Synthesis and biological studies of flexible brevetoxin/ciguatoxin models with marked conformational preference

Candenas, Luz; Pinto, Francisco M.; Cintado, Cristina G.; Morales, Ezequiel Q.; Brouard, Ignacio; Diaz, M. T.; Rico, Milagros; Rodrı́guez, Elsa; Rodrı́guez, Rosa Marı́a; Pérez, Ricardo; Pérez, Ruby L.; Martı́n, Julio D.

doi:10.1016/s0040-4020(02)00047-9

Cited by 33 publications

(7 citation statements)

References 118 publications

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“…Unfortunately, drastic simplification of the skeletal structure of marine polycyclic ether natural products without affecting their biological function has been a significant challenge at the interface of chemistry and biology. In fact, previous studies have not been successful in yielding truncated analogues with cellular activity. − …”

Section: Discussionmentioning

confidence: 99%

Design and Synthesis of Skeletal Analogues of Gambierol: Attenuation of Amyloid-β and Tau Pathology with Voltage-Gated Potassium Channel andN-Methyl-d-aspartate Receptor Implications

et al. 2012

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Gambierol is a potent neurotoxin that belongs to the family of marine polycyclic ether natural products and primarily targets voltage-gated potassium channels (K(v) channels) in excitable membranes. Previous work in the chemistry of marine polycyclic ethers has suggested the critical importance of the full length of polycyclic ether skeleton for potent biological activity. Although we have previously investigated structure-activity relationships (SARs) of the peripheral functionalities of gambierol, it remained unclear whether the whole polycyclic ether skeleton is needed for its cellular activity. In this work, we designed and synthesized two truncated skeletal analogues of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound, both of which surprisingly showed similar potency to gambierol on voltage-gated potassium channels (K(v)) inhibition. Moreover, we examined the effect of these compounds in an in vitro model of Alzheimer's disease (AD) obtained from triple transgenic (3xTg-AD) mice, which expresses amyloid beta (Aβ) accumulation and tau hyperphosphorylation. In vitro preincubation of the cells with the compounds resulted in significant inhibition of K(+) currents, a reduction in the extra- and intracellular levels of Aβ, and a decrease in the levels of hyperphosphorylated tau. In addition, pretreatment with these compounds reduced the steady-state level of the N-methyl-D-aspartate (NMDA) receptor subunit 2A without affecting the 2B subunit. The involvement of glutamate receptors was further suggested by the blockage of the effect of gambierol on tau hyperphosphorylation by glutamate receptor antagonists. The present study constitutes the first discovery of skeletally simplified, designed polycyclic ethers with potent cellular activity and demonstrates the utility of gambierol and its synthetic analogues as chemical probes for understanding the function of K(v) channels as well as the molecular mechanism of Aβ metabolism modulated by NMDA receptors.

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Section: Discussionmentioning

confidence: 99%

Design and Synthesis of Skeletal Analogues of Gambierol: Attenuation of Amyloid-β and Tau Pathology with Voltage-Gated Potassium Channel andN-Methyl-d-aspartate Receptor Implications

et al. 2012

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“…Thus, we prepared compounds 38 and 42 in a divergent manner from the common precursor 35 , which was obtained in accordance with Scheme . The starting alkyne 33 was alkylated with allyl bromide to afford the skipped enine 34 , in which dihydroxylation of the terminal alkene generated the diol 35 . Unfortunately any attempt to perform Sharpless asymmetric dihydroxylation in the enyne 34 did not show any diastereomeric excess.…”

Section: Resultsmentioning

confidence: 99%

Stereoselective Synthesis of Cyclic Ethers by Intramolecular Trapping of Dicobalt Hexacarbonyl-Stabilized Propargylic Cations

et al. 2003

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“…Snider et al [52] published a short synthesis of waol A, a butyrolactone which has a broad spectrum of activity against cultured tumor cell lines. activators of voltage-sensitive sodium channels in nerves, heart and muscles [54]. The formation of medium-sized rings remains a significant problem in intramolecular coiodination due to unfavorable entropy factors and transanular interaction that impede ring closure [56].…”

Section: Intramolecular Coiodination Of Alkenols and Unsaturated Ethementioning

confidence: 99%

A Centennial Methodology for the Preparation of Heterocyclic Compounds: The Intramolecular Coiodination of Alkenes with Internal Oxygenated Nucleophiles

Silva¹,

Jones²,

Mattos³

2005

COS

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A review on the intramolecular coiodination of alkenes with internal oxygenated nucleophiles (alkenols, unsaturated ethers, carboxylic acids and derivatives) is presented. The reactions are discussed with emphasis in the preparation of iodotetrahydrofurans, iodotetrahydropyrans and iodolactones and their utilization in organic synthesis. The intramolecular coiodination of alkenes with less common oxygenated nucleophiles (unsaturated carbonates, phosphates, isoxazolines, uretanes, hydroperoxides and silenols) is also presented. da Silva et al.Recently, we reported the intermolecular coiodination of alkenes with oxygenated nucleophiles [17], and the products (iodohydrins, β-iodoethers and β-iodoesters) proved to be

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Synthesis and biological studies of flexible brevetoxin/ciguatoxin models with marked conformational preference

Cited by 33 publications

References 118 publications

Design and Synthesis of Skeletal Analogues of Gambierol: Attenuation of Amyloid-β and Tau Pathology with Voltage-Gated Potassium Channel andN-Methyl-d-aspartate Receptor Implications

Design and Synthesis of Skeletal Analogues of Gambierol: Attenuation of Amyloid-β and Tau Pathology with Voltage-Gated Potassium Channel andN-Methyl-d-aspartate Receptor Implications

Stereoselective Synthesis of Cyclic Ethers by Intramolecular Trapping of Dicobalt Hexacarbonyl-Stabilized Propargylic Cations

A Centennial Methodology for the Preparation of Heterocyclic Compounds: The Intramolecular Coiodination of Alkenes with Internal Oxygenated Nucleophiles

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