Mahanine, A DNA Minor Groove Binding Agent Exerts Cellular Cytotoxicity with Involvement of C-7-OH and 鈭扤H Functional Groups

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• 作者：Suman K. Samanta ; Devawati Dutta ; Sarita Roy ; Kaushik Bhattacharya ; Sayantani Sarkar ; Anjan K. Dasgupta ; Bikas C. Pal ; Chhabinath Mandal ; Chitra Mandal
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 25, 2013
• 年：2013
• 卷：56
• 期：14
• 页码：5709-5721
• 全文大小：544K
• 年卷期：v.56,no.14(July 25, 2013)
• ISSN：1520-4804

文摘

Mahanine, a carbazole alkaloid is a potent anticancer molecule. To recognize the structure鈥揳ctivity correlation, mahanine was chemically modified. Antiproliferative activity of these derivatives was determined in 19 cancer cell lines from 7 different origins. Mahanine showed enhanced apoptosis compared to dehydroxy-mahanine-treated cells, indicating significant contribution of the C-7-OH group. O-Methylated-mahanine and N-methylated dehydroxy-mahanine-treated cells exhibited apoptosis only at higher concentrations, suggesting additional contribution of 9-NH group. Using biophysical techniques, we demonstrated that mahanine interacts with DNA through strong association with phosphate backbone compared to other derivatives but is unable to induce any conformational change in DNA, hence suggesting the possibility of being a minor groove binder. This was corroborated by molecular modeling and isothermal titration calorimetry studies. Taken together, the results of the current study represent the first evidence of involvement of C-7-OH and 9-NH group of mahanine for its cytotoxicity and its minor groove binding ability with DNA.