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  3. Synthesis and bioevaluation of diaryl urea derivatives as potential antitumor agents for the treatment of human colorectal cancer

Synthesis and bioevaluation of diaryl urea derivatives as potential antitumor agents for the treatment of human colorectal cancer

  • Eur J Med Chem. 2022 Feb 5;229:114055. doi: 10.1016/j.ejmech.2021.114055.
Chun-Feng Wu 1,  Qing-Chen Wang 2,  Rui Chen 1,  Hai-Ling Zhou 3,  Ting-Ting Wu 4,  Yao Du 1,  Na-Na Zhang 1,  Hui-Min Zhang 3,  Zu-Yan Fan 3,  Li-Li Wang 1,  Chu-Jiao Hu 1,  Zhi-Pei Sang 1,  Hong-Liang Li 5,  Ling Wang 6,  Lei Tang 7,  Ji-Quan Zhang 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550025, PR China.
  • 2 Department of Pharmacy, Guizhou Provincial People's Hospital, Guiyang, 550002, PR China.
  • 3 Joint International Research Laboratory of Synthetic Biology and Medicine, Ministry of Education, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, PR China.
  • 4 State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550025, PR China; Department of Pharmacy, the First People's Hospital of Bijie, Bijie, 551700, PR China.
  • 5 School of Medicine, Yunnan University, 2 Cuihu North Road, Kunming, 650091, PR China.
  • 6 Joint International Research Laboratory of Synthetic Biology and Medicine, Ministry of Education, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, PR China. Electronic address: [email protected].
  • 7 State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550025, PR China. Electronic address: [email protected].
  • 8 State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550025, PR China. Electronic address: [email protected].
PMID: 34971874 DOI: 10.1016/j.ejmech.2021.114055
Abstract

The development of inhibitors targeting the PI3K-Akt-mTOR signaling pathway has been greatly hindered by the on-target AEs, such as hyperglycemia and hepatotoxicities. In this study, a series of diaryl urea derivatives has been designed and synthesized based on clinical candidate gedatolisib (6aa), and most of the newly synthesized derivatives showed kinase inhibitory and antiproliferative activities within nanomolar and submicromolar level, respectively. The terminal l-prolineamide substituted derivative 6 ab showed 8.6-fold more potent PI3Kα inhibitory activity (0.7 nM) and 4.6-fold more potent antiproliferative effect against HCT116 cell lines (0.11 μM) compared with control 6aa. The potential antitumor mechanism and efficacy of 6 ab in HCT116 xenograft models have also been evaluated, and found 6 ab showed comparable in vivo antitumor activity with 6aa. The safety investigations revealed that compound 6 ab exhibited more safer profiles in the selectivity of liver cells (selectivity index: >6.6 vs 1.85) and blood glucose regulation than 6aa. In addition, the in vitro stability assays also indicated our developed compound 6 ab possessed good metabolic stabilities.

Keywords

Antitumor; Kinase inhibitor; Mammalian target of the rapamycin; Phosphatidylinositol 3-kinase; Structure-activity relationship; Synthesis.

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