Optimization of the Antitumor Activity of Sequence-specific Pyrrolobenzodiazepine Derivatives Based on their Affinity for ABC Transporters

Kaliszczak, M., Antonow, D., Patel, Katan I., Howard, P., Jodrell, D.I., Thurston, D.E. and Guichard, S.M. (2010) Optimization of the Antitumor Activity of Sequence-specific Pyrrolobenzodiazepine Derivatives Based on their Affinity for ABC Transporters. The AAPS Journal, 12 (4). pp. 617-627. doi:10.1208/s12248-010-9225-x.

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DOI: doi:10.1208/s12248-010-9225-x

Abstract

Pyrrolobenzodiazepine (PBD) derivatives are highly potent sequence-specific DNA cross-linking agents. The present study aimed to identify key physicochemical properties influencing the interaction of a series of PBDs (four dimers and 12 monomers) with the three major human ATP-binding cassette (ABC) transporters (P-gp, ABCG2, and MRP1). Isogenic cell lines expressing P-gp and ABCG2, cell lines with acquired resistance to cytotoxic agents due to the high expression of ABC transporters, and specific inhibitors against P-gp, ABCG2, and MRP1 were used. P-gp and ABCG2 decreased the permeability of the PBD dimers across cell membranes and their interaction with DNA, reducing DNA damage and the overall cytotoxic effect. PBD monomer SG-2823 formed a conjugate with glutathione and interacted with MRP1, reducing its cytotoxic effect in A549 cells. Structure–activity relationship revealed that the interaction of PBDs with the transporters could be predicted considering the molecular weight, the lipophilicity, the number of (N + O) atoms and aromatic rings, the polar surface area, the hydrogen bonding energy, and electrophilic centers. A rational design of novel PBDs with increased potency and reduced interaction with the ABC transporters is proposed.

Item Type:Article
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Department of Pharmaceutical and Biological Chemistry
ID Code:1885
Journal or Publication Title:The AAPS Journal
Deposited By:Library Staff
Deposited On:10 Mar 2011 11:47
Last Modified:10 Mar 2011 11:47

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