Structure‐Based Design of an RNA‐Binding <i>p</i>‐Terphenylene Scaffold that Inhibits HIV‐1 Rev Protein Function

González-Bulnes, Luis; Ibáñez, Ignacio; Bedoya, Luis Miguel; Beltrán, Manuela; Catalán, Silvia; Alcamı́, José; Fustero, Santos; Gallego, José

doi:10.1002/ange.201306665

Cited by 22 publications

(2 citation statements)

References 19 publications

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“…14 Some terphenyls exhibit cytotoxic, neuroprotective, and antithrombotic activities. 15,16 The classic syntheses of terphenyls involve free-radical substitutions of aromatic rings, Ullmann and related reactions, and condensations of quinones. 16 The KOBu t /DMSO-promoted addition of acetylarenes to arylacetylenes triggers the cascade assembly of acyl terphenyls 6 (Scheme 5).…”

Section: Acyl Terphenylsmentioning

confidence: 99%

Acetylenes in the Superbase-Promoted Assembly of Carbocycles and Heterocycles

Трофимов

Schmidt

2018

Acc. Chem. Res.

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In this Account, we briefly discuss the recently discovered and rapidly developing superbase-promoted self-organization reactions of several equivalents of acetylenes and ketones to afford complex compounds that represent promising synthetic building blocks common in natural products. Notably, acetylenes play a special role in these reactions because of their dual (acting as an electrophile and a nucleophile) and flexible reactivity. These unique properties of acetylenes are elegantly expressed in superbasic media, where acetylenes are more deprotonated and their electrophilicity increases as a result of complexation with alkali metal cations, with simultaneous enhancement of the nucleophilic reactants due to desolvation. Under these conditions, acetylenes behave as a driving and organizing force toward other reactants. Various combinations of nucleophilic addition to the triple bond and acetylene deprotonation in the presence of other reactants with dual reactivity (e.g., ketones) enables the self-organization of complex molecular architectures that are inaccessible by conventional reactions. Herein we analyze recent achievements in this area concerning the reactions of acetylenes with ketones in superbasic KOH/DMSO-type systems that selectively afford synthetically and pharmaceutically valuable carbo- and heterocycles. Most of the reactions are triggered by the nucleophilic addition of deprotonated ketones (enolate anions) to acetylenes (superbase-catalyzed C-vinylation of ketones with acetylenes, which was recently introduced by our group into a toolkit of organic chemistry). The β,γ-ethylenic ketones thus formed can then take part in cascade processes with ketones and acetylenes to afford either carbocycles (e.g., hexahydroazulenones, acyl terphenyls, functionalized and cyclopentenols) or heterocycles (e.g., furans, benzoxepines, dioxabicyclo[3.2.1]octanes, and dioxadispiro[5.1.5.2]pentadecanes), depending on the structure of the reactants and the reaction conditions. Most of these compounds are selectively built from several equivalents of ketones and acetylenes in different combinations, and despite the presence of two or more asymmetric carbons in the products, they are generated as single diastereomers. When other nucleophiles (hydroxylamine, hydrazines, guanidine, and oximes) and ketones are involved in these self-organization processes, the intermediate β,γ-ethylenic ketones allow the formation of diverse heterocyclic systems (pyrroles, isoxazolines, pyrazolines, aminopyrimidines, and azabicyclo[3.1.0]hexanes). The discovered unique chemical transformations do not require transition metal catalysts and proceed under mild and operationally simple conditions. Most of these syntheses involve cascade addition reactions and therefore represent pot-, atom-, step-, and energy-saving processes that meet the requirements of green chemistry. The significance of the approach discussed herein is that it represents a viable alternative to existing classic and modern transition-metal-based catalytic syntheses of some...

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Section: Acyl Terphenylsmentioning

confidence: 99%

Acetylenes in the Superbase-Promoted Assembly of Carbocycles and Heterocycles

Трофимов

Schmidt

2018

Acc. Chem. Res.

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“…[16] An alternative small-molecule approach has been postulated whereby a generic scaffold is used to mimic the spatial and angular projection of "hot-spot" side chains found on the key helix mediating the PPI of interest. [17] Such ligands have been termed proteomimetics, [18] a-helix mimetics, [19][20][21][22] and topographical mimics. [23] Several studies on this general class of ligand have illustrated that they can be used to selectively recognize their target protein in biophysical assays, [19,24,25] that they act in cells upon the pathway in which the PPI is found, [23,26,27,52] and that they exhibit the anticipated phenotypic effects in animals.…”

mentioning

confidence: 99%

Selective and Potent Proteomimetic Inhibitors of Intracellular Protein–Protein Interactions

et al. 2015

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Inhibition of protein–protein interactions (PPIs) represents a major challenge in chemical biology and drug discovery. α‐Helix mediated PPIs may be amenable to modulation using generic chemotypes, termed “proteomimetics”, which can be assembled in a modular manner to reproduce the vectoral presentation of key side chains found on a helical motif from one partner within the PPI. In this work, it is demonstrated that by using a library of N‐alkylated aromatic oligoamide helix mimetics, potent helix mimetics which reproduce their biophysical binding selectivity in a cellular context can be identified.

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Selective and Potent Proteomimetic Inhibitors of Intracellular Protein–Protein Interactions

et al. 2015

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Inhibition of protein–protein interactions (PPIs) represents a major challenge in chemical biology and drug discovery. α-Helix mediated PPIs may be amenable to modulation using generic chemotypes, termed “proteomimetics”, which can be assembled in a modular manner to reproduce the vectoral presentation of key side chains found on a helical motif from one partner within the PPI. In this work, it is demonstrated that by using a library of N-alkylated aromatic oligoamide helix mimetics, potent helix mimetics which reproduce their biophysical binding selectivity in a cellular context can be identified.

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Structure‐Based Design of an RNA‐Binding p‐Terphenylene Scaffold that Inhibits HIV‐1 Rev Protein Function

Cited by 22 publications

References 19 publications

Acetylenes in the Superbase-Promoted Assembly of Carbocycles and Heterocycles

Acetylenes in the Superbase-Promoted Assembly of Carbocycles and Heterocycles

Selective and Potent Proteomimetic Inhibitors of Intracellular Protein–Protein Interactions

Selective and Potent Proteomimetic Inhibitors of Intracellular Protein–Protein Interactions

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