149194-46-7Relevant articles and documents
The first potent diphenyl phosphonate KLK4 inhibitors with unexpected binding kinetics
Van Soom, Jeroen,Cuzzucoli Crucitti, Giuliana,Gladysz, Rafaela,Van Der Veken, Pieter,Di Santo, Roberto,Stuyver, Ingmar,Buck, Victoria,Lambeir, Anne-Marie,Magdolen, Viktor,Joossens, Jurgen,Augustyns, Koen
, p. 1954 - 1958 (2015)
KLK4 is a serine protease from the kallikrein family that is involved in cancer progression. The diphenyl phosphonate warhead is intended to bind irreversibly with serine proteases, but unexpectedly, very potent KLK4 diphenyl phosphonate inhibitors were d
Synthesis and structure-activity relationships of phosphonic arginine mimetics as inhibitors of the M1 and M17 aminopeptidases from plasmodium falciparum
Kannan Sivaraman, Komagal,Paiardini, Alessandro,Sieńczyk, Marcin,Ruggeri, Chiara,Oellig, Christine A.,Dalton, John P.,Scammells, Peter J.,Drag, Marcin,McGowan, Sheena
supporting information, p. 5213 - 5217 (2013/07/26)
The malaria parasite Plasmodium falciparum employs two metallo- aminopeptidases, PfA-M1 and PfA-M17, which are essential for parasite survival. Compounds that inhibit the activity of either enzyme represent leads for the development of new antimalarial drugs. Here we report the synthesis and structure-activity relationships of a small library of phosphonic acid arginine mimetics that probe the S1 pocket of both enzymes and map the necessary interactions that would be important for a dual inhibitor.
Synthesis and evaluation of diphenyl phosphonate esters as inhibitors of the trypsin-like granzymes A and K and mast cell tryptase
Jackson, Delwin S.,Fraser, Stephanie A.,Ni, Li-Ming,Kam, Chih-Min,Winkler, Ulrike,Johnson, David A.,Froelich, Christopher J.,Hudig, Dorothy,Powers, James C.
, p. 2289 - 2301 (2007/10/03)
Thirty-six new amino acid and peptidyl diphenyl phosphonate esters were synthesized and evaluated to identify potent and selective inhibitors for four trypsin-like proteases: lymphocyte granzymes A and K, human mast cell tryptase, and pancreatic trypsin. Among five Cbz derivatives of Lys and Arg homologues, Z-(4-AmPhe)(P)(OPh)2 is the most potent inhibitor for granzyme A, and Z-Lys(P)(OPh)2 is the best inhibitor for granzyme K, mast tryptase, and trypsin. The amidino P1 residue D,L-(4-AmPhGly)(P)(OPh)2 was utilized in a series of compounds with several different N-protecting groups and systematic substitutions at P2 in Cbz-AA derivatives and at P3 in Cbz-AA-Ala derivatives. Generally, these phosphonates inhibit granzyme A and trypsin more potently than granzyme K and tryptase. The P2 Thr and Ala dipeptide phosphonates, Cbz-AA-(4-AmPhGly)(P)(OPh)2, are the most potent inhibitors for granzyme A, and Cbz-Thr-(4-AmPhGly)(P)(OPh)2 (k(obs)[I] = 2220 M-1 s- 1) was quite specific with much lower inhibition rates for granzyme K and trypsin (k(obs)[I] = 3 and 97 M-1 s-1, respectively) and no inhibition with tryptase. The most effective inhibitor of granzyme A was Ph-SO2-Gly- Pro-(4-AmPhGly)(P)(OPh)2 with a second-order rate constant of 3650 M-1 s- 1. The most potent inhibitor for granzyme K was 3,3-diphenylpropanoyl-Pro- (4-AmPhGly)(P)(OPh)2 with a k(obs)/[I] = 1830 M-1 s-1; all other phosphonates inhibited granzyme K weakly (k(obs)/[I] -1 s-1). Human mast cell tryptase was inhibited slowly by these phosphonates with Cbz- Lys(P)(OPh)2 as the best inhibitor (k(obs)/[I] = 89 M-1 s-1). The overall results suggest that scaffolds of Phe-Thr-(4-AmPhe) and Phe-Pro-Lys will be useful to create selective phosphonate inhibitors for granzymes A and K, respectively, and that P4 substituents offer opportunities to further enhance selectivity and reactivity.
