Design, synthesis, and evaluation of mixed imine-amine pyrrolobenzodiazepine dimers with efficient DNA binding affinity and potent cytotoxicity

Abstract

Synthesis of mixed imine-amine pyrrolobenzodiazepine (PBD) dimers that are comprised of DC-81 and secondary amine (N10) of DC-81 subunits tethered to their C8 positions through alkanedioxy linkers (comprised of three and five carbons) is described. These noncross-linking unsymmetrical molecules exhibit significant DNA minor groove binding ability and one of them 5b linked through the pentanedioxy chain exhibits efficient DNA binding ability (ΔT m = 11.0°C) when compared to naturally occurring DC-81, 1 (ΔT m = 0.7°C). The imine-amine PBD dimers exhibit promising in vitro antitumor activity in a number of human cancer cell lines. © 2004 Elsevier Ltd. All rights reserved.