Synthesis and Anti-Renal Fibrosis Activity of Conformationally Locked Truncated 2-Hexynyl-N-6-Substituted-(N)-Methanocarba-nucleosides as A(3) Adenosine Receptor Antagonists and Partial Agonists
- 등재 SCIE, SCOPUS
- 발행기관 AMER CHEMICAL SOC
- 발행년도 2014
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000090876
- 본문언어 영어
- Published As http://dx.doi.org/10.1021/jm4015313
초록/요약
Truncated N-6-substituted-(N)-methanocarba-adenosine derivatives with 2-hexynyl substitution were synthesized to examine parallels with corresponding 4'-thioadenosines. Hydrophobic N-6 and/or C2 substituents were tolerated in A(3)AR binding, but only an unsubstituted 6-amino group with a C2-hexynyl group promoted high hA(2A)AR affinity. A small hydrophobic alkyl (4b and 4c) or N-6-cycloalkyl group (4d) showed excellent binding affinity at the hA(3)AR and was better than an unsubstituted free amino group (4a). A(3)AR affinities of 3-halobenzylamine derivatives 4f-4i did not differ significantly, with K-i values of 7.8-16.0 nM. N-6-Methyl derivative 4b (K-i = 4.9 nM) was a highly selective, low efficacy partial A(3)AR agonist. All compounds were screened for renoprotective effects in human TGF-beta 1-stimulated mProx tubular cells, a kidney fibrosis model. Most compounds strongly inhibited TGF-beta 1-induced collagen I upregulation, and their A(3)AR binding affinities were proportional to antifibrotic effects; 4b was most potent (IC50 = 0.83 mu M), indicating its potential as a good therapeutic candidate for treating renal fibrosis.
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