title: DNA binding potential and cytotoxicity of newly designed pyrrolobenzodiazepine dimers linked through a piperazine side-armed-alkane spacer.
abstract: New pyrrolobenzodiazepine (PBD) dimers have been developed that are composed of two DC-81 subunits tethered to their C8 positions through piperazine moiety side-armed with alkaneoxy linkers (composed of 2-5 carbons). DNA thermal denaturation studies show that after 18h of incubation with calf thymus DNA at a 1:5 ligand/DNA ratio, one of them, 6a, increases the DeltaT(m) value by 24.0 degrees C. Thus, incorporation of a piperazine moiety instead of an inert alkanedioxy linker alone significantly enhances the DNA binding ability, and the analogous dimer 4 that lacks a piperazine moiety in the linker spacer elevates melting by only 15.1 degrees C under identical experimental conditions. This illustrates the effect of introducing a piperazine ring in the middle of such an alkanedioxy linker which produces several hydrophobic interactions and could also achieve a superior isohelical fit within the DNA minor groove. Interestingly, these dimers 6a-d are significantly more cytotoxic than 4 in a number of human cancer cell lines, in particular, compound 6c is highly potent for almost all the nine human cancer cell lines.
authors.affiliation: Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India. ahmedkamal@iict.res.in
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.forename: P S Murali Mohan
authors.initials: PS
authors.lastname: Reddy
authors.forename: D Rajasekhar
authors.initials: DR
authors.lastname: Reddy
authors.forename: E
authors.initials: E
authors.lastname: Laxman
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry / Q000378:metabolism*; D002417:Cattle; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009691:Nucleic Acid Denaturation; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D010879:Piperazines; D001569:Benzodiazepines; D000077489:Piperazine; D004247:DNA