Novel myricetin derivatives: Design, synthesis and anticancer activity.

Telomere and telomerase were closely related to occurrence and development of some cancers. To enhance ability of myricetin moiety for inhibiting telomerase, we designed a series of novel myricetin derivatives based on reasonable analysis. The telomerase inhibition assay showed that compound 6d displayed the most potent inhibitory activity with IC50 value of 0.91 µM. The anticancer activity assay showed that 6d exhibited high activity against human breast cells MDA-MB-231. The docking simulation of compound 6d was performed to get the probable binding model, the results demonstrated that the furan ring inserted into the active site deeply and had hydrophobic interactions with residues of Phe 568, Pro 627, four methoxy groups had hydrophobic interactions with residues of Phe 568, Pro 627, Lys 902, Val 904 and Pro 929. Western blot results showed that expression of p65 and TERT protein was clearly down-regulated by compound 6d. These data support further studies for the rational design of more efficient p65 and TERT modulators.

Novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives: synthesis and anticancer activity.

A series of novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives were designed and synthesized. All compounds have been screened for their antiproliferative activity against MGC-803, SGC-7901 and Bcap-37 cell lines in vitro. The results revealed that compounds 8a, 8c and 8e exhibited strong inhibitory activity against MGC-803 cell line. The flow cytometric analysis result showed that compound 8e could inhibit MGC-803 proliferation. Some title compounds were tested against telomerase, and compound 8e showed the most potent inhibitory activity with IC50 value at 1.02 ± 0.08 µM. The docking simulation of compound 8e was performed to get the probable binding model, among them, LYS 189, LYS 372, LYS 249 and ASP 254 may be the key residues for the telomerase activity.

Design and synthesis of novel 5-phenyl-N-piperidine ethanone containing 4,5-dihydropyrazole derivatives as potential antitumor agents.

A series of novel 5-phenyl-N-piperidine ethanone-4,5-dihydropyrazole derivatives as potential telomerase inhibitors were synthesized. The bioassays demonstrated that compounds 4d, 4f, 7a and 7b occupied high antiproliferative activities against SGC-7901, MGC-803 and Bcap-37 cell lines. By a modified TRAP assay, some titled compounds were tested against telomerase, and compound 7b showed the most potent inhibitory activity with IC(50) value at 2.00 ± 0.40 µM. The active compound 4d was also docked into the telomerase TERT active site to determine the probable binding model. The results indicated that conserved residues Lys189, Asp254 and Gln308 were important for ligand binding via hydrogen bond interactions.

Design and synthesis of N-phenylacetyl (sulfonyl) 4,5-dihydropyrazole derivatives as potential antitumor agents.

A series of novel N-phenylacetyl (sulfonyl) 4,5-dihydropyrazole derivatives as potential telomerase inhibitors were synthesized. The bioassay tests show that compound 4a exhibited high activity against human gastric cancer cell SGC-7901, liver cancer Hep-G2 and human prostate PC-3 cell lines with IC(50) values of 21.23±0.99, 29.43±0.32 and 30.89±1.07 µM, respectively. All title compounds were assayed for telomerase inhibition by a modified TRAP assay, the results show that compound 4a can inhibit telomerase with IC(50) value of 4.0±0.32 µM. Docking simulation was performed to position compound 4a into the telomerase (3DU6) active site to determine the probable binding model.

Synthesis and molecular docking study of novel coumarin derivatives containing 4,5-dihydropyrazole moiety as potential antitumor agents.

A series of novel coumarin derivatives containing 4,5-dihydropyrazole moiety as potential telomerase inhibitors were synthesized. The bioassay tests show that compound 3d exhibited potentially high activity against human gastric cancer cell SGC-7901 with IC(50) value of 2.69 ± 0.60 µg/mL. All title compounds were assayed for telomerase inhibition by a modified TRAP assay, the results show that compounds 3d and 3f can strongly inhibit telomerase with IC(50) values of 2.0 ± 0.07 and 1.8 ± 0.35 µM, respectively. Docking simulation was performed to position compound 3d into the telomerase (3DU6) active site to determine the probable binding model.

Synthesis and molecular docking studies of novel 2-chloro-pyridine derivatives containing flavone moieties as potential antitumor agents.

A series of novel 2-chloro-pyridine derivatives containing flavone, chrome or dihydropyrazole moieties as potential telomerase inhibitors were synthesized. The bioassay tests showed that compounds 6e and 6f exhibited some effect against gastric cancer cell SGC-7901 with IC(50) values of 22.28+/-6.26 and 18.45+/-2.79 microg/mL, respectively. All title compounds were assayed for telomerase inhibition by a modified TRAP assay, the results showed that compound 6e can strongly inhibit telomerase with IC(50) value of 0.8+/-0.07 microM. Docking simulation was performed to position compound 6e into the active site of telomerase (3DU6) to determine the probable binding model.