Synthesis of DNA-Interactive Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs)

Abstract

Pyrrolobenzodiazepines (PBD) are an important class of sequence-selective DNA-interactive agents that bind covalently to guanine bases within the minor groove of DNA. The PBD monomers are remarkable in possessing a 3-dimensional shape that allows them to fit perfectly within the minor groove of DNA, partly due to the longitudinal twist created by the chiral center at their C11a-position. A PBD produced synthetically, semisynthetically, or isolated from natural sources can exist as a mixture of two or even three forms or can exist predominantly as just one. Various biochemical and structural studies on PBD-DNA adducts have suggested that the molecules locate themselves with their N10-position pointing toward the floor of the minor groove. A further important feature of the PBDs is that they interact selectively with specific DNA sequences. A significant effort has also been made to increase the base-pair span and sequence-selectivity of PBD molecules so that they might be used as gene-targeting agents in biological experiments and possibly as therapeutic agents.