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Optimization of the auxiliary ligand shell of cobalt(III)(8-hydroxyquinoline) complexes as model hypoxia-selective radiation-activated prodrugs SCIE SCOPUS

Title
Optimization of the auxiliary ligand shell of cobalt(III)(8-hydroxyquinoline) complexes as model hypoxia-selective radiation-activated prodrugs
Authors
Ahn, GOWare, DCDenny, WAWilson, WR
Date Issued
2004-09
Publisher
Radiation Research Society
Abstract
A potential approach for activating prodrugs; in hypoxic regions of tumors is to use ionizing radiation, rather than bioreductive enzymes, to effect reduction. This study investigates radiolytic release of 8-hydroxyquinoline (8-HQ), as a model for hydroxyaza-chloromethylbenzindoline DNA minor groove alkylators, from Co(III) complexes under hypoxia. 8-HQ release, measured by HPLC, showed higher efficiency (one-electron stoichiometry) when the auxiliary ligand was a tetraaza-macrocycle [e.g. 1,4,7,10-tetraazacyclododecane (cyclen)] rather than a triazamacrocycle [1,4,7-triazacyclononane (TACN)]. These complexes differ from the bioreductive cobalt complex SN 24771 in that their reduction provides stable cobalt-containing products rather than free (aquated) Co2+. Radiolytic release of 8-HQ from Co(cyclen)(8-HQ) and Co(TACN)(CN)(8-HQ) was also demonstrated in deoxygenated human plasma, selectively in the absence of oxygen, again with higher efficiency for the cyclen system. The cobalt complexes were >1000-fold less potent than free 8-HQ as inhibitors of cell proliferation and were metabolically stable in aerobic and hypoxic cell cultures. Investigation of cell uptake of total cobalt, by inductively coupled plasma mass spectrometry, showed that these complexes enter cells but do not accumulate to the high concentrations seen with SN 24771. The results demonstrate the feasibility of masking the cytotoxicity of hydroxyquinoline-based cytotoxins as Co(III) complexes and demonstrate the utility of cyclen-based auxiliary ligands for optimizing radiolytic activation of these novel prodrugs under hypoxia. (C) 2004 by Radiation Research Society.
Keywords
SQUAMOUS-CELL CARCINOMA; EXPLOITING TUMOR HYPOXIA; COBALT(III) COMPLEXES; BIOREDUCTIVE DRUGS; NITROGEN MUSTARDS; PULSE-RADIOLYSIS; AQUEOUS-SOLUTION; UTERINE CERVIX; SOLID TUMORS; CANCER
URI
https://oasis.postech.ac.kr/handle/2014.oak/16881
DOI
10.1667/RR3229
ISSN
0033-7587
Article Type
Article
Citation
RADIATION RESEARCH, vol. 162, no. 3, page. 315 - 325, 2004-09
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안지완AHN, G ONE
Div of Integrative Biosci & Biotech
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