Carbocyclic pyrimidine nucleosides as inhibitors of S-adenosylhomocysteine hydrolase

Abstract

The design, synthesis, and unexpected inhibitory activity against S-adenosyl-homocysteine (SAH) hydrolase (SAHase, EC 3.3.1.1) for a series of truncated carbocyclic pyrimidine nucleoside analogues is presented. Of the four nucleosides obtained, 10 was found to be active with a Ki value of 5.0 microM against SAHase.

Figure 1

Potent Carbocylic SAHase Inhibitors.

Figure 2

Carbocylic derivatives of uridine and cytidine

Figure 3

Carbocylic Targets.

Figure 4

Inhibition of SAHase by 10. Assay solutions contained 50 mM potassium phosphate at pH 7.4, 0.39 units of adenosine deaminase, 132 nM of SAHase, 10 μM of SAH (substrate), and various concentrations of 10. Consumption of substrate was monitored at 265 nm.

Figure 5

Inhibition of SAHase by 10. In the assay solution, the concentration of 10 was held constant at 45 μM while the concentration of substrate was varied. Rates in the presence (data points at bottom of plot) and absence (data points at top of plot) of inhibitors were measured.

Scheme 1

Reagents and comditions: (a) i. N³-Bz-uracil, PPh₃, DIAD, CH₃CN, 0 °C to rt, 70%, ii. NaOH in MeOH (1%),rt, 15h, 75%: (b) TFA:H₂O (2:1), rt, 3h, 95%; (c) i. TIPBSCI, NEt₃, DMAP, CH₃CN, rt, 4 h; ii. NH₄OH, rt, 15 h, 65%.

Scheme 2

Reagents and conditions: (a) H₂ (25 psi), Pd/C, EtOH, rt, 30 min, quant.; (b) TFA/H₂O (2:1), rt, 3 h, 95%; (c) i. TIPBSCI, NEt₃, DMAP, CH₃CN, rt, 4 h; ii. NH₄OH, rt, 15 h, 65%.