Adenosine deaminase inhibitors. Synthesis and biological evaluation of C1' and nor-C1' derivatives of (+)-erythro-9-[2(S)-hydroxy-3(R)-nonyl]adenine

Abstract

The synthesis of various chiral derivatives of (+)-erythro-9-(2-hydroxy-3-nonyl)adenine, (+)-EHNA, from (2S,3R)-3-amino-1,2-O-isopropylidene-1,2-nonanediol by condensation with 5-amino-4,6-dichloropyrimidine is described. The compounds synthesized were C1'- and nor-C1'-(+)-EHNA derivatives. When tested with calf spleen ADA, C1'-OH- and nor-C1'-(+)-EHNA had comparable inhibitory activity that was 1 order of magnitude lower than that of (+)-EHNA. Potency was reduced further in nor-C1' derivatives.

Adenosine Deaminase Inhibitors. Synthesis and Biological Evaluation of Putative Metabolites of (+)-erythro-9-(2S-Hydroxy-3R-nonyl)adenine

“…Compound 22 was prepared from 21, by following the procedure described for the formation of 8. The residue obtained after solvent removal was chromatographed over silica gel (EtOAchexanes, 1:5) to give 22 (28%): NMR (CDC13) 0.63-2.33 (m, 20 ), 3.03-5.13 (m, 11H, 3 D20 exchangeable), 7.13 (2S,3R)-2-(Benzyloxy)-3-(6-chloropurin-9-yl)nonan-8-0I (23). An acidified (concentrated HC1, 0.15 mL) solution of 22 (0.3 g, 0.63 mmol) in TEOF (15 mL) was stirred at room temperature for 24 h. The residue obtained, after removal of TEOF, was dissolved in absolute ethanol (10 mL), containing PPTS (0.025 g), and refluxed for 1 h. Solvent was then removed under reduced pressure, and the crude product was purified by silica gel column chromatography using EtOAchexanes (3:1) to give 23 (0.15 g, 60%): NMR (CDC13) ó 0.66-2.42 (m, 15H, 1 D20 exchangeable), 3.36-3.96 (m, 2H), 4.4 (qAB, J = 13.4 Hz, 2H), 4.46-4.79 (m, 1H), 7.19 (s, 5H), 8.26 (s, 1H), 8.62 (s, 1H).…”

Adenosine deaminase: Functional implications and different classes of inhibitors

“…212 It is a semi-tight competitive inhibitor of ADA with K i ranging from 1.6 to 7.0 Â 10 À9 , depending on experimental conditions M. 70,213 EHNA has been reported to have a particular mechanism of inhibition. [218][219][220][221] The lipophilic chain can be elongated up to C9; 218 furthermore a chlorine atom (12; CPC-405, 9 H -chloro-EHNA, K i 2.7 Â 10 À9 M on calf spleen ADA) or a bulky lypophilic groups, such as phthalimido (13; CPC-406, 9 H -phthalimido-EHNA, K i 0.95 Â 10 À9 M on calf spleen ADA) at the end of side chain are still well tolerated. 214 Chemically, EHNA is formed by adenine coupled in N9 to a chiral hydroxynonyl chain.…”

Activation of 6-Alkoxy-Substituted Methylenecyclopropane Nucleoside Analogs Requires Enzymatic Modification by Adenosine Deaminase-Like Protein 1

“…4), indicating that ADA and/or ADAL-1 is uniquely involved in the mechanism of action of the third generation of MCPNAs. To distinguish which enzyme, ADA or ADAL-1, is involved in this enzymatic conversion, MBX-2168 was coincubated with erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an inhibitor of only ADA (24,26), to directly examine whether ADA is the enzyme involved in the mechanism of action of MBX-2168. The results demonstrated no effect on the antiviral activity of MBX-2168 (data not shown), thus indicating that ADAL-1 is the enzyme most likely involved in the activation of MBX-2168.…”