North Adams, CA, United States
North Adams, CA, United States

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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.


Sharma S.V.,University of East Anglia | Jothivasan V.K.,University of East Anglia | Newton G.L.,University of California at San Diego | Upton H.,California State University, Fresno | And 6 more authors.
Angewandte Chemie - International Edition | Year: 2011

The full monty: The recently discovered thiol cofactor bacillithiol (BSH), its biosynthetic precursors, and its symmetrical disulfide are prepared in two ways. The fosfomycin resistance protein (FosB) is shown to be a BSH-utilizing enzyme. It displays bacillithiol-S-transferase activity with a strong preference for BSH over L-cysteine as its thiol substrate. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Beuzer P.,La Jolla Salk Institute | La Clair J.J.,La Jolla Salk Institute | La Clair J.J.,Xenobe Research Institute | Cang H.,La Jolla Salk Institute
ChemBioChem | Year: 2016

Although the development of super-resolution microscopy dates back to 1994, its applications have been primarily focused on visualizing cellular structures and targets, including proteins, DNA and sugars. We now report on a system that allows both monitoring of the localization of exogenous small molecules in live cells at low resolution and subsequent super-resolution imaging by using stochastic optical reconstruction microscopy (STORM) on fixed cells. This represents a powerful new tool to understand the dynamics of subcellular trafficking associated with the mode and mechanism of action of exogenous small molecules. Color coding: Understanding the subcellular trafficking and localization of small molecules is a fundamental aspect of chemical biology. We developed a practical five-step procedure that enables small-molecule imaging at super-resolution, by combining a color-coded system that allows rapid uptake and tracking using a blue fluorescent immunoaffinity tag, followed by antibody-based staining of cells for imaging. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.


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.


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.


Kumar K.A.,Purdue University | La Clair J.J.,Xenobe Research Institute | Fuchs P.L.,Purdue University
Organic Letters | Year: 2011

The cephalostatin and ritterazine natural products comprise a potent family of bis-steroidal pyrazines that display potent single-digit nanomolar inhibition of tumor cell growth. An active fluorescent ritterazine-cephalostatin hybrid probe was developed using detailed SAR data derived through total synthetic efforts. A combination of time course and confocal imaging studies indicate that this natural product family is rapidly taken up in tumor cells and localizes subcellularly within ER and surrounding the nuclear-ER interface. © 2011 American Chemical Society.


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.


Yu W.-L.,University of California at San Diego | Guizzunti G.,University of California at San Diego | Foley T.L.,University of California at San Diego | Burkart M.D.,University of California at San Diego | La Clair J.J.,Xenobe Research Institute
Journal of Natural Products | Year: 2010

Understanding the mode of action of small molecules is an integral facet of drug discovery. We report an optimized immunoaffinity fluorescent method that allows one to conduct parallel studies at both the cellular and molecular level using a single probe construct. Viability of the method has been evaluated analytically and applied using glycyrrhetic acid as a model. © 2010 The American Chemical Society and American Society of Pharmacognosy.


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.


La Clair J.J.,Xenobe Research Institute | Rheingold A.L.,University of California at San Diego | Burkart M.D.,University of California at San Diego
Journal of Natural Products | Year: 2011

Extracts of Ganoderma tsugae, also known as the Hemlock varnish shelf mushroom, and related Reishi mushrooms are well documented in traditional Chinese medicine. Several Ganoderma sp. are currently cultivated for use in coffee, teas, and dietary supplements. We now report on the isolation and characterization of an unprecedented benzofuran, ganodone (1), from the fruiting bodies of mature growth G. tsugae. This discovery provides a key next step in evaluating the active components in their associated herbal supplements. © 2011 The American Chemical Society and American Society of Pharmacognosy.

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