Design and synthesis of benzo[c,d]indolone-pyrrolobenzodiazepine conjugates as potential anticancer agents.
A series of benzo[c,d]indol-2(1H)one-PBD conjugates (11a-l) have been designed and synthesized as potential anticancer agents. These compounds were prepared by linking the C8-position of DC-81 with a benzo[c,d]indol-2(1H)one moiety through different alkane spacers in good yields and confirmed by (1)H NMR, mass and HRMS data. The DNA binding ability of these conjugates was evaluated by thermal denaturation studies and interestingly, compound 11l showed enhanced DNA binding ability. These compounds were also evaluated for their anticancer activity in selected human cancer cell lines of lung, skin, colon and prostate by using MTT assay method. These new conjugates showed promising anticancer activity with IC(50) values ranging from 1.05 to 36.49 μM. Moreover, cell cycle arrest in SubG1 phase was observed upon treatment of A549 cells with 1 and 2 μM (IC(50)) concentrations of compound 11l and it induced apoptosis. This is confirmed by Annexin V-FITC, Hoechst staining, caspase-3 activity as well as DNA fragmentation analysis.
Division of Organic Chemistry, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India. ahmedkamal@iict.res.in
Ahmed
A
Kamal
G
G
Ramakrishna
V
V
Lakshma Nayak
P
P
Raju
A V
AV
Subba Rao
A
A
Viswanath
M V P S
MV
Vishnuvardhan
Sistla
S
Ramakrishna
G
G
Srinivas
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D053938:DNA Fragmentation; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D009691:Nucleic Acid Denaturation; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
C572004:3-((7-methoxy-5-oxo-2,3,5,11a-tetrahydro-1H-benzo(e)pyrrolo(1,2-a)(1,4)diazepin-8-yl)oxy)hexyl-1,2-dihydro-1gamma6-naphtho(1,8-cd)isothiazole-1,1-dione; D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D052160:Benzothiazoles; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines; D004247:DNA; D053148:Caspase 3