Nucleic acid binding mechanism of flavone derivative, riviciclib: Structural analysis to unveil anticancer potential.

Despite burgeoned knowledge about the origin, growth, tissue interactions, and spread of cancer in recent years, the functional complexity and unique survival ability of cancer cells still make it difficult to target them. Riviciclib is a semi-synthetic derivative of rohitukine and possesses anticancer potential. Inhibition of nucleic acid activity in an uncontrolled dividing cell can form the basis for the development of new-age cancer therapeutics. The present study reports the molecular interaction between riviciclib and nucleic acid (DNA/tRNA) using spectroscopic and molecular docking studies in an attempt to comprehend its cellular toxicity as well as the nature and mode of binding between them. Vibrational spectroscopic results suggest that riviciclib intercalates DNA duplex and primarily binds with guanine, adenine, and thymine nucleobases. While in the case of riviciclib-tRNA complexation, riviciclib interacts mostly with uracil residues of the tRNA molecule. Besides nucleobases, riviciclib interacts with the sugar-phosphate backbone of both biomacromolecules. Conformationally, DNA alters from B-form to C-form, whereas tRNA shows no change in its native A-form. The order (104 M-1) of binding constant for riviciclib-nucleic acid complexation infer moderate to strong affinity of riviciclib with DNA and tRNA, respectively. Molecular docking explorations are further in corroboration with our spectroscopic outcomes.

Binding of platinum derivative, oxaliplatin to deoxyribonucleic acid: structural insight into antitumor action.

Platinum-derived chemodrugs constitute an active class in cancer therapeutics. Besides being potent against various solid tumors, oxaliplatin has been recognized as the first platinum compound to be approved for the treatment of colorectal cancer. Structurally, oxaliplatin consists of a platinum metal complexed to oxalate and diaminocyclohexane (DACH) and exert its anticancer action by inhibiting DNA replication and transcription. The present study highlights the binding properties of oxaliplatin with calf thymus DNA using spectroscopic methods to comprehend its binding mechanism at molecular level to overcome associated cellular resistance and side effects. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopic outcomes confirm that oxaliplatin is a covalent binding agent and also provide sequence specificity in DNA molecule. Infrared spectral results further indicate that oxaliplatin alkylates purine nitrogenous bases majorly guanine residues (G) in the major groove via formation of either interstrand or intrastrand guanine-guanine d(GpG) and guanine-adenine d(GpA) (N7 position) crosslinks accompanied with a slight external binding to sugar-phosphate backbone. Again, circular dichroism (CD) spectroscopic results suggest subtle conformational changes in DNA molecule due to its complexation with oxaliplatin and duplex attains an intermediate conformational state, having characteristics of both B- and C-forms. Further, a moderate binding strength of 4.12 ± 0.2 × 104 M-1 for the interaction has been estimated via ultraviolet-visible spectroscopy. The inferences obtained from these investigations are encouraging and can form the basis for further exploration in the field of rational drug development based on platinum compounds possessing preferential binding for nucleic acid with improved competence. Communicated by Ramaswamy H. Sarma.

Deciphering molecular aspects of interaction between anticancer drug mitoxantrone and tRNA.

Mitoxantrone (1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9,10-anthracenedione) is a synthetically designed antineoplastic agent and structurally similar to classical anthracyclines. It is widely used as a potent chemotherapeutic component against various kinds of cancer and possesses lesser cardio-toxic effects with respect to naturally occurring anthracyclines. In the present study, we have investigated the binding features of mitoxantrone-tRNA complexation at physiological pH using attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy, circular dichroism (CD) spectroscopy, isothermal titration calorimetry, and UV-visible absorption spectroscopic techniques. FTIR analysis reveals that mitoxantrone interacts mainly with heterocyclic base residues of tRNA along with slight external binding with phosphate-sugar backbone. In particular, mitoxantrone binds at uracil (C=O) and adenine (C=N) sites of biomolecule (tRNA). CD spectroscopic results suggest that there is no major conformational transition in native A-form of tRNA upon mitoxantrone-tRNA adductation except an intensification in the secondary structure of tRNA is evident. The association constant calculated for mitoxantrone-tRNA association is found to be 1.27 × 105 M-1 indicating moderate to strong binding affinity of drug with tRNA. Thermodynamically, mitoxantrone-tRNA interaction is an enthalpy-driven exothermic reaction. Investigation into drug-tRNA interaction can play an essential role in the rational development of RNA targeting chemotherapeutic agents, which also delineate the structural-functional relationship between drug and its target at molecular level.

Structural, conformational and thermodynamic aspects of groove-directed-intercalation of flavopiridol into DNA.

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.

SERS as an advanced tool for investigating chloroethyl nitrosourea derivatives complexation with DNA.

We report surface-enhanced Raman spectroscopic (SERS) studies on free calf thymus DNA and its complexes with anti-tumor chloroethyl nitrosourea derivatives; semustine and nimustine. Since, first incident of SERS in 1974, it has rapidly established into an analytical tool, which can be used for the trace detection and characterization of analytes. Here, we depict yet another application of SERS in the field of drug-DNA interaction and thereby, its promising role in rational designing of new chemotherapeutic agents. Vibrational spectral analysis has been performed in an attempt to delineate the anti-cancer action mechanism of above mentioned nitrosourea derivatives. Strong SERS bands associated with the complexation of DNA with semustine and nimustine have been observed, which reveal binding of nitrosourea derivatives with heterocyclic nitrogenous base pair of DNA duplex. Formation of dG-dC interstrand cross-link in DNA double helices is also suggested by the SERS spectral outcomes of CENUs-DNA adduct. Results, demonstrated here, reflect recent progress in the newly developing field of drug-DNA interaction analysis via SERS.