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

Antonow, D., Jenkins, T.C., Howard, P.W. and Thurston, D.E. (2007) 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. Bioorganic & Medicinal Chemistry Letters, 15 (8). pp. 3041-3053. 10.1016/j.bmc.2007.01.054.

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DOI: 10.1016/j.bmc.2007.01.054

Abstract

A 23-member C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione (PBD dilactam) library has been synthesized using Suzuki coupling, and the effect of base upon racemisation 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 introductin 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).

Item Type:Article
Uncontrolled Keywords:Antitumour agents; Dilactams; PBD; Racemisation; Suzuki coupling
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Department of Pharmaceutical and Biological Chemistry
ID Code:2900
Journal or Publication Title:Bioorganic & Medicinal Chemistry Letters
Deposited By:Library Staff
Deposited On:02 Mar 2012 17:54
Last Modified:02 Mar 2012 17:54

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