Recent Developments in the Design, Synthesis and Structure-Activity Relationship Studies of Pyrrolo[2,1-c][1,4]benzodiazepines as DNA-Interactive Antitumour Antibiotics

Abstract

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.

Biosynthesis of Sibiromycin, a Potent Antitumor Antibiotic

“…These studies also showed that O glycosylation at C7 significantly enhanced DNA-binding affinity ( Fig. 1) (17). The only known glycosylated PBDs are sibiromycin and sibanomicin produced by Streptosporangium sibiricum and Micromonospora sp., respectively, both containing a sibirosamine moiety (16,35).…”

“…Structure-activity relationship studies on the synthetically and naturally produced PBDs showed that the C-9 hydroxylation present in anthramycin is the source of the cardiotoxic properties of this compound ( Fig. 1) (3,17,26,38). These studies also showed that O glycosylation at C7 significantly enhanced DNA-binding affinity ( Fig.…”

Cloning and Characterization of the Biosynthetic Gene Cluster for Tomaymycin, an SJG-136 Monomeric Analog

“…1A). The chemical liability of the imine bond complicates the synthesis of PBDs, limiting the complexity of PBDs compounds synthetically accessible (2,16,17,29). Interest in the PBDs is driven by the remarkable antitumor properties of these compounds such as sibiromycin and tomaymycin (28).…”

DNA Sequence Preference and Adduct Orientation of Pyrrolo[2,1-c][1,4]benzodiazepine Antitumor Agents

“…KEYWORDS Pyrrolo[2,1-c] [1,4]benzodiazepine (PBD), antitumor agents, GWL-78, DNA, minor-groove binder T he pyrrolo [2,1-c] [1,4]benzodiazepines (PBDs) are a well-known class of sequence-selective covalent-binding DNA-interactive agents [1][2][3][4] that fit perfectly in the minor groove of DNA due to their chiral C11a(S)-position, which provides a right-handed longitudinal twist isohelical with double-stranded DNA. 3 They also possess an electrophilic N10-C11 imine moiety (or the carbinolamine or carbinolamine methyl ether equivalent) that can form a covalent aminal linkage between their C11-position and the nucleophilic C2-NH 2 group of a guanine base.…”