29-Methylidene-2,3-oxidosqualene Derivatives as Stereospecific Mechanism-Based Inhibitors of Liver and Yeast Oxidosqualene Cyclase

Ceruti, Maurizio; Rocco, Flavio; Viola, Franca; Balliano, Gianni; Milla, Paola; Arpicco, Silvia Maria; Cattel, Luigi

doi:10.1021/jm970534j

Cited by 25 publications

(41 citation statements)

References 73 publications

(120 reference statements)

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“…Obtained 12 was treated with NBS to give bromohydrin 13 in a 35% yield. 25 24,26) was used in the biomimetic cyclization of 1, because it is known as a popular Lewis acid to activate an epoxide, while MeAlCl 2 was used for the total synthesis of emindole SA. 17) SnCl 4 27) and TiCl 4 28) are general Lewis acids used in the synthesis of cyclic compounds for ringopening cyclization of epoxypolyene and polyene cyclization.…”

Section: Resultsmentioning

confidence: 99%

Biomimetic Cyclization of Epoxide Precursors of Indole Mono-, Sesqui- and Diterpene Alkaloids by Lewis Acids

Isaka¹,

Hasegawa²,

Toshima³

2011

Bioscience, Biotechnology, and Biochemistry

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Cyclization of the synthesized epoxide precursors of indole mono-, sesqui-and diterpene alkaloids was performed to elucidate the mechanism for biomimetic cationic cyclization to polycyclic structures. 3-(6,7-Epoxygeranyl)indole (11), 3-(10,11-epoxyfarnesyl)indole (2) and 3-(14,15-epoxygeranylgeranyl)indole (3) were respectively synthesized from geraniol, farnesol and geranylgeraniol in 6 or 7 steps. Four Lewis acids (MeAlCl 2 , BF 3 . OEt 2 , TiCl 4 and SnCl 4 ) were applied for biomimetic cyclization of the synthesized epoxide precursors. The cyclization products (one product from 11, four products from 2, and three products from 3) were isolated after separation by chromatography. Their structures were determined by using NMR (COSY, HSQC, HMBC, NOESY, etc.) and HRMS analyses. The results show that biomimetic cyclization gave new polycyclic compounds similar to natural indole terpene alkaloids. We conclude that the stability of cation intermediates should determine the preference for product formation by biomimetic cyclization when using a Lewis acid.

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Section: Resultsmentioning

confidence: 99%

Biomimetic Cyclization of Epoxide Precursors of Indole Mono-, Sesqui- and Diterpene Alkaloids by Lewis Acids

Isaka¹,

Hasegawa²,

Toshima³

2011

Bioscience, Biotechnology, and Biochemistry

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“…The methylidene derivatives 4, 6, 7, and 8 show comparable activities against the T. cruzi and pig liver enzyme whereas compound 5 is five times less effective on T. cruzi OSC. As already observed for mammalian enzyme, the isomers of inhibitor with the same configuration as the substrate are at least 10 times more effective (16). The presence of a vinyl function in position 2 as in the trans 2-vinyl-2-oxido-1,1-bisnorsqualene 8, as already observed in pig and S. cerevisiae OSC, is not effective for inhibition (18).…”

Section: Inhibition Of T Cruzi Osc In Cell-free Homogenate Ofmentioning

confidence: 60%

“…The closure of the last ring and the rearrangement are probably differently controlled in different OSC, as the 19-aza-derivative is very active only against pig liver OSC. The 29-methylidene derivatives 4-7, previously shown to be time-dependent inhibitors (16,22), similarly lack specificity.…”

Section: Discussionmentioning

confidence: 95%

Analogs of squalene and oxidosqualene inhibit oxidosqualene cyclase of Trypanosoma cruzi expressed in Saccharomyces cerevisiae

Oliaro‐Bosso

Ceruti

Balliano

et al. 2005

Lipids

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ABSTRACT:Recently, a number of inhibitors of the enzyme oxidosqualene cyclase (OSC; EC 5.4.99.7), a key enzyme in sterol biosynthesis, were shown to inhibit in mammalian cells the multiplication of Trypanosoma cruzi, the parasite agent of Chagas' disease. The gene coding for the OSC of T. cruzi has been cloned and expressed in Saccharomyces cerevisiae. The expression in yeast cells could be a safe and easy model for studying the activity and the selectivity of the potential inhibitors of T. cruzi OSC. Sterols are eukaryotic membrane components that are necessary to support cell growth and differentiation. Sterol biosynthesis is a well-established chemotherapeutic target in pathogenic eukaryotes, such as fungi (1,2). The final product of the sterol biosynthetic pathway in fungi is the 24-alkyl sterol ergosterol. Ergosterol or similar 24-alkyl sterols are also the final products of the sterol synthetic pathway of some pathogenic protozoa including Trypanosoma species. These organisms cannot completely substitute these sterols with the cholesterol biosynthesized in host mammalian cells and need to synthesize at least some of their own distinctive sterols (3-5). This dependence on sterols suggests that sterol biosynthesis inhibitors may be useful antiprotozoal drugs. The sterol biosynthetic pathway ( Fig. 1) offers many potential targets for therapeutic purposes. Many effective antifungal drugs already in use act by inhibiting different enzymes of sterol biosynthesis; the allylamine antifungal drug terbinafine inhibits squalene epoxidase (6), and azole drugs such as ketoconazole and itraconazole are inhibitors of lanosterol C 14 -demethylase (7). The activity of these inhibitors can be explained as a consequence either of depletion of the ergosterol or of accumulation of toxic intermediates or side products. In addition to the antifungal activity, some of these compounds Acetyl-CoAwere shown to inhibit the growth of Trypanosoma and other kinetoplastid parasites (8). Kinetoplastid parasites have also been shown recently to be susceptible to inhibitors of squalene synthase (9,10) and oxidosqualene cyclase (11,12). The enzyme oxidosqualene cyclase (OSC; EC 5.4.99.7), which catalyzes the formation of the first cyclic precursor of sterols, is considered a good target for the inhibition of sterol biosynthesis in both humans and fungi. Many inhibitors, designed on the basis of the complex cyclization mechanism of OSC (13), are active on the enzyme and have been investigated as potential cholesterol-lowering or antifungal drugs (1,2,13). The recent crystallization of human OSC as a complex with the potent inhibitor RO48-8071 opens the way to new structurebased studies of the cyclization mechanism (14).We have designed and tested against mammalian and fungal OSC many acyclic substrate analogs modified either to mimic the high-energy carbocationic intermediates (compounds 1-3 of Fig. 2) or to bear reactive functions able to interact with the active site residues, as the methylidene (compounds 4-8), vinyl sulfide (compounds 9...

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“…1 H-(300 MHz) and 13 C-NMR (75 MHz) were recorded at room temperature with a Bruker 300 Advance spectrometer. The spectra were recorded in CDCl 3 , and solvent signals for CHCl 3 /CDCl 3 (7.26 ppm) were used as a reference.…”

Section: Methodsmentioning

confidence: 99%

“…1) While several mammalian OSCs were being isolated, characterized, cloned and sequenced, 2-9) hundreds of OSC inhibitors have been designed and tested [10][11][12][13][14] as potential anti-fungal 15) or cholesterol-lowering drugs. 16) Recently, a novel series of orally active inhibitors have been tested on human liver microsomal OSC, and their effectiveness as cholesterol-lowering drugs has been evaluated in hyperlipidemic hamsters.…”

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confidence: 99%

Novel Squalene-Hopene Cyclase Inhibitors Derived from Hydroxycoumarins and Hydroxyacetophenones

Cravotto

Balliano

Tagliapietra

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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One of the most intensively studied enzymes of sterol biosynthesis, oxidosqualene cyclase (OSC), catalyzes the conversion of an acyclic compound, 2,3-oxidosqualene, to the first cyclic intermediate along the pathway. This is lanosterol in all non-photosynthetic organisms, and cycloartenol in plants.1) While several mammalian OSCs were being isolated, characterized, cloned and sequenced, 2-9) hundreds of OSC inhibitors have been designed and tested [10][11][12][13][14] as potential anti-fungal 15) or cholesterol-lowering drugs. 16) Recently, a novel series of orally active inhibitors have been tested on human liver microsomal OSC, and their effectiveness as cholesterol-lowering drugs has been evaluated in hyperlipidemic hamsters.17) OSC inhibitors are also under investigation as potential anti-trypanosomal agents. 18,19) The design of new OSC inhibitors received a further boost when the complete structure of a squalene hopene cyclase (SHC) was elucidated. 20) This bacterial enzyme, isolated from the thermophilic bacterium Alicyclobacillus acidocaldarius, proved particularly interesting because its sequence revealed a remarkable degree of homology and partial identity with eukaryotic OSCs. 21,22) SHC may therefore be used as a model to predict how newly designed inhibitors may interact with OSCs. Recently, the interaction of several new inhibitors of human OSC 17) with the active site of SHC was investigated by co-crystallization experiments.23) Because comparative studies on the two enzyme types 24,25) have shown close correspondence of their inhibitor activities, we recently investigated a group of meroterpenoids that proved to be excellent inhibitors of SHC.26) The basic structure of bioactive oxyprenylcoumarins is derived from umbelliprenine (7-farnesyloxycoumarin) by the insertion of either a tetrahydrofuran unit (farnesylferol C, 1) or 1-2 oxiran rings (2, 3) (Fig. 1). While farnesyferol C (IC 50 7.0 mM) is a naturally occurring compound, umbelliprenine-10Ј,11Ј-monoepoxyde (2) (IC 50 2.5 mM) and diepoxyde (3) (IC 50 1.5 mM) have been previously obtained by synthesis. 26)This encouraging start prompted us to extend the study of structure-activity relationships by modifying both the heterocyclic nucleus and the side chain, hopefully to improve molecular recognition. Results and DiscussionWe proceeded towards molecular simplification and also covered a few isosters, i.e. thiocoumarin and quinolindione derivatives. 2-and 4-thiocoumarin nuclei were accessed by a published procedure, 27,28) while 2,4-quinolinediol was commercially available. S-Geranylthiocoumarins 7 and 8 were prepared via a Mitsunobu reaction.29) 4-O-Geranyl-quinolin-2-one (10) was prepared according to Grundon. 30)The isosters synthesized by us (7-10) showed lower inhibitory activities compared to either the O-geranylcoumarins or the w-epoxy derivative 6. A shorter side chain, as in aurapten 31) (7-geranyloxycoumarin, 5) and 6Ј,7Ј-epoxyaurapten 32) (6) or prenyletin 33,34) (4) was also deleterious for the inhibitory activity.All relevant struct...

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29-Methylidene-2,3-oxidosqualene Derivatives as Stereospecific Mechanism-Based Inhibitors of Liver and Yeast Oxidosqualene Cyclase

Cited by 25 publications

References 73 publications

Biomimetic Cyclization of Epoxide Precursors of Indole Mono-, Sesqui- and Diterpene Alkaloids by Lewis Acids

Biomimetic Cyclization of Epoxide Precursors of Indole Mono-, Sesqui- and Diterpene Alkaloids by Lewis Acids

Analogs of squalene and oxidosqualene inhibit oxidosqualene cyclase of Trypanosoma cruzi expressed in Saccharomyces cerevisiae

Novel Squalene-Hopene Cyclase Inhibitors Derived from Hydroxycoumarins and Hydroxyacetophenones

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