Rebecca M Wilson

Columbia University, New York City, NY, United States

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Publications (18)146.74 Total impact

  • Rebecca M Wilson, Samuel J Danishefsky
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    ABSTRACT: Cancer cells may be distinguished from normal cells by cell surface displays of aberrant levels and types of carbohydrate domains. Accordingly, these tumor associated carbohydrate antigens (TACAs) represent promising target structures for the design of anticancer vaccines. Over the past 20 years, our laboratory has sought to use the tools of chemical synthesis to develop TACA-based anticancer vaccine candidates. We provide herein a personal accounting of our laboratory's progress toward the long-standing goal of developing clinically viable fully synthetic carbohydrate-based anticancer vaccines.
    Journal of the American Chemical Society 08/2013; · 10.68 Impact Factor
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    ABSTRACT: Die Totalsynthese eines homogenen Erythropoietins (EPO), das die native Aminosäuresequenz aufweist und Chitobioseglycane an jeder der drei N‐glycosylierten Wildtyp‐Stellen trägt, wurde in unserem Laboratorium erzielt. Wir beschreiben in diesem Kurzaufsatz unsere ein Jahrzehnt dauernden Forschungsbemühungen um die Synthese dieser anspruchsvollen Zielverbindung. Entscheidend für den Erfolg war das Zusammenspiel zwischen Biologie und Chemie, den beiden Grundpfeilern der Naturwissenschaften.
    Angewandte Chemie 07/2013; 125(30).
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    ABSTRACT: The identification of synthesizable substructural domains within more complex structural targets is of significant value in designing a workable plan of synthesis. We term this process "pattern recognition analysis" (PRA). In this paper we continued to build on the theme of PRA as a potential resource in retrosynthetic blueprints to reach highly challenging targets. The paper operates at two levels. First, there is provided a clear sense of definitions of categories by which patterns are related to hypothetical reaction types. Although the required reaction type may for the moment not exist, we believe that this method of analysis is likely to promote innovation that identifies unmet needs and opportunities to advance the cause of complex target synthesis. In addition, we describe reductions to practice in expanding the menu of achievable patterns. It is likely that the future value of PRA will be associated with its utility in leading the way to new and exploitable chemical innovation.
    Proceedings of the National Academy of Sciences 06/2013; · 9.81 Impact Factor
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    ABSTRACT: The total synthesis of a homogeneous erythropoietin (EPO), possessing the native amino acid sequence and chitobiose glycans at each of the three wild-type sites of N glycosylation, has been accomplished in our laboratory. We provide herein an account of our decade-long research effort en route to this formidable target compound. The optimization of the synergy of the two bedrock sciences we now call biology and chemistry was central to the success of the synthesis of EPO.
    Angewandte Chemie International Edition 06/2013; · 11.34 Impact Factor
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    ABSTRACT: We describe herein our recent explorations in the field of isonitrile chemistry. An array of broadly useful coupling methodologies has been developed for the formation of peptidyl and glycopeptidyl amide bonds. We further describe the application of these methods to the syntheses of complex systems, including the cyclic peptide cyclosporine A, constrained peptide systems, and heterocycles.
    Angewandte Chemie International Edition 02/2012; 51(12):2834-48. · 11.34 Impact Factor
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    ABSTRACT: In diesem Aufsatz berichten wir über unsere jüngsten Forschungen auf dem Gebiet der Isonitrile, die zur Entwicklung mehrerer breit anwendbarer Kupplungsmethoden zur Bildung von Peptidyl‐ und Glycopeptidyl‐Amidbindungen geführt haben. Weiterhin beschreiben wir die Anwendung dieser Methoden auf die Synthesen komplexer Verbindungen, darunter das cyclische Peptid Cyclosporin A, konformativ gehinderte Peptide und Heterocyclen.
    Angewandte Chemie 01/2012; 124(12).
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    ABSTRACT: We describe herein the discovery of a series of panaxytriol (PXT)-derived polyacetylene small molecules with promising cytoprotective activity. In mouse xenograft models, we have demonstrated the capacity of our synthetic analogs to mitigate a range of cancer therapeutic agent-induced toxicities, including body weight loss, lethality, neurotoxicity, and hematotoxicity. Our PXT analogs have also been found to reduce radiation-induced body weight loss and lethality in mouse models. Moreover, several PXT analogs appear to exhibit moderate in vivo antiinflammatory activity as well as in vitro immunoenhancing capabilities. These compounds appear to derive their activity through induction of cancer preventive phase 2 enzymes. The studies described herein suggest that coadministration of a PXT-derived agent with cancer chemotherapeutics or radiation therapy may serve to mitigate a range of therapy-associated toxicities.
    Proceedings of the National Academy of Sciences 08/2011; 108(34):14336-41. · 9.81 Impact Factor
  • Rebecca M Wilson, Samuel J Danishefsky
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    ABSTRACT: In this retrospective, we recall some select cases of synergy between very challenging chemical synthesis and the identification of promising new candidates for pharmaceutics development. The progression from targets, often referred to as small molecules, to those of a size commonly associated with biologics (including glycoproteins) is also charted.
    Angewandte Chemie International Edition 08/2010; · 11.34 Impact Factor
  • Rebecca M. Wilson, Samuel J. Danishefsky Prof
    Angewandte Chemie 07/2010; 122(35):6168 - 6193.
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    ABSTRACT: Traditionally, in the pharma sciences, there has been an unstated but operative bifurcation into small molecules and biologics. Small molecules were seen to be, at the discovery level, in the province of chemistry, based on targets provided through biology. By contrast, "biologics" were seen to arise solely from the province of biology exploiting its accessible replicative mechanisms. Our laboratory has been dedicated to the proposition that explosive advances in chemical synthesis have been such as to render so called "biologics" as being accessible to chemical synthesis. In this article, we focus particularly on the area of glycopeptides. Chemical synthesis, in principle, offers an advantage, in that it can lead to homogeneous glycopeptides characterized by a single glycoform of the glycosidic domain mounted at a particular amino acid in the polypeptide domain. In support of this defining goal, a variety of new methods have been developed. The key problem addressed is that of ligation. In this article, we review how insights available from mechanistic organic chemistry have been used to create an imposing framework for the synthesis of structures which would, in an earlier day, have been seen to be strictly in the realm of chemically inaccessible "biologics".
    Biopolymers 01/2010; 94(4):373-84. · 2.88 Impact Factor
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    ABSTRACT: The epothilones represent a promising class of natural product-based antitumor drug candidates. Although these compounds operate through a microtubule stabilization mechanism similar to that of taxol, the epothilones offer a major potential therapeutic advantage in that they retain their activity against multidrug-resistant cell lines. We have been systematically synthesizing and evaluating synthetic epothilone congeners that are not accessible through modification of the natural product itself. We report herein the results of biological investigations directed at two epothilone congeners: iso-fludelone and iso-dehydelone. Iso-fludelone, in particular, exhibits a number of properties that render it an excellent candidate for preclinical development, including biological stability, excellent solubility in water, and remarkable potency relative to other epothilones. In nude mouse xenograft settings, iso-fludelone was able to achieve therapeutic cures against a number of human cancer cell lines, including mammarian-MX-1, ovarian-SK-OV-3, and the fast-growing, refractory, subcutaneous neuroblastoma-SK-NAS. Strong therapeutic effect was observed against drug-resistant lung-A549/taxol and mammary-MCF-7/Adr xenografts. In addition, iso-fludelone was shown to exhibit a significant therapeutic effect against an intracranially implanted SK-NAS tumor.
    Proceedings of the National Academy of Sciences 10/2008; 105(35):13157-62. · 9.81 Impact Factor
  • Rebecca M Wilson, Samuel J Danishefsky
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    ABSTRACT: This tutorial review provides a historical sampling of synthetic efforts undertaken in our laboratory, which have led to the total syntheses of a range of small molecule natural products of potential interest in oncology. It has become evident that natural products, and structures clearly derivable from natural products, have a remarkable record in the treatment of cancer at the clinical level. It is likely that, with the growing power of chemical synthesis, small molecule natural products will play a continuing role in providing lead anticancer compounds.
    Chemical Society Reviews 09/2007; 36(8):1207-26. · 24.89 Impact Factor
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    Rebecca M Wilson, Samuel J Danishefsky
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    ABSTRACT: In this Perspective, the value of small molecule natural products (SMNPs) in the discovery of active biological agents is discussed. The usefulness of the natural products-based method of potential pharma discovery is much augmented by the capacities of chemical synthesis. The great advances in synthetic methodology allow for major editing of the natural product in the hopes of optimizing potency and therapeutic index. As a consequence of the enormous increase in the power of multistep chemical synthesis, one can now approach structures of previously impractical complexity. In constructing a plan for a multistep synthesis, two complementary thought styles are often encountered. One is the traditional and extremely powerful concept of prioritized strategic bond disconnections. The other, which we term "pattern recognition," involves the identification of moieties within the target, which are associated with reliable chemistry, and can serve to facilitate progress to the target. Recognition of such targets may require substantial recasting of the target structure to connect it to well-established types of transformations. Some of our older ventures, where ideas about pattern recognition were first being fashioned and used productively, are revisited. In addition, we provide snapshots of recently achieved total syntheses of SMNPs of novel biological potential. These vignettes serve to harmonize insights occasioned by pattern recognition, in concert with transformations enabled by the enormous growth in the power of synthesis.
    The Journal of Organic Chemistry 07/2007; 72(12):4293-305. · 4.56 Impact Factor
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    Rebecca M. Wilson, Samuel J. Danishefsky
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    ABSTRACT: This account traces the development of our synthetic glycopeptide- and glyco- protein-based research program over the past decade. We recount the syntheses of a number of biologically relevant, natural product-inspired glycopeptide constructs, including those as- sociated with prostate specific antigen (PSA) and with the gp120 surface envelope protein of HIV. We also describe our progress toward the synthesis of the multiply glycosylated protein, erythropoietin (EPO). Particular emphasis is placed on the development of enabling method- ologies which allow for the ligation of complex glycopeptide fragments, thus rendering it possible to access, through purely synthetic means, homogeneous, multidomainal glyco- peptide and glycoprotein constructs.
    Pure and Applied Chemistry - PURE APPL CHEM. 01/2007; 79(12):2189-2216.
  • Rebecca M Wilson, Samuel J Danishefsky
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    ABSTRACT: Natural products have been a rich source of agents of value in medicine. They have also inspired, at various levels, the fashioning of nonnatural agents of pharmaceutical import. Hitherto, these nonnatural derivatives have been primarily synthesized by manipulating the natural product. As a consequence of major innovations in the subscience of synthetic methodology, the capacity of synthesis to deal with molecules of considerable complexity has increased dramatically. In this paper, we show by example some total syntheses which draw from strategy-enabling advances in methodology. Moreover, we show how these capabilities can be used to discover and develop new agents of potential pharmaceutical value without recourse to the natural product itself.
    The Journal of Organic Chemistry 11/2006; 71(22):8329-51. · 4.56 Impact Factor
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    Rebecca M Wilson, Samuel J Danishefsky
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    ABSTRACT: The possibility for the application of organic synthesis to the discovery of new agents in combating neurodegenerative disorders is described. Our focus has been on agents derived from natural-product leads and natural products themselves prepared through total synthesis. Herein, we describe some of the chemistry as well as interesting observations made along the way.
    Accounts of Chemical Research 09/2006; 39(8):539-49. · 20.83 Impact Factor
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    ABSTRACT: Several novel, fully synthetic, carbohydrate-based antitumor vaccines have been assembled. Each construct consists of multiple cancer-related antigens displayed on a single polypeptide backbone. Recent advances in synthetic methodology have allowed for the incorporation of a complex oligosaccharide terminating in a sialic acid residue (i.e., GM2) as one of the carbohydrate antigens. Details of the vaccine synthesis as well as the results of preliminary immunological investigations are described herein.
    Journal of the American Chemical Society 04/2006; 128(8):2715-25. · 10.68 Impact Factor
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    ABSTRACT: The development of a clinically effective, carbohydrate-based antitumor vaccine is a longstanding ambition in the prevention and treatment of cancer. This review seeks to provide a discussion of some of the unique challenges facing this particular field of immunology. The authors present a historic account of their ongoing research program devoted to the development of fully synthetic, carbohydrate-based anticancer vaccines of clinical value. As will be seen, remarkable advances in carbohydrate and glycopeptide assembly techniques have allowed for the preparation of synthetic constructs of progressively increasing structural complexity. The authors describe the evolution of their synthetic carbohydrate program from first-generation constructs, which were monovalent in nature, to highly complex unimolecular multivalent vaccines, in which multiple carbohydrate antigens are displayed in the context of a single polypeptide backbone. It is the hope that each generation of vaccines represents a move closer to achieving the ultimate objective of developing broadly useful, robust anticancer vaccines.
    Expert Review of Vaccines 11/2005; 4(5):677-85. · 4.22 Impact Factor

Publication Stats

293 Citations
146.74 Total Impact Points

Institutions

  • 2010–2013
    • Columbia University
      • Department of Chemistry
      New York City, NY, United States
  • 2005–2013
    • Memorial Sloan-Kettering Cancer Center
      • • Laboratory for Bioorganic Chemistry
      • • Division of Molecular Pharmacology & Chemistry
      New York City, New York, United States
  • 2006–2007
    • Cornell University
      Ithaca, New York, United States