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OBJECTIVE To design and synthesize novel CDK9 inhibitors 1-(2-adamantan-1-yl-1H-indole-5-yl)-3-substituted thiourea derivatives and study their anti-gastric cancer activities. METHODS A series of target compounds 7a-7m were synthesized from adamantan formyl chloride by 6-step reactions. The structures of the target compounds were identified by 1H-NMR, 13C-NMR, and HRMS. MTT assay was used to detect the inhibitory effect of synthetic compounds on the growth of gastric cancer cells, ADP-Glo kinase assay was used to detect the effect of synthetic compounds on CDK9 kinase activity and Western blot assay was used to detect the regulatory effect of hit compound on downstream signaling pathways. RESULTS The target compounds had certain inhibitory activity on the growth of gastric cancer cells, among which compound 7l had the best activity on the gastric cancer cell line (SGC-7901) with IC50 value of (2.26±0.04) μmol·L-1, and 7l had little toxicity on normal gastric epithelial cells (IC50 >100 μmol·L-1). In addition, 7l showed specific inhibitory effect on CDK9 kinase activity in vitro. Upon 1 μmol·L-1 7l treatment, CDK9 kinase activity was only (21.67±1.47)%, and in gastric cancer cells 7l inhibited CDK9 downstream protein p-ser2 expression in a concentration-dependent manner. Finally, molecular docking study showed that 7l could stably bind to the active site of CDK9 and had a high binding affinity. CONCLUSION This series of compounds have good anti-gastric cancer activity and are worth of further study.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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