Amos B Smith

University of Pennsylvania, Filadelfia, Pennsylvania, United States

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Publications (399)2435.1 Total impact

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    ABSTRACT: The synthesis of a C(1)-C(24) advanced southern hemisphere fragment towards the total synthesis of spirastrellolide E has been achieved. Highlights of the route include a highly convergent Type I Anion Relay Chemistry (ARC) tactic for fragment assembly, in conjunction with a directed, regioselective gold-catalyzed alkyne functionalization to generate the central unsaturated [6,6]-spiroketal.
    Tetrahedron Letters 06/2015; 56(23):3160-3164. DOI:10.1016/j.tetlet.2014.12.026 · 2.39 Impact Factor
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    ABSTRACT: A convergent total synthesis of the architecturally complex indole diterpenoid (-)-nodulisporic acid D has been achieved. Key synthetic transformations include vicinal difunctionalization of an advanced α,β-unsaturated aldehyde to form the E,F-trans-fused 5,6-ring system of the eastern hemisphere and a cascade cross-coupling/indolization protocol leading to the CDE multisubstituted indole core.
    Journal of the American Chemical Society 06/2015; 137(22). DOI:10.1021/jacs.5b04728 · 11.44 Impact Factor
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    ABSTRACT: Die Tedanolide sind biologisch aktive Polyketide, deren Makrolaktonring aus einem primären Alkohol aufgebaut ist. Da Polyketidumwandlungen nur sekundäre Alkohole erzeugen, postulierte Taylor, dass das Tedanolid-Lakton aus einer intramolekularen Umesterung hervorgegangen ist. Um diese Hypothese zu prüfen und das biologische Profil des vermuteten Vorläufers aller Mitglieder der Tedanolidfamilie zu untersuchen, unternahmen wir die Synthese von Desepoxyisotedanolid und dessen biologische Evaluierung im Vergleich zum Desepoxytedanolid. Die biologischen Experimente deckten ein zweites Zielprotein für Desepoxytedanolid auf und erbrachten Hinweise, dass die vorgeschlagene Umesterung dem produzierenden Mikroorganismus einen evolutionären Vorteil erbringt.
    Angewandte Chemie 04/2015; 127(23). DOI:10.1002/ange.201501526
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    ABSTRACT: The tedanolides are biologically active polyketides that exhibit a macrolactone constructed from a primary alcohol. Since polyketidal transformations only generate secondary alcohols, it has been hypothesized by Taylor that this unique lactone could arise from a postketidal transesterification. In order to probe this hypothesis and to investigate the biological profile of the putative precursor of all members of the tedanolide family, we embarked on the synthesis of desepoxyisotedanolide and its biological evaluation in comparison to desepoxytedanolide. The biological experiments unraveled a second target for desepoxytedanolide and provided evidence that the proposed transesterification indeed provides a survival advantage for the producing microorganism. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Angewandte Chemie International Edition 04/2015; 54(23). DOI:10.1002/anie.201501526 · 11.34 Impact Factor
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    ABSTRACT: Synthetic analysis of spirastrellolide E envisioned to entail a cross-metathesis union of the northern and southern hemispheres followed by a Sharpless epoxidation/methylation sequence to achieve the C(22,23) stereogenicity leads to the design of a C(1)-C(23) advanced southern hemisphere exploiting a gold-catalyzed directed spiroketalization as a key step. Stereochemical analysis of this strategic transformation provides insight on the impact of the directing group carbinol stereogenicity on the reaction efficiency and, in turn, permits the conversion of the minor isomer of the spiroketal precursor to the requisite congener for successful spiroketalization.
    Organic Letters 04/2015; 17(8). DOI:10.1021/acs.orglett.5b00595 · 6.32 Impact Factor
  • Stephen P Brown, Amos B Smith
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    ABSTRACT: Protocols have been achieved that permit facile introduction of s-tetrazine into unprotected peptides and the protein, thioredoxin, between two cysteine sulfhydryl groups (i.e., staple), followed by photochemical release (i.e., unstaple) and regeneration of the peptide/protein upon removal of the cyano groups from the derived bisthiocyanate. The S,S-tetrazine macrocycles in turn provide a convenient handle for probe introduction by exploiting the inverse electron demand Diels-Alder reactivity of the tetrazine.
    Journal of the American Chemical Society 03/2015; 137(12). DOI:10.1021/ja512880g · 11.44 Impact Factor
  • Artem Shvartsbart, Amos B Smith
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    ABSTRACT: Presented here a full account on the development of a strategy culminating in the first total synthesis of the architecturally complex daphniphyllum alkaloid, (-)-calyciphylline N. Highlights of the approach include a highly diastereoselective, intramolecular Diels-Alder reaction of a silicon-tethered acrylate; an efficient Stille carbonylation of a sterically encumbered vinyl triflate; a one-pot Nazarov cyclization/proto-desilylation sequence; and the chemoselective hydrogenation of a fully substituted diene ester.
    Journal of the American Chemical Society 03/2015; 137(10). DOI:10.1021/ja503899t · 11.44 Impact Factor
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    ABSTRACT: Extra-virgin olive oil (EVOO), a principal component of the Mediterranean diet (Med diet), is one of the most ancient known foods and has long been associated with health benefits. Many phenolic compounds extracted from Olea europea L. have attracted attention since their discovery. Among these phenolic constituents, oleocanthal has recently emerged as a potential therapeutic molecule for different diseases, showing relevant pharmacological properties in various pathogenic processes, including inflammation, cancers and neurodegenerative diseases. Here, we discuss and summarize the most recent pharmacological evidence for the medical relevance of oleocanthal, focusing our attention on its anti-inflammatory and chemotherapeutic roles. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Drug Discovery Today 11/2014; 20(4). DOI:10.1016/j.drudis.2014.10.017 · 5.96 Impact Factor
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    ABSTRACT: The HIV-1 envelope (Env) mediates viral entry into host cells. To enable the direct imaging of conformational dynamics within Env we introduced fluorophores into variable regions of the gp120 subunit and measured single-molecule fluorescence resonance energy transfer (smFRET) within the context of native trimers on the surface of HIV-1 virions. Our observations revealed unliganded HIV-1 Env to be intrinsically dynamic, transitioning between three distinct pre-fusion conformations, whose relative occupancies were remodeled by receptor CD4 and antibody binding. The distinct properties of neutralization-sensitive and neutralization-resistant HIV-1 isolates support a dynamics-based mechanism of immune evasion and ligand recognition.
    Science 10/2014; 346(6210). DOI:10.1126/science.1254426 · 31.48 Impact Factor
  • Brett D Williams, Amos B Smith
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    ABSTRACT: The evolution of an enantioselective total synthesis of (+)-18-epi-latrunculol A, a congener of the marine-sponge-derived latrunculins A and B, is reported. Key steps include a late-stage Mitsunobu macrolactonization to construct the 16-membered macrolactone, a mild Carreira alkynylation to unite the northern and southern hemispheres, a diastereoselective, acid-mediated δ-hydroxy enone cyclization/equilibration sequence, and a functional-group-tolerant cross-metathesis to access the enone cyclization precursor.
    The Journal of Organic Chemistry 09/2014; 79(19). DOI:10.1021/jo501733m · 4.64 Impact Factor
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    ABSTRACT: A series of derivatives of the known thromboxane A2 prostanoid (TP) receptor antagonists, 3-(6-((4-chlorophenyl)sulfonamido)-5,6,7,8-tetrahydronaphthalen-1-yl)propanoic acid and 3-(3-(2-((4-chlorophenyl)sulfonamido)ethyl)phenyl) propanoic acid, were synthesized in which the carboxylic acid functional group was replaced with substituted cyclopentane-1,3-dione (CPD) bioisosteres. Characterization of these molecules led to the discovery of remarkably potent new analogues, some of which were considerably more active than the corresponding parent carboxylic acid compounds. Depending on the choice of the C2 substituent of the CPD unit, these new derivatives can produce either a reversible or an apparent irreversible inhibition of the human TP receptor. Given the potency and the long-lasting inhibition of TP receptor signaling, these novel antagonists may comprise promising leads for the development of antithromboxane therapies.
    ACS Medicinal Chemistry Letters 09/2014; 5(9):1015-20. DOI:10.1021/ml5002085 · 3.07 Impact Factor
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    ABSTRACT: Cycloalkylpolyones hold promise in drug design as carboxylic acid bio-isosteres. To investigate cyclopentane-1,2-diones as potential surrogates of the carboxylic acid functional group, the acidity, tautomerism, and geometry of hydrogen bonding of representative compounds were evaluated. Prototypic derivatives of the known thromboxane A2 prostanoid (TP) receptor antagonist, 3-(3-(2-((4-chlorophenyl)sulfonamido)-ethyl)phenyl)propanoic acid, in which the carboxylic acid moiety is replaced by the cyclopentane-1,2-dione unit, were synthesized and evaluated as TP receptor antagonists. Cyclopentane-1,2-dione derivative 9 was found to be a potent TP receptor antagonist with an IC50 value comparable to that of the parent carboxylic acid. These results indicate that the cyclopentane-1,2-dione may be a potentially useful carboxylic acid bio-isostere.
    Bioorganic & Medicinal Chemistry Letters 07/2014; 24(17). DOI:10.1016/j.bmcl.2014.07.047 · 2.33 Impact Factor
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    ABSTRACT: Microtubule (MT) stabilizing drugs hold promise as potential treatments for Alzheimer's disease (AD) and related tauopathies. However, thus far epothilone D has been the only brain-penetrant MT-stabilizer to be evaluated in tau transgenic mice and in AD patients. Furthermore, this natural product exhibits potential deficiencies as a drug candidate, including an intravenous route of administration and the inhibition of the P-glycoprotein (Pgp) transporter. Thus, the identification of alternative CNS-active MT-stabilizing agents that lack these potential limitations is of interest. Toward this objective, we have evaluated representative compounds from known classes of non-naturally occurring MT-stabilizing small molecules. This led to the identification of selected triazolopyrimidines and phenylpyrimidines that are orally bioavailable and brain-penetrant without disruption of Pgp function. Pharmacodynamic studies confirmed that representative compounds from these series enhance MT-stabilization in the brains of wild-type mice. Thus, these classes of MT-stabilizers hold promise for the development of orally active, CNS-directed MT-stabilizing therapies.
    Journal of Medicinal Chemistry 07/2014; 57(14). DOI:10.1021/jm5005623 · 5.48 Impact Factor
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    ABSTRACT: Approaches to prevent human immunodeficiency virus (HIV-1) transmission are urgently needed. Difficulties in eliciting antibodies that bind conserved epitopes exposed on the unliganded conformation of the HIV-1 envelope glycoprotein (Env) trimer represent barriers to vaccine development. During HIV-1 entry, binding of the gp120 Env to the initial receptor, CD4, triggers conformational changes in Env that result in the formation and exposure of the highly conserved gp120 site for interaction with the coreceptors, CCR5 or CXCR4. The DMJ compounds, (+)-DMJ-I-228 and (+)-DMJ-II-121, bind gp120 within the conserved Phe 43 cavity near the CD4-binding site, block CD4 binding and inhibit HIV-1 infection. Here we show that the DMJ compounds sensitize primary HIV-1, including transmitted/founder viruses, to neutralization by monoclonal antibodies directed against CD4-induced (CD4i) epitopes and the V3 region, two gp120 elements involved in coreceptor binding. Importantly, the DMJ compounds rendered primary HIV-1 sensitive to neutralization by antisera elicited by immunization of rabbits with HIV-1 gp120 cores engineered to assume the CD4-bound state. Thus, small molecules like the DMJ compounds may be useful as microbicides to inhibit HIV-1 infection directly and to sensitize primary HIV-1 to neutralization by readily elicited antibodies. Preventing human immunodeficiency virus (HIV-1) transmission is a priority for global health. Eliciting antibodies that can neutralize many different strains of HIV-1 is difficult, creating problems for the development of a vaccine. We found that certain small-molecule compounds can sensitize HIV-1 to particular antibodies. These antibodies can be elicited in rabbits. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine.
    Journal of Virology 04/2014; 88(12). DOI:10.1128/JVI.00540-14 · 4.65 Impact Factor
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    ABSTRACT: The dialdehydes oleacein (2) and oleocanthal (4) are closely related to oleuropein (1) and ligstroside (3), the two latter compounds being abundant iridoids of Olea europaea. By exploiting oleuropein isolated from the plant leaf extract, an efficient procedure has been developed for a one-step semisynthesis of oleacein under Krapcho decarbomethoxylation conditions. Highlighted is the fact that 5-lipoxygenase is a direct target for oleacein with an inhibitory potential (IC50: 2 μM) more potent than oleocanthal (4) and oleuropein (1). This enzyme catalyzes the initial steps in the biosynthesis of pro-inflammatory leukotrienes. Taken together, the methodology presented here offers an alternative solution to isolation or total synthesis for the procurement of oleacein, thus facilitating the further development as a potential anti-inflammatory agent.
    Journal of Natural Products 02/2014; 77(3). DOI:10.1021/np401010x · 3.95 Impact Factor
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    ABSTRACT: Conspectus This Account provides an overview of a multidisciplinary consortium focused on structure-based strategies to devise small molecule antagonists of HIV-1 entry into human T-cells, which if successful would hold considerable promise for the development of prophylactic modalities to prevent HIV transmission and thereby alter the course of the AIDS pandemic. Entry of the human immunodeficiency virus (HIV) into target T-cells entails an interaction between CD4 on the host T-cell and gp120, a component of the trimeric envelope glycoprotein spike on the virion surface. The resultant interaction initiates a series of conformational changes within the envelope spike that permits binding to a chemokine receptor, formation of the gp41 fusion complex, and cell entry. A hydrophobic cavity at the CD4-gp120 interface, defined by X-ray crystallography, provided an initial site for small molecule antagonist design. This site however has evolved to facilitate viral entry. As such, the binding of prospective small molecule inhibitors within this gp120 cavity can inadvertently trigger an allosteric entry signal. Structural characterization of the CD4-gp120 interface, which provided the foundation for small molecule structure-based inhibitor design, will be presented first. An integrated approach combining biochemical, virological, structural, computational, and synthetic studies, along with a detailed analysis of ligand binding energetics, revealed that modestly active small molecule inhibitors of HIV entry can also promote viral entry into cells lacking the CD4 receptor protein; these competitive inhibitors were termed small molecule CD4 mimetics. Related congeners were subsequently identified with both improved binding affinity and more potent viral entry inhibition. Further assessment of the affinity-enhanced small molecule CD4 mimetics demonstrated that premature initiation of conformational change within the viral envelope spike, prior to cell encounter, can lead to irreversible deactivation of viral entry machinery. Related congeners, which bind the same gp120 site, possess different propensities to elicit the allosteric response that underlies the undesired enhancement of CD4-independent viral entry. Subsequently, key hotspots in the CD4-gp120 interface were categorized using mutagenesis and isothermal titration calorimetry according to the capacity to increase binding affinity without triggering the allosteric signal. This analysis, combined with cocrystal structures of small molecule viral entry agonists with gp120, led to the development of fully functional antagonists of HIV-1 entry. Additional structure-based design exploiting two hotspots followed by synthesis has now yielded low micromolar inhibitors of viral entry.
    Accounts of Chemical Research 02/2014; 47(4). DOI:10.1021/ar4002735 · 24.35 Impact Factor
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    ABSTRACT: Efforts to develop therapeutic agents that inhibit HIV-1 entry have led to the identification of several small molecule leads. One of the most promising is the NBD series, which binds within a conserved gp120 cavity and possesses para-halogen substituted aromatic rings, a central oxalamide linker, and a tetramethylpiperidine moiety. In this study, we characterized structurally the interactions of four NBD analogues containing meta-fluoro substitution on the aromatic ring and various heterocyclic ring replacements of the tetramethylpiperidine group. The addition of a meta-fluorine to the aromatic ring improved surface complementarity and did not alter the position of the analogue relative to gp120. By contrast, heterocyclic ring replacements of the tetramethylpiperidine moiety exhibited diverse positioning and interactions with the vestibule of the gp120 cavity. Overall, the biological profile of NBD-congeners was modulated by ligand interactions with the gp120-cavity vestibule. Herein, six co-crystal structures of NBD-analogues with gp120 provide a structural framework for continued small molecule-entry inhibitor optimization.
    PLoS ONE 01/2014; 9(1):e85940. DOI:10.1371/journal.pone.0085940 · 3.53 Impact Factor
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    ABSTRACT: The development of new bifunctional linchpins that permit the union of diverse building blocks is essential for the synthetic utility of anion relay chemistry (ARC). The design, synthesis, and validation of three vinylepoxide linchpins for through-bond/through-space ARC are now reported. For negative charge migration, this class of bifunctional linchpins employs initial through-bond ARC by an SN 2' reaction, followed by through-space ARC exploiting a 1,4-Brook rearrangement. The trans-disubstituted vinylepoxide linchpin yields a mixture of E/Z isomers, whereas the cis-disubstituted and the trans-trisubstituted vinylepoxide linchpins proceed to deliver three-component adducts with excellent E selectivity.
    Angewandte Chemie International Edition 01/2014; 53(5). DOI:10.1002/anie.201309270 · 11.34 Impact Factor
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    ABSTRACT: Small-molecule ligands, amenable to positron emission tomography (PET) imaging of different types of neurodegenerative disease-associated amyloid deposits in the CNS of living patients, hold considerable promise for diagnostic purposes, as well as for monitoring disease progression and the effectiveness of treatments. The patent entitled 'Heterocyclic Compounds as Imaging Probes of Tau Pathology' (WO2013090497) discloses the identification of a novel class of tau imaging agents, the aminothienopyridazines. Selected compounds from this class are described that can stain selectively tau pathology in brain tissue sections. Moreover, examples of this class of compounds exhibit absorption, distribution, metabolism, excretion and pharmacokinetics (ADME-PK) properties that are appropriate for CNS PET ligands.
    Expert Opinion on Therapeutic Patents 01/2014; DOI:10.1517/13543776.2014.871526 · 3.44 Impact Factor
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    ABSTRACT: Microtubules (MTs), cytoskeletal elements found in all mammalian cells, play a significant role in cell structure and in cell division. They are especially critical in the proper functioning of post-mitotic central nervous system neurons, where MTs serve as the structures on which key cellular constituents are trafficked in axonal projections. MTs are stabilized in axons by the MT-associated protein tau, and in several neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease, tau function appears to be compromised due to the protein dissociating from MTs and depositing into insoluble inclusions referred to as neurofibrillary tangles. This loss of tau function is believed to result in alterations of MT structure and function, resulting in aberrant axonal transport that likely contributes to the neurodegenerative process. There is also evidence of axonal transport deficiencies in other neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington's disease, which may result, at least in part, from MT alterations. Accordingly, a possible therapeutic strategy for such neurodegenerative conditions is to treat with MT-stabilizing agents, such as those that have been used in the treatment of cancer. Here, we review evidence of axonal transport and MT deficiencies in a number of neurodegenerative diseases, and summarize the various classes of known MT-stabilizing agents. Finally, we highlight the growing evidence that small molecule MT-stabilizing agents provide benefit in animal models of neurodegenerative disease and discuss the desired features of such molecules for the treatment of these central nervous system disorders.
    Bioorganic & medicinal chemistry 12/2013; DOI:10.1016/j.bmc.2013.12.046 · 2.95 Impact Factor

Publication Stats

9k Citations
2,435.10 Total Impact Points

Institutions

  • 1977–2015
    • University of Pennsylvania
      • • Department of Chemistry
      • • Department of Medicine
      • • Laboratory for Research on the Structure of Matter
      Filadelfia, Pennsylvania, United States
  • 1977–2014
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 1974–2014
    • Monell Chemical Senses Center
      Filadelfia, Pennsylvania, United States
  • 2013
    • Bryn Mawr College
      • Department of Chemistry
      Bryn Mawr, PA, United States
  • 2009
    • Dana-Farber Cancer Institute
      • Department of Cancer Immunology and AIDS
      Boston, MA, United States
  • 2004–2009
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2001–2006
    • Albert Einstein College of Medicine
      • Department of Molecular Pharmacology
      New York City, NY, United States
  • 2005
    • Konkuk University
      Sŏul, Seoul, South Korea
  • 1990–2004
    • Philadelphia University
      • Department of Chemistry
      Philadelphia, Pennsylvania, United States
  • 2000
    • The University of Arizona
      Tucson, Arizona, United States
  • 1971–1995
    • The Rockefeller University
      • Laboratory of Mass Spectrometry and Gaseous Ion Chemistry
      New York, New York, United States
  • 1994
    • Yale University
      • Department of Chemistry
      New Haven, Connecticut, United States
  • 1993
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem, Israel
    • Drexel University
      • Department of Chemistry
      Philadelphia, Pennsylvania, United States