화학공학소재연구정보센터
Biochemical and Biophysical Research Communications, Vol.276, No.3, 1235-1239, 2000
Asymmetric preference of serine proteases toward phosphonate and phosphinate esters
We have previously reported the asymmetric synthesis of (alpha-aminoalkyl) diphenylphosphonate and phosphinate derivatives designed as inhibitors of chymotrypsin- and elastase-like proteases. This paper reports the first kinetic evaluation of individual epimers of the (alpha-aminoalkyl) diphenylphosphonates as inactivators of chymotrypsin, cathepsin G and neutrophil elastase (HNE). Results show that the (R)-epimers consistently function as more potent irreversible inactivators of their respective target proteases than the corresponding (S)-epimers. Additionally, phosphinate analogues were found to be consistently superior to their diphenylphosphonate counterparts. For example, Cbz . Phe(P)(OPh)-(CH2)(2)-CO2Et inactivates cathepsin Gr approximately 45-fold more rapidly (k(i)/K-i = 1.2 x 10(5) M-1.min(-1)) than the analogous Cbz.Phe(P)(OPh)(2) (2.6 x 10(8) M-1.min(-1)). Similarly, Cbz.Val(P)(OPh)-(CH2)(2)-CO2Et was found to inactivate HNE some 3-fold more efficiently than Cbz.ValP(OPh), (6.5 x 10(3) and 2.0 x 10(3) M-1.min(-1), respectively).