Stereoselective synthesis of peptidyl trifluoromethyl alcohols and ketones: Inhibitory potency against human leucocyte elastase, cathepsin G, porcinepancreatic elastase and HIV-1 protease
A. Amour et al., Stereoselective synthesis of peptidyl trifluoromethyl alcohols and ketones: Inhibitory potency against human leucocyte elastase, cathepsin G, porcinepancreatic elastase and HIV-1 protease, J PHARM PHA, 50(6), 1998, pp. 593-600
New fluorinated inhibitors have been designed to target two major proteases
-human leucocyte elastase and HIV-1 protease.
Two series of beta-peptidyl trifluoromethyl alcohols (TFMAs) Z-L-Val-NH-*CH
(Y)-*CH(OH)-CF3, where *C is the chiral centre, varied in the nature of the
substituent Y, a phenylethyl [-(CH2)(2)-(CH5)-H-6] or an isopropyl [-CH(CH
3)(2)] group. These TFMAs were first synthesized as two pairs of the syn an
d anti diastereoisomers. The inhibitory effects of these mixtures were then
assessed on three serine proteases chosen on the basis of the aromatic and
aliphatic nature of the substituents-human leucocyte elastase (HLE), human
cathepsin G (HCG) and porcine pancreatic elastase (PPE). In the presence o
f detectable inhibition, each epimer at C2 was separated to determine its i
nhibition constant (K-i) towards HLE, HCG and PPE. The stereoisomerically p
ure TFMAs were then oxidized into peptidyl trifluoromethyl ketones (TFMKs)
for similar inhibition assays. The absolute configuration of the compounds
remained unknown. One epimer at C2 of each syn and anti TFMA with the pheny
lethyl substituent behaved as a competitive inhibitor towards HLE and HCG w
ith inhibition constants below the millimolar range, whereas their TFMK cou
nterparts were non-inhibitors. In the second series, the two ketones inhibi
ted both elastases with K-i values in the micromolar range, whereas only th
e syn TFMA was active towards HLE (K-i = 5.65 x 10(-4)M). The tested compou
nds also had structural properties compatible with recognition by HIV-1 pro
tease. The inhibition of the enzyme was observed with TFMK only (IC50 = 15-
200 mu M). The phenylethyl substituent promoted inhibition by a factor of 1
0 (IC50 = 15 mu M) compared with the isopropyl substituent (IC50 = 200 mu M
) leading to selective inhibition of HIV-1 protease.
Isomerically pure TFMKs were more potent towards HLE than the alcohols from
which they were obtained. However, an enantiomerically pure TFMA selective
ly inhibited HLE unlike its TFMK analogue which also inhibited PPE. This la
st result together with the selective inhibition of HIV-1 protease by TFMK
with a phenylethyl substituent might be relevant to the design of specific
HLE and HIV-1 inhibitors as therapeutic agents.