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2,3-oxidosqualene cyclase: From azasqualenes to new site-directed inhibitors

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Lipids

Abstract

2,3-Oxidosqualene cyclases (OSC) are enzymes which convert 2,3-oxidosqualene (OS) into polycyclic triterpenoids such as lanosterol, cycloartenol, and α-and β-amyrin. Our interest in the study of OSC is the development of new OSC inhibitors for potential use as hypocholesterolemic, antifungal, or phytotoxic drugs. In particular, we describe the biological activity and the mechanism of a series of acyclic azasqualene derivatives mimicking the C-2, C-8, and C-20 carbonium ions formed during OS cyclization. Some of these carbonium ion analogues are very promising as specific hypocholesterolemic agents. The toxicity, the biodistribution, and the pharmacokinetics of different azasqualene derivatives in mice are also presented. In order to obtain new, site-directed irreversible inhibitors of OSC, a series of squalene derivatives containing functional groups that can link covalently to an active-site thiol group was designed. Among these compounds, squalene maleimide was the most active toward mammalian OSC, whereas squalene Ellman behaved as an irreversible inhibitor of OSC from yeast

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Abbreviations

CNDT:

3-carboxy-4-nitrophenyldithio-1,1′,2-tris-norsqualene

DTNB:

5,5′-dithio-bis(2-nitrobenzoic) acid

HEI:

high energy intermediate

HPLC:

high-performance liquid chromatography

IC50 :

the concentration of inhibitor which reduces the enzymatic conversion by 50%

ip:

intraperitoneal

iv:

intravenous

LD50 :

dose that kills 50% of animals

OSC:

2,3-oxidosqualene cyclase

OS:

2,3-oxidosqualene

TLC:

thin-layer chromatography

TNB:

thionitrobenzoate

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Authors and Affiliations

  1. Istituto di Chimica Farmaceutica Applicata, Facoltà di Farmacia, Corso Raffaello 31, 10125, Torino, Italy

    Luigi Cattel, Maurizio Ceruti, Gianni Balliano, Franca Viola, Giorgio Grosa, Flavio Rocco & Paola Brusa

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  1. Luigi Cattel
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  2. Maurizio Ceruti
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  3. Gianni Balliano
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  4. Franca Viola
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  5. Giorgio Grosa
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  6. Flavio Rocco
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  7. Paola Brusa
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Cattel, L., Ceruti, M., Balliano, G. et al. 2,3-oxidosqualene cyclase: From azasqualenes to new site-directed inhibitors. Lipids 30, 235–246 (1995). https://doi.org/10.1007/BF02537827

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  • DOI: https://doi.org/10.1007/BF02537827

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