Agarwal, Shweta and Chadha, Deepti and Mehrotra, Ranjana (2015) Molecular modeling and spectroscopic studies of semustine binding with DNA and its comparison with lomustine-DNA adduct formation. Journal of Biomolecular Structure and Dynamics, 33 (8). 1653-1668 . ISSN 0739-1102
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Abstract
Chloroethyl nitrosoureas constitute an important family of cancer chemotherapeutic agents, used in the treatment of various types of cancer. They exert antitumor activity by inducing DNA interstrand cross-links. Semustine, a chloroethyl nitrosourea, is a 4-methyl derivative of lomustine. There exist some interesting reports dealing with DNA-binding properties of chloroethyl nitrosoureas; however, underlying mechanism of cytotoxicity caused by semustine has not been precisely and completely delineated. The present work focuses on understanding semustine-DNA interaction to comprehend its anti-proliferative action at molecular level using various spectroscopic techniques. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy is used to determine the binding site of semustine on DNA. Conformational transition in DNA after semustine complexation is investigated using circular dichroism (CD) spectroscopy. Stability of semustine-DNA complexes is determined using absorption spectroscopy. Results of the present study demonstrate that semustine performs major-groove-directed DNA alkylation at guanine residues in an incubation-time-drug-concentration-dependent manner. CD spectral outcomes suggest partial transition of DNA from native B-conformation to C-form. Calculated binding constants (K-a) for semustine and lomustine interactions with DNA are 1.53 x 10(3)M(-1) and 8.12 x 10(3)M(-1), respectively. Moreover, molecular modeling simulation is performed to predict preferential binding orientation of semustine with DNA that corroborates well with spectral outcomes. Results based on comparative study of DNA-binding properties of semustine and lomustine, presented here, may establish a correlation between molecular structure and cytotoxicity of chloroethyl nitrosoureas that may be instrumental in the designing and synthesis of new nitrosourea therapeutics possessing better efficacy and fewer side effects.
| Item Type: | Article |
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| Uncontrolled Keywords: | semustine; lomustine; molecular modeling; FTIR spectroscopy; CD spectroscopy; Drug–DNA interaction |
| Subjects: | Biochemistry & Molecular Biology Biophysics |
| Divisions: | UNSPECIFIED |
| Depositing User: | Dr. Rajpal Walke |
| Date Deposited: | 05 Oct 2016 05:43 |
| Last Modified: | 05 Oct 2016 05:43 |
| URI: | http://npl.csircentral.net/id/eprint/1906 |
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