Synthesis of analogs of forodesine HCl, a human purine nucleoside phosphorylase inhibitor—Part II

Kamath, Vivek; Xue, Jie; Juarez-Brambila, Jesus J.

doi:10.1016/j.bmcl.2009.04.018

Cited by 8 publications

(4 citation statements)

References 22 publications

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“…The selectivity observed in this case is not surprising, since deazaguanines are well-known inhibitors of the mammalian PNPs. 1,3,[26][27][28][29][30][31][32][33] On the other hand, the nucleoside analogs (8-10) showed good selectivity towards the parasite enzyme (from about 2 to 6.4-fold). This set of compounds with different activity against the two PNPs, allowed SSRs to be quantitatively described and categorized.…”

Section: Resultsmentioning

confidence: 99%

Structural basis for selective inhibition of purine nucleoside phosphorylase from Schistosoma mansoni: Kinetic and structural studies

Castilho

Postigo

Pereira

et al. 2010

Bioorganic & Medicinal Chemistry

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Section: Resultsmentioning

confidence: 99%

Structural basis for selective inhibition of purine nucleoside phosphorylase from Schistosoma mansoni: Kinetic and structural studies

Castilho

Postigo

Pereira

et al. 2010

Bioorganic & Medicinal Chemistry

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“…Hence, the need remains for repeating these studies in which serum concentrations of all purines are replicated for [129]. ImmH 32 and ImmG 37 also proved to be strong inhibitors of hPNP and ImmH 32 (K i * hPNP = 56 pM) is currently in advanced stages of clinical trials as Forodesine HCl for relapsed/resistant T-cell leukemia and cutaneous T-cell leukemia [157,[169][170][171][172]. These kind of compounds do not require any form of bioactivation (e.g.…”

Section: First Generation Immucillinsmentioning

confidence: 96%

Inhibitors of the Purine Salvage Pathway: A Valuable Approach for Antiprotozoal Chemotherapy?

Berg

Veken²,

Goeminne³

et al. 2010

CMC

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For many years, the purine salvage pathway of parasitic protozoa has been regarded as an attractive chemotherapeutic target. Parasitic protozoa lack de novo synthesis and rely entirely on the purine salvage pathway to meet their purine demands. Because of the great phylogenetic difference between parasite and host, there are often sufficient distinctions that can be exploited to design specific inhibitors for the parasitic enzymes. As a result, this pathway has been thoroughly investigated over the last twenty years. It is only quite recently that the genome studies of Trypanosoma, Leishmania and Plasmodium have been published. Based on these genomic data however, the existence of by-pass mechanisms by other enzymes and transporter systems could be suggested. Taking into account such proposition, the question might arise as to whether inhibition of a single salvage enzyme will be able or not to cause parasite death or growth arrest. In this paper, the key enzymes in the purine salvage pathways of relevant pathogenic species from the genera Trypanosoma, Leishmania and Plasmodium are reviewed. Their potential as drug targets is critically evaluated and where possible, correlated to literature data on antiparasitic activity of their inhibitors. While many studies over the past ten years have yielded contradictory results, this review attempts to clarify these findings by discussing the latest elements of progress in the field. Additionally, as part of a broader discussion on substrate analogue types of inhibitors, special attention is paid to iminoribitol derivatives, serving as transition state analogues of nucleoside-processing enzymes and comprising the most potent inhibitors reported for purine salvage enzymes. More specifically, the development of three generations of immucillins and a newer series of N-(arylmethyl-) substituted iminoribitol derivatives will be discussed. Finally, this review also covers subversive substrates of salvage enzymes: compounds that are transformed by enzymatic activity into cytotoxic agents. Although not by directly intervening in the process of purine recovery, the subversive substrate approach might deliver antiprotozoal compounds that rely on salvage enzymes for their activity.

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“…The unique sensitivity of human immature T-cells to deficiency of purine nucleoside phosphorylase (PNP) has been a leading base for the design of several novel classes of PNP inhibitors that may be useful for the treatment of T-cell-mediated tumour diseases, such as cutaneous T-cell lymphoma and acute lymphoblastic leukaemia, as well as other T-cell disorders (28).…”

Section: Methodsmentioning

confidence: 99%

Antiproliferative Activity of Purine Nucleoside Phosphorylase Multisubstrate Analogue Inhibitors Containing Difluoromethylene Phosphonic Acid against Leukaemia and Lymphoma Cells

et al. 2010

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Potent inhibitors of purine nucleoside phosphorylase (PNP) are expected to act as selective agents against T‐cell tumours. Five compounds with guanine, three with hypoxanthine, and five with 9‐deazaguanine, all connected by a linker with difluoromethylene phosphonic acid, were studied on their inhibitory potential against human and calf PNPs. Antiproliferative activity of these analogues against lymphocytes as well as lymphoma and leukaemia cells has been also investigated. All tested compounds act as multisubstrate analogue inhibitors of PNP with the apparent inhibition constants in the range 5–100 nm, and also show a slight antiproliferative activity. Analogues with 9‐deazaguanine aglycone have better anti‐leukaemic and anti‐lymphoma activities compared to the guanine and hypoxanthine analogues, and applied in the concentration of 100 μm, caused a statistically significant decrease in the cell viability in all human leukaemia and lymphoma cells used. Despite the high PNP inhibitory potential of tested analogues, no differences were observed between the effects on the growth of tumour cells sensible to the inhibition of PNP, such as human adult T‐cell leukaemia and lymphoma cells, and other investigated cells. Obtained poor effects on cell proliferation could be explained probably by a poor ability of tested compounds to penetrate cell membranes.

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Synthesis of analogs of forodesine HCl, a human purine nucleoside phosphorylase inhibitor—Part II

Cited by 8 publications

References 22 publications

Structural basis for selective inhibition of purine nucleoside phosphorylase from Schistosoma mansoni: Kinetic and structural studies

Structural basis for selective inhibition of purine nucleoside phosphorylase from Schistosoma mansoni: Kinetic and structural studies

Inhibitors of the Purine Salvage Pathway: A Valuable Approach for Antiprotozoal Chemotherapy?

Antiproliferative Activity of Purine Nucleoside Phosphorylase Multisubstrate Analogue Inhibitors Containing Difluoromethylene Phosphonic Acid against Leukaemia and Lymphoma Cells

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