Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are naturally occurring compounds isolated from various Streptomyces species. The PBDs exert their biological activity through covalent binding and exhibit cytotoxicity. Extensive studies have been carried out on the synthetic strategies of PBDs, and a sound understanding of structure activity relationships within this class of compounds has been developed. The PBDs have shown to interfere with the interaction of endonuclease enzymes of DNA and block the transcription by inhibiting RNA polymerase in a sequence specific manner. These processes have been thought to account for the biological activity of PBDs. The PBDs have also been used as a scaffold to attach different type of moieties leading to novel sequence selective DNA cleaving and cross-linking agents. The design and synthesis of C8-linked PBD dimers and other hybrids of PBDs has given a new insight towards the development of molecules with enhanced DNA binding affinity and sequence specificity compared to the naturally occurring PBDs. This improvement in the biological profile has been explained on the basis of certain factors like DNA cross-linking and doubling of DNA binding sites. There seems to be enough potential for further changing the substitution pattern and to design structurally modified PBDs by retaining the PBD core intact. In this review both the synthetic strategies and the structure-activity relationships, particularly the DNA binding and cytotoxicity studies of PBDs have been discussed.

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New sequence selective mixed imine-amide pyrrolobenzodiazepine (PBD) dimers have been developed that are comprised of DC-81 and dilactam of DC-81 subunits tethered to their C8 positions through alkanedioxy linkers (comprised of three to five and eight carbons). Thermal denaturation studies show that after 18 h of incubation with calf thymus DNA at a 5:1 DNA/ligand ratio, one of them (5c) increases the DeltaT(m) value by 17.0 degrees C. Therefore, these unsymmetrical molecules exhibit significant DNA minor groove binding affinity and 5c linked through the pentanedioxy chain exhibits efficient DNA binding ability that compares with the cross-linking DSB-120 PBD dimer (DeltaT(m) = 15.4 degrees C). Interestingly, this imine-amide PBD dimer has been linked with a five carbon chain linker unlike DSB-120, which has two DC-81 subunits with a three carbon chain linker, illustrating the effect of the noncross-linking aspect by introducing the noncovalent subunit. The binding affinity of the compounds has been measured by restriction endonuclease digestion assay based on inhibition of the restriction endonuclease BamHI. This study reveals the significance of noncovalent interactions in combination with covalent bonding aspects when two moieties of structural similarities are joined together. This allows the mixed imine-amide PBD dimer with a five carbon chain linker to achieve an isohelical fit within the DNA minor groove taking in to account both the covalent bonding and the noncovalent binding components. This has been supported by molecular modeling studies, which indicate that the PBD dimer with a five carbon chain linker gives rise to maximum stabilization of the complex with DNA at the minor groove as compared to the other PBD dimers with three, four, and eight carbon chain linkers. The energy of interaction in all of the complexes studied is correlated to the DeltaT(m) values. Furthermore, this dimer 5c has significant cytotoxicity in a number of human cancer cell lines.

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