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一种不对称的C8/C8'-三吡咯连接的序列选择性吡咯并[2,1-c][1,4]苯并二氮杂卓（PBD）二聚体DNA链间交联剂，跨度为11个DNA碱基对。

An asymmetric C8/C8'-tripyrrole-linked sequence-selective pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer DNA interstrand cross-linking agent spanning 11 DNA base pairs.

作者信息

Tiberghien Arnaud C, Evans David A, Kiakos Konstantinos, Martin Christopher R H, Hartley John A, Thurston David E, Howard Philip W

机构信息

Spirogen Ltd, 29/39 Brunswick Square, London WC1N 1AX, UK.

出版信息

Bioorg Med Chem Lett. 2008 Mar 15;18(6):2073-7. doi: 10.1016/j.bmcl.2008.01.096. Epub 2008 Jan 30.

DOI:10.1016/j.bmcl.2008.01.096
PMID:18272367
Abstract

A novel sequence-selective extended PBD dimer 4 has been synthesized that binds with high affinity to an interstrand cross-linking site spanning 11 DNA base pairs. Despite its molecular weight (984.07) and length, the molecule has significant DNA interstrand cross-linking potency (approximately 100-fold greater than the clinically used agent melphalan) and sub-micromolar cytotoxicity in a number of tumour cell lines, suggesting that it readily penetrates cellular and nuclear membranes to reach its DNA target.

摘要

已合成一种新型的序列选择性扩展型PBD二聚体4，它能与跨越11个DNA碱基对的链间交联位点高亲和力结合。尽管该分子分子量为984.07且长度较长，但它在许多肿瘤细胞系中具有显著的DNA链间交联活性（比临床使用的药物美法仑大约高100倍）和亚微摩尔级的细胞毒性，这表明它能轻易穿透细胞膜和核膜以到达其DNA靶点。

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