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El-Elimat T.,University of North Carolina at Greensboro | Figueroa M.,University of North Carolina at Greensboro | Ehrmann B.M.,University of North Carolina at Greensboro | Cech N.B.,University of North Carolina at Greensboro | And 2 more authors.
Journal of Natural Products | Year: 2013

A major problem in the discovery of new biologically active compounds from natural products is the reisolation of known compounds. Such reisolations waste time and resources, distracting chemists from more promising leads. To address this problem, dereplication strategies are needed that enable crude extracts to be screened for the presence of known compounds before isolation efforts are initiated. In a project to identify anticancer drug leads from filamentous fungi, a significant dereplication challenge arises, as the taxonomy of the source materials is rarely known, and, thus, the literature cannot be probed to identify likely known compounds. An ultraperformance liquid chromatography- photodiode array-high-resolution tandem mass spectrometric (UPLC-PDA-HRMS-MS/MS) method was developed for dereplication of fungal secondary metabolites in crude culture extracts. A database was constructed by recording HRMS and MS/MS spectra of fungal metabolites, utilizing both positive- and negative-ionization modes. Additional details, such as UV-absorption maxima and retention times, were also recorded. Small-scale cultures that showed cytotoxic activities were dereplicated before engaging in the scale-up or purification processes. Using these methods, approximately 50% of the cytotoxic extracts could be eliminated from further study after the confident identification of known compounds. The specific attributes of this dereplication methodology include a focus on bioactive secondary metabolites from fungi, the use of a 10 min chromatographic method, and the inclusion of both HRMS and MS/MS data. © 2013 The American Chemical Society and American Society of Pharmacognosy.

Strader C.R.,University of North Carolina at Greensboro | Pearce C.J.,Mycosynthetix, Inc. | Oberlies N.H.,University of North Carolina at Greensboro
Journal of Natural Products | Year: 2011

Fingolimod (Gilenya; FTY720), a synthetic compound based on the fungal secondary metabolite myriocin (ISP-I), is a potent immunosuppressant that was approved (September 2010) by the U.S. FDA as a new treatment for multiple sclerosis (MS). Fingolimod was synthesized by the research group of Tetsuro Fujita at Kyoto University in 1992 while investigating structure-activity relationships of derivatives of the fungal metabolite ISP-I, isolated from Isaria sinclairii. Fingolimod becomes active in vivo following phosphorylation by sphingosine kinase 2 to form fingolimod-phosphate, which binds to extracellular G protein-coupled receptors, sphingosine 1-phosphates, and prevents the release of lymphocytes from lymphoid tissue. Fingolimod is orally active, which is unique among current first-line MS therapies, and it has the potential to be used in the treatment of organ transplants and cancer. This review highlights the discovery and development of fingolimod, from an isolated lead natural product, through synthetic analogues, to an approved drug. © 2011 The American Chemical Society and American Society of Pharmacognosy.

Vandermolen K.M.,University of North Carolina at Greensboro | McCulloch W.,Alba BioPharma Advisors | Pearce C.J.,Mycosynthetix, Inc. | Oberlies N.H.,University of North Carolina at Greensboro
Journal of Antibiotics | Year: 2011

Romidepsin (Istodax), a selective inhibitor of histone deacetylases (HDACs), was approved for the treatment of cutaneous T-cell lymphoma in November 2009 by the US Food and Drug Administration. This unique natural product was discovered from cultures of Chromobacterium violaceum, a Gram-negative bacterium isolated from a Japanese soil sample. This bicyclic compound acts as a prodrug, its disulfide bridge being reduced by glutathione on uptake into the cell, allowing the free thiol groups to interact with Zn ions in the active site of class I and II HDAC enzymes. Due to the synthetic complexity of the compound, as well as the low yield from the producing organism, analogs are sought to create synthetically accessible alternatives. As a T-cell lymphoma drug, romidepsin offers a valuable new treatment for diseases with few effective therapies. © 2011 Japan Antibiotics Research Association All rights reserved.

El-Elimat T.,University of North Carolina at Greensboro | Zhang X.,Ohio State University | Jarjoura D.,Ohio State University | Moy F.J.,University of North Carolina at Greensboro | And 4 more authors.
ACS Medicinal Chemistry Letters | Year: 2012

A collaborative project has been undertaken to explore filamentous fungi, cyanobacteria, and tropical plants for anticancer drug leads. Through principal component analysis, the chemical space covered by compounds isolated and characterized from these three sources over the last 4 years was compared to each other and to the chemical space of selected FDA-approved anticancer drugs. Using literature precedence, nine molecular descriptors were examined: molecular weight, number of chiral centers, number of rotatable bonds, number of acceptor atoms for H-bonds (N, O, F), number of donor atoms for H-bonds (N and O), topological polar surface area using N, O polar contributions, Moriguchi octanol-water partition coefficient, number of nitrogen atoms, and number of oxygen atoms. Four principal components explained 87% of the variation found among 343 bioactive natural products and 96 FDA-approved anticancer drugs. Across the four dimensions, fungal, cyanobacterial, and plant isolates occupied both similar and distinct areas of chemical space that collectively aligned well with FDA-approved anticancer agents. Thus, examining three separate resources for anticancer drug leads yields compounds that probe chemical space in a complementary fashion. © 2012 American Chemical Society.

Sy-Cordero A.A.,University of North Carolina at Greensboro | Graf T.N.,University of North Carolina at Greensboro | Adcock A.F.,North Carolina Central University | Kroll D.J.,North Carolina Central University | And 5 more authors.
Journal of Natural Products | Year: 2011

Two new cyclodepsipeptides (1 and 2), two new sesquiterpenoids (3 and 4), and the known compounds guangomide A (5), roseotoxin S, and three simple trichothecenes were isolated from the cytotoxic organic extract of a terrestrial filamentous fungus, Trichothecium sp. The structures were determined using NMR spectroscopy and mass spectrometry. Absolute configurations of the cyclodepsipeptides were established by employing chiral HPLC, while the relative configurations of 3 and 4 were determined via NOESY data. The isolation of guangomide A was of particular interest, since it was reported previously from a marine-derived fungus. © 2011 The American Chemical Society and American Society of Pharmacognosy.

Ayers S.,University of North Carolina at Greensboro | Graf T.N.,University of North Carolina at Greensboro | Adcock A.F.,North Carolina Central University | Kroll D.J.,North Carolina Central University | And 7 more authors.
Journal of Natural Products | Year: 2011

As part of our ongoing investigation of filamentous fungi for anticancer leads, an active fungal extract was identified from the Mycosynthetix library (MSX 63935; related to Phoma sp.). The initial extract exhibited cytotoxic activity against the H460 (human non-small cell lung carcinoma) and SF268 (human astrocytoma) cell lines and was selected for further study. Bioactivity-directed fractionation yielded resorcylic acid lactones (RALs) 1 (a new natural product) and 3 (a new compound) and the known RALs zeaenol (2), (5E)-7-oxozeaenol (4), (5Z)-7-oxozeaenol (5), and LL-Z1640-1 (6). Reduction of (5E)-7-oxozeaenol (4) with sodium borohydride produced 3, which allowed assignment of the absolute configuration of 3. Other known resorcylic acid lactones (7-12) were purchased and assayed in parallel for cytotoxicity with isolated 1-6 to investigate structure-activity relationships in the series. Moreover, the isolated compounds (1-6) were examined for activity in a suite of biological assays, including antibacterial, mitochondria transmembrane potential, and NF-κB. In the latter assay, compounds 1 and 5 displayed sub-micromolar activities that were on par with the positive control, and as such, these compounds may serve as a lead scaffold for future medicinal chemistry studies. (Chemical Equation Presented). © 2011 The American Chemical Society and American Society of Pharmacognosy.

Acuna U.M.,Ohio State University | Wittwer J.,Ohio State University | Ayers S.,University of North Carolina at Greensboro | Pearce C.J.,Mycosynthetix, Inc. | And 2 more authors.
Anticancer Research | Year: 2012

Aim: As part of an on going investigation of novel anticancer agents from natural origin, the biological and cellular effects of (5Z)-7-oxozeaenol on cancer cells were investigated. Materials and Methods: The expression of nuclear factor kappa B (NF-κB), IκB kinase (IKKα), IKKβ and caspase-3 were analyzed by western blot. Reactive oxygen species (ROS) fluorescence and caspase luminescent assays were used to assess the intracellular effects in HeLa cervical and HT-29 colon cancer cell lines. The mitochondrial transmembrane potential (MTP) was analyzed by fluorescence- activated cell sorting (FACS). Results: Cells treated with (5Z)-7-oxozeaenol exhibited down-regulation of NF-κ B in a dose-dependent manner. Treatment with (5Z)-7-oxozeaenol significantly enhanced the levels of ROS in HeLa and HT-29 cells. MTP was reduced in HT-29 cells. The expression of caspase-3 and -7 was induced in (5Z)-7-oxozeaenol treated HeLa cells, in comparison with those treated with paclitaxel. Conclusion: Our findings suggest that (5Z)-7-oxozeaenol is a potent inhibitor of the NF-κB pathway and potentiates the production of ROS, as well as induces caspase-3 and -7 in HeLa and HT-29 cancer cells. Thus, (5Z)-7-oxozeaenol represents a new lead compound for drug development, particularly as a new cancer chemotherapeutic agent, since programmed cell death might be mediated through the activation of a caspase-arbitrated pathway.

PubMed | University of North Carolina at Greensboro and Mycosynthetix, Inc.
Type: | Journal: The Journal of antibiotics | Year: 2017

Effective and rapid dereplication is a hallmark of present-day drug discovery from natural sources. This project strove to both decrease the time and expand the structural diversity associated with dereplication methodologies. A 5min liquid chromatographic run time employing heated electrospray ionization (HESI) was evaluated to determine whether it could be used as a faster alternative over the 10min ESI method we reported previously. Results revealed that the 5min method was as sensitive as the 10min method and, obviously, was twice as fast. To facilitate dereplication, the retention times, UV absorption maxima, full-scan HRMS and MS/MS were cross-referenced with an in-house database of over 300 fungal secondary metabolites. However, this strategy was dependent upon the makeup of the screening in-house database. Thus, mass defect filtering (MDF) was explored as an additional targeted screening strategy to permit identification of structurally related components. The use of a dereplication platform incorporating the 5min chromatographic method together with MDF facilitated rapid and effective identification of known compounds and detection of structurally related analogs in extracts of fungal cultures.The Journal of Antibiotics advance online publication, 11 January 2017; doi:10.1038/ja.2016.145.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 225.00K | Year: 2014

DESCRIPTION (provided by applicant): Title: Fungal Metabolites as Novel Anthelmintics against Soil-Transmitted Helminthes Project Summary/Abstract It is estimated that over 2 billion people worldwide are suffering from complications due to infections withsoil transmitted helminthes (STHs), but very little research is being conducted by human health pharmaceutical companies. In the USA, it is estimated that in distressed areas of poverty, just under 4 million people harbor undiagnosed STH infections. STH infections typically affect those living in poverty and underrepresented minority populations. Increased immigration, international travel and US soldiers returning from STH endemic countries are bringing undiagnosed helminth infections with them. There is an urgent need for new anti-parasitic agents for treating human gastrointestinal diseases caused by the STHs such as hookworm, ascarid, whipworm and strongyloides. Current treatment is by anthelmintics, which were derived from veterinary medicine rathe

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 241.40K | Year: 2016

DESCRIPTION provided by applicant Small free living amoebae FLA are ubiquitous in nature and are found in soil fresh water and marine environments Most FLA feed on bacteria and are of no medical importance yet several FLA are known to cause serious usually fatal disease in humans and animals Naegleria fowleri and Acanthamoeba spp are the best known examples of pathogenic FLA N fowleri is the causative agent of primary amoebic meningoencephalitis PAM a disease characterized by a fulminant rapidly fatal encephalitic disease that most often afflicts healthy young humans Acanthamoeba spp cause granulomatous amoebic encephalitis GAE a chronic disease seen most often in immune compromised hosts and those at risk of opportunistic infections Acanthamoeba spp also cause amoebic keratitis skin nasopharyngeal and disseminated infections The major problem for infections with pathogenic FLA is the lack of effective therapeutics and the absence of drug discovery research for this emerging infectious disease Treatment of PAM is empirical and based upon the first few cases of successful treatment with amphotericin B combination therapy Importantly most victims with neurological disease die from PAM or GAE despite treatment with amphotericin B combined with other antimicrobial drugs Despite the severity of infections caused by FLA there are few data available on new drugs and very few modern drug discovery or development efforts The majority of the research literature on drug discovery for FLA consists of limited in vitro or in vivo studies with only a few drugs already approved for other uses Most of the new chemical entities NCEandapos s approved by the Food and Drug Administration in the past years are from natural products research Among treatments for parasites only of the small molecule drugs approved for treatment of parasites in the last years are totally synthetic all others are either natural products or their derivatives or are based on a natural product template Whether as native natural products or as the basis for synthetic analogues it is clear that drug discovery continues to be dominated by small molecules found in nature Despite the promise of natural products research there have been no large scale screens of natural products for discovery of new drugs to treat pathogenic FLA infections We hypothesize that natural products are a rich source of chemical diversity that can be used to identify new chemical scaffolds with potential for development as new drugs for FLA Herein we propose to discover new drugs and drug leads that can be used in combination with amphotericin B for the treatment of pathogenic FLA We will apply modern tenets of drug discovery and natural products research for the first time with pathogenic FLA to discover novel hits that can serve as the basis for lead optimization and development of new drugs to treat pathogenic FLA infections Many new chemotypes have emerged from natural products research yet most efforts have focused on the same terrestrial regions of high biodiversity Conversely many other regions of the world and other sources of remarkable biodiversity have been understudied We will investigate several niche sources of microbial biodiversity in the search for new chemotypes to treat FLA These include the worldandapos s largest collection of filamentous fungi Mycosynthetix endophytic fungi from mangrove plants and marine invertebrate associated eubacteria from Antarctica Baker Lab at the University of South Florida In Phase I we will screen extracts for activity against N fowleri and de replicat the active hits andgt inhibition at g ml and cytotoxicity index andgt In Phase II we will conduct bioassay guided fractionation of the hits to identify novel natural product chemical scaffolds for lead optimization as new therapies for pathogenic FLA In addition we will expand the screening campaign to increase the biodiversity being sampled to identify new drugs for these deadly diseases PUBLIC HEALTH RELEVANCE Amoeba are found everywhere and some can cause fatal diseases in humans and animals We will evaluate natural products for their ability to kill these disease causing amoeba and develop new medicines from those that show promising activity

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