4.6 Article

Benzothiazole Amides as TRPC3/6 Inhibitors for Gastric Cancer Treatment

期刊

ACS OMEGA
卷 6, 期 13, 页码 9196-9203

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acsomega.1c00514

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资金

  1. Key Research Project of Yantai [2019XDHZ102]
  2. National Natural Science Foundation of China [82073888, 81773674]
  3. Science and Technology Support Program for Youth Innovation in Universities of Shandong [2019KJM009]
  4. Top Talents Program for One Case Discussion of Shandong Province
  5. National Key R&D Program of China [2020YFA0908800]
  6. Shenzhen Science and Technology Research Grant [JCYJ20190808152019182]
  7. Hubei Province Scientific and Technical Innovation Key Project [2020BAB058]
  8. Applied Basic Research Program of Wuhan Municipal Bureau of Science and Technology [2019020701011429]
  9. Local Development Funds of Science and Technology Department of Tibet [XZ202001YD0028C]
  10. Fundamental Research Funds for the Central Universities [ZNJC201931]

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The study identified a benzothiazole amide derivative as a TRPC6 activator and showed that compound 1s exhibited good anti-gastric cancer activity and inhibited invasion and migration of MKN-45 cells in vitro. The design and synthesis of similar compounds with potential TRPC6 inhibitory activity is discussed.
Transient receptor potential canonical channel 6 (TRPC6) has been implicated in many kinds of malignant tumors, but very few potent TRPC6 antagonists are available. In this study, a benzothiazole amide derivative 1a was discovered as a TRPC6 activator in a cell-based high-throughput screening. A series of benzothiazole amide derivatives were designed and synthesized. The docking analyses indicated that the conformations of the compounds bound to TRPC6 determined the agonistic or antagonistic activity of the compounds against TRPC6, and compound 1s with the tetrahydronaphthalene group in R-1 position fit well into the binding pocket of the antagonist-bound conformation of TRPC6. Compound 1s showed an inhibitory potency order of TRPC3 (IC50 3.3 +/- 0.13 mu M) approximate to C6 (IC50 4.2 +/- 0.1 mu M) > C7 with good anti-gastric cancer activity in a micromolecular range against AGS and MKN-45, respectively. In addition, 1s inhibited the invasion and migration of MKN-45 cells in vitro.

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