Inhibitors of squalene biosynthesis and metabolism

Abe, Ikuro; Tomesch, John C.; Wattanasin, Sompong; Prestwich, Glenn D.

doi:10.1039/np9941100279

Cited by 115 publications

(71 citation statements)

References 105 publications

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“…Although terbinafi ne and its derivatives do not show any obvious structural similarities to squalene, FAD or NADPH, it seems that they act as substrate analogs (Abe et al , 1994 ). The point mutation studies of squalene monooxygenases from terbinafi ne resistant strains indicate amino acids critical for terbinafi ne-enzyme recognition (Laber et al , 2003 ;Ruckenstuhl et al , 2005Ruckenstuhl et al , , 2007.…”

Section: Antimycotic Compoundsmentioning

confidence: 99%

“…As a result of substitution of cinnamyl group in naftifi ne with a 6,6-dimethyl-2-hepten-4-ynyl, a 4-t-butylbenzyl, and a [4-(1-methyl-1-phentylethyl) phenyl]methyl terbinafi ne (2), butenafi ne (3), and SDZ SBA 586 (4) respectively, have been obtained. They have a higher inhibitory activity than the starting compound and are reversible, non-competitive inhibitors of C. albicans squalene monooxygenase with respect to squalene, FAD, NADH and NADPH (Ryder and Dupont , 1985 ;Abe et al , 1994 ). IC 50 values for mammalian SE are several orders of magnitude higher than for the fungal enzyme (e.g., IC 50 for terbinafi ne for C. albicans = 30 n m , for rat > 100000 n m ) (Ryder et al , 1986 ).…”

Section: Antimycotic Compoundsmentioning

confidence: 99%

“…Naftifi ne (1) (see Table 2 ) is the fi rst antifungal agent, which blocks biosynthesis of ergosterol, the crucial component of all fungal cell membranes, by inhibiting epoxidation of squalene (Georgopoulos et al , 1981 ;Abe et al , 1994 (Georgopoulos et al , 1981 ;Ryder and Dupont , 1984 ;Kan et al , 1986 ). Currently it is used in the treatment of infections caused by pathogenic fungi, e.g., C. albicans and Trichophyton rubrum (Abe et al , 1994 ).…”

Section: Antimycotic Compoundsmentioning

confidence: 99%

“…Currently it is used in the treatment of infections caused by pathogenic fungi, e.g., C. albicans and Trichophyton rubrum (Abe et al , 1994 ). It was a starting point for a series of successive squalene monooxygenase inhibitors (2 -11) ( Table 2 ).…”

Section: Antimycotic Compoundsmentioning

confidence: 99%

“…The removal of methyl group from the tertiary amine (16) or the substitutions Table 3 Antimycotic squalene monooxygenase inhibitors. Terbinafi ne and its derivatives (Ryder and Dupont, 1985;Abe et al, 1994 (Table 3 ) (Favre and Ryder , 1996 ).…”

Section: Antimycotic Compoundsmentioning

confidence: 99%

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Squalene monooxygenase – a target for hypercholesterolemic therapy

Belter¹,

Skupińska²,

Giel-Pietraszuk

et al. 2011

BCHM

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Squalene monooxygenase catalyzes the epoxidation of C-C double bond of squalene to yield 2,3-oxidosqualene, the key step of sterol biosynthesis pathways in eukaryotes. Sterols are essential compounds of these organisms and squalene epoxidation is an important regulatory point in their synthesis. Squalene monooxygenase downregulation in vertebrates and fungi decreases synthesis of cholesterol and ergosterol, respectively, which makes squalene monooxygenase a potent and attractive target of hypercholesterolemia and antifungal therapies. Currently some fungal squalene monooxygenase inhibitors (terbinafi ne, naftifi ne, butenafi ne) are in clinical use, whereas mammalian enzymes ' inhibitors are still under investigation. Research on new squalene monooxygenase inhibitors is important due to the prevalence of hypercholesterolemia and the lack of both suffi cient and safe remedies. In this paper we (i) review data on activity and the structure of squalene monooxygenase, (ii) present its inhibitors, (iii) compare current strategies of lowering cholesterol level in blood with some of the most promising strategies, (iv) underline advantages of squalene monooxygenase as a target for hypercholesterolemia therapy, and (v) discuss safety concerns about hypercholesterolemia therapy based on inhibition of cellular cholesterol biosynthesis and potential usage of squalene monooxygenase inhibitors in clinical practice. After many years of use of statins there is some clinical evidence for their adverse effects and only partial effectiveness. Currently they are drugs of choice but are used with many restrictions, especially in case of children, elderly patients and women of childbearing potential. Certainly, for the next few years, statins will continue to be a suitable tool for cost-effective cardiovascular prevention; however research on new hypolipidemic drugs is highly desirable. We suggest that squalene monooxygenase inhibitors could become the hypocholesterolemic agents of the future.

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Section: Antimycotic Compoundsmentioning

confidence: 99%

Section: Antimycotic Compoundsmentioning

confidence: 99%

Section: Antimycotic Compoundsmentioning

confidence: 99%

Section: Antimycotic Compoundsmentioning

confidence: 99%

Section: Antimycotic Compoundsmentioning

confidence: 99%

See 3 more Smart Citations

Squalene monooxygenase – a target for hypercholesterolemic therapy

Belter¹,

Skupińska²,

Giel-Pietraszuk

et al. 2011

BCHM

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Saragossasäure A/Squalestatin S1: synthetische und retrosynthetische Untersuchungen

Nicolaou¹,

Yue²,

Naniwa³

et al. 1994

Angewandte Chemie

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Schritt um Schritt zur ersten Totalsynthese: Saragossasäuren/Squalestatine können möglicherweise als Therapeutica für die Senkung des Serum‐Cholesterinspiegels eingesetzt werden. Die wichtigste Verbindung dieser neuartigen Naturstoffklasse, der wirkungsvolle Squalensynthase‐ Inhibitor Saragossasäure A/Squalestatin S1 1, wurde nun über die Schlüsselzwischenstufen 2und 3 synthetisiert. Zunächst wurden dazu die Schlußsequenz (2 → 1) erarbeitet und die Seitenketten an C1 und C6 in effizienten asymmetrischen Synthesen hergestellt. Die erste Synthese des hochoxygenierten Gerüstes der Saragossasäuren/Squalestatine gelang ausgehend von einem einfachen prochiralen Dien über die Zwischenstufe 3. Darauf aufbauend wurde ein Syntheseweg 3 → 2 entwickelt, so daß die Totalsynthese erfolgreich abgeschlossen werden konnte. Bb = Benzyl, PMB = para‐Methoxybenzyl, TMS = Trimethylsilyl.magnified image

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Chemie und Biologie der Saragossasäuren/Squalestatine

Nadin

Nicolaou

1996

Angewandte Chemie

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Inhibitors of squalene biosynthesis and metabolism

Cited by 115 publications

References 105 publications

Squalene monooxygenase – a target for hypercholesterolemic therapy

Squalene monooxygenase – a target for hypercholesterolemic therapy

Saragossasäure A/Squalestatin S1: synthetische und retrosynthetische Untersuchungen

Chemie und Biologie der Saragossasäuren/Squalestatine

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