Synthesis of a novel C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione library:: Effect of C2-aryl substitution on cytotoxicity and non-covalent DNA binding

被引：31

作者：

Antonow, Dyeison

Jenkins, Terence C.

Howard, Philip W.

Thurston, David E.

机构：

[1] Univ London, Sch Pharm, Canc Res UK Gene Targeted Drug Design Res Grp, London WC1N 1AX, England

[2] Morvus Technol Ltd, Salisbury SP4 0JQ, Wilts, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2007年 / 15卷 / 08期

基金：

英国工程与自然科学研究理事会;

关键词：

PBD; dilactams; Suzuki coupling; racemisation; antitumour agents;

D O I：

10.1016/j.bmc.2007.01.054

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A 23-member C2-aryl pyrrolo[2, 1-c][ 1,4]benzodiazepine-5,1 1-dione (PBD dilactam) library has been synthesized using Suzuki coupling, and the effect of base upon racernisation at the C11a-position during the cross-coupling reaction studied. Three library members (21, 30 and 33) were sufficiently cytotoxic in the NCI's preliminary screen to warrant further evaluation, and one (30, R = p-Br) was found to be cytotoxic at the sub-micromolar level in the A498 renal cancer cell line. DNA thermal denaturation studies suggested that this activity may be associated with non-covalent DNA interaction, and also demonstrated that introduction of C2-C3 unsaturation and addition of C2-aryl functionalities to the PBD dilactam skeleton significantly enhanced helix stabilisation compared to the unsubstituted PBD dilactam (6). (c) 2007 Elsevier Ltd. All rights reserved.

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页码：3041 / 3053

页数：13

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