Total Synthesis and Biological Evaluation of the Resveratrol-Derived Polyphenol Natural Products Hopeanol and Hopeahainol A

Nicolaou, K. C.; Kang, Qiang; Wu, Tingting; Lim, Chek Shik; Chen, David Y.‐K.

doi:10.1021/ja102623j

Cited by 135 publications

(70 citation statements)

References 38 publications

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“…27 By contrast, wholly stepwise, non-biomimetic sequences empowered by retrosynthetic analysis can produce single dimeric members with control, but do not possess the strategic power to deliver a family-level solution for all frameworks. 5,6,28,29,30,31 Herein, we establish an approach with the potential to lead to the entire resveratrol collection controllably, one member at a time.…”

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confidence: 99%

Regioselective reactions for programmable resveratrol oligomer synthesis

Snyder

Gollner

Chiriac

2011

Nature

190

112

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Although much attention has been devoted to resveratrol, a unique polyphenol produced by plants throughout the world and credited as potentially being responsible for the so-called “French paradox” given its broad spectrum activity, the hundreds of oligomeric materials derived from it have been largely ignored despite their similarly high biochemical potential. Challenges in achieving their isolation in quantity from natural sources, coupled with an inability to rationally prepare them in the laboratory, are the main culprits. Here we show that a programmable, controlled, and potentially scaleable synthesis of the resveratrol family is possible through a unique three-stage design. These efforts required novel tactics coupled with strategy- and reagent-guided functionalizations to differentiate two distinct cores possessing multiple sites with the same and/or similar reactivity, ultimately leading to five higher-order natural products. We anticipate that this work 1) demonstrates that challenging, positionally-selective functionalizations of complex materials are possible where biosynthetic studies have indicated otherwise, 2) provides materials and tools to finally unlock the full biochemical potential of the family, particularly from the standpoint of activity and drug-property optimization, and 3) affords an intellectual framework to potentially access other oligomeric families controllably.

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mentioning

confidence: 99%

Regioselective reactions for programmable resveratrol oligomer synthesis

Snyder

Gollner

Chiriac

2011

Nature

190

112

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“…2A). The absolute ( S )- or (+)-configuration of naturally occurring hopeahainol A has been inferred from molecular modeling and the crystal structure of permethylated hopeahainol A (where four phenolic hydroxyl groups are methylated) [23, 29]. Our preliminary molecular modeling indicated that hopeahainol A is too bulky to be accommodated within the long but narrow AChE active site gorge without severe distortion of the gorge as depicted in AChE crystal structures.…”

Section: Resultsmentioning

confidence: 97%

“…Basic methanol is known to convert hopeahainol A to hopeanol through methanolysis of the χ-lactone moiety [24, 29], and incubation of hopeahainol A here in 3 mM NaPi (pH 7.0) gave UV spectral changes consistent with conversion to hopeanol [23] over a 2-day period. Hopeanol is reported to have no inhibitory activity with AChE [23, 29]. …”

Section: Resultsmentioning

confidence: 99%

Hopeahainol A binds reversibly at the acetylcholinesterase (AChE) peripheral site and inhibits enzyme activity with a novel higher order concentration dependence

Rosenberry

Martin

Nix

et al. 2016

Chemico-Biological Interactions

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Natural product inhibitors of AChE are of interest both because they offer promise as inexpensive drugs for symptomatic relief in Alzheimer’s disease and because they may provide insights into the structural features of the AChE catalytic site. Hopeahainol A is an uncharged polyphenol AChE inhibitor from the stem bark of H. hainanensis with a constrained, partially dearomatized bicyclic core. Molecular modeling indicates that hopeahainol A binds at the entrance of the long but narrow AChE active site gorge because it is too bulky to be accommodated within the gorge without severe distortion of the gorge as depicted in AChE crystal structures. We conducted inhibitor competition experiments in which AChE inhibition was measured with hopeahainol A together with either edrophonium (which binds at the base of the gorge) or thioflavin T (which binds to the peripheral or P-site near the gorge mouth). The results agreed with the molecular modeling and indicated that hopeahainol A at lower concentrations (< 200 µM) bound only to the P-site, as hopeahainol A and thioflavin T were unable to form a ternary complex with AChE while hopeahainol A and edrophonium did form a ternary complex with essentially no competition between them. Inhibition increased to a striking extent at higher concentrations of hopeahainol A, with plots analogous to classic Dixon plots showing a dependence on hopeahainol A concentrations to the third- or fourth order. The inhibition at higher hopeahainol A concentrations was completely reversed on dilution and blocked by bound edrophonium. We hypothesize that bound hopeahainol A induces conformational changes in the AChE active site that allow binding of additional hopeahainol A molecules, a phenomenon that would be unprecedented for a reversible inhibitor that apparently forms no covalent bonds with AChE.

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“…The final step in AFS catalysis is reminiscent (although not identical) to intramolecular Friedel-Crafts reactions reported in the literature. 78 Biosynthesis of farnesene serves as an excellent example of how enzymes use allylic carbocation chemistry to conduct different chemical transformations which are not unfamiliar in the world of synthetic organic chemistry.…”

Section: Discussion Of Chemical Insightsmentioning

confidence: 99%

In Vitro Reconstitution of Metabolic Pathways: Insights into Nature’s Chemical Logic

Lowry

Walsh

Khosla

2015

Synlett

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In vitro analysis of metabolic pathways is becoming a powerful method to gain a deeper understanding of Nature’s core biochemical transformations. With astounding advancements in biotechnology, purification of a metabolic pathway’s constitutive enzymatic components is becoming a tractable problem, and such in vitro studies allow scientists to capture the finer details of enzymatic reaction mechanisms, kinetics, and the identity of organic product molecules. In this review, we present eleven metabolic pathways that have been the subject of in vitro reconstitution studies in the literature in recent years. In addition, we have selected and analyzed subset of four case studies within these eleven examples that exemplify remarkable organic chemistry occurring within biology. These examples serves as tangible reminders that Nature’s biochemical routes obey the fundamental principles of organic chemistry, and the chemical mechanisms are reminiscent of those featured in traditional synthetic organic routes. The illustrations of biosynthetic chemistry depicted in this review may inspire the development of biomimetic chemistries via abiotic chemical techniques.

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Total Synthesis and Biological Evaluation of the Resveratrol-Derived Polyphenol Natural Products Hopeanol and Hopeahainol A

Cited by 135 publications

References 38 publications

Regioselective reactions for programmable resveratrol oligomer synthesis

Regioselective reactions for programmable resveratrol oligomer synthesis

Hopeahainol A binds reversibly at the acetylcholinesterase (AChE) peripheral site and inhibits enzyme activity with a novel higher order concentration dependence

In Vitro Reconstitution of Metabolic Pathways: Insights into Nature’s Chemical Logic

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