Enantioselective inhibition of squalene synthase by aziridine analogues of presqualene diphosphate.
Squalene synthase catalyzes the conversion of two molecules of (E,E)-farnesyl diphosphate to squalene via the cyclopropylcarbinyl intermediate, presqualene diphosphate (PSPP). Since this novel reaction constitutes the first committed step in sterol biosynthesis, there has been considerable interest and research on the stereochemistry and mechanism of the process and in the design of selective inhibitors of the enzyme. This paper reports the synthesis and characterization of five racemic and two enantiopure aziridine analogues of PSPP and the evaluation of their potencies as inhibitors of recombinant yeast squalene synthase. The key aziridine-2-methanol intermediates (6-OH, 7-OH, and 8-OH) were obtained by N-alkylations or by an N-acylation-reduction sequence of (+/-)-, (2R,3S)-, and (2S,3R)-2,3-aziridinofarnesol (9-OH) protected as tert-butyldimethylsilyl ethers. S(N)2 displacements of the corresponding methanesulfonates with pyrophosphate and methanediphosphonate anions afforded aziridine 2-methyl diphosphates and methanediphosphonates bearing N-undecyl, N-bishomogeranyl, and N-(alpha-methylene)bishomogeranyl substituents as mimics for the 2,6,10-trimethylundeca-2,5,9-trienyl side chain of PSPP. The 2R,3S diphosphate enantiomer bearing the N-bishomogeranyl substituent corresponding in absolute stereochemistry to PSPP proved to be the most potent inhibitor (IC(50) 1.17 +/- 0.08 muM in the presence of inorganic pyrophosphate), a value 4-fold less than that of its 2S,3R stereoisomer. The other aziridine analogues bearing the N-(alpha-methylene)bishomogeranyl and N-undecyl substituents, and the related methanediphosphonates, exhibited lower affinities for recombinant squalene synthase.
Koohang
Ali
A
Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
Bailey
Jessica L
JL
Coates
Robert M
RM
Erickson
Hans K
HK
Owen
David
D
Poulter
C Dale
CD
D001388:Aziridines / Q000737:chemistry*; D002384:Catalysis; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D015394:Molecular Structure; D011106:Polyisoprenyl Phosphates / Q000737:chemistry*; D012717:Sesquiterpenes / Q000737:chemistry*; D013185:Squalene / Q000737:chemistry*; D013237:Stereoisomerism
D001388:Aziridines; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C017672:presqualene pyrophosphate; C033132:aziridine; C004808:farnesyl pyrophosphate; D013185:Squalene; D013186:Farnesyl-Diphosphate Farnesyltransferase