Design, Synthesis and Molecular Docking Analysis of Flavonoid Derivatives as Potential Telomerase Inhibitors

Abstract

Based on the structural scaffolds of natural products, two series of flavonoid derivatives, for a total of twelve compounds, were designed and synthesized as potential human telomerase inhibitors. Using a modified TRAP-PCR assay, compound 5c exhibited the most potent inhibitory activity against human telomerase with an IC50 value of less than 50 μM. In vitro, the results demonstrated that compound 5c had potent anticancer activity against five classes of tumor cell lines. The molecular docking and molecular dynamics analyses binding to the human telomerase holoenzyme were performed to elucidate the binding mode of active compound 5c. This finding helps the rational design of more potent telomerase inhibitors based on the structural scaffolds of natural products.

In Silico Screening of DNA Gyrase B Potent Flavonoids for the Treatment of Clostridium difficile Infection from PhytoHub Database

“…The spheres in blue, red, and green colors indicate the high toxicity, low toxicity, and no toxicity, respectively. After calculations, only 25 S1) were found to have no mutagenicity, tumorigenicity, irritant, and reproductive effect, in good agreement with the reported biogical activities [81,82,[84][85][86]. Therefore, these molecules were then subjected to binding affinity prediction against the ATPase domain of GyrB using molecular docking analysis.…”

Recent Advances in Bioactive Flavonoid Hybrids Linked by 1,2,3-Triazole Ring Obtained by Click Chemistry

“…Considering that telomerase is widely expressed in human tumors and tumor-derived cell lines, whereas in the normal stem cell this enzyme activity is proportionally low, the inhibition of this enzyme is a strategy for anticancer drug discovery [ 80 ]. Fan et al (2019) reported the synthesis and telomerase inhibitory potential of 1,2,3-linked flavonol-glycosyl hybrid 40 ( Figure 14 ) [ 81 ]. The synthesis was performed by Click Chemistry, with previously obtained O -propargylated flavonol and glycosyl azide.…”

“…Interestingly, 40 revealed no cytotoxic effect against two normal cells (Hacat and human bronchial epithelial BEAS-2B), with IC 50 values > 200 μM, showing selectivity for cancer cells. Molecular docking studies and molecular dynamics analyses allowed us to conclude that 40 has similar interactions with telomerase to those observed for BIBR1532, a highly specific inhibitor of this enzyme [ 81 ].…”

In Silico Design, Synthesis, and Biological Evaluation of Anticancer Arylsulfonamide Endowed with Anti-Telomerase Activity

“…Several other compounds designed using in silico approaches have been tested as potential inhibitors of the catalytic subunit of telomerase such as benzylidene-hydrazone analogs [22], dihydropyrazole [23][24][25][26][27][28][29], dibenzopyrroles [30], flavone pyridines [31], 1,3,4-oxadiazole derivatives [32][33][34][35][36], pyrazole-5-carboxamides and pyrazole-pyrimidines [37], spiroketals [37], celastrol derivatives [38], myricetin derivatives [39], indolyl-2'-deoxynucleotide analogs [40], flavonoid derivatives [41], and chrolactomycin derivatives [42]. Other classes of compounds developed as telomerase inhibitors are reported in two recent reviews [43,44].…”