Design, synthesis, anticancer evaluation and docking studies of new pyrimidine derivatives as potent thymidylate...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Cancer remains a significant global health challenge, necessitating the development of novel therapeutic agents.
• Pyrimidine derivatives are a class of compounds with diverse biological activities, including anticancer properties.

Purpose of the Study:

• To design, synthesize, and evaluate novel 6-aryl-5-cyano-pyrimidine derivatives for anticancer activity.
• To investigate the mechanism of action, including thymidylate synthase (TS) inhibition and apoptosis induction.

Main Methods:

• Synthesis of 6-aryl-5-cyano-pyrimidine derivatives.
• In vitro anticancer activity evaluation against HePG-2, MCF-7, and HCT-116 cell lines.
• Enzyme inhibition assays for thymidylate synthase (TS).
• Apoptosis studies using caspase-3 and Bax/Bcl2 ratio analysis.
• Molecular docking studies to predict binding interactions with TS.

Main Results:

• Several compounds exhibited significant anticancer activity, comparable to 5-fluorouracil.
• All tested compounds showed marked TS inhibitory activity, with IC50 values ranging from 3.89 to 15.74 nM.
• Compound 8 demonstrated potent proapoptotic effects by increasing active caspase-3 and the Bax/Bcl2 ratio.

Conclusions:

• The synthesized 6-aryl-5-cyano-pyrimidine derivatives possess promising anticancer properties.
• Inhibition of thymidylate synthase and induction of apoptosis are key mechanisms underlying their efficacy.
• These compounds represent potential leads for the development of new anticancer drugs.