Design, synthesis, in vitro and in silico evaluation of indole-based tetrazole derivatives as putative anti-breast cancer agents
Abstract
A series of new indole-tetrazole derivatives were designed and synthesized to develop potential anti-breast cancer agents. The compounds exhibited in vitro anti-proliferative activity against ER-α positive T-47D (IC50 = 3.82-24.43 μM), MCF-7 (IC50 = 3.08-22.65 μM), and ER-α negative MDA-MB-231 (IC50 = 7.69-19.4 μM) human breast cancer cell lines. Compounds 5d and 5f displayed significant anti-proliferative activity compared to bazedoxifene (IC50 = 14.23 ± 0.68 μM), with IC50 values of 10.00 ± 0.59 and 3.83 ± 0.74 μM, respectively, against the ER-α dominant T-47D cell line. Also, both compounds showed non-significant cytotoxicity against normal cells HEK-293. Further, the ER-α binding affinity of 5d and 5f was assessed through a fluorescence polarization-based competitive binding assay, where 5d and 5f have shown significant binding with IC50 = 5.826 and 110.6 nM, respectively, as compared to the standard drug bazedoxifene (IC50 = 339.2 nM). Western blot analysis confirmed that compound 5d reduced ER-α protein expression in T-47D cells, hindering its transactivation and signalling pathways. Additionally, a molecular docking study suggests that compounds 5d and 5f bind in such a fashion that induces conformational changes in the protein, culminating in their antagonistic effect. Pharmacokinetic profiles showed that the compounds possessed drug-like properties. Furthermore, molecular dynamics simulation studies establish the dynamic stability and conformational behaviour of the…
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Evidence Hub reads this as a simulation / modelling, done in cell cultures (in vitro) and computer models (in silico), not in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
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