4.6 Article

Design, synthesis, and cytotoxic activities of isaindigotone derivatives as potential anti-gastric cancer agents

Journal

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 37, Issue 1, Pages 1212-1226

Publisher

TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2022.2065672

Keywords

Isaindigotone; cytotoxicity; MMP; apoptosis; PI3K; AKT; mTOR

Funding

  1. Key Research and Development Program of Gansu Province [21YF5FA112]
  2. Technological Innovation Guidance Program of Gansu Province [21CX6QA127]
  3. Key Program for International S&T Cooperation Projects of China Gansu Province [18YF1WA115]
  4. College Students' innovation and entrepreneurship training program of Lanzhou University [20220260010]

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A series of novel derivatives of isaindigotone showed significant anti-proliferative activity on human gastrointestinal cancer cells, with Compound 6 being the most effective inhibitor on AGS cells. The potential mechanism suggested that Compound 6 induced apoptosis and suppressed the PI3K/AKT/mTOR signal pathway, possibly through its interaction with AKT1.
A series of novel derivatives of isaindigotone, which comes from the root of isaits indinatca Fort, were synthesised (Compound 1-26). Four human gastrointestinal cancer cells (HCT116, PANC-1, SMMC-7721, and AGS) were employed to evaluate the anti-proliferative activity. Among them, Compound 6 displayed the most effective inhibitory activity on AGS cells with an IC50 (50% inhibitory concentration) value of 2.2 mu M. The potential mechanism study suggested that Compound 6 induced apoptosis in AGS cells. The collapse of mitochondrial membrane potential (MMP) in AGS cells was proved. In docking analysis, good affinity interaction between Compound 6 and AKT1 was discovered. Treatment of AGS cells with Compound 6 also resulted in significant suppression of PI3K/AKT/mTOR signal pathway. The collapse of MMP and suppression of PI3K/AKT/mTOR signal pathway may be responsible for induction of apoptosis. This derivative Compound 6 could be useful as an underlying anti-tumour agent for treatment of gastric cancer.

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