Enantioselective Inhibition of Squalene Synthase by Aziridine Analogues of Presqualene Diphosphate

Abstract

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-butyldi-methylsilyl ethers. SN2 displacements of the corresponding methanesulfonates with pyrophosphate and methanediphosphonate anions afforded aziridine 2-methyl diphosphates and methanediphosphonates bearing N-undecyl, N-bishomogeranyl, and N-(α-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 (IC50 1.17 ± 0.08 μM 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-(α-methylene)bishomogeranyl and N-undecyl substituents, and the related methanediphosphonates, exhibited lower affinities for recombinant squalene synthase.

Combinatorial evolution of site- and enantioselective catalysts for polyene epoxidation

“…Would catalysts be found that would functionalize the allylic alkene 20 , or other olefins of 1 ? Oxidation of 1 with (+) or (−)-DIPT/Ti(O i -Pr) 4 under the conditions of Sharpless has been reported over the years to deliver 3 with excellent selectivity (82–95% ee; Fig 1c) 21,22,23,24,25,26 . However, we lacked a clear structure-based hypothesis for how peptide-based catalysts might achieve our goals.…”

Galacto configured N-aminoaziridines: a new type of irreversible inhibitor of β-galactosidases

“…In our case, quinazolinone 3 and PIDA were the most efficient reagents and the aziridination of cyclohexene 2 was carried out in analogy to a reported procedure to control the diastereoselectivity of the aziridination reactions of chiral allylic alcohols. A described procedure 24 consisting in the treatment of the N-substituted aziridine 4 with Na or Li/NH 3 liq. At this point, we decided to explore its conversion to the desired final galactoconfigured compounds of interest 1a and 1b.…”

Applications of Chiral Three-membered Rings for Total Synthesis: A Review

“…In 2010, the cyclization of other chiral 2-azido alcohols was investigated by Coates et al in the course of synthesizing aziridine analogues of presqualene diphosphates as inhibitors of squalene synthase [29]. As shown in Scheme 18, 2,3-aziridinofarnesol 39 was prepared as the only detected stereoisomer in 83% yield from the corresponding azido mesylate 40 by treatment with LiAlH 4 latter was subsequently converted into a diphosphate exhibiting squalene synthase inhibitory activity.…”