Synthetic strategies toward carbocyclic purine-pyrimidine hybrid nucleosides

Abstract

The blending of key structural features from the purine and pyrimidine nucleobase scaffolds gives rise to a new class of hybrid nucleosides. The purine-pyrimidine hybrid nucleosides can be viewed as either N-3 ribosylated purines or 5,6-disubstituted pyrimidines, thus recognition by both purine- and pyrimidine-metabolizing enzymes is possible. Given the increasing reports of the development of resistance in many enzymatic systems, a drug that could be recognized by more than one enzyme could prove highly advantageous in overcoming resistance mechanisms related to binding site mutations. In that regard, the design, synthesis and results of preliminary biological activity for a series of carbocyclic uracil derivatives with either a fused imidazole or thiazole ring are presented herein.

Figure 1

Isoadenosine (IsoA) and DHCe-isoA.

Figure 2

Purine-pyrimidine hybrid nucleosides.

Figure 3

Hybrid tragets.

Figure 4

Inhibition of SAHase by 3. Assay solutions contained 50 mM potassium phosphate at pH 7.4, 0.39 units of adenosine deaminase, 132 nM of SAHase, 10 1M of SAH (substrate), and various concentrations of 10. Consumption of substrate was monitored at 265 nM.

Figure 5

The concentration of inhibitor 3 was held constant at 45 °M while the concentration of substrate was varied. Initial rates in the presence (data points at the bottom of the plot) and absence (data points at the top of the plot) of inhibitors were measured. There was no change in absorbance at 265 nM in the absence of SAH.

Scheme 1

Reagents and conditions: a, LDA, THF, I₂, -78 °C, 5 h; b, NaN₃, DMF, rt, 1h; c, 10% Pd/C, MeOH, H₂, rt, 1h; d, NaHCO₃, Br₂, rt 1h; e, HC(OEt)₃, reflux, 1.5h; f, TFA/H₂O (2:1), rt, 2h.

Scheme 2

Reagents and conditions: a, 33% NH₂Me, EtOH, rt, 1.5h, 94%; b, SOCI₂, pyridine, reflux, 3h

Scheme 3

Reagents and conditions: a, LDA, THF, I₂, -78 °C, 3h, 58%; b, 33% NH₂Me, EtOH, rt, 1.5h, 94%; c, SOCI₂, pyridine, reflux, 3h, 80%; d, i, TFA:H₂O (2:1), rt, 18h; ii. Ac₂O, pyridine, DMAP, CH₂CI₂, 12h, 82% for 2 steps; e, 10:1 CH₃CN:H₂O, CAN, 55 °C, 3h, 86%; f NH₃, MeOH, rt, 15h, 65%.

Scheme 4

Reagents and conditions: a, LDA, THF, I₂, -78 °C, 3h, 58%; b, 33% NH₂Me, EtOH, rt, 1.5h, 94%; c, SOCI₂, pyridine, reflux, 3h, 80%; d, i. TFA:H₂O (2:1), rt, 18h; ii. Ac₂O, pyridine, DMAP, CH₂CI₂, 12h, 82% for 2 steps; e, 10:1 CH₃CN:H₂O, CAN, 55 °C, 3h, 86%; f, NH₃, MeOH, rt, 15h, 65%.