Hydroxy Cinnamic Acid Derivatives as Partial PPARγ Agonists: In silico Studies, Synthesis and Biological Characterization Against Chronic Myeloid Leukemia Cell Line (K562).
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 phytoconstituents.


METHODS
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.


CONCLUSIONS
Collectively, these results suggest that these molecules could play a role as a novel therapeutic strategy for chronic myeloid leukemia.
Bharati Vidyapeeth's College of Pharmacy, CBD Belapur, Navi Mumbai, India.
Hardik
H
Joshi
Bharati Vidyapeeth's College of Pharmacy, CBD Belapur, Navi Mumbai, India.
Kavita
K
Marulkar
Tata Memorial's Advance Centre in Treatment, Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai, India.
Vikram
V
Gota
Bharati Vidyapeeth's College of Pharmacy, CBD Belapur, Navi Mumbai, India.
C S
CS
Ramaa
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D003373:Coumaric Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology*; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D003373:Coumaric Acids; D047493:PPAR alpha; C004999:ferulic acid
K562; Partial PPARγ agonists; cell cycle; hydroxycinaamic acid; western blot analysis