Cyclic nucleoside phosphonates

De Clercq E (2011) The clinical potential of the acyclic (and cyclic) nucleoside phosphonates the magic of the phosphonate bond. Biochem Pharmacol 82 99-109... 

Figure 20 Praziquantel and cyclic nucleoside phosphonates as antischistosomal agents.

Scheme 8 Synthesis of nucleoside 2 , 3 -0,0-cyclophosphorothioates 22a-d via the 2 ,3 - 0,0-cyclic i/-phosphonates 20a-d...

Nucleosides. Nucleotides, and Derivatives.- 2, 3 ,5 -Trl-0 -acetyl-adenosine and -guanosine, 4- -ethyl-thymidlne, N -methyl-2 -deoxyadenoslne, 5-raethoxymethyl-2 -deoxy-urldlne and its 0-D-threo-isomer, 5-fluoroarablnosylcytoslne, the 2 -deoxynucleo-side (17), cls-thymldine 3 ,5 -cyclic methyl phosphonate and the corresponding 3, 5 -cycllc N,N-dlmethylphosphoramldate,a cobalt(II) complex with 2 -deoxyinosine 5 -monophosphate,... 

The 2, 3 - (9,0-cyclic //-phosphonates 20a-d were formed, as ca 1 1 mixture of diastereomers (as monitored by 31P-NMR ), in the reaction of 5 -protected ribonu-cleosides 16a-d with diphenyl //-phosphonate in pyridine. Their sulfurization readily afforded the expected cyclic phosphorothioates 21a-d which upon subsequent removal of the 5 -protecting group afforded the respective nucleoside 2, 3 -0,0-cyclophosphorothioates 22a-d in excellent yields (70-90%) (Scheme 8) [23],... 

An estimate of the rate enhancement associated with the intramolecular phosphorylation can be made by using isopropyl p-nitrophenyl methyl-phosphonate as a model for the covalent intermediate formed in the initial step of the reaction of cycloheptaamylose with bis (p-nitrophenyl) me thy 1-phosphonate. The first-order rate constant for the alkaline hydrolysis of isopropyl p-nitrophenyl methylphosphonate at pH 9.86 can be obtained from the data of van Hooidonk and Groos (1970) kun = 1.4 X 10-5 sec-1. This value may be compared with the maximal rate constant for the reaction of cycloheptaamylose with bis(p-nitrophenyl) methylphosphonate— k2 = 1.59 X 10-1 sec-1 at pH 9.86—which must be a minimal value for the rate of the intramolecular phosphorylation. This comparison implies a kinetic acceleration of at least 104 which is similar to rate enhancements associated with the formation of cyclic phosphates from nucleoside phosphate diesters. 

Cyclic phosphonate analogues of PMEA (36) have been obtained after stereoselective cyclisation of an acyclic phosphonyl intermediate to the phos-phonyltetrahydrofuran nucleoside derivative. A series of cyclopropylphos-phonate analogues (37) has been synthesised stereoselectively via intramolecular epoxide opening reaction of y,5-epoxyalkanephosphonates with subsequent Mitsunobu coupling reaction to purine bases. Acyclic phosphonate derivatives of thymine (38-43) have been prepared and evaluated as multisubstrate analogue inhibitors of Escherichia coli thymidine phosphor-... 

Nucleoside Pyrophosphonates. Rosenberg et al. have reported that treatment of the geminal hydroxyphosphonate moiety of 2 -thymidine-3 -C-phosphonate with acetic anhydride yielded the phosphonate anhydride derivative (85a), the cyclic dinucleoside diphosphonate (85b) and the tetranucleoside diphosphonate (85c). ... 

The synthesis of the cyclic 2 -deoxyribodinucleotides 82 by a solution-phase H-phosphonate method has been described in which a 5 -protected nucleoside-3 -H-phosphonate (83) is first coupled to a nucleoside 3 -H-phosphonate diester (84). Removal of the cyanoethyl group from the 3 -phosphonate group reveals an H-phosphonate monoester function which remains intact during oxidation of the internucleoside H-phosphonate diester linkage. After further deprotection, this 3 -H-phosphonate is reacted to produce the cyclic derivative 82 in 15% overall yield. 

Scheme 4.30 Fluoromethyl phosphonate analogs of phosphoenol pyruvate (irreversible inhibitor of 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase) [71], of cyclic inositol phosphate (lipolipase C inhibitor) [72], and of the transition state of the purine nucleoside phosphorylase (PNP) reaction [73].

Triesters of type 182 (n = 2-5) have been prepared from the nucleoside 3 -H-phosphonate, via the cyclic phosphites. Methods were also developed for making H-phosphonates and phosphodiesters involving just one of the hydroxy-groups of the diols. ... 

A series of nucleosides monophosphates have been evaluated as selective P GXPRT inhibitors. Among them, the cycfrc phosphonates (R)-cycfrc-HPMPG 154 and (S)-cyclic-HPMPG 58 (see Section 3.1, Antiviral activities) are representative stmctures (Figure 19). 

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. 

Diethyl pyrocarbonate has been used to convert uridine 2 - or 3 -phosphate into the 2, 3 -cyclic phosphate in high yield, and an adamantyl 2, 3 -cyclic phosphonate (421) was obtained when uridine reacted with I-adamantylphos-phonyl chloride. Phosphorylation of ribonucleosides with pyrophosphoryl chloride followed by hydrolysis in neutral solution afforded a simple synthesis of ribonucleoside 2, 3 -cyclic phosphate 5 -phosphates. Two phosphorylating agents mentioned earlier in this section can also yield 3, 5 -cyclic phosphates either by treatment of nucleoside 5 -(2-iV7V-dimethylamino-4-nitrophenyl phosphates) with acetic acid in pyridine (Scheme I4i) i, 83 qj. treatment of nucleoside 5 -(5 -methyl phosphorothioates) with iodine in pyridine. Another route to 3, 5 -cyclic phosphates involved cyclization of the nucleoside 5 -trichIoro-methylphosphonates (422) (obtained by the action of trichloromethylphosphonyl... 

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