The squalene‐2,3‐epoxide cyclase as a model for the development of new drugs

Abstract

The 2,3-oxido squalene (SO) cyclases represent a group of enzymes which convert SO into polycyclic triterpenoids such as lanosterol, cycloartenol, cucurbitadienol and beta-amyrin. Taking into account the postulated model of the enzymatic cyclization of SO, we have investigated the possibility of designing compounds that would be selective and potent inhibitors of SO cyclases. Due to the fundamental role of sterols in animal, higher plant and fungal tissues, these inhibitors might behave as very selective (ipocholesterolemic, antifungal or phytotoxic) drugs. Our first approach was the synthesis and biological evaluation of 2-aza-2,3-dihydrosqualene and its derivatives which, being protonated at physiological pH, would present some similarities to the C-2 carbon ion generated by the opening of the oxirane ring of SO. Microsomes from different sources (germinated pea cotyledons, maize seedlings, rat liver and yeasts) were utilized to determine the inhibition values (I50: concentration of inhibitor producing 50% inhibition at a given substrate concentration). From the results obtained so far we conclude that 2-aza-2-dihydrosqualene and its derivatives strongly inhibited the cyclases, the site of the enzyme responsible for binding to the inhibitor is quite sensitive to the steric hindrance, and the degree of the inhibitory activity is greater in higher plants than in rat liver or fungi.

Quercetin 3-Glucoside Protects Neuroblastoma (SH-SY5Y) Cells in Vitro against Oxidative Damage by Inducing Sterol Regulatory Element-binding Protein-2-mediated Cholesterol Biosynthesis

“…We observed that mevastatin inhibited the protective effect of Q3G under oxidative stress, and this effect was reversed by the addition of IPP indicative of rescue of the mevalonate pathway. In the cholesterol synthesis pathway, OSC catalyzes the cyclization of monooxidosqualene to lanosterol (61). Since farnesylpyrophosphate is located upstream of OSC in the cholesterol synthesis pathway, inhibition of OSC should not block the formation of isoprenoids or affect protein prenylation or CoQ production.…”

Vinyl sulfide derivatives of truncated oxidosqualene as selective inhibitors of oxidosqualene and squalene‐hopene cyclases

“…The resulting oil was purified by flash chromatography with petroleum ether/diethyl ether, 97:3, to give 32 mg (35% yield from 1) of compound 6, as a mixture (about 1:1) of 1E and 1Z isomers, as a colorless oil. 1 (5E,9E)-13,14-Epoxy-6,10,14-trimethyl-1-methylthio-1,5,9-pentadecatriene (7, Scheme 2). Compound 7 was obtained starting from aldehyde 2 by using the same method as described for 6, as a mixture (about 1:1) of 1E and 1Z isomers, in 33% yield.…”

“…Initially we obtained effective inhibitors of OSC by mimicking the carbocationic intermediates formed during cyclization of OS, designing squalene-derived structures in which the positively charged carbocation was replaced by a nitrogen (1,(24)(25)(26). Another strategy that has been adopted is to intercept the enzymatic active-site nucleophiles with a stable allylic cation, resulting in an irreversible covalent modification of OSC.…”

Potent Anti- Trypanosoma cruzi Activities of Oxidosqualene Cyclase Inhibitors

“…This is a remarkably complex cyclization-rearrangement reaction involving the formation of a total of six new carboncarbon bonds by a single enzyme (2). Inhibitors of OSC are under investigation as potential antifungal drugs (12) and cholesterol-lowering drugs (1,6). One series of OSC inhibitors was designed as electron-poor aromatic mimics of a monocyclized transition state or high-energy intermediate formed from oxidosqualene (21).…”