Targeting genomic DNAs and oligonucleotide on base specificity: A comparative spectroscopic, computational and in vitro study.

Autor: Mati SS; Department of Chemistry, Government General Degree College, Keshiary, Paschim Medinipur,WB 721135, India. Electronic address: soumyamati@gmail.com., Chowdhury S; Structural Biology and Bio-informatics division, CSIR Indian Institute of Chemical Biology, Kolkata 700032, India., Sarkar S; Department of Chemistry, Balurghat College, Dakshin Dinajpur, WB 733101, India., Bera N; Department of Chemistry, Indian Institute of Technology, Kharagpur, Paschim Medinipur, WB 721302, India., Sarkar N; Department of Chemistry, Indian Institute of Technology, Kharagpur, Paschim Medinipur, WB 721302, India. Electronic address: nilmoni@chem.iitkgp.ac.in.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2023 Jul 01; Vol. 242 (Pt 3), pp. 124933. Date of Electronic Publication: 2023 May 23.
DOI: 10.1016/j.ijbiomac.2023.124933
Abstrakt: Drug discovery in targeted nucleic acid therapeutics encompass several stages and rigorous challenges owing to less specificity of the DNA binders and high failure rate in different stages of clinical trials. In this perspective, we report newly synthesized ethyl 4-(pyrrolo[1,2-a]quinolin-4-yl)benzoate (PQN) with minor groove A-T base pair binding selectivity and encouraging in cell results. This pyrrolo quinolin derivative has shown excellent groove binding ability with three of our inspected genomic DNAs (cpDNA 73 % AT, ctDNA58% AT and mlDNA 28 % AT) with varying A-T and G-C content. Notably in spite of similar binding patterns PQN have strong binding preference with A-T rich groove of genomic cpDNA over the ctDNA and mlDNA. Spectroscopic experiments like steady state absorption and emission results have established the relative binding strengths (K abs  = 6.3 × 10 5  M -1 , 5.6 × 10 4  M -1 , 4.3 × 10 4  M -1 and K emiss  = 6.1 × 10 5  M -1 , 5.7 × 10 4  M -1 and 3.5 × 10 4  M -1 for PQN-cpDNA, PQN-ctDNA and PQN-mlDNA respectively) whereas circular dichroism and thermal melting studies have unveiled the groove binding mechanism. Specific A-T base pair attachment with van der Waals interaction and quantitative hydrogen bonding assessment were characterized by computational modeling. In addition to genomic DNAs, preferential A-T base pair binding in minor groove was also observed with our designed and synthesized deca-nucleotide (primer sequences 5 / -GCGAATTCGC-3 / and 3 / -CGCTTAAGCG-5 / ). Cell viability assays (86.13 % in 6.58 μM and 84.01 % in 9.88 μM concentrations) and confocal microscopy revealed low cytotoxicity (IC 50 25.86 μM) and efficient perinuclear localization of PQN. We propose PQN with excellent DNA-minor groove binding capacity and intracellular permeation properties, as a lead for further studies encompassing nucleic acid therapeutics.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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