ml8b00050_si_001.pdf (1.6 MB)
Stereochemical Structure Activity Relationship Studies (S-SAR) of Tetrahydrolipstatin
journal contribution
posted on 2018-02-21, 00:00 authored by Xiaofan Liu, Yanping Wang, Richard I. Duclos, George A. O’DohertyTetrahydrolipstatin
(THL), its enantiomer, and an additional six
diastereomers were evaluated as inhibitors of the hydrolysis of p-nitrophenyl butyrate by porcine pancreatic lipase. IC50s were found for all eight stereoisomers ranging from a low
of 4.0 nM for THL to a high of 930 nM for the diastereomer with the
inverted stereocenters at the 2,3,2′-positions. While the enantiomer
of THL was also significantly less active (77 nM) the remaining five
stereoisomers retained significant inhibitory activities (IC50s = 8.0 to 20 nM). All eight compounds were also evaluated against
three human cancer cell lines (human breast cancers MCF-7 and MDA-MB-231,
human large-cell lung carcinoma H460). No appreciable cytotoxicity
was observed for THL and its seven diastereomers, as their IC50s in a MTT cytotoxicity assay were all greater than 3 orders
of magnitude of camptothecin.