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Hydroxy Cinnamic Acid Derivatives as Partial PPARγ Agonists: In silico Studies, Synthesis and Biological
Hardik Joshi1, Kavita Marulkar1, Vikram Gota2
1Bharati Vidyapeeth's College of Pharmacy, CBD Belapur, Navi Mumbai, India.
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.
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.
Insights
Novel PPARγ agonists derived from p-coumaric and ferulic acid show potent anti-proliferative effects. These compounds selectively activate PPARγ, inhibit cell cycle progression, and offer a potential therapeutic strategy for chronic myeloid leukemia.
Area of Science:
- Medicinal Chemistry
- Molecular Pharmacology
- Cancer Therapeutics
Background:
- Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor crucial in regulating genes associated with carcinogenesis.
- Selective PPARγ agonists are being explored as potential chemotherapeutic agents, analogous to selective estrogen receptor modulators in cancer treatment.
Purpose of the Study:
- To design and synthesize novel derivatives of p-coumaric acid and ferulic acid with enhanced selective PPARγ activation.
- To achieve a more potent anti-proliferative effect at lower doses compared to natural phytoconstituents.
Main Methods:
- Rational design and virtual screening of p-coumaric (3a-3y) and ferulic acid (4a-4y) derivatives.
- Synthesis of selected derivatives and characterization using NMR, Mass spectrometry, and elemental analysis.
- Evaluation of anti-proliferative activity (SRB assay), PPARγ activation, cell cycle analysis (propidium iodide), and Western blot analysis (PCNA, cyclin D1).
Main Results:
- Several synthesized molecules (3c, 3m, 4c, 4m) exhibited significant anti-proliferative activity with GI50 values below 50μM.
- These compounds effectively blocked the G0/G1 phase of the cell cycle in a dose-dependent manner.
- Western blot analysis confirmed the inhibition of proliferating cell nuclear antigen (PCNA) and cyclin D1 expression.
Conclusions:
- The novel PPARγ agonists demonstrate significant anti-proliferative effects against cancer cells.
- These findings suggest a potential therapeutic role for these compounds in the treatment of chronic myeloid leukemia.
- Further development of these selective PPARγ agonists could lead to novel therapeutic strategies for cancer chemotherapy.
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