2. Academic Validation
  3. Discovery of N-(3-((7H-purin-6-yl)thio)-4-hydroxynaphthalen-1-yl)-sulfonamide derivatives as novel protein kinase and angiogenesis inhibitors for the treatment of cancer: Synthesis and biological evaluation. Part III

Discovery of N-(3-((7H-purin-6-yl)thio)-4-hydroxynaphthalen-1-yl)-sulfonamide derivatives as novel protein kinase and angiogenesis inhibitors for the treatment of cancer: Synthesis and biological evaluation. Part III

  • Bioorg Med Chem. 2014 Feb 15;22(4):1487-95. doi: 10.1016/j.bmc.2013.11.052.
Fuming Xu 1,  Hao Xu 2,  Xuejian Wang 3,  Lei Zhang 4,  Qingli Wen 5,  Yingjie Zhang 6,  Wenfang Xu 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan 250012, PR China.
  • 2 Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu-Weiqi Road, Ji'nan 250021, PR China.
  • 3 Department of Pharmacology, Pharmacy and Biological Science College, WeiFang Medical University, Weifang 261053, PR China.
  • 4 Department of Pharmacy, School of Medicine, Qingdao University, Qingdao 266071, PR China.
  • 5 Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, PR China.
  • 6 Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan 250012, PR China. Electronic address: zhangyingjie@sdu.edu.cn.
  • 7 Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan 250012, PR China. Electronic address: xuwenf@sdu.edu.cn.
PMID: 24440479 DOI: 10.1016/j.bmc.2013.11.052
Abstract

A novel series of N-(3-((7H-purin-6-yl)thio)-4-hydroxynaphthalen-1-yl)-sulfonamides were designed and synthesized. Biological characterization revealed that several compounds exerted enhanced anti-proliferative activity against human umbilical vein endothelial cells (HUVECs) and several Cancer cell lines and high specific protein kinase and angiogenesis inhibitory activities. Compared with our previously synthesized compounds, the substitution of sulfonamide structure for amide fragment played an essential role for the advance of inhibitory activities. In addition, the replacement of 1H-1,2,4-triazole ring by 7H-purine did not result in obvious decrease of inhibition efficacy, indicating that the sulfonamide structure contributes even more to the inhibition efficacy than the 1H-1,2,4-triazole ring. Among these compounds, compound 9n demonstrated comparable in vitro antiangiogenic activities to pazopanib in both HUVEC tube formation assay and the rat thoracic aorta rings (TARs) test. Meanwhile, compound 9n was identified to inhibit Akt1 (IC₅₀=1.73 μM) and Abl tyrosine kinase (IC₅₀=1.53 μM) effectively.

Keywords

Abl; Angiogenesis; HUVEC tube formation; Protein kinase B/Akt; Rat thoracic aorta rings.

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