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

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

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19 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1344-1354
Number of pages11
JournalJournal of Medicinal Chemistry
Issue number4
StatePublished - Feb 27 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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