Synthesis, biological evaluation and anti-proliferative mechanism of fluorine-containing proguanil derivatives.

Di Xiao, Zhicheng Lu, Zhiren Wang, Sichun Zhou, Mengru Cao, Jun Deng, Xin Hu, Mei Peng, Caimei He, Jingtao Wu, Simeng Xu, Huihui Zhang, Cangcang Xu, Wei Wang, Aiying Guan, Xiaoping Yang

Bioorganic & medicinal chemistry 2020 Jan 15

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Proguanil, a member of biguanide family, has excellent anti-proliferative activities. Fluorine-containing compounds have been demonstrated to have super biological activities including enhanced binding interactions, metabolic stability, and reduced toxicity. In this study, based on the intermediate derivatization methods, we synthesized 13 new fluorine-containing proguanil derivatives, and found that 7a,7d and 8e had much lower IC50 than proguanil in 5 human cancerous cell lines. The results of clonogenic and scratch wound healing assays revealed that the inhibitory effects of derivatives 7a,7d and 8e on proliferation and migration of human cancer cell lines were much better than proguanil as well. Mechanistic study based on representative derivative 7a indicated that this compound up-regulates AMPK signal pathway and downregulates mTOR/4EBP1/p70S6K. In conclusion, these new fluorine-containing derivatives show potential for the development of cancer chemotherapeutic drugs. Copyright © 2019 Elsevier Ltd. All rights reserved.

Citation

Di Xiao, Zhicheng Lu, Zhiren Wang, Sichun Zhou, Mengru Cao, Jun Deng, Xin Hu, Mei Peng, Caimei He, Jingtao Wu, Simeng Xu, Huihui Zhang, Cangcang Xu, Wei Wang, Aiying Guan, Xiaoping Yang. Synthesis, biological evaluation and anti-proliferative mechanism of fluorine-containing proguanil derivatives. Bioorganic & medicinal chemistry. 2020 Jan 15;28(2):115258