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.
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.
Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan 250012, PR China.
Fuming
F
Xu
Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu-Weiqi Road, Ji'nan 250021, PR China.
Hao
H
Xu
Department of Pharmacology, Pharmacy and Biological Science College, WeiFang Medical University, Weifang 261053, PR China.
Xuejian
X
Wang
Department of Pharmacy, School of Medicine, Qingdao University, Qingdao 266071, PR China.
Lei
L
Zhang
Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, PR China.
Qingli
Q
Wen
Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan 250012, PR China. Electronic address: zhangyingjie@sdu.edu.cn.
Yingjie
Y
Zhang
Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan 250012, PR China. Electronic address: xuwenf@sdu.edu.cn.
Wenfang
W
Xu
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D045325:HCT116 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000096926:Benzenesulfonamides
D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D016315:Proto-Oncogene Proteins c-abl; D051057:Proto-Oncogene Proteins c-akt; D011687:Purines; D013449:Sulfonamides; C000591915:N-(3-((7H-purin-6-yl)thio)-4-hydroxynaphthalen-1-yl)-3,4-dimethoxybenzenesulfonamide; D000096926:Benzenesulfonamides
Abl; Angiogenesis; HUVEC tube formation; Protein kinase B/Akt; Rat thoracic aorta rings