Dinuclear Pt(II)-bisphosphonate complexes: a scaffold for multinuclear or different oxidation state platinum drugs.
Geminal bisphosphonates (BPs), used in the clinic for the treatment of hypercalcaemia and skeletal metastases, have been also exploited for promoting the specific accumulation of platinum antitumor drugs in bone tissue. In this work, the platinum dinuclear complex [{Pt(en)}(2)(μ-AHBP-H(2))](+) (1) (the carbon atom bridging the two phosphorous atoms carrying a 2-ammonioethyl and a hydroxyl group, AHBP-H(2)) has been used as scaffold for the synthesis of a Pt(II) trinuclear complex, [{Pt(en)}(3)(μ-AHBP)](+) (2), and a Pt(IV) adamantane-shaped dinuclear complex featuring an oxo-bridge, [{Pt(IV)(en)Cl}(2)(μ-O)(μ-AHBP-H(2))](+) (3) (X-ray structure). Compound 2 undergoes a reversible, pH dependent, rearrangement with a neat switch point around pH = 5.4. Compound 3 undergoes a one-step electrochemical reduction at E(pc) = -0.84 V affording compound 1. Such a potential is far lower than that of glutathione (-0.24 V), nevertheless compound 3 can undergo chemical reduction to 1 by GSH, most probably through a different (inner-sphere) mechanism. In vitro cytotoxicity of the new compounds, tested against murine glioma (C6) and human cervix (HeLa) and hepatoma (HepG2) cell lines, has shown that, while the Pt(IV) dimer 3 is inactive up to a concentration of 50 μM, the two Pt(II) polynuclear compounds 1 and 2 have a cytotoxicity comparable to that of cisplatin with the trinuclear complex 2 generally more active than the dinuclear complex 1.
Dipartimento Farmaco-Chimico, Università degli Studi di Bari, Via E. Orabona 4, 70125 Bari, Italy.
Sara
S
Piccinonna
Nicola
N
Margiotta
Concetta
C
Pacifico
Antonio
A
Lopalco
Nunzio
N
Denora
Serena
S
Fedi
Maddalena
M
Corsini
Giovanni
G
Natile
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004164:Diphosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D010084:Oxidation-Reduction; D010984:Platinum / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D004164:Diphosphonates; D010984:Platinum