2. Academic Validation
  3. Synthesis and biological evaluation of novel benzylidene-succinimide derivatives as noncytotoxic antiangiogenic inhibitors with anticolorectal cancer activity in vivo

Synthesis and biological evaluation of novel benzylidene-succinimide derivatives as noncytotoxic antiangiogenic inhibitors with anticolorectal cancer activity in vivo

  • Eur J Med Chem. 2019 Oct 1:179:805-827. doi: 10.1016/j.ejmech.2019.06.094.
Kaixiu Luo 1,  Yafeng Bao 2,  Feifei Liu 2,  Chuanfan Xiao 1,  Ke Li 3,  Conghai Zhang 1,  Rong Huang 1,  Jun Lin 4,  Jihong Zhang 5,  Yi Jin 6
Affiliations

Affiliations

  • 1 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, PR China.
  • 2 Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming, 650500, PR China.
  • 3 Biomedical Department, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, PR China.
  • 4 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, PR China. Electronic address: linjun@ynu.edu.cn.
  • 5 Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming, 650500, PR China. Electronic address: zhjihong2000@126.com.
  • 6 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, PR China. Electronic address: jinyi@ynu.edu.cn.
PMID: 31295714 DOI: 10.1016/j.ejmech.2019.06.094
Abstract

A novel series of benzylidene-succinimide derivatives were synthesized, characterized and evaluated for their cytotoxicities against HCT116, and SW480 Cancer cells and NCM460 normal human cells. Their antiangiogenic capabilities were evaluated using a chick chorioallantoic membrane (CAM) assay. The compound, XCF-37b, was selected as the most potent antiangiogenic inhibitor with noncytotoxicity to evaluate the pharmacological effects on human umbilical vein endothelial cells (HUVECs) and Cancer cells in vivo and in vitro. The results showed that XCF-37b inhibited HT29-cell colon tumor growth in vivo, without showing cytotoxicity against the five other Cancer cell lines in vitro. Experiments confirmed that XCF-37b had obvious antiangiogenic activity by HUVEC migration and invasion and rat aortic ring angiogenesis ex vivo. Mechanism studies showed that XCF-37b inhibited the Akt/mTOR and VEGFR2/KDR/Flk-1 signaling pathways, as evidenced by decreased expressions of phosphor-AKT (p-AKT), p-mTOR, p-VEGFR2 (Tyr175), p-Src (Tyr416), p-FAK (Tyr925), and p-Erk1/2 (Thr202/Tyr204). Moreover, XCF-37b significantly decreased the protein expressions of matrix metalloproteinase-2 (MMP-2), MMP-9 and hypoxia-inducible factor-1α (HIF-1α). XCF-37b generally regulated angiogenic inhibition through several regulatory pathways, without significantly interfering with colorectal Cancer cell growth.

Keywords

Angiogenesis; Arylmethylene succinimide; Colon cancer; Hypoxia-inducible factor-1α; Matrix metalloproteinase; Noncytotoxic; mTOR.

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