Valery V Fokin

The Scripps Research Institute, La Jolla, California, United States

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Publications (150)899.49 Total impact

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    ABSTRACT: The α7 nicotinic acetylcholine receptor (nAChR) is a recognized drug target for dementias of aging and certain developmental disorders. Two selective and potent α7-nAChR agonists, winnowed from a list of 43 compounds characterized in a companion article (DOI: 10.1021/acschemneuro.5b00058), 5-((quinuclid-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indole (IND8) and 3-(4-hydroxyphenyl-1,2,3-triazol-1-yl) quinuclidine (QND8), were evaluated for cognitive improvement in both short- and long-term memory. Tacrine, a centrally active acetylcholinesterase inhibitor, and PNU-282987, a congeneric α7 nAChR agonist, were employed as reference standards. Three behavioral tests, modified Y-maze, object recognition test (ORT), and water maze, were performed in scopolamine-induced amnesic mice. Intraperitoneal injection of these two compounds significantly improved the cognitive impairment in a modified Y-maze test (5 μmol/kg for IND8 and 10 μmol/kg for QND8), ORT (10 μmol/kg), and water maze test (25 μmol/kg). For delay induced memory deficit or natural memory loss in mice, IND8 and QND8 at 10 μmol/kg were able to enhance memory comparable to PNU-282987 when evaluated using ORT time delay model. Cognitive enhancement of IND8 and QND8 was mediated through α7-nAChRs as evidenced by its complete abolition after pretreatment with a selective α7-nAChR antagonist, methyllycaconitine. These data demonstrate that IND8 and QND8 and their congeners are potential candidates for treatment of cognitive disorders, and the substituted triazole series formed by cycloaddition of alkynes and azides warrant further preclinical optimization.
    ACS Chemical Neuroscience 05/2015; DOI:10.1021/acschemneuro.5b00059 · 4.21 Impact Factor
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    ABSTRACT: Three series of substituted anti-1,2,3-triazoles (IND, PPRD, and QND), synthesized by click- chemistry, were designed to enhance selectivity and efficacy profiles of a lead α7 nicotinic acetylcholine receptor (α7-nAChR) agonist, TTIn-1. Designed compounds were synthesized and screened for affinity by a radioligand binding assay. Functional characterization as agonists and antagonists was performed by fluorescence resonance energy transfer (FRET) assay using cells expressing transfected cDNA's α7-nAChRs, α4β2-nAChRs, and 5HT3A receptors and a fluorescence cell reporter. In the IND series, a tropane ring of TTIn-1, substituted at N1, was replaced by mono- and bicyclic amines to vary length and flexibility of carbon linker between nitrogen atom and N1 of triazole, a hydrogen bond acceptor. Compounds with 2-carbon atom linker optimized binding with Kd's at the submicromolar level. Further modification at the hydrophobic indole of TTIn-1 was made in PPRD and QND series by fixing the basic center with those of potent compounds in IND series. Among three series, compounds in IND series are the most potent and selective. Compounds from IND and PPRD series are selective over α4β2-nAChRs. The most promising compound is in IND series which is a selective α7-nAChR agonist with EC50 of 170 nM, while three less-selective compounds are more potent with EC50's of 28, 52, and 37 nM.
    ACS Chemical Neuroscience 05/2015; DOI:10.1021/acschemneuro.5b00058 · 4.21 Impact Factor
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    ABSTRACT: Exposure to the nerve agent soman is difficult to treat due to the rapid dealkylation of soman-acetylcholinesterase (AChE) conjugate known as aging. Oxime antidotes commonly used to reactivate organophosphate inhibited AChE are ineffective against soman, while the efficacy of the recommended nerve agent bioscavenger butyrylcholinesterase is limited by strictly stoichiometric scavenging. To overcome this limitation, we tested ex vivo, in human blood, and in vivo, in soman exposed mice, the capacity of aging-resistant human AChE mutant Y337A/F338A in combination with oxime HI-6 to act as a catalytic bioscavenger of soman. HI-6 was previously shown in vitro to efficiently reactivate this mutant upon soman, as well as VX, cyclosarin, sarin and paraoxon inhibition. We here demonstrate that ex vivo, in whole human blood, 1 µM soman was detoxified within 30 minutes when supplemented with 0.5 µM Y337A/F338A AChE and 100 µM HI-6. This combination was further tested in vivo. Catalytic scavenging of soman in mice improved the therapeutic outcome and resulted in the delayed onset of toxicity symptoms. Furthermore, in a preliminary in vitro screen we identified an even more efficacious oxime than HI-6, in a series of forty-two pyridinium aldoximes, and five imidazole 2-aldoxime N-propyl pyridinium derivatives. One of the later imidazole aldoximes, RS-170B, was a 2-3 -fold more effective reactivator of Y337A/F338A AChE than HI-6 due to the smaller imidazole ring, as indicated by computational molecular models, that affords a more productive angle of nucleophilic attack.
    Chemical Research in Toxicology 04/2015; 28(5). DOI:10.1021/acs.chemrestox.5b00060 · 4.19 Impact Factor
  • James S. Oakdale, Rakesh K. Sit, Valery V. Fokin
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    ABSTRACT: (Cyclopentadienyl)(cyclooctadiene) ruthenium(II) chloride [CpRuCl(cod)] catalyzes the reaction between nitrile oxides and electronically deficient 1-choro-, 1-bromo-, and 1-iodoalkynes leading to 4-haloisoxazoles. Organic azides are also suitable 1,3-dipoles, resulting in 5-halo-1,2,3-triazoles. These air-tolerant reactions can be performed at room temperature with 1.25 equivalents of the respective 1,3-dipole relative to the alkyne component. Reactive 1-haloalkynes include propiolic amides, esters, ketones, and phosphonates. Post-functionalization of the halogenated azole products can be accomplished by using palladium-catalyzed cross-coupling reactions and by manipulation of reactive amide groups. The lack of catalysis observed with [Cp*RuCl(cod)] (Cp*=pentamethylcyclopentadienyl) is attributed to steric demands of the Cp* (η5-C5Me5) ligand in comparison to the parent Cp (η5-C5H5). This hypothesis is supported by the poor reactivity of [(η5-C5Me4CF3)RuCl(cod)], which serves as a an isosteric mimic of Cp* and as an isoelectronic analogue of Cp.
    Chemistry - A European Journal 03/2015; 46(9). DOI:10.1002/chem.201402559 · 5.70 Impact Factor
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    ABSTRACT: A series of conformationally flexible furan-derived allocolchicinoids was prepared from commercially available colchicine in good to excellent yield using a three-step reaction sequence. Cytotoxicity studies indicated a potent activity of compounds 10c and 10d against human epithelial and lymphoid cell lines (AsPC-1, HEK293 and Jurkat). The results of in vitro experiments demonstrated that the major effect of these compounds was the induction of cell cycle arrest in G2/M phase which is a direct consequence of the effective tubulin binding. Application of furanoallocolchicinoid 10c for in vivo mice treatment indicated significant inhibition of the tumor growth without symptoms of neurotoxicity.
    Journal of Medicinal Chemistry 12/2014; 58(2). DOI:10.1021/jm501678w · 5.48 Impact Factor
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    ABSTRACT: The synthesis of several new heterocyclic structural analogs of the natural antimitotic agent allocolchicine is reported. As a key step an intramolecular Pd-catalyzed C–H arylation reaction was used to close the seven-membered ring fused with two electron-rich aryl fragments. The stereostructure of the target compounds was determined by X-ray crystal analysis. The primary biological assessment of the synthesized compounds was carried out on human lymphoma cells. Several allocolchicinoids were determined to possess antiproliferative and apoptosis-inducing activity in the micromolar concentration range.
    European Journal of Organic Chemistry 10/2014; 46(12). DOI:10.1002/ejoc.201402850 · 3.15 Impact Factor
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    ABSTRACT: A convenient one-pot asymmetric synthesis of 2,3-dihydropyrroles from in situ generated triflated triazoles and olefins is described that further expands the utility of azavinyl carbene chemistry and provides access to an important class of cyclic enamides. Mechanistic investigations support the involvement of triflated cyclopropylaldimine intermediates in the formation of 2,3-dihydropyrrole. To the best of our knowledge, this is the first example of a chiral Brønsted acid catalyzed rearrangement of cyclopropylimines into enantioenriched 2,3-dihydropyrroles.
    Angewandte Chemie International Edition 09/2014; 45(36). DOI:10.1002/anie.201306706 · 11.26 Impact Factor
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    ABSTRACT: High-molecular-weight polysulfates are readily formed from aromatic bis(silyl ethers) and bis(fluorosulfates) in the presence of a base catalyst. The reaction is fast and proceeds well under neat conditions or in solvents, such as dimethyl formamide or N-methylpyrrolidone, to provide the desired polymers in nearly quantitative yield. These polymers are more resistant to chemical degradation than their polycarbonate analogues and exhibit excellent mechanical, optical, and oxygen-barrier properties.
    Angewandte Chemie 09/2014; 126(36). DOI:10.1002/ange.201403758
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    ABSTRACT: High-molecular-weight polysulfates are readily formed from aromatic bis(silyl ethers) and bis(fluorosulfates) in the presence of a base catalyst. The reaction is fast and proceeds well under neat conditions or in solvents, such as dimethyl formamide or N-methylpyrrolidone, to provide the desired polymers in nearly quantitative yield. These polymers are more resistant to chemical degradation than their polycarbonate analogues and exhibit excellent mechanical, optical, and oxygen-barrier properties.
    Angewandte Chemie International Edition 09/2014; 53(36). DOI:10.1002/anie.201403758 · 11.26 Impact Factor
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    ABSTRACT: The siglec family of sialic acid-binding proteins are endocytic immune cell receptors that are recognized as potential targets for cell directed therapies. CD33 and CD22 are prototypical members and are validated candidates for targeting acute myeloid leukaemia and non-Hodgkin's lymphomas due to their restricted expression on myeloid cells and B-cells, respectively. While nanoparticles decorated with high affinity siglec ligands represent an attractive platform for delivery of therapeutic agents to these cells, a lack of ligands with suitable affinity and/or selectivity has hampered progress. Herein we describe selective ligands for both of these siglecs, which when displayed on liposomal nanoparticles, can efficiently target the cells expressing them in peripheral human blood. Key to their identification was the development of a facile method for chemo-enzymatic synthesis of disubstituted sialic acid analogues, combined with iterative rounds of synthesis and rapid functional analysis using glycan microarrays.
    Chemical Science 06/2014; 5(6):2398-2406. DOI:10.1039/C4SC00451E · 8.60 Impact Factor
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    ABSTRACT: A convenient one-pot asymmetric synthesis of 2,3-dihydropyrroles from in situ generated triflated triazoles and olefins is described that further expands the utility of azavinyl carbene chemistry and provides access to an important class of cyclic enamides. Mechanistic investigations support the involvement of triflated cyclopropylaldimine intermediates in the formation of 2,3-dihydropyrrole. To the best of our knowledge, this is the first example of a chiral Brønsted acid catalyzed rearrangement of cyclopropylimines into enantioenriched 2,3-dihydropyrroles.
    Angewandte Chemie 03/2014; 126(13). DOI:10.1002/ange.201306706
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    ABSTRACT: Intoxication by organophosphate (OP) nerve agents and pesticides should be addressed by efficient, quickly deployable countermeasures such as antidotes reactivating acetylcholinesterase or scavenging the parent OP. We present here synthesis and initial in vitro characterization of 14 imidazole aldoximes and their structural refinement into three efficient reactivators of human butyrylcholinesterase (hBChE) inhibited covalently by nerve agent OPs, sarin, cyclosarin, VX, and the OP pesticide metabolite, paraoxon. Rapid reactivation of OP-hBChE conjugates by uncharged and nonprotonated tertiary imidazole aldoximes allows the design of a new OP countermeasure by conversion of hBChE from a stoichiometric to catalytic OP bioscavenger with the prospect of oral bioavailability and central nervous system penetration. The enhanced in vitro reactivation efficacy determined for tertiary imidazole aldoximes compared to that of their quaternary N-methyl imidazolium analogues is attributed to ion pairing of the cationic imidazolium with Asp 70, altering a reactive alignment of the aldoxime with the phosphorus in the OP-hBChE conjugate.
    Journal of Medicinal Chemistry 02/2014; 57(4):1378-89. DOI:10.1021/jm401650z · 5.48 Impact Factor
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    ABSTRACT: A new method based on Negishi cross-coupling of alkenylzinc reagent (I) with aryl halides allows the synthesis of various Isocombretastatins.
    ChemInform 02/2014; 45(5). DOI:10.1002/chin.201405220
  • Brady T Worrell, Shelby P Ellery, Valery V Fokin
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    ABSTRACT: Fully loaded: Readily accessible and shelf-stable 1-bismuth(III) acetylides react rapidly and regiospecifically with organic azides in the presence of a copper(I) catalyst. The reaction tolerates many functional groups and gives excellent yields of the previously unreported 5-bismuth triazolides. This uniquely reactive intermediate is functionalized under mild reaction conditions to give fully substituted 1,2,3-triazoles.
    Angewandte Chemie International Edition 12/2013; 52(49). DOI:10.1002/anie.201306192 · 11.26 Impact Factor
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    ABSTRACT: Rhodium(II) azavinyl carbenes, conveniently generated from 1-sulfonyl-1,2,3-triazoles, undergo a facile, mild and convergent formal 1,3-insertion into N-H and O-H bonds of primary and secondary amides, various alcohols, and carboxylic acids to afford a wide range of vicinally bis-functionalized Z-olefins with perfect regio- and stereoselectively. Utilizing the distinctive functionality installed through these reactions, a number of subsequent rearrangements and cyclizations expand the repertoire of valuable organic building blocks constructed by reactions of transition metal carbene complexes, including α-allenyl ketones and amino-substituted heterocycles.
    Journal of the American Chemical Society 12/2013; 136(1). DOI:10.1021/ja408185c · 11.44 Impact Factor
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    ABSTRACT: Metronidazole and other 5-nitroimidazoles (5-NI) are among the most effective antimicrobials available against many important anaerobic pathogens, but evolving resistance is threatening their long-term clinical utility. The common 5-NIs were developed decades ago, yet little 5-NI drug development has since taken place, leaving the true potential of this important drug class unexplored. Here we report on a unique approach to the modular synthesis of diversified 5-NIs for broad exploration of their antimicrobial potential. Many of the more than 650 synthesized compounds, carrying structurally diverse functional groups, have vastly improved activity against a range of microbes, including the pathogenic protozoa Giardia lamblia and Trichomonas vaginalis, and the bacterial pathogens Helicobacter pylori, Clostridium difficile, and Bacteroides fragilis. Furthermore, they can overcome different forms of drug resistance, and are active and nontoxic in animal infection models. These findings provide impetus to the development of structurally diverse, next-generation 5-NI drugs as agents in the antimicrobial armamentarium, thus ensuring their future viability as primary therapeutic agents against many clinically important infections.
    Proceedings of the National Academy of Sciences 10/2013; 110(43). DOI:10.1073/pnas.1302664110 · 9.81 Impact Factor
  • Valery V. Fokin
    ChemInform 06/2013; 44(25). DOI:10.1002/chin.201325206
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    ABSTRACT: The ring expansion and rearrangement of diazo compounds, specifically rhodium carbenes (derived from the corresponding diazo species), is an efficient and operationally simple method for the construction of structurally unique frameworks.[ 1] Products derived from these reactions normally consist of large carbocyclic rings (7, 8, and 9 membered) and multiple substituted olefins, which are ubiquitous in natural products and drug molecules.[2] Indeed, these robust methods have found widespread use in organic synthesis, both for the synthesis of complex natural products and in pharmaceutical research.[3] Bolstered by our recent success utilizing readily available and stable 1-sulfonyl-1,2,3-triazoles 1 as direct precursors to rhodium(II) azavinyl carbenes 2 (Scheme 1),[4,5] we hypothesized that these diazo progenitors could be effective in these ring expansion/rearrangement reactions, to deliver unique products that are not accessible via conventional diazo compounds (Scheme 2). Herein, we report the rhodium(II)-catalyzed ring-expansion and rearrangement reactions of azavinyl carbenes (2), to access various enaminones and substituted olefins, which, in the case of the expanded enaminones can be further reacted to form a variety of heterocycles and ketone-based products.
    Angewandte Chemie International Edition 05/2013; 51(52). DOI:10.1002/anie.201207820 · 11.26 Impact Factor
  • Mikhail Zibinsky, Valery V Fokin
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    ABSTRACT: As easy as 1,2,3: Readily available and shelf-stable 1-sulfonyl-1,2,3-triazoles react with aldehydes and aldimines in the presence of Rh(II) catalysts to produce 4-oxazolines and 1,2,5-trisubstituted imidazoles.
    Angewandte Chemie International Edition 05/2013; 52(5). DOI:10.1002/anie.201206388 · 11.26 Impact Factor
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    ABSTRACT: The Siglec family of sialic acid-binding proteins are differentially expressed on white blood cells of the immune system and represent an attractive class of targets for cell-directed therapy. Nanoparticles decorated with high-affinity Siglec ligands show promise for delivering cargo to Siglec-bearing cells, but this approach has been limited by a lack of ligands with suitable affinity and selectivity. Building on previous work employing solution-phase sialoside library synthesis and subsequent microarray screening, we herein report a more streamlined 'on-chip' synthetic approach. By printing a small library of alkyne sialosides and subjecting these to 'on-chip' click reactions, the largest sialoside analog library to date was generated. Siglec-screening identified a selective Siglec-7 ligand, which when displayed on liposomal nanoparticles, allows for targeting of Siglec-7+ cells in peripheral human blood. In silico docking to the crystal structure of Siglec-7 provides a rational for the affinity gains observed for this novel sialic acid analog.
    ACS Chemical Biology 04/2013; 8(7). DOI:10.1021/cb400125w · 5.36 Impact Factor

Publication Stats

13k Citations
899.49 Total Impact Points

Institutions

  • 2002–2015
    • The Scripps Research Institute
      • • Department of Chemistry
      • • Skaggs Institute for Chemical Biology
      La Jolla, California, United States
  • 2014
    • Nizhny Novgorod State University
      • Department of Organic Chemistry
      Gorkey, Nizjnij Novgorod, Russia
    • Novgorod State University
      Nowgorod, Novgorod, Russia
  • 2011–2012
    • University of San Diego
      San Diego, California, United States
  • 2009
    • Queensland Institute of Medical Research
      Brisbane, Queensland, Australia
  • 2007
    • Technical University of Denmark
      • Department of Chemistry
      Lyngby, Capital Region, Denmark
    • University of California, Santa Barbara
      • Materials Research Laboratory
      Santa Barbara, California, United States
  • 2005
    • The Hong Kong University of Science and Technology
      • Department of Chemistry
      Chiu-lung, Kowloon City, Hong Kong