Synthesis and antitumor activity of novel enediyne-linked pyrrolo[2,1- c][1,4]benzodiazepine hybrids

• Published in: Bioorganic & medicinal chemistry 2009-02, Vol.17 (3), p.1172-1180
• Main Authors: Hu, Wan-Ping, Liang, Jium-Jia, Kao, Chai-Lin, Chen, You-Chiang, Chen, Chung-Yu, Tsai, Feng-Yuan, Wu, Ming-Jung, Chang, Long-Sen, Chen, Yeh-Long, Wang, Jeh-Jeng
• 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; Caspase 3 - metabolism; Cell Line, Tumor; DC-81; Drug Screening Assays, Antitumor; Enediyne; Enediynes - chemical synthesis; Enediynes - chemistry; General aspects; Humans; Indoles - chemical synthesis; Indoles - chemistry; Medical sciences; Organophosphorus Compounds - chemical synthesis; Organophosphorus Compounds - chemistry; Organophosphorus Compounds - pharmacology; Pharmacology. Drug treatments; Pyrrolo[2,1- c][1,4]benzodiazepine; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.12.036

(A) Structure of the enediyne-PBD conjugate agents. (B) The apoptotic morphology after treatment with compound ( 6, 18) on 293T. A series of novel pyrrolo[2,1- c][1,4]benzodiazepine (PBD) hybrids linked with enediyne is described. These compounds were prepared by linking C-8 of DC-81 ( 1) with an enediyne ( 10– 16) through carbon chain linkers to afford PBD hybrid agents 17– 23 in good yields. Most of the hybrids on human cancer cell lines exhibited higher cytotoxicity, and an increase in the sub-G1 population than 1. In a previous article, we have demonstrated that DC-81-indole conjugate agents ( 3–6) are potent inducers of cell apoptosis in melanoma. In the present article, we investigated whether DC-81-enediyne agents possess more cytotoxicity than 6 on human 293T cells. Our data revealed that treatment of 293T cells with DC-81-enediyne resulted in a significant increase of annexin V binding, caspase-3 degradation, and p53 arrest to identify apoptotic cells than 6. These results suggest that the DC-81-enediyne agents are more efficient in inducing apoptosis than DC-81-indole in 293T cells.