2. Academic Validation
  3. Synthesis, biological evaluation and anti-proliferative mechanism of fluorine-containing proguanil derivatives

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

  • Bioorg Med Chem. 2020 Jan 15;28(2):115258. doi: 10.1016/j.bmc.2019.115258.
Di Xiao 1,  Zhicheng Lu 2,  Zhiren Wang 1,  Sichun Zhou 1,  Mengru Cao 3,  Jun Deng 1,  Xin Hu 1,  Mei Peng 1,  Caimei He 1,  Jingtao Wu 1,  Simeng Xu 1,  Huihui Zhang 1,  Cangcang Xu 1,  Wei Wang 4,  Aiying Guan 5,  Xiaoping Yang 6
Affiliations

Affiliations

  • 1 Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China.
  • 2 State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals R&D Company Ltd., Shenyang, China.
  • 3 TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medical Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China.
  • 4 TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medical Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China. Electronic address: [email protected].
  • 5 State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals R&D Company Ltd., Shenyang, China. Electronic address: [email protected].
  • 6 Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China. Electronic address: [email protected].
PMID: 31864776 DOI: 10.1016/j.bmc.2019.115258
Abstract

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.

Keywords

AMPK; Anti-proliferative; Biguanides; Fluorine-containing compounds.

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