Efficient Synthesis of 2,3'-Spirobi (Indolin)-2'-Ones and Preliminary Evaluation of Their Damage to Mitochondria in HeLa Cells.

Bo Liu,Ying Zhi,Meiling Wang,Zhe Shao,Qingqiang Yao,Huajie Li,Haoyi Sun,Weilin Xie,Zhenjie Yu,Xingang Yao,Xin Wang

doi:10.3389/fphar.2021.821518

Abstract

A novel formal (4 + 1) annulation between N-(o-chloromethyl)aryl amides and 3-chlorooxindoles through in situ generated aza-ortho-QMs with 3-chlorooxindoles is reported for the synthesis of a series of 2,3′-spirobi (indolin)-2′-ones in high yields. Under structured illumination microscopy, compound 3a is found to change the mitochondrial morphology and induce mitophagy pathway, which might then trigger mitophagy in cancer cells.

Highlights

The high prevalence and fatal incidence of cancer in the population worldwide has fueled an intensified search for new therapeutic treatment options
Mitophagy is a process by which cells remove and degrade damaged mitochondria, and its typical feature is the overlap of lysosomes and mitochondria. (Chen et al, 2020b; Chen Q. et al, 2021) After clarifying that 3a can damage mitochondria, we further studied whether drug-induced mitochondrial damage is involved in the mitophagy pathway
Compared with that in untreated cells, the overlap of mitochondria and lysosome in cells treated with 3a for 24 h was increased significantly (Figure 2G). These results suggested that 3a induced the change of mitochondrial morphology, and triggered the mitophagy pathway

Summary

Introduction

The high prevalence and fatal incidence of cancer in the population worldwide has fueled an intensified search for new therapeutic treatment options. (Cho et al, 2020) Recent studies demonstrated dramatic alterations in mitochondrial form during the early stages of cell apoptosis that is a fragmentation of the network and the remodeling of the cristae, indicating mitochondria are closely associated with apoptotic pathways. (Karbowski and Youle, 2003) accumulating evidence indicates that the occurrence, development and metastasis of tumors has been linked to mitochondrial dysfunction and malfunctions, whose morphology is sensitive to their effects, featuring mitochondria a striking target in the design of anti-cancer drugs. (Mo et al, 2012; Hao et al, 2019) So far, some interesting and innovative examples have been reported, such as the increased anti-tumor effect of photodynamic therapy through the regulation of mitochondrial form by paclitaxel. Zhong’s group reported an ioide salts catalyzed functionalization of carbonyl compounds with sulfonamides

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Conclusion