Purine nucleoside phosphorylase inhibitor

A. Secrist, III, Application of crystallographic and modelling methods in the design of purine nucleoside phosphorylase inhibitors, Proc. Natl. Acad. Sci. USA 88 11540 (1991). 

Gilbertsen RB, Scott ME, Dong MK, Kossarek LM, Bennett MK, Schrier DJ, Sircar JC. Preliminary report on 8-amino-9-(2-thienylmethyl) guanine (PD 119,229), a novel and potent purine nucleoside phosphorylase inhibitor. Agents and Actions 1987 21 272-4. 

The (ft)-4-phenyl-2-oxazolidinonc auxiliary was used in the process development and scale up of Novartis purine nucleoside phosphorylase inhibitor PNP405 (16) (Scheme 23.2).43 Asymmetric alkylation of 17 with bromoacetonitrile provided a 7 1 diastereoisomeric ratio of crude 18. Recrystallization afforded 18 in 80% yield and >99% de. Simple addition of sodium borohydride in tetrahydrofuran (THF)-water at room temperature44 resulted in the desired y-cyano alcohol 19 and recovery of the auxiliary. 

Halazy, S., and Danzin, C., PhosphonoaUcylpurine derivatives as purine nucleoside phosphorylase inhibitors, Merrell Dow Pharmaceuticals, Eur. Patent Appl. EP 338168, 1989 Chem. Abstr., 112, 158267, 1990. 

Yokomatsu, L, Hayakawa, Y, Kihara, T., Soeda, S., Urano, K., and Shibuya, A., Purine derivatives and purine nucleoside phosphorylase inhibitors containing them, Hisamitsu Pharmaceutical, Japanese Patent Appl. JP 2002080486, 2002 Chem. Abstr., 136, 241663, 2002. 

C11H14N4O5 282.255 Purine nucleoside phosphorylase inhibitor. Potential immunotherapeutic and antileu-kaemic agent. 

C11H13N3O5 267.241 Inhibits Pneumocystis carinii in vitro and in vivo. Purine nucleoside phosphorylase inhibitor. Antileishmanial and potential antileukaemic agent. Struct, originally assigned to Pyrrolosine, P-117. 

The enantioselective synthesis of phosphonothioate (146) and fluoromethylene phosphonate (147) analogues of cyclic phosphatidic acid, the novel antagonists of lysophosphatidic acid receptors, has been presented. Synthesis of difluoromethy-lene analogue of sphingomyelin (148) in optically active form as a new sphingomyelinase inhibitor has been achieved. The synthesis and biological evaluation of 9-(5, 5 -difluoro-5 -phosphonopentyl)guanine derivatives (149), for use as a purine nucleoside phosphorylase inhibitor, has been described. 

M. Carson, Z. Yang, Y. S. Babu, and J. A. Montgomery, Acta Crystallogr., D51,536 (1995). Calculation of Relative Binding Affinities of Purine Nucleoside Phosphorylase Inhibitors. 

The susceptibilities of some of these fluorinated purine nucleosides to the action of enzymes are now described. In contrast to the inertness of the 2 -deoxy-2 -fluoro- and 3 -deoxy-3 -fluorocytidine analogs 739, 744, and 821 towards cytidine deaminase, the adenosine compounds 867, 883, and 906 are readily deaminated - by the adenosine deaminase in erythrocytes and calf intestine, but the resulting (deaminated) inosine compounds (from 867 and 883), as well as 888, are highly resistant - to cleavage by purine nucleoside phosphorylase (to give hypoxanthine base for the first two). The reason was discussed. Both 867 and 883 can form the 5 -triphosphates, without deamination, in human erythrocytes or murine sarcoma cells in the presence of 2 -deoxycoformycin, an adenosine deaminase inhibitor, but... 

The review articles by Schramm (1998, 2003) provide a number of examples of the successful application of this protocol to the design of enzyme-specific transition state-like inhibitors. Among these, the transition state inhibitors of human purine nucleoside phosphorylase (PNP) are particularly interesting from a medicinal chemistry perspective, as examples of these compounds have entered human clinical trials for the treatment of T-cell cancers and autoimmune disorders. 

Secrist, S. Y. Babu, C. E. Bugg, W. C. Guida, and S. E. Ealick, Structure-based design of inhibitors of purine nucleoside phosphorylase, 3,9-arylmethyl derivatives of a 9-deazaguanine substituted on the methylene group, J. Med. Chem. 36 3771 (1993). 

A series of purine acyclonucleosides with guanine and a four-carbon chain having a 2 -substituent (F, NH2, N3) and 3, 4 -dihydroxy had been evaluated as inhibitors of mammalian purine nucleoside phosphorylase (91MI8). 

This rational approach to drug design has been adopted in developing a specific inhibitor of the human cellular enzyme, purine nucleoside phosphorylase (PNP). PNP functions in the purine salvage pathway, catalysing the reversible reaction shown below ... 

Figure 2.5. Diagramatic representation of the goal of rational drug design (a) illustrates the normal catalytic activity exhibited by purine nucleoside phosphorylase (PNP) (b) represents an effective inhibitor of PNP, which hts well into the active site thereby blocking its normal enzymatic activity...

Fluorescence and phosphorescence emission spectroscopy were employed to study the interaction of E. coli purine nucleoside phosphorylase (PNP) with its specific inhibitor, FA. The results show, for the first time, the application of phosphorescence spectroscopy to the identification of the tautomeric form of the inhibitor bound by the enzyme <2004MI377>. 

The dialkoxyphosphinydifluoromethyllithium reagent has also been used in the preparation of bioactive compounds such as 2-amino-7,7-difluoro-7-phos-phonoheptanoic acid for evaluation in the -methyl-D-aspartic acid binding assay [265], 9-(5,5-difluoro-5-phosphonopentyl)quanine as a multisubstrate analog inhibitor of purine nucleoside phosphorylase [266], fluorinated phosphoserine analog [267, 268] (Scheme 91) and nucleoside 5 -deoxy-5 -di-fluoromethylphosphonates [267,269] (Scheme 92). 

Montgomery JA, Niwas S, Rose JD, Secrist JA 3d., Babu YS, Bugg CE, Erion MD, Guida WC, Ealick SE. Structure-based design of inhibitors of purine nucleoside phosphorylase. 1. 9-(arylmethyl) derivatives of 9-deazaguinine. J Med Chem 1993 36 55-69. 

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