Synthesis and anti-renal fibrosis activity of conformationally locked truncated 2-hexynyl-N(6)-substituted-(N)-methanocarba-nucleosides as A3 adenosine receptor antagonists and partial agonists.
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 A3AR binding, but only an unsubstituted 6-amino group with a C2-hexynyl group promoted high hA2AAR 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. N(6)-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.
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
Akshata
A
Nayak
Girish
G
Chandra
Inah
I
Hwang
Kyunglim
K
Kim
Xiyan
X
Hou
Hea Ok
HO
Kim
Pramod K
PK
Sahu
Kuldeep K
KK
Roy
Jakyung
J
Yoo
Yoonji
Y
Lee
Minghua
M
Cui
Sun
S
Choi
Steven M
SM
Moss
Khai
K
Phan
Zhan-Guo
ZG
Gao
Hunjoo
H
Ha
Kenneth A
KA
Jacobson
Lak Shin
LS
Jeong
D058909:Adenosine A3 Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D058918:Adenosine A3 Receptor Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005355:Fibrosis / Q000517:prevention & control*; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007674:Kidney Diseases / Q000517:prevention & control*; D008968:Molecular Conformation; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use
D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D009705:Nucleosides