Cross-Bridged Cyclen or Cyclam Co(III) Complexes Containing Cytotoxic Ligands as Hypoxia-Activated Prodrugs
| Autor: | 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 |
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| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Ethylene Stereochemistry chemistry.chemical_element Antineoplastic Agents Crystallography X-Ray Cyclams Ligands Electrochemistry Inorganic Chemistry Mice chemistry.chemical_compound Cyclen Coordination Complexes Heterocyclic Compounds Cell Line Tumor Neoplasms Cyclam Animals Humans Prodrugs Physical and Theoretical Chemistry Cytotoxicity Ligand Cobalt Cell Hypoxia chemistry Selectivity |
| Zdroj: | Inorganic Chemistry. 52:7688-7698 |
| ISSN: | 1520-510X 0020-1669 |
| DOI: | 10.1021/ic4006967 |
| Popis: | 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'-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 81-212-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. |
| Databáze: | OpenAIRE |
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