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Application to the Synthesis of Enantiopure Phosphonates Analogous to Triglycerides: A New Class of Inhibitors of Lipases
Author(s) -
Marguet Frank,
Cavalier JeanFrançois,
Verger Robert,
Buono Gérard
Publication year - 1999
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/(sici)1099-0690(199907)1999:7<1671::aid-ejoc1671>3.0.co;2-z
Subject(s) - enantiopure drug , chemistry , diastereomer , phosphonate , lipase , synthon , hydrolysis , stereochemistry , covalent bond , triacylglycerol lipase , organic chemistry , enzyme , enantioselective synthesis , catalysis
Phosphonate compounds mimic the first transition state occurring during enzymatic carboxyester hydrolysis of natural substrates by forming a covalent bond with the catalytic serine. However, until now the organophosphorus compounds used in the inhibition studies more or less resembled a natural triglyceride substrate. In order to elucidate the interfacial activation and the mechanism of action of lipases, specific inhibitors need to be prepared. To achieve this goal, enantiomerically pure sn ‐1,2‐ and sn ‐2,3‐ O ‐didecanoylglycerol compounds were prepared – starting from a C‐4 chiral synthon, 3‐buten‐1,2‐diol – and treated with n ‐pentylphosphonic dichloride and p ‐nitrophenol to afford the corresponding diastereomeric phosphonates, which were acylglycerol analogs. Subsequent separation of each of the phosphonate diastereomers A / B or ent ‐ A / ent ‐ B , performed by HPLC, led to four enantiopure stereoisomers that will be investigated as inhibitors of Human Pancreatic Lipase (HPL) and Human Gastric Lipase (HGL) using the monomolecular film technique.