1546958-19-3Relevant academic research and scientific papers
Synthesis and anti-renal fibrosis activity of conformationally locked truncated 2-hexynyl-N6-substituted-(N)-methanocarba-nucleosides as A3 adenosine receptor antagonists and partial agonists
Nayak, Akshata,Chandra, Girish,Hwang, Inah,Kim, Kyunglim,Hou, Xiyan,Kim, Hea Ok,Sahu, Pramod K.,Roy, Kuldeep K.,Yoo, Jakyung,Lee, Yoonji,Cui, Minghua,Choi, Sun,Moss, Steven M.,Phan, Khai,Gao, Zhan-Guo,Ha, Hunjoo,Jacobson, Kenneth A.,Jeong, Lak Shin
, p. 1344 - 1354 (2014/03/21)
Truncated N6-substituted-(N)-methanocarba-adenosine derivatives with 2-hexynyl substitution were synthesized to examine parallels with corresponding 4′-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 N 6-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-4i did not differ significantly, with Ki values of 7.8-16.0 nM. N6-Methyl derivative 4b (Ki = 4.9 nM) was a highly selective, low efficacy partial A3AR agonist. All compounds were screened for renoprotective effects in human TGF-β1-stimulated mProx tubular cells, a kidney fibrosis model. Most compounds strongly inhibited TGF-β1-induced collagen I upregulation, and their A3AR binding affinities were proportional to antifibrotic effects; 4b was most potent (IC50 = 0.83 μM), indicating its potential as a good therapeutic candidate for treating renal fibrosis.
