title: Structural, conformational and thermodynamic aspects of groove-directed-intercalation of flavopiridol into DNA.
abstract: Certain plant-derived alkaloids and flavonoids have shown propitious cytotoxic acitvity against different types of cancer, having deoxyribose nucleic acid (DNA) as their main cellular target. Flavopiridol, a semi-synthetic derivative of rohitukine (a natural compound isolated from Dysoxylum binectariferum plant), has attained much attention owing to its anticancer potential against various haematological malignancies and solid tumours. This work focuses on investigating interaction between flavopiridol and DNA at molecular level in order to decipher its underlying mechanism of action, which is not well understood. To define direct influence of flavopiridol on the structural, conformational and thermodynamic aspects of DNA, various spectroscopic and calorimetric techniques have been used. ATR-FTIR and SERS spectral outcomes indicate a novel insight into groove-directed-intercalation of flavopiridol into DNA via direct binding with nitrogenous bases guanine (C6=O6) and thymine (C2=O2) in DNA groove together with slight external binding to its sugar-phosphate backbone. Circular dichroism spectral analysis of flavopiridol-DNA complexes suggests perturbation in native B-conformation of DNA and its transition into C-form, which may be localized up to a few base pairs of DNA. UV-visible spectroscopic results illustrate dual binding mode of flavopiridol when interacts with DNA having association constant, Ka = 1.18 × 10(4) M(-1). This suggests moderate type of interaction between flavopiridol and DNA. Further, UV melting analysis also supports spectroscopic outcomes. Thermodynamically, flavopiridol-DNA complexation is an enthalpy-driven exothermic process. These conclusions drawn from this study could be helpful in unveiling mechanism of cytoxicity induced by flavopiridol that can be further applied in the development of flavonoid-based new chemotherapeutics with more specificity and better efficacy.
authors.affiliation: a Academy of Scientific & Innovative Research (AcSIR) , CSIR-National Physical Laboratory Campus , New Delhi 110012 , India.|b Quantum Phenomena and Applications , CSIR-National Physical Laboratory , Dr. K. S. Krishnan Marg, New Delhi 110012 , India.
authors.forename: Bhumika
authors.initials: B
authors.lastname: Ray
authors.affiliation: a Academy of Scientific & Innovative Research (AcSIR) , CSIR-National Physical Laboratory Campus , New Delhi 110012 , India.|b Quantum Phenomena 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.affiliation: c Department of Biochemistry , All India Institute of Medical Sciences , Ansari Nagar, New Delhi 110029 , India.
authors.forename: Neelam
authors.initials: N
authors.lastname: Lohani
authors.affiliation: c Department of Biochemistry , All India Institute of Medical Sciences , Ansari Nagar, New Delhi 110029 , India.
authors.forename: Moganty R
authors.initials: MR
authors.lastname: Rajeswari
authors.affiliation: a Academy of Scientific & Innovative Research (AcSIR) , CSIR-National Physical Laboratory Campus , New Delhi 110012 , India.|b Quantum Phenomena and Applications , CSIR-National Physical Laboratory , Dr. K. S. Krishnan Marg, New Delhi 110012 , India.
authors.forename: Ranjana
authors.initials: R
authors.lastname: Mehrotra
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry*; D005419:Flavonoids / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D009690:Nucleic Acid Conformation; D010880:Piperidines / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C077990:alvocidib; D004247:DNA
keywords: CD spectroscopy; drug-DNA interaction; flavopiridol; groove-directed-intercalation; vibrational spectroscopy