title: Synthesis, DNA-binding ability and anticancer activity of benzothiazole/benzoxazole-pyrrolo[2,1-c][1,4]benzodiazepine conjugates.
abstract: A series of benzothiazole and benzoxazole linked pyrrolobenzodiazepine conjugates attached through different alkane or alkylamide spacers was prepared. Their anticancer activity, DNA thermal denaturation studies, restriction endonuclease digestion assay and flow cytometric analysis in human melanoma cell line (A375) were investigated. One of the compounds of the series 17d showed significant anticancer activity with promising DNA-binding ability and apoptosis caused G0/G1 phase arrest at sub-micromolar concentrations. To ascertain the binding mode and understand the structural requirement of DNA binding interaction, molecular docking studies using GOLD program and more rigorous 2 ns molecular dynamic simulations using Molecular Mechanics-Poisson-Boltzman Surface Area (MM-PBSA) approach including the explicit solvent were carried out. Further, the compound 17d was evaluated for in vivo efficacy studies in human colon cancer HT29 xenograft mice.
authors.affiliation: Chemical Biology Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500607, India. ahmedkamal@iict.res.in
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.forename: K Srinivasa
authors.initials: KS
authors.lastname: Reddy
authors.forename: M Naseer A
authors.initials: MN
authors.lastname: Khan
authors.forename: Rajesh V C R N C
authors.initials: RV
authors.lastname: Shetti
authors.forename: M Janaki
authors.initials: MJ
authors.lastname: Ramaiah
authors.forename: S N C V L
authors.initials: SN
authors.lastname: Pushpavalli
authors.forename: Chatla
authors.initials: C
authors.lastname: Srinivas
authors.forename: Manika
authors.initials: M
authors.lastname: Pal-Bhadra
authors.forename: Mukesh
authors.initials: M
authors.lastname: Chourasia
authors.forename: G Narahari
authors.initials: GN
authors.lastname: Sastry
authors.forename: Aarti
authors.initials: A
authors.lastname: Juvekar
authors.forename: Surekha
authors.initials: S
authors.lastname: Zingde
authors.forename: Madan
authors.initials: M
authors.lastname: Barkume
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D017209:Apoptosis; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000627:therapeutic use; D052160:Benzothiazoles / Q000737:chemistry*; D001583:Benzoxazoles / Q000737:chemistry*; D001665:Binding Sites; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy; D004247:DNA / Q000737:chemistry*; D016193:G1 Phase; D006801:Humans; D051379:Mice; D056004:Molecular Dynamics Simulation; D009691:Nucleic Acid Denaturation; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000627:therapeutic use; D016192:Resting Phase, Cell Cycle; D012984:Software; D014183:Transplantation, Heterologous
chemical_list: C559568:7-methoxy-8-(5-(4-(1,3-benzothiazol-2-yl)-2-methoxyphenoxy)pentyl)oxy-(11aS)1,2,3,11a-tetra-hydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepin-5-one; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D001583:Benzoxazoles; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines; D004247:DNA; C005465:benzothiazole