Design, Synthesis, and Biophysical and Biological Evaluation of a Series of Pyrrolobenzodiazepine-Poly(N-methylpyrrole) Conjugates

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• 作者：Geoff Wells ; Christopher R. H. Martin ; Philip W. Howard ; Zara A. Sands ; Charles A. Laughton ; Arnaud Tiberghien ; Chi Kit Woo ; Luke A. Masterson ; Marissa J. Stephenson ; John A. Hartley ; Terence C. Jenki
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：September 7, 2006
• 年：2006
• 卷：49
• 期：18
• 页码：5442 - 5461
• 全文大小：1136K
• 年卷期：v.49,no.18(September 7, 2006)
• ISSN：1520-4804

文摘

A novel series of methyl ester-terminated C8-linked pyrrolobenzodiazepine (PBD)-poly(N-methylpyrrole)conjugates (50a-f) has been synthesized and their DNA interaction evaluated by thermal denaturation,DNA footprinting, and in vitro transcription stop assays. The synergistic effect of attaching a PBD unit toa polypyrrole fragment is illustrated by the large increase in DNA binding affinity (up to 50-fold) comparedto the individual PBD and pyrrole components. 50a-f were found to bind mainly to identical DNA sequencesbut with apparent binding site widths increasing with molecular length and the majority of sites conformingto the consensus motif 5'-XGXW_z (z = 3 ± 1; W = A or T; X = any base but preferably a purine). Theyalso provided robust sequence-selective blockade of transcription at sites corresponding approximately totheir DNA footprints. 50a-f were shown to have good cellular/nuclear penetration properties, and a degreeof correlation between cytotoxicity and DNA-binding affinity was observed.