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Stereoselective Synthesis, Anticolon Cancer Activity, Molecular Docking, and Dynamics Simulation Studies of
Rajat Ghosh1, Afzal B Shaik2,3, Richie R Bhandare4,5
1Department of Pharmacy, Tripura University (A Central University), Suryamaninagar, 799022, Tripura, India.
Background:
Spirooxindoles have been reported to be effective anticancer drug candidates by displaying promising pre-clinical results. Therefore, to find out a lead spirocyclic oxindole template, a series of spirooxindole derivatives bearing pyrrolizidine (14a-e) and N-methyl pyrrolidine (15a-e) were synthesized using an efficient multicomponent, one-pot, and stereoselective [3+2] cycloaddition reaction and evaluated in vitro against HT29 and HCT116 human colon cancer cell lines.
Methods:
The pyrrolizidine and N-methyl pyrrolidine spirooxindole derivatives were synthesised in excellent regio- and stereoselectivity using previously optimized reaction conditions. They were evaluated in vitro against cell lines HT29 and HCT116. In silico ADME profiling, molecular docking, and dynamics simulation studies were performed to ascertain the probable mode of action of the lead derivative.
Results And Discussion:
The spirooxindoles were characterized using FTIR, ESI-MS, 1H and 13C NMR, purity was determined by RP-HPLC, and stereochemistry was confirmed by X-ray crystallography. Compound 14a produced the best anti-colon cancer activity with IC50 values of 62.66 and 9.55 μM against HT29 and HCT116 human colon cancer cell lines, respectively. The in silico studies revealed that MDM2 protein inhibition is a probable mode of anti-colon cancer activity, supported by the data obtained in the molecular docking and molecular dynamics study.
Conclusion:
The described [3+2] cycloaddition reaction proved to be a highly efficient and catalyst- free reaction. The in vitro cell viability assays and in silico studies revealed that more spirooxindoles can be designed with a varied degree of substitution to target colon cancer.
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