Synthesis of 24(S)-hydroxycholesterol esters responsible for the induction of neuronal cell death

Abstract

We synthesized several candidates of 24(S)-hydroxycholesterol (24S-OHC) esters, which are involved in neuronal cell death, through catalysis with acyl-CoA:cholesterol acyltransferase-1 (ACAT-1). We studied the regioselectivity of the acylation of the secondary alcohol at the 3- or 24-position of 24S-OHC. The appropriate saturated and unsaturated long-chain fatty acids were esterified with the protected 24S-OHC and then de-protected to afford the desired esters at a satisfactory yield. We then confirmed by HPLC monitoring that the retention times of four esters of 24S-OHC, namely 3-oleate, 3-linoleate, 3-arachidonoate and 3-docosahexaenoate, were consistent with those of 24S-OHC esters observed in 24S-OHC-treated SH-SY5Y cells.

Esterification of 24S-OHC induces formation of atypical lipid droplet-like structures, leading to neuronal cell death

“…The 24S-OHC and various forms of esterified 24S-OHC were synthesized as we previously reported (26). All fatty acids and Nile red were obtained from Sigma-Aldrich (St. Louis, MO).…”

“…For further identification of these four peaks, we synthesized candidate 24S-OHC esters (26), such as 24S-OHC-DHA, 24S-OHC-AA, 24S-OHC-LA, and 24S-OHC-OA (supplemental Fig. S1).…”

Cholesterol-Based Compounds: Recent Advances in Synthesis and Applications

“…Shibuya et al reported in 2016 the synthesis of (24 S )-hydroxycholesterol (24 S -OHChol) esters, which are involved in neuronal cell death, through catalysis with acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) [99]. The authors studied the esterification of (24 S )-OHChol 417 with cis -oleoyl chloride under basic conditions and obtained mono-oleates 418 and 419 and bis-oleate 420 in 39%, 9%, and 20% yields, respectively (Scheme 97).…”

“…The authors studied the esterification of (24 S )-OHChol 417 with cis -oleoyl chloride under basic conditions and obtained mono-oleates 418 and 419 and bis-oleate 420 in 39%, 9%, and 20% yields, respectively (Scheme 97). The protection of (24 S )-OH with a trifluoroacetyl group was also attempted, affording mono-trifluoroacetates 421 and 422 in 33% and 14% yields, respectively, and the bis-trifluoroacetate 423 in 21% yield (Scheme 97) [99]. The authors took advantage of the mono-trifluoroacetate 421 to prepare the stearoyl and palmitoyl esters 427 and 428 in 68% and 75% yields, respectively, as depicted in Scheme 98 [99].…”

“…The protection of (24 S )-OH with a trifluoroacetyl group was also attempted, affording mono-trifluoroacetates 421 and 422 in 33% and 14% yields, respectively, and the bis-trifluoroacetate 423 in 21% yield (Scheme 97) [99]. The authors took advantage of the mono-trifluoroacetate 421 to prepare the stearoyl and palmitoyl esters 427 and 428 in 68% and 75% yields, respectively, as depicted in Scheme 98 [99]. Finally, the authors also reported the use of esters of unsaturated long-chain fatty acids, such as linoleic (LA), arachidonic (AA), and docosahexaenoic (DHA), to react with cholesterol derivative 422 in order to prepare linoleate 430 , arachidonoate 431, and docosahexaenoate 432 esters, in 52%, 74%, and 66% yields, respectively, in a two-step synthetic route, as depicted in Scheme 99 [99].…”