Synthesis and Evaluation of Stable Bidentate Transition Metal Complexes of 1-(Chloromethyl)-5-hydroxy-3-(5,6,7-trimethoxyindol-2-ylcarbonyl)-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline (seco-6-azaCBI-TMI) as Hypoxia Selective Cytotoxins
SCIE
SCOPUS
- Title
- Synthesis and Evaluation of Stable Bidentate Transition Metal Complexes of 1-(Chloromethyl)-5-hydroxy-3-(5,6,7-trimethoxyindol-2-ylcarbonyl)-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline (seco-6-azaCBI-TMI) as Hypoxia Selective Cytotoxins
- Authors
- Milbank, JBJ; Stevenson, RJ; Ware, DC; Chang, JYC; Tercel, M; Ahn, GO; Wilson, WR; Denny, WA
- Date Issued
- 2009-11-12
- Publisher
- American Chemical Society
- Abstract
- A series of metal complexes were prepared as potential prodrugs of the extremely toxic DNA minor groove alkylator 1-(chloromethyl)-5-hydroxy-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline (seco-6-azaCBI-TMI) and close analogues. The pyrrolo[3,2-f]quinoline cytotoxins were prepared from 2-methoxy-4-nitroaniline in a nine-step synthesis involving a Skraup construction of a quinoline intermediate, its appropriate functionalization, and a final radical cyclization. The metal complexes were prepared from these and the labile metal complex synthons [Co-(cyclen)(OTf)(2)](+), [Cr(acac)(2)(H2O)(2)](+,) and [Co-2(Me(2)dtc)(5)](+). The cobalt complexes were considerably more stable than the free effectors and showed significant attenuation of the cytotoxicity of the latter, with IC50 ratios (complex/effector) of 50- to 150-fold, and substantial hypoxic cell selectivity, with IC50 ratios (oxic/hypoxic cells) of 20- to 40-fold. The cobalt complexes were also efficiently activated by ionizing radiation, with G values for loss of the compound close to the theoretical value for one-electron reduction of 0.68 mu mol/J. This work extends earlier observations that cobalt cyclen complexes are suitable for both the bioreductive and radiolytic release of potent pyrrolo[3,2-f]quinoline effectors.
- Keywords
- RADIATION-ACTIVATED PRODRUGS; GROOVE ALKYLATING-AGENTS; EXPLOITING TUMOR HYPOXIA; N-O BONDS; COBALT(III) COMPLEXES; REDUCTIVE CLEAVAGE; ANTICANCER DRUGS; CBI-TMI; DUOCARMYCINS; MUSTARDS
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/16887
- DOI
- 10.1021/JM9008746
- ISSN
- 0022-2623
- Article Type
- Article
- Citation
- JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, no. 21, page. 6822 - 6834, 2009-11-12
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