Development of bimetallic titanocene-ruthenium-arene complexes as anticancer agents: relationships between structural and biological properties.
A series of bimetallic titanium-ruthenium complexes of general formula [(η(5)-C(5)H(5))(μ-η(5):κ(1)-C(5)H(4)(CR(2))(n)PR'R'')TiCl(2)](η(6)-p-cymene)RuCl(2) (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 [(η(5)-C(5)H(5))(μ-η(5):κ(1)-C(5)H(4)(CH(2))(n)PPh(2))TiCl(2)] [(η(6)-p-cymene)RuCl](BF(4)) (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.
Pelletier
Frédéric
F
Institut de Chimie Moléculaire de l'Université de Bourgogne, UMR 5260 CNRS-Université de Bourgogne, 9 Avenue A. Savary, BP 47870, 21078 Dijon, France.
Comte
Virginie
V
Massard
Alexandre
A
Wenzel
Margot
M
Toulot
Stéphanie
S
Richard
Philippe
P
Picquet
Michel
M
Le Gendre
Pierre
P
Zava
Olivier
O
Edafe
Fabio
F
Casini
Angela
A
Dyson
Paul J
PJ
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D002417:Cattle; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D012428:Ruthenium; D013329:Structure-Activity Relationship; D014025:Titanium
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D012428:Ruthenium; D014025:Titanium; D002401:Cathepsin B