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

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.

Graphical Abstract

Keywords:

• Isaindigotone
• cytotoxicity
• MMP
• apoptosis
• PI3K/AKT/mTOR

Disclosure statement

The authors declare that they do not have competing financial interest or personal relationships that could have appeared to influence the work reported in this paper.

Supplementary material

Supplementary material includes ¹H NMR, ¹³C NMR, HRESIMS, and HPLC Spectra of the derivatives and molecular docking analysis of Compound 6.

Additional information

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].