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

Research output: Contribution to journalArticle

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Abstract

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
Volume57
Issue number4
DOIs
StatePublished - Feb 27 2014
Externally publishedYes

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Adenosine A3 Receptor Antagonists
Fibrosis
Kidney
Adenosine
Inhibitory Concentration 50
Up-Regulation
Collagen
5-carboxy-methylaminomethyl-2'-O-methyluridine
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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.

In: Journal of Medicinal Chemistry, Vol. 57, No. 4, 27.02.2014, p. 1344-1354.

Research output: Contribution to journalArticle

Nayak, A, Chandra, G, Hwang, I, Kim, K, Hou, X, Kim, HO, Sahu, PK, Roy, KK, Yoo, J, Lee, Y, Cui, M, Choi, S, Moss, SM, Phan, K, Gao, ZG, Ha, H, Jacobson, KA & Jeong, LS 2014, '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', Journal of Medicinal Chemistry, vol. 57, no. 4, pp. 1344-1354. https://doi.org/10.1021/jm4015313
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. / 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. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 4. pp. 1344-1354.
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abstract = "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.",
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T1 - 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

AU - Nayak, Akshata

AU - Chandra, Girish

AU - Hwang, Inah

AU - Kim, Kyunglim

AU - Hou, Xiyan

AU - Kim, Hea Ok

AU - Sahu, Pramod K.

AU - Roy, Kuldeep K.

AU - Yoo, Jakyung

AU - Lee, Yoonji

AU - Cui, Minghua

AU - Choi, Sun

AU - Moss, Steven M.

AU - Phan, Khai

AU - Gao, Zhan Guo

AU - Ha, Hunjoo

AU - Jacobson, Kenneth A.

AU - Jeong, Lak Shin

PY - 2014/2/27

Y1 - 2014/2/27

N2 - 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.

AB - 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.

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