444564-97-0Relevant articles and documents
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
Milbank, Jared B. J.,Stevenson, Ralph J.,Ware, David C.,Chang, John Y. C.,Tercel, Moana,Ahn, G.-One,Wilson, William R.,Denny, William A.
experimental part, p. 6822 - 6834 (2010/04/28)
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 [Co2(Me2dtc) 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 μmol/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. 2009 American Chemical Society.
