Substituent effect of benzyl moiety in nitroquinoxaline small molecules upon DNA binding: Cumulative destacking of DNA nucleobases leading to histone eviction

• Published in: European journal of medicinal chemistry 2022-02, Vol.229, p.113995-113995, Article 113995
• Main Authors: Pal, Ritesh, Chakraborty, Jeet, Mukhopadhyay, Titas Kumar, Kanungo, Ajay, Saha, Rimita, Chakraborty, Amit, Patra, Dipendu, Datta, Ayan, Dutta, Sanjay
• Format: Article
• Language: English
• Subjects: Cell Line; Cell Survival - drug effects; DNA - chemistry; DNA - metabolism; DNA Damage - drug effects; Drug Design; Entropically favored; Histones - metabolism; Humans; Hydrogen bond disruption; Hydrogen Bonding; Hydrophobic interaction; In-vitro nucleosome disassembly; Mammalian cell cytotoxicity; Molecular Conformation; Nucleobase destacking; Quantum Theory; Quinoxalines - chemistry; Quinoxalines - metabolism; Quinoxalines - pharmacology; Thermodynamics
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113995

Cooperative disruption of Watson-Crick hydrogen bonds, as well as base-destacking, is shown to be triggered by a quinoxaline-based small molecule consisting of an N,N-dimethylaminopropyl tether, and a para-substituted benzyl moiety. This events lead to superstructure formation and DNA condensation as evident from biophysical experiments and classical molecular dynamics simulations. The DNA superstructure formation by mono-quinoxaline derivatives is highly entropically favored and predominantly driven by hydrophobic interactions. Furthermore, oversupercoiling of DNA and base-destacking cumulatively induces histone eviction from in-vitro assembled nucleosomes at lower micromolar concentrations implicating biological relevance. The DNA structural modulation and histone eviction capacity of the benzyl para-substituents are in the order: –I > –CF3> -Br > -Me > -OMe > –OH, which is largely guided by the polarity of benzyl para-substituent and the resulting molecular topology. The most hydrophobic derivative 3c with para-iodo benzyl moiety causes maximal disruption of base pairing and generation of superstructures. Both these events gradually diminish as the polarity of the benzyl para-substituent increases. On the other hand, quinoxaline derivatives having heterocyclic ring instead of benzyl ring, or in the absence of N,N-dimethylamino head-group, is incapable of inducing any DNA structural change and histone eviction. Further, the quinoxaline compounds displayed potent anticancer activities against different cancer cell lines which directly correlates with the hydrophobic effects of the benzyl para-substituents. Overall, the present study provides new insights into the mechanistic approach of DNA structural modulation driven histone eviction guided by the hydrophobicity of synthesized compounds leading to cellular cytotoxicity towards cancer cells. [Display omitted] •Hydrophobicity driven DNA structural change through H-bonds disruption and nucleobases destacking depending on stereo-electronic nature of the para-substituents of benzyl moiety in 6-nitroquinoxaline scaffold.•Histone eviction from the in-vitro assembled nucleosome in accordance with the hydrophobicity of the para-substituents.•Synthesized derivatives exert toxicity towards cancer cells depending on DNA structure altering abilities, with maximal potency towards human colorectal carcinoma cell line.•Quinoxaline derivative is capable to induce DNA damage through ds-DNA breaks, induction of γ-H2AX, DN