Structure−Activity Relationships of 2-Chloro-N⁶-substituted-4‘-thioadenosine-5‘-uronamides as Highly Potent and Selective Agonists at the Human A₃ Adenosine Receptor

Abstract

We have established structure-activity relationships of novel 4'-thionucleoside analogues as the A(3) adenosine receptor (AR) agonists. Binding affinity, selectivity toward other AR subtypes, and efficacy in inhibition of adenylate cyclase were studied. From this study, 2-chloro-N(6)-methyl-4'-thioadenosine-5'-methyluronamide (36a) emerged as the most potent and selective agonist at the human A(3) AR. We have also revealed that, similar to 4'-oxoadenosine analogues, at least one hydrogen on the 5'-uronamide moiety was necessary for high-affinity binding at the human A(3) AR, presumably to allow this group to donate a H bond within the binding site. Furthermore, bulky substituents on the 5'-uronamide reduced binding affinity, but in some cases large 5'-uronamide substituents, such as substituted benzyl and 2-phenylethyl groups, maintained moderate affinity with reduced efficacy, leading to A(3) AR partial agonists or antagonists. In several cases for which the corresponding 4'-oxonucleosides have been studied, the 4'-thionucleosides showed higher binding affinity to the A(3) AR.

Design, Synthesis, and Anti-Tumor Activity of 4′-Thionucleosides as Potent and Selective Agonists at the Human A3Adenosine Receptor

“…[5] From this study, 2-chloro-N 6 -methyl-and 2-chloro-N 6 -(3-iodobenzyl)-4 -thioadenosine-5 -methyluronamides (K i = 0.28 ± 0.09 nM and K i = 0.38 ± 0.07 nM, respectively) were discovered as highly potent and selective agonists at the human A 3 AR. It was also found that 5 -monoalkyl amide SCHEME 1 Reagents and conditions: a) R 1 NH 2 , Et 3 N; b) 80% AcOH; c) TBSOTf, pyridine; d) NaOMe, MeOH; e) PDC, DMF; f) amines, EDC, HOBT, DIPEA, CH 2 Cl 2 ; g) TBAF, THF.…”

“…[5] Treatment of 4 with various alkyl-and arylalkyl amines in EtOH produced N 6 -alkyl-or arylalkylamino-4 -thioadenosine derivatives 5. Because removal of the isopropylidene group under acidic conditions at the final step resulted in deglycosylation, the isopropylidene group in 5 was changed to di-O-TBS ether 6.…”

Modified Nucleosides as Selective Modulators of Adenosine Receptors for Therapeutic Use

“…The A 3 agonists IB-MECA [N 6 -(3-iodobenzyl)-5 0 -N-methylcarboxamidoadenosine; CF101] and its 2-chloro analogue Cl-IB-MECA (CF102) were the first selective agonists of the A 3 AR. Currently, more selective agonists are available, including the conformationally locked Northern (N) methanocarba derivative, MRS3558 (((1 0 R,2 0 R,3 0 S,4 0 R,5 0 S)-4-(2-chloro-6-[(3-chlorophenylmethyl)amino] purin-9-yl)-1-(methylaminocarbonyl)bicyclo[3.1.0]hexane-2,3-diol)), and the 4 0 -thio analogue of Cl-IB-MECA, LJ-529 [6,66]. MRS3558 maintains a receptor-preferred (N) conformation of the ribose-like ring.…”

“…IB-MECA is also entering clinical trials for chronic plaque psoriasis, keratoconjunctivitis sicca, and dry eye syndrome. [3,4,6,13,16,52,66].…”

N6-Substituted 5′-N-Methylcarbamoyl-4′-selenoadenosines as Potent and Selective A3 Adenosine Receptor Agonists with Unusual Sugar Puckering and Nucleobase Orientation

“…Compound 1 is in a phase II clinical trial for hepatocellular carcinoma and is projected to enter a clinical trial for nonalcoholic steatohepatitis. 7 On the basis of the structure of 1 , its bioisosteric 4′-thio analogue 2 (thio-Cl-IB-MECA, X = S, R 1 = 3-iodobenzyl, R 2 = Cl, K i = 0.38 nM for A 3 AR) 8 was discovered as the second generation A 3 AR agonist. Compound 2 exhibited potent biological activities in models of cancer 9 and cerebral ischemia 10 with novel mechanisms of action.…”