Phosphonamidate analogs

Bartlett and Marlowe (153) designed a series of five phosphonamidate analogs of the peptide carbobenzoxy-Gly-Leu-X (X = NH2, Gly, Phe, Ala, Leu), where a -POz-NH- replaces the Gly-Leu peptide bond, and showed that these compounds were potent transition-state analog inhibitors of the zinc endopeptidase thermolysin. They also synthesized the corresponding phos-phonate analogs, where the -NH- (13A) is replaced by -O- (I3B). The... 

Also the affinity constants of the phosphonamidate analogs (1, Table 1) confirm the additivity concept of group contributions to biological activity values. The different residues R are separated from the bridge atom X by two carbon atoms all affinity values of the three series with X = —NH—, —O —, and — CH2— are closely correlated [137]. 

Phosphonamidates,424/425 phosphonate esters, and oxo-methylene substrate analogs, which presumably mimic the geometry of the tetrahedral intermediate or transition state of the intermediate or transition state... 

Phosphonates and phosphonamidates were selected as transition-state analogs for carbonate and ester hydrolysis they are relatively stable molecules, they are known inhibitors of acyl transfer enzymes and they imitate the initial negative charge of the tetrahedral oxyanion of acyl transfer enzymes (such as serine proteases) in the dipole of the P=0 bond. 

Amide hydrolysis is energetically more demanding than ester hydrolysis or transacylation, and its catalysis by antibodies represents a formidable challenge. Although phosphonamidates would appear to be excellent transition-state analogs, numerous attempts in many laboratories to use these compounds to produce... 

Bartlett PA, Marlowe CK. Phosphonamidates as transition-state analog inhibitors of thermolysin. Biochemistry 1983 22(20) 4618 624. 

Bartlett PA, Lamden LA. Inhibition of chymotrypsin by phos-phonate and phosphonamidate peptide analogs. Bioorg. Chem. 1986 14(4) 356-377. 

Figure 17.22. (a) Thermolysin-catalyzed hydrolysis of peptide analogs showing putative transition state, (b) phosphonamidate peptide analog, and (c) lluoroalkane peptide analog. 

An analysis of phosphonamidate and phosphonate transition-state analogs for the thermolysin reaction was reported (95, 96) and the data were interpreted to suggest that one hydrogen bond could contribute 4 kcal/mol binding to stabilize the formation of the tetrahedral transition state. A reevaluation was re-... 

Fig. 2 Therrnolysin phosphonamide and analog inhibitors with dissociation constants of enzyme-inhibitor complexes...

Another motivation to use phosphorus-containing peptides is related to their good structural analogy with what is called the substrate structure in the transition-state. As shown in Fig. 3, three possibilities can be envisaged and have been explored to develop potent inhibitors. Phosphonamide peptides seem the most obvious choice, as the analogy is almost perfect [11, 12]. If such compounds have been proved to yield potent inhibitors towards some zinc-metalloproteases, the limited stability of the P-N bond through hydrolysis has prevented further use of this chemistry [13-15]. Phosphonates have been reported to yield one of the most potent inhibitor ever reported for carboxypeptidase A (Ki in the fM range) [13]. However, when tested with endoproteases, phosphonates turned out to be less potent [15]. 

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