Remarkable enhancement in the DNA-binding ability of C2-fluoro substituted pyrrolo[2,1-c][1,4]benzodiazepines and their anticancer potential.

Abstract

C2-Fluoro substituted DC-81, and its dimers that comprise of two C2-fluoro substituted DC-81 subunits tethered to their C8-position through simple alkane spacers as well as piperazine moiety side-armed with symmetrical alkyloxy spacers have been designed and synthesized. These fluoro substituted pyrrolo[2,1-c][1,4]benzodiazepines have shown remarkable DNA-binding ability and most of them possess promising anticancer activity, having GI(50) values in micromolar to nanomolar concentration range. DNA thermal denaturation studies show that some of these compounds (14a-c and 15) increase the DeltaT(m) values in the range of 28.9-38 degrees C, and this is further confirmed by the restriction endonuclease studies. This study illustrates the importance of introducing fluoro substitution at the C2-position apart from the incorporation of a piperazine ring in between the alkyloxy linker for enhancement of the DNA-binding ability in comparison to DSB-120 and SJG-136 (DeltaT(m)=10.2 and 25.7 degrees C). Moreover, the variations in the DNA-binding ability with respect to fluoro substitution in this class of dimers has been investigated by molecular modeling studies. Some representative C2-fluoro substituted dimers (8a and 14a) have also exhibited significant anticancer activity in the 60 cancer cell line assay of the National Cancer Institute (NCI).

DOI: 10.1016/j.bmc.2008.12.068

Cite this paper

@article{Kamal2009RemarkableEI, title={Remarkable enhancement in the DNA-binding ability of C2-fluoro substituted pyrrolo[2,1-c][1,4]benzodiazepines and their anticancer potential.}, author={Ahmed Tashrif Kamal and Rajender and DR.Swetha Reddy and Methuku Kashi Reddy and Gorre Balakishan and Thokhir Basha Shaik and Mukesh Chourasia and G. Narahari Sastry}, journal={Bioorganic & medicinal chemistry}, year={2009}, volume={17 4}, pages={1557-72} }