Structure-Activity Relationships of C1 and C6 Side Chains of Zaragozic Acid A Derivatives

Ponpipom, Mitree M.; Girotra, N. N.; Bugianesi, Rossana; Roberts, Cathleen D.; Berger, Gregory D.; Burk, Robert M.; Marquis, Robert W.; Parsons, William H.; Bartizal, Ken

doi:10.1021/jm00049a022

Cited by 23 publications

(12 citation statements)

References 27 publications

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“…The degradation of zaragozic acid A into the relay compound 2 is summarized in Scheme 1. As reported by Ponpipom and co-workers, tri- tert -butyl ester 3 is formed in excellent yield when zaragozic acid A is treated with O - tert -butyl- N,N ‘-diisopropylisourea in methylene chloride at reflux. The selective cleavage of the C6 α,β-unsaturated ester was readily effected by treatment of 3 with hydroxylamine, , providing 4 as a crystalline solid in virtually quantitative yield.…”

supporting

confidence: 66%

“…As reported by Ponpipom and co-workers, tri- tert -butyl ester 3 is formed in excellent yield when zaragozic acid A is treated with O - tert -butyl- N,N ‘-diisopropylisourea in methylene chloride at reflux. The selective cleavage of the C6 α,β-unsaturated ester was readily effected by treatment of 3 with hydroxylamine, , providing 4 as a crystalline solid in virtually quantitative yield. Removal of the acetate from 4 was also accomplished by using the general method of Ponpipom and co-workers .…”

supporting

confidence: 66%

“…The selective cleavage of the C6 α,β-unsaturated ester was readily effected by treatment of 3 with hydroxylamine, , providing 4 as a crystalline solid in virtually quantitative yield. Removal of the acetate from 4 was also accomplished by using the general method of Ponpipom and co-workers . Thus, treatment of 4 with ethylmagnesium bromide and cerium(III) chloride at low temperature afforded the desired tetrol 5 in good yield.…”

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confidence: 99%

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Total Synthesis of Zaragozic Acid A (Squalestatin S1). Degradation to a Relay Compound and Reassembly of the Natural Product

1996

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Zaragozic acid A (squalestatin S1) (1) was converted into the simpler derivative 2, which was reconverted into the natural product, thus establishing 2 as a viable relay compound for total synthesis of 1. The degradation (Scheme 1) consisted of formation of the tri-tert-butyl ester (3), from which the two side chains were sequentially removed to obtain 8. Aldehyde 8 was converted into dimethyl acetal 2 in standard fashion. The C6 acyl side chain 14 was prepared from (S)-2methylbutanol ("active amyl alcohol"), and the desired 4S configuration was obtained by use of Evans asymmetric enolate methylation (Scheme 2). The C1 alkyl side chain was prepared as stannane 23a from (R)-2-methyl-3-phenylpropanol (21) as shown in Scheme 5. For conversion of 2 back into zaragozic acid A, the dimethyl acetal was first converted into the cyclic acetal 17, thus protecting the C7 hydroxyl group. The remaining hydroxyl group was then acylated with acid 14 to obtain 18, which was transformed into aldehyde 20 (Scheme 4). The C1 alkyl chain was elaborated by the addition of a chiral R-alkoxyorganocerium reagent, obtained from 23a, to aldehyde 20. The resulting mixture of diastereomeric secondary alcohols was converted into zaragozic acid A (1) in six steps (Scheme 6).

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confidence: 66%

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confidence: 66%

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confidence: 99%

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Total Synthesis of Zaragozic Acid A (Squalestatin S1). Degradation to a Relay Compound and Reassembly of the Natural Product

1996

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“…This suggests that the saragosic acid may efficiently mimic the attachment ofpresqualene pyrophosphate to the enzyme [77,85]. As was strictly established, the action of saragosic acid A on squalene synthetase in mammalian cells consists in a competitive inhibition of the enzyme, followed by its irreversible inactivation as a result of the covalent binding of an cq[B-unsaturated fragment of the antibiotic to the functional residue in the active center of squalene synthetase [81].…”

Section: Antibiotics Inhibiting the Late Stages Of Cholesterol Biosynmentioning

confidence: 99%

Antibiotics inhibiting the biosynthesis of cholesterol (a review)

Тренин

Катруха

1997

Pharm Chem J

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The several decades that have passed since the introduction of penicillin into medical practice is essentially the age of antibiotics. Their wide application was very fruitful and allowed the solution of a number of fundamental problems both in the field of infection pathology and in treating diseases of a non-infection nature [ 1,2]. As is well known, antibiotics are not only successfully used as antimicrobial preparations, but are also applied in oncology as antitumor drugs. Moreover, it was the discovery of microbial metabolites-immunomodulators and the creation of immunodepressants such as eyclosporin A and FK 506 that made possible surgical operations involving the transplantation of organs and tissues [3 -5].

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“…This would result in a 50% lower final optical density at 600 nm compared to growth arrest in the absence of the compound. To test this hypothesis, eight switchdown strains (ERG9 [10], ERG11 [12], ERG1 [9], LCB1 [20], AUR1 [19], PKC1 [15], ERG7 [4], and ERG8 [29]) were grown in the presence of the following six control compounds: zaragozic acid (22), fluconazole (13), terbinafine (23,24), myriocin (3), aureobasidin A (8), and staurosporine (31). Invariably, down-regulation of a target led to hypersusceptibility to its genuine inhibitor (Table 1), thus providing proof of principle of the approach taken.…”

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Utilization of Target-Specific, Hypersensitive Strains of Saccharomyces cerevisiae To Determine the Mode of Action of Antifungal Compounds

Buurman

Andrews

Blodgett³

et al. 2005

Antimicrob Agents Chemother

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Target-specific hypersusceptible strains of Saccharomyces cerevisiae were used to screen antifungal compounds. Two novel Erg7p inhibitors were identified, providing proof of principle of the approach taken. However, observed hypersensitivities to antifungals acting via other targets imply that use of this tool to identify the mode of action requires significant deconvolution.Overexpression of a target gene can decrease the cell's susceptibility to inhibitors acting via that target (28, 30). Conversely, underexpression of a target can lead to an increased susceptibility to its inhibitors (2, 5). Here we describe how the well-studied GAL system of Saccharomyces cerevisiae (11) can be used for the identification of target-inhibitor pairs using target-specific, hypersusceptible strains of S. cerevisiae.Genes encoding putative targets that have been shown to be essential for growth of S. cerevisiae were selected (18, 26). Target-specific hypersensitive, or "switch-down," strains were constructed as previously described (17) using S. cerevisiae MEY121 (MATa his3 leu2-3,112 ura3-52 trp1 rme1) (derived from JK9-3da [14]) and a HIS3-GAL1 promoter integration cassette; correct integration was verified by a number of diagnostic PCRs. As a result, when a switch-down strain was grown at 30°C in YP (1)-2% galactose medium and transferred to YP-2% glucose medium, growth continued unabated for a number of generations until the cellular pool of target protein was presumed depleted. Since this number was constant for each target, the final density of the culture was proportional to its initial density.When wild-type strains of S. cerevisiae were incubated with growth inhibitors at sub-MICs, the growth rates of the strains were lowered but the final optical density at 600 nm was unchanged. Switch-down strains growing in the presence of glucose were expected to behave identically except when they were incubated with a compound that mediated its antifungal effect via the down-regulated target. At its 50% inhibitory concentration (IC 50 ), a target-specific compound would decrease the cellular target activity by 50% and the number of doublings the culture could undergo before the growth arrest would be one fewer. This would result in a 50% lower final optical density at 600 nm compared to growth arrest in the absence of the compound. (8), and staurosporine (31). Invariably, down-regulation of a target led to hypersusceptibility to its genuine inhibitor (Table 1), thus providing proof of principle of the approach taken. However, in some cases hypersensitivity to other compounds resulted as well (Table 1); the most striking example is the ERG1 switch-down strain that was hypersensitive to both terbinafine and fluconazole but not to any other control compound.In order to assess the utility of switch-down strains in cellbased screening of antifungal compounds, a set of 34 switchdown strains was tested against a library of 2,500 antifungal compounds with IC 50 s below 400 M against wild-type S. cerevisiae and Candida albicans. Dose respo...

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Structure-Activity Relationships of C1 and C6 Side Chains of Zaragozic Acid A Derivatives

Cited by 23 publications

References 27 publications

Total Synthesis of Zaragozic Acid A (Squalestatin S1). Degradation to a Relay Compound and Reassembly of the Natural Product

Total Synthesis of Zaragozic Acid A (Squalestatin S1). Degradation to a Relay Compound and Reassembly of the Natural Product

Antibiotics inhibiting the biosynthesis of cholesterol (a review)

Utilization of Target-Specific, Hypersensitive Strains of Saccharomyces cerevisiae To Determine the Mode of Action of Antifungal Compounds

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