Synthesis and antiviral activities of isonucleosides and their monophosphates.

Abstract

Although several isonucleoside triphosphates can be incorporated into a DNA chain and elongated to various degrees, none of the corresponding nucleosides exhibited significant inhibitory potency against virus in vitro. The active anti-retroviral form of a nucleoside analog is its triphosphate anabolic products. However, a monophosphorylation catalyzed by a kinases is usually restricted. In order to bypass the first phosphorylation step, a series of isonucleoside analogs and their bis(isopropyl) monophosphates were designed and the synthesis of the target compds. was achieved by a selective microwave-mediated method using bis(1-methylethyl)phosphoramidous acid bis(1-methylethyl) ester and L-sugars [2-(6-amino-9H-purin-9-yl)-1,4-anhydro-2-deoxy-L-arabinitol, 1,4-anhydro-2-deoxy-2-(3,4-dihydro-5-methyl-2,4-dioxo-1(2H)-pyrimidinyl)-L-arabinitol 2-(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)-1,4-anhydro-2-deoxy-L-arabinitol] and corresponding D-sugars as reactants. The synthesis of corresponding 4-(6-amino-9H-purin-9-yl)-2,5-anhydro-4-deoxy-L-lyxose di-Me acetal, 2,5-anhydro-4-deoxy-4-(3,4-dihydro-5-methyl-2,4-dioxo-1(2H)-pyrimidinyl)-L-lyxose di-Me acetal and 4-(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)-2,5-anhydro-4-deoxy-L-lyxose di-Me acetal was also reported. The cell-based assay results showed that bis(isopropyl) isonucleoside monophosphates displayed improved potency against HSV-2 and HIV-1. [on SciFinder(R)]