title: Molecular modeling and spectroscopic studies of semustine binding with DNA and its comparison with lomustine-DNA adduct formation.
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 (Ka) for semustine and lomustine interactions with DNA are 1.53 × 10(3) M(-1) and 8.12 × 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.
authors.affiliation: a Quantum Phenomenon and Applications, CSIR-National Physical Laboratory , Dr. K. S. Krishnan Marg, New Delhi 110012 , India.
authors.forename: Shweta
authors.initials: S
authors.lastname: Agarwal
authors.forename: Deepti
authors.initials: D
authors.lastname: Chadha
authors.forename: Ranjana
authors.initials: R
authors.lastname: Mehrotra
mesh_terms: D000465:Algorithms; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry* / Q000378:metabolism; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry*; D008130:Lomustine / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D012673:Semustine / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D012673:Semustine; D008130:Lomustine; D004247:DNA
keywords: CD spectroscopy; Drug–DNA interaction; FTIR spectroscopy; lomustine; molecular modeling; semustine