Synthesis and Anti-Renal Fibrosis Activity of Conformationally Locked Truncated 2-Hexynyl-N6-Substituted-(N)-Methanocarba-nucleosides as A3 Adenosine Receptor Antag

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• 作者：Akshata Nayak ; Girish Chandra ; Inah Hwang ; Kyunglim Kim ; Xiyan Hou ; Hea Ok Kim ; Pramod K. Sahu ; Kuldeep K. Roy ; Jakyung Yoo ; Yoonji Lee ; Minghua Cui ; Sun Choi ; Steven M. Moss ; Khai Phan ; Zhan-Guo Gao ; Hunjoo Ha ; Kenneth A. Jacobson ; Lak Shin Jeong
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 27, 2014
• 年：2014
• 卷：57
• 期：4
• 页码：1344-1354
• 全文大小：420K
• 年卷期：v.57,no.4(February 27, 2014)
• ISSN：1520-4804

文摘

Truncated N⁶-substituted-(N)-methanocarba-adenosine derivatives with 2-hexynyl substitution were synthesized to examine parallels with corresponding 4鈥?thioadenosines. Hydrophobic N⁶ and/or C2 substituents were tolerated in A₃AR binding, but only an unsubstituted 6-amino group with a C2-hexynyl group promoted high hA_2AAR affinity. A small hydrophobic alkyl (4b and 4c) or N⁶-cycloalkyl group (4d) showed excellent binding affinity at the hA₃AR and was better than an unsubstituted free amino group (4a). A₃AR affinities of 3-halobenzylamine derivatives 4f鈥?b>4i did not differ significantly, with K_i values of 7.8鈥?6.0 nM. N⁶-Methyl derivative 4b (K_i = 4.9 nM) was a highly selective, low efficacy partial A₃AR agonist. All compounds were screened for renoprotective effects in human TGF-尾1-stimulated mProx tubular cells, a kidney fibrosis model. Most compounds strongly inhibited TGF-尾1-induced collagen I upregulation, and their A₃AR binding affinities were proportional to antifibrotic effects; 4b was most potent (IC₅₀ = 0.83 渭M), indicating its potential as a good therapeutic candidate for treating renal fibrosis.