title: Mahanine, a DNA minor groove binding agent exerts cellular cytotoxicity with involvement of C-7-OH and -NH functional groups.
abstract: Mahanine, a carbazole alkaloid is a potent anticancer molecule. To recognize the structure-activity 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.
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology , 4 Raja S. C. Mullick Road, Kolkata 700032, India.
authors.forename: Suman K
authors.initials: SK
authors.lastname: Samanta
authors.forename: Devawati
authors.initials: D
authors.lastname: Dutta
authors.forename: Sarita
authors.initials: S
authors.lastname: Roy
authors.forename: Kaushik
authors.initials: K
authors.lastname: Bhattacharya
authors.forename: Sayantani
authors.initials: S
authors.lastname: Sarkar
authors.forename: Anjan K
authors.initials: AK
authors.lastname: Dasgupta
authors.forename: Bikas C
authors.initials: BC
authors.lastname: Pal
authors.forename: Chhabinath
authors.initials: C
authors.lastname: Mandal
authors.forename: Chitra
authors.initials: C
authors.lastname: Mandal
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008745:Methylation; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D017382:Reactive Oxygen Species; C465290:mahanine; D004247:DNA