Phosphate bioisosteres

Phosphinic acids are probably, with the phosphonic acids, the simplest phosphate bioisosteres [8]. Because of their tetrahedral geometry, phosphinic acids remain quite similar in shape and are approximately isosteric with phosphates. The main difference is the presence of two phosphorus-carbon bonds (phosphinic acids) or one phosphorus-carbon bond and a phosphoms-hydrogen bond (/f-phosphinic acids). One intrinsic character of the P-C bond is its chemical and enzymatic stability when compared to P-O or P-N bonds [9]. As a consequence, phosphinates (as well as phosphonates) are often used when hydrolysis becomes a bottleneck for the activity. The number of acidic functions but also pA a values are different between phosphate and phosphinic acids [10-12]. Indeed, the replacement of oxygen atoms by hydrogens in hypophosphorous acid slightly changed the pAa when compared to the first acidity of phosphoric acid (Fig. 1). However, the presence of an alkyl group directly bonded to the phosphoms results in an increase... 

Phosphonate analogs to phosphate esters, in which the P—0 bond is formally replaced by a P—C bond, have attracted attention due to their stability toward the hydrolytic action of phosphatases, which renders them potential inhibitors or regulators of metabolic processes. Two alternative pathways, in fact, may achieve introduction of the phosphonate moiety by enzyme catalysis. The first employs the bioisosteric methylene phosphonate analog (39), which yields products related to sugar 1-phosphates such as (71)/(72) (Figure 10.28) [102,107]. This strategy is rather effective because of the inherent stability of (39) as a replacement for (25), but depends on the individual tolerance of the aldolase for structural modification close... 

Figure 4.21 Phosphates, which are sensitive to hydrolysis and enzymatic degradation, can be replaced by the corresponding bioisosteric methylphosphonates and their mono- and difluori-nated analogs [65], The acidity of the phosphate group (second pK ) is best matched by iso-acidic a-fluoromethylphosphonates, the polarity by isopolar a,a-difluoromethylphosphonates.

JMC5309). Phosphate function is known to be advantageously replaced by a phosphonate, and a-fluoromethylene- or a,a -difluoromethylene-phosphonates are considered as better bioisosteres of the phosphate group. Replacement of one or two hydrogens of a methylene group is classically used to modulate metabolism or off-target activity. 

Several organophosphorus heterocycles have been synthesized and tested for their antiviral activity. Most of the time, the phosphate function is replaced by a non-hydrolyzable phosphonate bioisostere. The following section illustrates the compounds encountered for this purpose. 

A number of organophosphonates have been synthesized as bioisosteric analogues for biochemically important non-nucleoside and nucleoside phosphates (3). For example, the S-enantiomer of 3,4-dihydroxybutyl-l-phos-phonic acid (DHBP) has been synthesized as the isosteric analogue of... 

In addition to the potential of triazoles in mimicking the amide moiety and consequently the peptide bond, their capability to act as bioisosteres of the acyl phosphate and h ns-olefinic moieties has also been predicted [18]. The... 

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