2,3-oxidosqualene cyclase: From azasqualenes to new site-directed inhibitors |
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Authors: | Luigi Cattel Maurizio Ceruti Gianni Balliano Franca Viola Giorgio Grosa Flavio Rocco Paola Brusa |
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Affiliation: | (1) Istituto di Chimica Farmaceutica Applicata, Facoltà di Farmacia, Corso Raffaello 31, 10125 Torino, Italy |
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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
Based on a paper presented at the symposium on the “Regulation of Biosynthesis and Function of Isopentenoids” Atlanta, Georgia,
May 1994. |
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