Cross-Bridged Cyclen or Cyclam Co(III) Complexes Containing Cytotoxic Ligands as Hypoxia-Activated Prodrugs

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• 作者：John Yu-Chih Chang ; Guo-Liang Lu ; Ralph J. Stevenson ; Penelope J. Brothers ; George R. Clark ; K. Jane Botting ; Dianne M. Ferry ; Moana Tercel ; William R. Wilson ; William A. Denny ; David C. Ware
• 刊名：Inorganic Chemistry
• 出版年：2013
• 出版时间：July 1, 2013
• 年：2013
• 卷：52
• 期：13
• 页码：7688-7698
• 全文大小：426K
• 年卷期：v.52,no.13(July 1, 2013)
• ISSN：1520-510X

文摘

A series of cobalt(III) complexes of the potent DNA minor groove alkylator (1-(chloromethyl)-5-hydroxy-1H-pyrrolo[3,2-f]quinolin-3(2H)-yl)(5,6,7-trimethoxy-1H-indol-2-yl)methanone (3; seco-CPyI-TMI), with cyclam or cyclen auxiliary ligands (L3 and L5) containing a cross-bridging ethylene (CH₂CH₂) group or the N,N鈥?dimethyl derivatives of these (L4 and L6), was prepared. Two 8-quinolinato (2) model complexes of these, [Co(L3)(2)](ClO₄)₂ and [Co(L6)(2)](ClO₄)₂, and the aquated derivative [Co(L6)(H₂O)₂](OTf)₃ were characterized by X-ray crystallography. Electrochemistry of the 8-quinolinato model complexes showed that the Co(III)/(II) reduction potential was lowered relative to the unsubstituted cyclen ligand. Evaluation of the cytotoxicity of the racemic seco-CPyI cobalt complexes in vitro showed considerable attenuation of their cytotoxicity relative to the free alkylator and marked hypoxic selectivity, especially [Co(L3)(3)]²⁺ (9), which was 81鈥?12-fold more potent under hypoxia than 20% oxygen in a panel of 10 human tumor cell lines. However, 9 did not elicit significant killing of hypoxic cells in HT29 tumor xenografts, suggesting possible pharmacological limitations in vivo.