Design, synthesis, and biological evaluation of pyrrolo[2,1-c][1,4]benzodiazepine and indole conjugates as anticancer agents.
A series of novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD) hybrids linked with indole carboxylates is described. These compounds were prepared by linking C-8 of 3 (DC-81) with an indole 2-carbonyl moiety (9) through carbon chain linkers to afford PBD hybrid agents 17-21 in good yields. Preliminary in vivo tests show that these hybrid agents have potent antitumor activity. The cytotoxic studies of the hybrid agents on human melanoma A2058 cells indicate most of the hybrids induced higher cytotoxicity, better DNA-binding ability, an increase in the apoptotic sub-G1 population, and a significant reduction in deltapsi(mt) relative to compound 3. In addition, DNA flow cytometric analysis shows that hybrids actively induce a marked loss of cells from the G2/M phase of the cell cycle, which progresses to early apoptosis as detected by flow cytometry after double-staining with annexin V and propidium iodide (PI). Thus, we suggest that the hybrid agents are potent inducers of cell apoptosis in A2058 cells.
Faculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. jjwang@kmu.edu.tw
Jeh-Jeng
JJ
Wang
Yu-Kai
YK
Shen
Wan-Ping
WP
Hu
Ming-Chu
MC
Hsieh
Fu-Lung
FL
Lin
Ming-Kuan
MK
Hsu
Mei-Hui
MH
Hsu
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008545:Melanoma; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D008958:Models, Molecular; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D001569:Benzodiazepines; D004247:DNA