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 (se

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• 作者：Jared B. J. Milbank ; Ralph J. Stevenson ; David C. Ware ; John Y. C. Chang ; Moana Tercel ; G-One Ahn ; William R. Wilson ; William A. Denny
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：November 12, 2009
• 年：2009
• 卷：52
• 期：21
• 页码：6822-6834
• 全文大小：1070K
• 年卷期：v.52,no.21(November 12, 2009)
• ISSN：1520-4804

文摘

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.