Synthesis, DNA-binding ability and anticancer activity of benzothiazole/benzoxazole-pyrrolo[2,1-c][1,4]benzodiazepine conjugates.
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.
Kamal
Ahmed
A
Chemical Biology Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500607, India. ahmedkamal@iict.res.in
Reddy
K Srinivasa
KS
Khan
M Naseer A
MN
Shetti
Rajesh V C R N C
RV
Ramaiah
M Janaki
MJ
Pushpavalli
S N C V L
SN
Srinivas
Chatla
C
Pal-Bhadra
Manika
M
Chourasia
Mukesh
M
Sastry
G Narahari
GN
Juvekar
Aarti
A
Zingde
Surekha
S
Barkume
Madan
M
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
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