Development of Bimetallic Titanocene−Ruthenium−Arene Complexes As Anticancer Agents: Relationships between Structural and Biological Properties

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• 作者：Frdric Pelletier ; Virginie Comte ; Alexandre Massard ; Margot Wenzel ; Stphanie Toulot ; Philippe Richard ; Michel Picquet ; Pierre Le Gendre ; Olivier Zava ; Fabio Edafe ; Angela Casini ; Paul J. Dyson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：October 14, 2010
• 年：2010
• 卷：53
• 期：19
• 页码：6923-6933
• 全文大小：1005K
• 年卷期：v.53,no.19(October 14, 2010)
• ISSN：1520-4804

文摘

A series of bimetallic titanium−ruthenium complexes of general formula [(η⁵-C₅H₅)(μ-η⁵:κ¹-C₅H₄(CR₂)_nPR′R′′)TiCl₂](η⁶-p-cymene)RuCl₂ (n = 0, 1, 2 or 4; R = H or Me; R′ = H, Ph, or Cy; R′′ = Ph or Cy) have been synthesized, including two novel compounds as well as two cationic derivatives of formula [(η⁵-C₅H₅)(μ-η⁵:κ¹-C₅H₄(CH₂)_nPPh₂)TiCl₂] [(η⁶-p-cymene)RuCl](BF₄) (n = 0 or 2). The solid state structure of two of these compounds was also established by X-ray crystallography. The complexes showed a cytotoxic effect on human ovarian cancer cells and were markedly more active than their Ti or Ru monometallic analogues titanocene dichloride and RAPTA-C, respectively. Studies of cathepsin B inhibition, an enzyme involved in cancer progression, showed that enzyme inhibition by the bimetallic complexes is influenced by the length of the alkyl chain in between the metal centers. Complementary ESI-MS studies provided evidence for binding of a Ru(II) fragment to proteins.