
• Subjects: Alkenes - chemistry; Alkenes - therapeutic use; Alkenes - toxicity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - therapeutic use; Antineoplastic Agents - toxicity; bioorganometallic chemistry; Cancer; cell culture; Cell Line, Tumor; Chemical Sciences; Cheminformatics; Crystallography, X-Ray; cytotoxicity; drug discovery; Drug Screening Assays, Antitumor; ferrocenes; Ferrous Compounds - chemistry; Ferrous Compounds - therapeutic use; Ferrous Compounds - toxicity; Humans; Kinetics; Life Sciences; Metallocenes; Molecular Conformation; Neoplasms - drug therapy; Organic chemistry
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201000286

Herein we report the antiproliferative effects of a series of 28 compounds against the MDA‐MB‐231 breast cancer cell line, including the synthesis of seven new [3]ferrocenophanyl and four new ferrocenyl compounds. For each p‐R‐phenyl substitution pattern investigated, the [3]ferrocenophanyl derivatives were more cytotoxic than the corresponding ferrocenyl derivative, with the highest activity found for compounds with protic substituents. Theoretical calculations of the HOMO–LUMO gap for the molecules in the Fe3+ oxidation state suggest a higher reactivity for the [3]ferrocenophanyl derivatives. A lead compound from each series, a [3]ferrocenophanyl and a ferrocenyl compound, possessing two phenol groups, were screened against the NCI/DTP 60‐cell‐line panel. The mean activity over all cell lines was better than cisplatin for both compounds, and both compounds showed subpanel selectivity for leukemia, CNS cancer, and renal cancer. Low systemic toxicity and lack of interaction with DNA (when in the reduced form), suggest that the compounds may act as prodrugs. A vicious cycle! A 28‐compound structure–activity relationship study of ferrocene derivatives revealed that [3]ferrocenophanes are more cytotoxic than the corresponding ferrocene compounds, with the best IC50 values at approximately 10−8 M. Two leads were further tested against a panel of approximately 60 cell lines.