Novel p-Functionalized Chromen-4-on-3-yl Chalcones Bearing Astonishing Boronic Acid Moiety as MDM2 Inhibitor: Synthesis, Cytotoxic Evaluation and Simulation Studies
| Autor: | Ruchika Garg, Richa Kaur Bhatia, Manmohan Yadav, Satyavathi Kancherla, Lakhwinder Singh, Jitender Madan, Maninder Kaur, Evans C. Coutinho, Raghuvir R. S. Pissurlenkar |
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| Rok vydání: | 2020 |
| Předmět: |
Chalcone
Protein Conformation Stereochemistry Antineoplastic Agents Chemistry Techniques Synthetic Molecular Dynamics Simulation 010402 general chemistry 01 natural sciences Hydrophobic effect Structure-Activity Relationship chemistry.chemical_compound Chalcones Cell Line Tumor Drug Discovery Humans Moiety Benzopyrans Phenylboronic acid Cytotoxicity 010405 organic chemistry Hydrogen bond Proto-Oncogene Proteins c-mdm2 Boronic Acids 0104 chemical sciences Molecular Docking Simulation chemistry Docking (molecular) Drug Design Drug Screening Assays Antitumor Boronic acid |
| Zdroj: | Medicinal Chemistry. 16:212-228 |
| ISSN: | 1573-4064 |
| DOI: | 10.2174/1573406415666190531123751 |
| Popis: | Background: Novel 4-[3-(6/7/8-Substituted 4-Oxo-4H-chromen-3-yl)acryloyl]phenylboronic acid derivatives (5a-h) as well as other 6/7/8-substituted-3-(3-oxo-3-(4-substitutedphenyl) prop-1-enyl)-4H-chromen-4-one derivatives (3a-u) have been designed as p53-MDM2 pathway inhibitors and reported to possess significant cytotoxic properties against several cancer cell lines. Objectives: The current project aims to frame the structure-anticancer activity relationship of chromen-4-on-3-yl chalcones (3a-u/5a-h). In addition, docking studies were performed on these chromeno-chalcones in order to have an insight into their interaction possibilities with MDM2 protein. Methods: Twenty-nine chromen-4-on-3-yl chalcone derivatives (3a-u/5a-h) were prepared by utilizing silica supported-HClO4 (green route with magnificent yield) and tested against four cancer cell lines (HCT116, MCF-7, THP-1, NCIH322). Results: Among the series 3a-u, compound 3b exhibited the highest anticancer activity (with IC50 values ranging from 8.6 to 28.4 µM) overall against tested cancer cell lines. Interestingly, para- Boronic acid derivative (5b) showed selective inhibition against colon cancer cell line, HCT-116 with an IC50 value of 2.35 µM. Besides the emblematic hydrophobic interactions of MDM2 inhibitors, derivative 5b was found to exhibit extra hydrogen bonding with GLN59 and GLN72 residues of MDM2 in molecular dynamics (MD) simulation. All the compounds were virtually nontoxic against normal fibroblast cells. Conclusion: Novel compounds were obtained with good anticancer activity especially 6- Chlorochromen-4-one substituted boronic acid derivative 5b. The molecular docking study proposed good activity as a MDM-2 inhibitor suggesting hydrophobic as well as hydrogen bonding interactions with MDM2. |
| Databáze: | OpenAIRE |
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