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Simon O.,National University of Singapore | Reux B.,National University of Singapore | La Clair J.J.,Xenobe Research Institute | Lear M.J.,National University of Singapore
Chemistry - An Asian Journal | Year: 2010

Laetirobin, isolated from a parasitic fungus host-plant relationship, was synthesized in six practical steps with an overall yield of 12% from commercially available 2,4-dihydroxyacetophenone. Because the product is a pseudosymmetric tetramer of benzo[b]-furans, each step of the synthesis was designed to involve tandem operations. Highlights include: 1) the double Sonogashira reaction of a bisACHTUNGTRENUNG(alkyne), 2) the practical copper(I)-mediated formation of a bisACHTUNGTRENUNG(benzo[b]furan), and 3) the biomimetic [4+2] dimerization and unexpected cationic [5+2] annulation of gem-diaryl alkene precursors. Preliminary structure-activity relationship data between the isomeric [4+2] and [5+2] tetramers revealed only the natural product to possess promising anticancer potential. Specifically, laetirobin is capable of blocking tumor cell division (mitosis) and invoking programmed cell death (apoptosis). © 2010 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim. Source


La Clair J.J.,Xenobe Research Institute
Natural Product Reports | Year: 2010

In our understanding of matter, natural products deliver plots that would stun even the best productions of the legendary filmmaker, Sergio Leone. While every decade heralds a new genre of film (as well as avenues of small-molecule discovery), natural products and their "untamed prehistoric" plots continue to dazzle the fields of biotechnology, drug discovery, fragrances, food additives and agrochemistry. This review provides an abridged synopsis of the modes of natural product action discovered within the last decade and the tools and methods used in their discovery. Their stories are united in a common theme that unveils one of the more vital aspects of chemical biological research: understanding the global activity of Nature's arsenal of secondary metabolites. © 2010 The Royal Society of Chemistry. Source


La Clair J.J.,Xenobe Research Institute | Rodriguez A.D.,University of Puerto Rico at San Juan
Bioorganic and Medicinal Chemistry | Year: 2011

New approaches are vital to the development of marine natural products (MNP) as therapeutic leads. One of the more time consuming aspects of MNP research arises in the connection between structure and function. Here, we describe an isolation protocol that adapts tumor cell proteomes as a vehicle for MNP isolation therein uniting structural and functional analysis. Application of this method to extracts of the sponge Agelas conifera led to the isolation of a unique poly-hydroxybutyrated β-galactosphingolipid, coniferoside. © 2011 Elsevier Ltd. All rights reserved. Source


Vera B.,University of Puerto Rico at San Juan | Rodriguez A.D.,University of Puerto Rico at San Juan | La Clair J.J.,Xenobe Research Institute
Angewandte Chemie - International Edition | Year: 2011

A bidirectional affinity system has been developed for the identification of cancer-related natural products and their biological targets. Aplysqualenol A is thus selectively identified as a ligand of the dynein light chain. The use of forward and reverse affinity methods suggests that both small-molecule isolation and target identification can be conducted using conventional molecular biological methods. © 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Kang M.J.,University of Arizona | Wu T.,University of Arizona | Wijeratne E.M.K.,University of Arizona | Lau E.C.,University of Arizona | And 7 more authors.
ChemBioChem | Year: 2014

Access to lead compounds with defined molecular targets continues to be a barrier to the translation of natural product resources. As a solution, we developed a system that uses discrete, recombinant proteins as the vehicles for natural product isolation. Here, we describe the use of this functional chromatographic method to identify natural products that bind to the AAA+ chaperone, p97, a promising cancer target. Application of this method to a panel of fungal and plant extracts identified rheoemodin, 1-hydroxydehydroherbarin, and phomapyrrolidone A as distinct p97 modulators. Excitingly, each of these molecules displayed a unique mechanism of p97 modulation. This discovery provides strong support for the application of functional chromatography to the discovery of protein modulators that would likely escape traditional high-throughput or phenotypic screening platforms. Picking p97's pockets: Functional chromatography was used to identify natural products that bind to p97. Application of this method to a panel of fungal and plant extracts identified rheoemodin, 1-hydroxy-dehydroherbarin, and phomapyrrolidinone A, each with a unique mechanism of p97 modulation. This strongly supports the application of functional chromatography to discover discrete protein modulators. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

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