Recent developments in the design, synthesis and structure-activity relationship studies of pyrrolo[2,1-c][1,4]benzodiazepines as DNA-interactive antitumour antibiotics.
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.
Kamal
Ahmed
A
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India. ahmedkamal@iict.ap.nic.in
Rao
Maddamsetty V
MV
Laxman
N
N
Ramesh
G
G
Reddy
G S K
GS
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004273:DNA, Neoplasm / Q000187:drug effects*; D015195:Drug Design; D006801:Humans; D007202:Indicators and Reagents; D011355:Prodrugs; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D007202:Indicators and Reagents; D011355:Prodrugs; D011758:Pyrroles; D001569:Benzodiazepines