Synthesis and Biological Evaluation of Small Molecules as Potential Anticancer Multitarget Agents

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Drug Discovery

Background:

• Cancer cells evade immune surveillance via PD-L1 (programmed death receptor ligand 1).
• Tumor growth and metastasis are driven by angiogenesis, regulated by VEGFR-2 (vascular endothelial growth factor receptor 2).
• Targeting multiple pathways, including c-Myc, offers a promising strategy for cancer therapy.

Purpose of the Study:

• To design, synthesize, and evaluate novel triazole-based compounds as multitarget inhibitors.
• To investigate the inhibition of VEGFR-2, PD-L1, and c-Myc proteins.
• To assess the antiproliferative, antiangiogenic, and antivascular activities of these derivatives.

Main Methods:

• Synthesis of 26 triazole-based derivatives.
• Biological evaluation of antiproliferative activity against HT-29, A-549, MCF-7, and HEK-293 cell lines.
• Assessment of target engagement (VEGFR-2, PD-L1, c-Myc) for selected compounds.
• Endothelial microtube formation assay to determine antiangiogenic and antivascular effects.

Main Results:

• Compound 23 demonstrated potent downregulation of VEGFR-2 compared to sorafenib.
• Compound 23 exhibited comparable inhibition of PD-L1 and c-Myc to BMS-8.
• Chloro-substituted derivatives showed significant antiangiogenic and antivascular activities.

Conclusions:

• Triazole derivatives represent a viable scaffold for developing multitarget cancer therapeutics.
• Compound 23 is a promising lead candidate for further investigation due to its dual inhibition of VEGFR-2 and PD-L1/c-Myc pathways.
• The antiangiogenic and antivascular properties highlight the potential of these compounds in preventing tumor growth and metastasis.