Fluorophosphonate derivatives of N9-benzylguanine as potent, slow-binding multisubstrate analogue inhibitors of purine nucleoside phosphorylase

Halazy, S.; Ehrhard, A.; Eggenspiller, A.; Berges‐Gross, V.; Danzin, Charles

doi:10.1016/0040-4020(95)00891-b

Cited by 50 publications

(17 citation statements)

References 17 publications

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“…The derivatives with o‐ configuration on the phenyl ring 176–181 possessed the best activity within the series, and again, the data confirmed the superiority of the fluorinated phosphonate linkers over the nonfluorinated ones. The most active compound within the series was the o ‐isomer 177 bearing CHF‐CF 2 linker ( h PNP, K i = 1.3 nM; calf spleen PNP, K i = 0.6 nM) …”

Section: Acyclic Nucleoside Phosphonatesmentioning

confidence: 99%

“…The most active compound within the series was the o-isomer 177 bearing CHF-CF 2 linker (hPNP, K i = 1.3 nM; calf spleen PNP, K i = 0.6 nM). 177 Further design of the PNP inhibitors led to a group of the compounds 184-191 (Fig. 46) bearing a double bond or a cyclopropyl ring within the acyclic chain.…”

Section: Anps With Fluorine Atom(s) At Phosphonate α-Carbonmentioning

confidence: 99%

“…Also fluorinated phosphonate derivatives of N 9 ‐benzylguanine, the compounds 176–183 (Fig. ) prepared by Halazy et al., were shown to be potent, slow binding, multisubstrate inhibitors of PNP. The derivatives with o‐ configuration on the phenyl ring 176–181 possessed the best activity within the series, and again, the data confirmed the superiority of the fluorinated phosphonate linkers over the nonfluorinated ones.…”

Section: Acyclic Nucleoside Phosphonatesmentioning

confidence: 99%

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Medicinal Chemistry of Fluorinated Cyclic and Acyclic Nucleoside Phosphonates

Baszczyňski

Janeba

2013

Medicinal Research Reviews

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The fluorine atom plays an important role in medicinal chemistry because fluorine substitution has a strong impact on the physical, chemical, and biological properties of bioactive compounds. Such fluorine modifications have also been extensively studied among the pharmaceutically important class of nucleoside phosphonates, nucleotide analogues in which the phosphate group is replaced by the enzymatically and chemically stable phosphonate moiety. The fluorinated nucleoside phosphonates abound with antiviral, antiparasitic, and anticancer properties because they are able to act as inhibitors of important enzymes of nucleoside/nucleotide metabolism. In this paper, we review the biological properties of cyclic and acyclic nucleoside phosphonates modified by the attachment of one or more fluorine atoms to various parts of the molecule, namely to nucleobases, alkylphosphonate groups, cyclic or acyclic linkers, or to prodrug moieties.

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Section: Acyclic Nucleoside Phosphonatesmentioning

confidence: 99%

Section: Anps With Fluorine Atom(s) At Phosphonate α-Carbonmentioning

confidence: 99%

Section: Acyclic Nucleoside Phosphonatesmentioning

confidence: 99%

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Medicinal Chemistry of Fluorinated Cyclic and Acyclic Nucleoside Phosphonates

Baszczyňski

Janeba

2013

Medicinal Research Reviews

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“…Hence the early design of efficient enzyme inhibitors has often relied on the use of phosphonates 3a , in which the esterified oxygen atom of the phosphate is replaced with a CH 2 unit [ 1 ]. The pioneering work of Blackburn and McKenna in the early eighties resulted in the design and use of the α,α–difluoromethylphosphonates 3b as closer isosters of the phosphate [ 2 ]. Structural and electronic studies by Chambers and O’Hagan on the zwitterionic species 6 have since then confirmed this fact and firmly established the monofluorophosphonates and difluorophosphonates as closely related, hydrolytically and enzymatically stable mimics of the phosphate ( Table 1 ) [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

The Preparation of New Phosphorus-Centered Functional Groups for Modified Oligonucleotides and Other Natural Phosphates

et al. 2005

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Efforts to develop synthetic methodologies allowing the preparation of α,α–difluorophosphonothioates, α,α–difluorophosphonodithioates, α,α–difluorophosphono-trithioates, and α,α–difluorophosphinates are reviewed in the light of applications in the field of modified oligonucleotides and cyclitol phosphates. Two successful approaches have been developed, based either on the addition of phosphorus-centered radicals onto gem–difluoroalkenes or on a process involving the addition of lithiodifluorophosphono-thioates 91 onto a ketone and the subsequent deoxygenation reaction of the adduct. The radical route successfully developed a practical route to α,α–difluoro–H–phosphinates which proved to be useful intermediates to a variety of phosphate isosters. The ionic route led to the first preparation of phosphonodifluoromethyl analogues of nucleoside–3’–phosphates.

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“…In the Protein Data Bank there are no reported structures of the complexes of trimeric PNPs with multisubstrate analogue inhibitors. We describe here for the first time the high resolution X-ray structure of trimeric calf spleen PNP, highly homologous to the human PNP, with the potent (K i app = 16 and 18 nM at pH 7.4 with calf and human enzymes, respectively [4]) multisubstrate analogue inhibitor 9-(5,5-difluoro-5-phosphonopentyl)guanine.…”

mentioning

confidence: 99%