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

J Enzyme Inhib Med Chem. 2022 Dec;37(1):1212-1226. doi: 10.1080/14756366.2022.2065672.

Abstract

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 μM. 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.

Keywords: Isaindigotone; MMP; PI3K/AKT/mTOR; apoptosis; cytotoxicity.

MeSH terms

  • Alkaloids
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-akt / pharmacology
  • Quinazolines
  • Stomach Neoplasms* / drug therapy
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Alkaloids
  • Antineoplastic Agents
  • isaindigotone
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Quinazolines
  • TOR Serine-Threonine Kinases

Grants and funding

This work was supported by the Key Research and Development Program of Gansu Province [Grant No. 21YF5FA112], the Technological Innovation Guidance Program of Gansu Province [Grant No. 21CX6QA127], the Key Program for International S&T Cooperation Projects of China Gansu Province [Grant No. 18YF1WA115], and The College Students’ innovation and entrepreneurship training program of Lanzhou University [Grant No. 20220260010].