2. Academic Validation
  3. Design, synthesis, molecular docking, and evaluation of sulfonyl quinazoline analogues as promising liver cancer drugs

Design, synthesis, molecular docking, and evaluation of sulfonyl quinazoline analogues as promising liver cancer drugs

  • Bioorg Chem. 2024 Sep 1:153:107777. doi: 10.1016/j.bioorg.2024.107777.
Gopalakrishnan Venkatesan 1,  Chong Yong Ping 2,  Hong Chen 3,  S Perumal 4,  Aneesh V Karkhanis 5,  Giorgia Pastorin 6
Affiliations

Affiliations

  • 1 Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Lower Kent Ridge Road, 4 Science Drive 2, Singapore 117544, Singapore. Electronic address: gopal.venkatesan@u.nus.edu.
  • 2 Critical Analytics for Manufacturing Personalized-Medicine Programme (CAMP), Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, #12-02 CREATE Tower, Singapore 138602, Singapore.
  • 3 School of Biological Sciences (SBS), Nanyang Technological University, 60 Nanyang Dr, Singapore 637551, Singapore.
  • 4 Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, Engineering Block 4, Singapore 117583, Singapore.
  • 5 Certara UK Ltd., Certara Predictive Technologies Division, Level 2-Acero, 1 Concourse Way, Sheffield S1 2B1, UK.
  • 6 Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Lower Kent Ridge Road, 4 Science Drive 2, Singapore 117544, Singapore.
PMID: 39244968 DOI: 10.1016/j.bioorg.2024.107777
Abstract

Inhibiting cyclin-dependent kinases (CDK) offers an important arsenal for Cancer treatments by interfering with apoptotic proteins related to Cancer. Novel selective cyclin-dependent kinases inhibitors using the Quinazoline as the cap with multiple electronic donating (EDG) and/or electron withdrawing group (EWG) substituted Aniline chain at the C-2 position were designed, synthesized, and evaluated for activity against liver Cancer. Among the tested compounds, compounds B34 and B35 emerged as potent candidates in the series, with IC50 values of 0.102 ± 0.04 µM and 0.058 ± 0.003 µM, respectively. They also suppressed the enzymatic activity of CDK2/cyclinA2 selectively. Further biological studies revealed that compounds B34 and B35 arrested the cell cycle, and induced Apoptosis in HepG-2 Cancer cells through a Caspase-mediated mechanism, facilitating the release of Cyt-c through modulation of Caspase-3 expression. More importantly, compounds B34 and B35 suppressed the xenografted tumor growth in mice in a dose-dependent manner. Finally, through a molecular docking study, it was confirmed that compoundsB34 andB35 retained crucial hydrogen bonding and hydrophobic interactions with CDK receptor, rationalizing their higher efficacy compared to Other compounds in the series. Taken together, the Quinazoline derivatives B34 and B35 may serve as novel chemotherapeutic agents through inhibition of CDK.

Keywords

Apoptosis; Cyclin-dependent kinase; Hepatocellular carcinoma; Molecular docking; Quinazoline.

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