| Abstrakt: |
Diarylheptanoids are a major class of plant secondary metabolites characterized by 1, 7-diphenyl heptanes in a seven-member carbon frame. In the present study, diarylheptanoids (garuganins 1, 3, 4 and 5) isolated from Garuga pinnatastem bark were evaluated for cytotoxic activity against MCF-7 and HCT15 cancer cell lines. Among the tested compounds, garuganin 5and 3exhibited the highest cytotoxic activity against HCT15 and MCF-7 with IC502.9 ± 00.8 μg/mL, 3.3 ± 0.1 μg/mL and 3.2 ± 0.1 μg/mL, and 3.5 ± 0.3 μg/mL, respectively. The molecular docking of garuganin 1, 3, 4 and 5 exhibited significant affinity toward the tested EGFR 4Hjo protein. The free energy and inhibitory constant of the compounds ranged from − 7.47 to − 8.49 kcal/mol and 3.34 micromolar to 944.20 nM nanomolar, respectively. Based on the results of cytotoxic activity, garuganin 5 and 3 were further evaluated for time- and concentration-dependent intracellular accumulation studies. The time-dependent intracellular concentration of garuganin 3 and 5 after 5 h of incubation increased about 5.5- and 4.5-fold, 204.16 ± 0.02 and 145.4 ± 0.36 nmol/L mg, respectively. The concentration-dependent intracellular concentration of garuganin 3 and 5 at 200 µg/mL increased of about > 12- and ninefold, 186.22 ± 0.05 and 98.73 ± 0.02 nmol/L mg, respectively. The intracellular concentrations of garuganin 3 and 5, in the presence of verapamil, cyclosporine and MK 571, was found to be significant in the basal direction compared to the apical directions. The results indicate that, garuganin 3 and 5 exhibited significant cytotoxic activity against MCF-7 and HCT15 cancer cell lines and also exhibited high binding affinity toward EGFR protein compared to garuganin 1 and 4. |
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