Journal ArticleDOI
The squalene-2,3-epoxide cyclase as a model for the development of new drugs
Luigi Cattel,Maurizio Ceruti,Franca Viola,Laura Delprino,Gianni Balliano,Albert Duriatti,Pierrette Bouvier-Navé +6 more
TLDR
2-aza-2,3-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.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 fungiread more
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Book ChapterDOI
Biosynthesis of triterpenoid saponins in plants.
TL;DR: Significant advances have recently been made in the area of 2,3-oxidosqualene cyclisation, and a number of genes encoding the enzymes that give rise to the diverse array of plant triterpenoid skeletons have been cloned.
Journal ArticleDOI
Ro 48-8.071, a new 2,3-oxidosqualene:lanosterol cyclase inhibitor lowering plasma cholesterol in hamsters, squirrel monkeys, and minipigs: comparison to simvastatin.
Olivier Morand,Johannes Aebi,Henrietta Dehmlow,Yu-Hua Ji,N Gains,Hans Lengsfeld,Jacques Himber +6 more
TL;DR: Findings clearly differentiate the OSC inhibitor Ro 48-8.071 from simvastatin, and support the view that OSC is a distinct key component in the regulation of the cholesterol synthesis pathway.
Journal ArticleDOI
Inhibitors of sterol biosynthesis and growth in plants and fungi
TL;DR: There is a need to evaluate precisely how sterols and their derivatives control growth and developmental processes to optimise performance of fungicides, herbicides and PGRs and the judicious use of inhibitors of the type described here may help in this undertaking.
Journal ArticleDOI
Synthesis and biological activity of azasqualenes, bis-azasqualenes and derivatives
TL;DR: AzasQualenes, bis-azasqualenes and derivatives, designed as inhibitors of squalene 2,3-epoxide cyclase, a key enzyme in sterol biosynthesis, were synthesized and their in vitro activities against a variety of yeasts, fungi, gram-positive and gram-negative bacteria were determined.
References
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Journal ArticleDOI
Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent.
Alfred W. Alberts,Julie S. Chen,G Kuron,V Hunt,Jesse W. Huff,Carl H. Hoffman,John W. Rothrock,Lopez Maria B,Henry Joshua,Elbert E. Harris,Arthur A. Patchett,R L Monaghan,S Currie,E Stapley,George Albers-Schonberg,Otto D. Hensens,J Hirshfield,Karst Hoogsteen,Jerrold M. Liesch,James P. Springer +19 more
TL;DR: It was shown that mevinolin was an orally active cholesterol-lowering agent in the dog and orally administered sodium mevinolinate was an active inhibitor of cholesterol synthesis in an acute assay.
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Zur Kenntnis der Triterpene. 190. Mitteilung. Eine stereochemische Interpretation der biogenetischen Isoprenregel bei den Triterpenen
TL;DR: In this article, the biogenetic isoprene rule in its application to the triterpenes is discussed from a stereochemical standpoint, and a scheme has been developed leading from squalene to the formulae of the basic representatives of all known cyclic triterpene groups in their full structural and configurational detail.
Journal ArticleDOI
Transition State Analog Inhibitors and Enzyme Catalysis
TL;DR: It can be shown, on the basis of any rate theory that assumes the existence of an equilibrium of activation, that the substrate in its passage to product acquires a fleeting, but greatly elevated, affinity for the enzyme.
Journal ArticleDOI
Essential role for mevalonate synthesis in DNA replication
TL;DR: The data demonstrate that HMG CoA reductase activity, and therefore the production of mevalonate, plays an essential role in the synthesis of DNA specifically during the S phase of the cell cycle and indicates that this function of meValonate in regulating DNA replication is independent of its conversion to cholesterol.