Background: Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that regulates
the expression of many genes relevant to carcinogenesis. By analogy to selective estrogen receptor modulator for treatment
of cancer, selective or partial PPARγ agonists are considered clinically important for chemotherapy of cancer.
Objective: In this study we have rationally modified the structure of existing p-coumaric acid and ferulic acid, which
would selectively activate PPARγ and exert their anti-proliferative effect at lower dose as compared to natural
Method: A series of p-coumaric (3a-3y) and ferulic acid (4a-4y) derivatives were designed as docked and virtually
studied for their molecular properties using suitable software. Synthesized derivatives were assessed to check their
effect on non-transformed hepatocytes using MTT assay. The final products, 3a-3y and 4a-4y, substituted 4-
hydroxycinnamic acid derivatives and ferulic acid derivatives respectively were synthesized by stirring compound 1a
or 1b with compounds 2a-2y (molar ratio- 1:2) for 24 hours, in presence of K2CO3, using dimethyl formamide (DMF)
as the solvent. Synthesized molecules were characterized by 1HNMR, 13C NMR, Mass and elemental analysis.
Synthesized molecules were studied for their antiproliferative activity by SRB assay. Compounds were screened
further evaluated for PPARγ activating assay, cell cycle analysis (propidium iodide) and westernblot analysis.
Results: Molecules 3c, 3m, 4c and 4m were found to have GI50 value less than 50μM. These molecules were found to
block G0/G1 phase of cell cycle in dose dependent manner. Western blot analysis revealed that these molecules inhibit
proliferating cell nuclear antigen (PCNA) and cyclin D1 expression.
Conclusion: Collectively, these results suggest that these molecules could play a role as a novel therapeutic strategy
for chronic myeloid leukemia.