Accommodation of ring C expanded deoxyvasicinone in the HDAC inhibitory pharmacophore culminates into a tractable anti-lung cancer agent and pH-responsive nanocarrier.

Abstract

A fragment recruitment process was conducted to pinpoint a suitable fragment for installation in the HDAC inhibitory template to furnish agents endowed with the potential to treat lung cancer. Resultantly, Ring C expanded deoxyvasicinone was selected as an appropriate surface recognition part that was accommodated in the HDAC three-component model. Delightfully, fused quinazolinone 6 demonstrating a magnificent anticancer profile against KRAS and EGFR mutant lung cancer cell lines (IC50 = 0.80-0.96 μM) was identified. Results of the mechanistic studies confirmed that the cell growth inhibitory effects of compound 6 stems for HDAC6 (IC50 = 12.9 nM), HDAC1 (IC50 = 49.9 nM) and HDAC3 inhibition (IC50 = 68.5 nM), respectively. Compound 6 also suppressed the colony formation ability of A549 cells, induced apoptosis, and increased autophagic flux. Key interactions of HDAC inhibitor 6 within the active site of HDAC isoforms were figured out through molecular modeling studies. Furthermore, a pH-responsive nanocarrier (Hyaluronic acid - fused quinazolinone 6 nanoparticles) was designed and assessed using a dialysis bag approach under both normal and acidic circumstances that confirmed the pH-sensitive nature of NPs. Delightfully, the nanoparticles demonstrated selective cell viability reduction potential towards the lung cancer cell lines (A549 lung cancer cell lines) and were found to be largely devoid of cell growth inhibitory effects under normal settings (L929, mouse fibroblast cells).

• Authors: Ram Sharma, Esha Chatterjee, Jacob Mathew, Sachin Sharma, N Vijayakameswara Rao, Chun-Hsu Pan, Sung-Bau Lee, Ashwani Dhingra, Ajmer S Grewal, Jing Ping Liou, Santosh K Guru, Kunal Nepali
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 240 Pg. 114602 (Oct 05 2022) ISSN: 1768-3254 [Electronic] France
• PMID: 35858522 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Nanoparticle Drug Delivery System
• Quinazolines
• Quinazolinones
• 2,3-trimethylene-4-quinazolone

Topics

• Animals
• Antineoplastic Agents (administration & dosage, chemistry, pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation
• Histone Deacetylase Inhibitors (chemistry)
• Hydrogen-Ion Concentration
• Lung Neoplasms (drug therapy, metabolism)
• Mice
• Nanoparticle Drug Delivery System
• Quinazolines
• Quinazolinones (administration & dosage, chemistry, pharmacology, therapeutic use)