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  • Artikel  (22)
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  • Organic Synthesis Toward Small-Molecule Probes and Drugs Special Feature  (22)
  • PNAS - Proceedings of the National Academy of Sciences  (22)
  • 113
  • 1
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    Organic synthesis toward small-molecule probes and drugs [Perspectives] (2011)
    National Academy of Sciences
    Details
    Publikationsdatum: 2011-04-27
    Beschreibung: “Organic synthesis” is a compound-creating activity often focused on biologically active small molecules. This special issue of PNAS explores innovations and trends in the field that are enabling the synthesis of new types of small-molecule probes and drugs. This perspective article frames the research described in the special issue but also explores how these modern capabilities can both foster a new and more extensive view of basic research in the academy and promote the linkage of life-science research to the discovery of novel types of small-molecule therapeutics [Schreiber SL (2009) Chem Bio Chem 10:26–29]. This new view of basic research aims to bridge the chasm between basic scientific discoveries in life sciences and new drugs that treat the root cause of human disease—recently referred to as the “valley of death” for drug discovery. This perspective article describes new roles that modern organic chemistry will need to play in overcoming this challenge.
    Schlagwort(e): Organic Synthesis Toward Small-Molecule Probes and Drugs Special Feature
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Publiziert von National Academy of Sciences
    Standort Signatur Erwartet Verfügbarkeit
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  • 2
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    Biology-oriented synthesis of a natural-product inspired oxepane collection yields a small-molecule activator of the Wnt-pathway [Research Articles] (2011)
    National Academy of Sciences
    Details
    Publikationsdatum: 2011-04-27
    Beschreibung: In Biology Oriented Synthesis the scaffolds of biologically relevant compound classes inspire the synthesis of focused compound collections enriched in bioactivity. This criterion is met by the structurally complex scaffolds of natural products (NPs) selected in evolution. The synthesis of NP-inspired compound collections approaching the complexity of NPs calls for the development of efficient synthetic methods. We have developed a one pot 4–7 step synthesis of mono-, bi-, and tricyclic oxepanes that resemble the core scaffolds of numerous NPs with diverse bioactivities. This sequence entails a ring-closing ene-yne metathesis reaction as key step and makes productive use of polymer-immobilized scavenger reagents. Biological profiling of a corresponding focused compound collection in a reporter gene assay monitoring for Wnt-signaling modulation revealed active Wntepanes. This unique class of small-molecule activators of the Wnt pathway modulates the van-Gogh-like receptor proteins (Vangl), which were previously identified in noncanonical Wnt signaling, and acts in synergy with the canonical activator protein (Wnt-3a).
    Schlagwort(e): Organic Synthesis Toward Small-Molecule Probes and Drugs Special Feature
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Publiziert von National Academy of Sciences
    Standort Signatur Erwartet Verfügbarkeit
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  • 3
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    Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities [Chemistry] (2011)
    National Academy of Sciences
    Details
    Publikationsdatum: 2011-04-27
    Beschreibung: Amphotericin B is the archetype for small molecules that form transmembrane ion channels. However, despite extensive study for more than five decades, even the most basic features of this channel structure and its contributions to the antifungal activities of this natural product have remained unclear. We herein report that a powerful series of functional group-deficient probes have revealed many key underpinnings of the ion channel and antifungal activities of amphotericin B. Specifically, in stark contrast to two leading models, polar interactions between mycosamine and carboxylic acid appendages on neighboring amphotericin B molecules are not required for ion channel formation, nor are these functional groups required for binding to phospholipid bilayers. Alternatively, consistent with a previously unconfirmed third hypothesis, the mycosamine sugar is strictly required for promoting a direct binding interaction between amphotericin B and ergosterol. The same is true for cholesterol. Synthetically deleting this appendage also completely abolishes ion channel and antifungal activities. All of these results are consistent with the conclusion that a mycosamine-mediated direct binding interaction between amphotericin B and ergosterol is required for both forming ion channels and killing yeast cells. The enhanced understanding of amphotericin B function derived from these synthesis-enabled studies has helped set the stage for the more effective harnessing of the remarkable ion channel-forming capacity of this prototypical small molecule natural product.
    Schlagwort(e): Organic Synthesis Toward Small-Molecule Probes and Drugs Special Feature
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Publiziert von National Academy of Sciences
    Standort Signatur Erwartet Verfügbarkeit
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  • 4
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    Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV) [Chemistry] (2011)
    National Academy of Sciences
    Details
    Publikationsdatum: 2011-04-27
    Beschreibung: The search for novel therapeutic interventions for viral disease is a challenging pursuit, hallmarked by the paucity of antiviral agents currently prescribed. Targeting of viral proteins has the inextricable challenge of rise of resistance. Safe and effective vaccines are not possible for many viral pathogens. New approaches are required to address the unmet medical need in this area. We undertook a cell-based high-throughput screen to identify leads for development of drugs to treat respiratory syncytial virus (RSV), a serious pediatric pathogen. We identified compounds that are potent (nanomolar) inhibitors of RSV in vitro in HEp-2 cells and in primary human bronchial epithelial cells and were shown to act postentry. Interestingly, two scaffolds exhibited broad-spectrum activity among multiple RNA viruses. Using the chemical matter as a probe, we identified the targets and identified a common cellular pathway: the de novo pyrimidine biosynthesis pathway. Both targets were validated in vitro and showed no significant cell cytotoxicity except for activity against proliferative B- and T-type lymphoid cells. Corollary to this finding was to understand the consequences of inhibition of the target to the host. An in vivo assessment for antiviral efficacy failed to demonstrate reduced viral load, but revealed microscopic changes and a trend toward reduced pyrimidine pools and findings in histopathology. We present here a discovery program that includes screen, target identification, validation, and druggability that can be broadly applied to identify and interrogate other host factors for antiviral effect starting from chemical matter of unknown target/mechanism of action.
    Schlagwort(e): Organic Synthesis Toward Small-Molecule Probes and Drugs Special Feature
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Publiziert von National Academy of Sciences
    Standort Signatur Erwartet Verfügbarkeit
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  • 5
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    Diversity-oriented synthesis of macrocyclic peptidomimetics [Chemistry] (2011)
    National Academy of Sciences
    Details
    Publikationsdatum: 2011-04-27
    Beschreibung: Structurally diverse libraries of novel small molecules represent important sources of biologically active agents. In this paper we report the development of a diversity-oriented synthesis strategy for the generation of diverse small molecules based around a common macrocyclic peptidomimetic framework, containing structural motifs present in many naturally occurring bioactive compounds. Macrocyclic peptidomimetics are largely underrepresented in current small-molecule screening collections owing primarily to synthetic intractability; thus novel molecules based around these structures represent targets of significant interest, both from a biological and a synthetic perspective. In a proof-of-concept study, the synthesis of a library of 14 such compounds was achieved. Analysis of chemical space coverage confirmed that the compound structures indeed occupy underrepresented areas of chemistry in screening collections. Crucial to the success of this approach was the development of novel methodologies for the macrocyclic ring closure of chiral α-azido acids and for the synthesis of diketopiperazines using solid-supported N methylmorpholine. Owing to their robust and flexible natures, it is envisaged that both new methodologies will prove to be valuable in a wider synthetic context.
    Schlagwort(e): Organic Synthesis Toward Small-Molecule Probes and Drugs Special Feature
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Publiziert von National Academy of Sciences
    Standort Signatur Erwartet Verfügbarkeit
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  • 6
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    Route to three-dimensional fragments using diversity-oriented synthesis [Chemistry] (2011)
    National Academy of Sciences
    Details
    Publikationsdatum: 2011-04-27
    Beschreibung: Fragment-based drug discovery (FBDD) has proven to be an effective means of producing high-quality chemical ligands as starting points for drug-discovery pursuits. The increasing number of clinical candidate drugs developed using FBDD approaches is a testament of the efficacy of this approach. The success of fragment-based methods is highly dependent on the identity of the fragment library used for screening. The vast majority of FBDD has centered on the use of sp2-rich aromatic compounds. An expanded set of fragments that possess more 3D character would provide access to a larger chemical space of fragments than those currently used. Diversity-oriented synthesis (DOS) aims to efficiently generate a set of molecules diverse in skeletal and stereochemical properties. Molecules derived from DOS have also displayed significant success in the modulation of function of various “difficult” targets. Herein, we describe the application of DOS toward the construction of a unique set of fragments containing highly sp3-rich skeletons for fragment-based screening. Using cheminformatic analysis, we quantified the shapes and physical properties of the new 3D fragments and compared them with a database containing known fragment-like molecules.
    Schlagwort(e): Organic Synthesis Toward Small-Molecule Probes and Drugs Special Feature
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Publiziert von National Academy of Sciences
    Standort Signatur Erwartet Verfügbarkeit
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  • 7
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    Ammonia synthons for the multicomponent assembly of complex {gamma}-lactams [Chemistry] (2011)
    National Academy of Sciences
    Details
    Publikationsdatum: 2011-04-27
    Beschreibung: The synthesis of γ-lactams that are unsubstituted at the 1-position (nitrogen) as well as their subsequent N-functionalization is reported. A recently discovered four-component reaction (4CR) is employed with either an ammonia precursor or a protected form of ammonia that can be deprotected in a subsequent synthetic step. These methods represent the first multicomponent assembly of complex lactam structures that are unsubstituted at nitrogen. In addition, two methods for the introduction of nitrogen substituents that are not possible through the original 4CR are reported. X-ray crystallographic analysis of representative structures reveals conformational changes in the core structure that will enable future deployment of this chemistry in the design and synthesis of diverse collections of lactams suitable for the discovery of new biological probes.
    Schlagwort(e): Organic Synthesis Toward Small-Molecule Probes and Drugs Special Feature
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Publiziert von National Academy of Sciences
    Standort Signatur Erwartet Verfügbarkeit
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  • 8
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    Quantifying structure and performance diversity for sets of small molecules comprising small-molecule screening collections [Research Articles] (2011)
    National Academy of Sciences
    Details
    Publikationsdatum: 2011-04-27
    Beschreibung: Using a diverse collection of small molecules we recently found that compound sets from different sources (commercial; academic; natural) have different protein-binding behaviors, and these behaviors correlate with trends in stereochemical complexity for these compound sets. These results lend insight into structural features that synthetic chemists might target when synthesizing screening collections for biological discovery. We report extensive characterization of structural properties and diversity of biological performance for these compounds and expand comparative analyses to include physicochemical properties and three-dimensional shapes of predicted conformers. The results highlight additional similarities and differences between the sets, but also the dependence of such comparisons on the choice of molecular descriptors. Using a protein-binding dataset, we introduce an information-theoretic measure to assess diversity of performance with a constraint on specificity. Rather than relying on finding individual active compounds, this measure allows rational judgment of compound subsets as groups. We also apply this measure to publicly available data from ChemBank for the same compound sets across a diverse group of functional assays. We find that performance diversity of compound sets is relatively stable across a range of property values as judged by this measure, both in protein-binding studies and functional assays. Because building screening collections with improved performance depends on efficient use of synthetic organic chemistry resources, these studies illustrate an important quantitative framework to help prioritize choices made in building such collections.
    Schlagwort(e): Organic Synthesis Toward Small-Molecule Probes and Drugs Special Feature
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Publiziert von National Academy of Sciences
    Standort Signatur Erwartet Verfügbarkeit
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  • 9
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    Synthesis and receptor profiling of Stemona alkaloid analogues reveal a potent class of sigma ligands [Chemistry] (2011)
    National Academy of Sciences
    Details
    Publikationsdatum: 2011-04-27
    Beschreibung: Reported biological activities of Stemona natural products, such as antitussive activity, inspired the development of synthetic methods to access several alkaloids within this family and in so doing develop a general route to the core skeleta shared by the class of natural products. The chemistry was subsequently adapted to afford a series of analogue sets bearing simplified, diverse Stemona-inspired skeleta. Over 100 of these analogues were subjected to general G protein-coupled receptor profiling along with the known antitussive compound, neostenine; this led to the identification of hit compounds targeting several receptor types. The particularly rich hit subset for sigma receptors was expanded with two focused library sets, which resulted in the discovery of a fully synthetic, potent chemotype of sigma ligands. This collaborative effort combined the development of synthetic methods with extensive, flexible screening resources and exemplifies the role of natural products in bioactivity mining.
    Schlagwort(e): Organic Synthesis Toward Small-Molecule Probes and Drugs Special Feature
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Publiziert von National Academy of Sciences
    Standort Signatur Erwartet Verfügbarkeit
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  • 10
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    Chemistry of mycolactones, the causative toxins of Buruli ulcer [Chemistry] (2011)
    National Academy of Sciences
    Details
    Publikationsdatum: 2011-04-27
    Beschreibung: Buruli ulcer is a severe and devastating skin disease caused by Mycobacterium ulcerans infection, yet it is one of the most neglected diseases. The causative toxin, referred to as mycolactone A/B, was isolated and characterized as a polyketide-derived macrolide in 1999. The current status of the mycolactone chemistry is described, highlighting the stereochemistry assignment of mycolactone A/B; total synthesis; the structure determination of mycolactone congeners from the human pathogen M. ulcerans, the frog pathogen Mycobacterium liflandii, and the fish pathogen Mycobacterium marinum; the structural diversity in the mycolactone class of natural products; the highly sensitive detection/structure-analysis of mycolactones; and some biological activity.
    Schlagwort(e): Organic Synthesis Toward Small-Molecule Probes and Drugs Special Feature
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Publiziert von National Academy of Sciences
    Standort Signatur Erwartet Verfügbarkeit
    BibTip Andere fanden auch interessant ...
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