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. 2009 Dec 10;52(23):7580-92.
doi: 10.1021/jm900426g.

Functionalized congeners of A3 adenosine receptor-selective nucleosides containing a bicyclo[3.1.0]hexane ring system

Dilip K Tosh  1 , Moshe Chinn, Andrei A Ivanov, Athena M Klutz, Zhan-Guo Gao, Kenneth A Jacobson
Affiliations

Functionalized congeners of A3 adenosine receptor-selective nucleosides containing a bicyclo[3.1.0]hexane ring system

Dilip K Tosh et al. J Med Chem. .

Abstract

(N)-Methanocarba nucleosides containing bicyclo[3.1.0]hexane replacement of the ribose ring previously demonstrated selectivity as A(3) adenosine receptor (AR) agonists (5'-uronamides) or antagonists (5'-truncated). Here, these two series were modified in parallel at the adenine C2 position. N(6)-3-Chlorobenzyl-5'-N-methyluronamides derivatives with functionalized 2-alkynyl chains of varying length terminating in a reactive carboxylate, ester, or amine group were full, potent human A(3)AR agonists. Flexibility of chain substitution allowed the conjugation with a fluorescent cyanine dye (Cy5) and biotin, resulting in binding K(i) values of 17 and 36 nM, respectively. The distal end of the chain was predicted by homology modeling to bind at the A(3)AR extracellular regions. Corresponding l-nucleosides were nearly inactive in AR binding. In the 5'-truncated nucleoside series, 2-Cl analogues were more potent at A(3)AR than 2-H and 2-F, functional efficacy in adenylate cyclase inhibition varied, and introduction of a 2-alkynyl chain greatly reduced affinity. SAR parallels between the two series lost stringency at distal positions. The most potent and selective novel compounds were amine congener 15 (K(i) = 2.1 nM) and truncated partial agonist 22 (K(i) = 4.9 nM).

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Figures

Figure 1
Figure 1
Inhibition of radioligand binding by (N)-methanocarba nucleoside analogues in membranes of CHO cells expressing the human A3AR. Inhibition curves are shown for the agonist analogues containing a 5′-N-methyluronamide group and compounds 15 (amine functionalized congener), 17b (biotinylated probe), and 18 (fluoresecent probe) and for the truncated partial agonist 22. All of the analogues shown were highly selective for the A3AR in comparison to the A1 and A2aARs.
Figure 2
Figure 2
Functional agonism by the tested in an assay of adenylate cyclase in membranes of CHO cells expressing the hA3AR. Each experiment was repeated three times. (A) Activity of the 5′-N-methyluronamide (N)-methanocarba analogues 17a and 18. The EC50 values of 17a and 18 were 2.50 ±0.42 and 1.09 ±0.28 nM, respectively. (B) Activity of the truncated (N)-methanocarba analogues 2b and 2c at the hA3AR. The full agonist 51 was included for comparison (representing 100% efficacy). The percent relative efficacy of 2b and 2c was 46 ± 4% and 44 ± 6%, respectively. The EC50 values of 2b and 2c were 4.2± 0.6 and 12± 1 nM, respectively.
Figure 3
Figure 3
Binding mode of amine congener 15 in the 5′-N-methyluronamide series obtained after InducedFit docking to the A3AR homology model built based on the crystal structure of the A2AAR.
Scheme 1<sup>a</sup>
Scheme 1a
a (A) (i) HC≡C(CH2)nCOOMe, Pd(PPh3)2Cl2, CuI, Et3N, DMF, room temp; (ii) 10% TFA, MeOH, 70 °C; (iii) appropriate alkyldiamine, MeOH, room temp; (iv) KOH, MeOH, room temp. (B) (v) For 17a: biotin, HATU, DIEA, DMF, room temp. For 17b: biotin-ε-aminocaproyl N-succinimidyl ester, Et3N, DMF, room temp. (vi) N-succinimidyl ester of chain-derivatized Cy5 cyanine dye, bicarbonate buffer, DMF.
Scheme 2 <sup>a</sup>
Scheme 2 a
a (i) 2-Iodo-6-chloropurine, Ph3P, DIAD, THF, room temp; (ii) 3-chlorobenzylamine, Et3N, MeOH, room temp; (iii) 10% methylamine, MeOH, room temp; (iv) HC≡C(CH2)nCOOMe, Pd(PPh3)2Cl2, Cul, Et3N, DMF, room temp; (v) KOH, MeOH; (vi) ethylenediamine, MeOH, room temp; (vii) 10% TFA, MeOH, 70 °C.
Scheme 3<sup>a</sup>
Scheme 3a
a (i) NaBH4, CeCl3 ·7H2O, MeOH, 0 °C; (ii) Et2Zn, CH2I2, CH2Cl2, room temp; (iii) 2-substituted-6-chloropurine, Ph3P, DIAD, THF, room temp; (iv) 3-iodo- or 3-chlorobenzylamine or cyclopentylamine, Et3N, MeOH, room temp; (v) 10% TFA, MeOH, 70 °C; (vi) HC≡C(CH2)2COOMe, Pd(PPh3)2Cl2, CuI, Et3N, DMF, room temp; (vii) ethylenediamine, MeOH, room temp.
Chart 1
Chart 1
(N)-Methanocarba Derivatives of Adenosine as A3AR-Selective Agonists (1a, 1b) and Antagonists (2a, 2b)a aGeneral formulas I and II represent two parallel structural series included in the present study. The agonist corresponding to X = Cl, n = 3, m = 2, R = H in series II was already reported.
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