The Design of Forodesine HCl and Other Purine Nucleoside Phosphorylase Inhibitors

Abstract

Purine nucleoside phosphorylase (PNP) is a purine-metabolizing enzyme that catalyzes the reversible phosphorolysis of purine nucleosides such as 2 0 -deoxyguanosine (dGuo) and 2 0 -deoxyinosine to their respective bases and deoxyribose-a-1-phosphate [1][2][3][4][5]. In cells, PNP normally acts in the phosphorolytic direction, since the 6-oxopurine metabolic products are further metabolized. The importance of PNP to the integrity of the immune system became apparent with the description of a rare form of immune deficiency found in children who are genetically deficient in the PNP enzyme [6]. Children lacking the PNP enzyme have severe T-cell immunodeficiency while, in most cases, maintaining normal or high B-cell function. The biochemical mechanism underlying the T-cell selective immunosuppression in PNP-deficient patients has been extensively studied. Metabolically, these patients have a low uric acid concentration as they lack the necessary hypoxanthine or guanine substrates. These patients also have elevated levels of the nucleosides 2 0 -deoxyguanosine, 2 0 -deoxyinosine, inosine and guanosine as they lack the PNP enzyme necessary to catabolize these materials. While all nucleoside levels are elevated, only dGuo affects the T-cell population. As the concentration of dGuo increases within cells, it accumulates and is phosphorylated to 2 0 -deoxyguanosine phosphate (dGMP) by the enzyme 2 0 -deoxycytidine kinase. Subsequently, dGMP is converted to 2 0 -deoxyguanosine diphosphate (dGDP), which is then further converted to the triphosphate (dGTP) [7,8]. The elevated dGTP level creates an imbalance in the endogenous nucleotide pool, which in turn induces apoptosis (Figure 18.1).The unique sensitivity of human T cells to PNP deficiency is attributed to a relatively high level of kinase and a low level of nucleotidase activity compared to other cell types. This unique enzyme ratio is especially characteristic of immature T cells. Based upon these observations, several novel classes of PNP inhibitors have been designed for the treatment of T-cell-mediated diseases. Among the diseases Modified Nucleosides: in Biochemistry, Biotechnology and Medicine. Edited by Piet Herdewijn

Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs

“… , The protonated nitrogen of the iminoribitol ring of forodesine exhibits a similar charge distribution to the ribosyl moiety oxocarbenium ion of the transition state. Furthermore, the 9-deazapurine of forodesine can be protonated at N7, which provides additional interaction with a residue of the purine nucleoside phosphorylase active site . In addition, instead of a natural glycosidic bond, forodesine has a carbon–carbon bond which is not readily cleaved by purine nucleoside phosphorylase …”

“…Furthermore, the 9-deazapurine of forodesine can be protonated at N7, which provides additional interaction with a residue of the purine nucleoside phosphorylase active site. 644 In addition, instead of a natural glycosidic bond, forodesine has a carbon−carbon bond which is not readily cleaved by purine nucleoside phosphorylase. 630 Forodesine was shown to be a potent purine nucleoside phosphorylase inhibitor.…”