title: 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).
authors.affiliation: Division of Organic Chemistry, Chemical Biology Laboratory, Indian Institute of Chemical Technology, Hyderabad, India. ahmedkamal@iict.res.in
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.lastname: Rajender
authors.forename: D Rajasekhar
authors.initials: DR
authors.lastname: Reddy
authors.forename: M Kashi
authors.initials: MK
authors.lastname: Reddy
authors.forename: G
authors.initials: G
authors.lastname: Balakishan
authors.forename: T Basha
authors.initials: TB
authors.lastname: Shaik
authors.forename: Mukesh
authors.initials: M
authors.lastname: Chourasia
authors.forename: G Narahari
authors.initials: GN
authors.lastname: Sastry
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001569:Benzodiazepines / Q000378:metabolism* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004247:DNA / Q000187:drug effects* / Q000378:metabolism*; D004262:DNA Restriction Enzymes / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011759:Pyrrolidines; D001569:Benzodiazepines; D004247:DNA; D004262:DNA Restriction Enzymes