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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-02, Vol.49 (4), p.1442-1449
Main Authors: Wang, Jeh-Jeng, Shen, Yu-Kai, Hu, Wan-Ping, Hsieh, Ming-Chu, Lin, Fu-Lung, Hsu, Ming-Kuan, Hsu, Mei-Hui
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Apoptosis
Benzodiazepines - chemical synthesis
Benzodiazepines - chemistry
Benzodiazepines - pharmacology
Biological and medical sciences
Cell Cycle - drug effects
Cell Line, Tumor
DNA - chemistry
Drug Design
Drug Screening Assays, Antitumor
General aspects
Humans
Indoles - chemical synthesis
Indoles - chemistry
Indoles - pharmacology
Medical sciences
Melanoma
Membrane Potentials - drug effects
Mitochondrial Membranes - drug effects
Mitochondrial Membranes - physiology
Models, Molecular
Pharmacology. Drug treatments
Pyrroles - chemical synthesis
Pyrroles - chemistry
Pyrroles - pharmacology
Structure-Activity Relationship
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Summary: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 ΔΨmt 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm050956q