Quinazolinone linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates: Design, synthesis and biological evaluation as potential anticancer agents.
A series of novel quinazolinone linked pyrrolobenzodiazepine (PBD) conjugates were synthesized. These compounds 4a-f and 5a-f were prepared in good yields by linking C-8 of DC-81 with quinazolinone moiety through different alkane spacers. These conjugates were tested for anticancer activity against 11 human cancer cell lines and found to be very potent anticancer agents with GI(50) values in the range of <0.1-26.2microM. Among all the PBD conjugates, one of the conjugate 5c was tested against a panel of 60 human cancer cells. This compound showed activity for individual cancer cell lines with GI(50) values of <0.1microM. The thermal denaturation studies exhibited effective DNA binding ability compared to DC-81 and these results are further supported by molecular modeling studies. The detailed biological aspects of these conjugates on A375 cell line were studied. It was observed that compounds 4b and 5c induced the release of cytochrome c, activation of caspase-3, cleavage of PARP and subsequent cell death. Further, these compounds when treated with A375 cells showed the characteristic features of apoptosis like enhancement in the levels of p53, p21 and p27 inhibition of cyclin dependent kinase-2 (CDK2) and suppression of NF-kappaB. Moreover, these two compounds 4b and 5c control the cell proliferation by regulating anti-apoptotic genes like (B-cell lymphoma 2) Bcl-2. Therefore, the data generated suggests that these PBD conjugates activate p53 and inhibit NF-kappaB and thereby these compounds could be promising anticancer agents with better therapeutic potential for the suppression of tumours.
Kamal
Ahmed
A
Chemical Biology Laboratory, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India. ahmedkamal@iict.res.in
Vijaya Bharathi
E
E
Janaki Ramaiah
M
M
Dastagiri
D
D
Surendranadha Reddy
J
J
Viswanath
A
A
Sultana
Farheen
F
Pushpavalli
S N C V L
SN
Pal-Bhadra
Manika
M
Srivastava
Hemant Kumar
HK
Narahari Sastry
G
G
Juvekar
Aarti
A
Sen
Subrata
S
Zingde
Surekha
S
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001569:Benzodiazepines / Q000737:chemistry* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology; D052999:Quinazolinones / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011758:Pyrroles; D052999:Quinazolinones; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines