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4,5-diazafenylfluorene-rhodanine conjugates promote anoikis in A375 cells via inhibiting PPAR-γ expression

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Abstract

Regulation of PPAR-γ protein activity has anti-tumor effects, both activation, and inhibition. Based on the PPAR-γ protein and previous work in our laboratory, we designed and synthesized a series of 4,5-diazafenylfluorene-rhodanine conjugates and explored their anti-tumor activity and mechanism in vitro. This series of 4,5-diazafenylfluorene-rhodanine conjugates could induce rapid ubiquitin degradation of PPAR-γ to inhibit its function. And the cytotoxicity in vitro showed that these compounds had selective cytotoxicity to several kinds of tumor cells. Among them, the compound YINQ-9 possessed the best activity against melanoma A375 cells, with an IC50 value of 4.11 μM. Further experiments demonstrated that YINQ-9 could affect the A375 cell’s adhesion to the extracellular matrix and induce anoikis by inhibiting the MAPK/ERK pathway and activating the mitochondrial endogenous apoptosis pathway. This series of novel 4,5-diazafenylfluorene-rhodanine conjugates could inhibit the function of PPAR-γ by inducing ubiquitin degradation, thus inducing A375 cells to anoikis. This study provides a new direction for the design of anti-tumor drugs targeting PPAR-γ.

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Abbreviations

BCA:

Butyleyanoacrylate

CCK-8:

Cell Counting Kit-8

DAPI:

4,6-diamidino-2-phenylindole

DMSO:

Dimethyl sulfoxide

ECM:

Extracellular matrix

PI:

Propidium Iodide

PPARs:

Peroxisome proliferators-activated receptors

TZD:

Thiazolidinedione

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (NSFC, grant numbers 21572207, 21877101), the Zhejiang Leading Innovation and Entrepreneurship Team (grant number 2018R01015), and the Zhejiang Provincial Key Discipline of Chemical Biology.

Author contributions

WZ, YW, QY, and AA conceived and designed the experiments. QY, AA, and YZ performed the experiments. QY, AA, Y.Z., MW, and XX acquired and analyzed the experimental data. QY, and AA wrote the manuscript. WZ, AA, YW, and QY revised the manuscript. All authors reviewed the manuscript.

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Authors and Affiliations

  1. Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, China

    Qiang Yin, Annoor Awadasseid, Yongnan Zhou, Ming Wang, Xuqiong Xiong & Wen Zhang

  2. Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou, 310014, China

    Qiang Yin, Annoor Awadasseid, Yongnan Zhou, Ming Wang, Xuqiong Xiong & Wen Zhang

  3. Lab of Molecular Immunology, Virus Inspection Department, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, 310051, China

    Yanling Wu

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  1. Qiang Yin
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Yin, Q., Awadasseid, A., Zhou, Y. et al. 4,5-diazafenylfluorene-rhodanine conjugates promote anoikis in A375 cells via inhibiting PPAR-γ expression. Med Chem Res 31, 1476–1487 (2022). https://doi.org/10.1007/s00044-022-02928-5

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