Design, synthesis and biological evaluation of N-benzylaryl cinnamide derivatives as tubulin polymerization...

Area of Science:

• Medicinal Chemistry
• Molecular Pharmacology
• Cancer Biology

Background:

• The N-benzylaryl derivative 9 served as a lead compound for developing novel anticancer agents.
• Molecular hybridization was employed, introducing cinnamoyl fragments to synthesize new chemical entities.

Purpose of the Study:

• To design and synthesize novel N-benzylaryl cinnamide derivatives.
• To evaluate the in vitro antiproliferative activities of these compounds against various cancer cell lines.
• To investigate the structure-activity relationship and identify potent anticancer candidates.

Main Methods:

• Synthesis of 33 N-benzylaryl cinnamide derivatives (15a–15ag).
• In vitro antiproliferative assays against MGC-803, HCT-116, KYSE450, SGC-7901, and 13 other tumor cell lines.
• Mechanism of action studies including tubulin polymerization inhibition, YAP degradation, cell cycle analysis, apoptosis induction, and protein expression profiling.

Main Results:

• Most synthesized compounds showed significant antiproliferative activity (IC50 < 0.5 μM).
• Compound 15e (MY-1076) displayed superior potency (IC50 values as low as 0.017 μM) against multiple cancer cell lines, outperforming colchicine and the lead compound.
• Compound 15e (MY-1076) inhibits tubulin polymerization, induces YAP degradation, causes G2/M phase arrest, promotes apoptosis, and alters cell cycle/apoptosis protein expression.

Conclusions:

• Compound 15e (MY-1076) is a potent N-benzylaryl cinnamide derivative with dual anticancer mechanisms: tubulin polymerization inhibition and YAP degradation.
• MY-1076 demonstrates significant potential as a novel anti-gastric cancer agent.