The difluoromethylenesulfonic acid group as a monoanionic phosphate surrogate for obtaining PTP1B inhibitors.
Three peptides, 7-9, bearing sulfono(difluoromethyl)phenylalanine (F(2)Smp, 2), a nonhydrolyzable, monoanionic phosphotyrosine mimetic, were prepared and evaluated as PTP1B inhibitors. The most effective inhibitor was the nonapeptide, ELEF(F(2)Smp)MDYE-NH(2), (9) which exhibited a K(i) of 360 nM. A comparison of F(2)Smp-bearing peptides 7 [DADE(F(2)Smp)LNH(2), K(i)=3.4 microM] and 8 [EEDE(F(2)Smp)LNH(2), K(i)=0.74 microM] with their phosphono(difluoromethyl)phenylalanine (F(2)Pmp)-bearing analogues indicated that F(2)Smp is not as effective a pTyr mimetic as F(2)Pmp by 100- to 130-fold. Although F(2)Smp is not as effective as F(2)Pmp, a comparison of peptide 7 with analagous peptides bearing other monoanionic pTyr mimetics recently reported in the literature indicates that F(2)Smp is about 65-fold more effective than any other non-hydrolyzable, monanionic pTyr mimetic reported to date. To further assess the difluoromethylenesulfonic acid (DFMS) group as a monoanionic phosphate mimetic, a series of 24 nonpeptidyl biaryl compounds bearing the DFMS group were prepared using polymer-supported methodologies and screened for PTP1B inhibition. Several of these compounds were selected for further study and their IC(50)'s compared to their difluoromethylenephosphonic (DFMP) analogues. The differences in IC(50)'s between the DFMS and DFMP non-peptidyl compounds was not as great as with the F(2)Smp- and F(2)Pmp-bearing peptides. Possible reasons for this and its implication to the design of small molecule PTP1B inhibitors is discussed.
Leung
Carmen
C
Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1.
Grzyb
Justyna
J
Lee
Jason
J
Meyer
Natalie
N
Hum
Gabriel
G
Jia
Chenguo
C
Liu
Shifeng
S
Taylor
Scott D
SD
D000595:Amino Acid Sequence; D004002:Clodronic Acid / Q000031:analogs & derivatives / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D008969:Molecular Sequence Data; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013057:Spectrum Analysis
D004791:Enzyme Inhibitors; C465523:difluoromethylenesulfonic acid; D004002:Clodronic Acid; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases