Cedric Pearce

Mycosynthetix, Inc.

Despite the presence of cytotoxic T lymphocytes (CTLs) in the tumor microenvironment, the majority of immunogenic human colon cancers do not respond to immune checkpoint inhibitor immunotherapy and microsatellite instable (MSI) tumors are not naturally eliminated. The molecular mechanism underlying the inactivity of tumor-infiltrating CTLs is unkno...

Precursor-directed biosynthesis was used to generate a series of fluorinated verticillins. The biosynthesis of these epipolythiodioxopiperazine alkaloids was monitored in situ via the droplet liquid microjunction surface sampling probe (droplet probe), and a suite of NMR and mass spectrometry data were used for their characterization. All analogues...

Burkholderia is a multi-talented genus of Gram-negative bacteria, which in recent years has become increasingly recognised as a promising source of bioactive natural products. Metabolite profiling of Burkholderia gladioli BCC0238 showed that it produces the asymmetric lipopeptidiolide antibiotic icosalide A1, originally isolated from a fungus. Geno...

Cover paper for CIR March Issue

Despite the presence of cytotoxic T lymphocytes (CTLs) in the tumor microenvironment, the majority of immunogenic human colon cancer does not respond to immune checkpoint inhibitor immunotherapy, and microsatellite instable (MSI) tumors are not naturally eliminated. The molecular mechanism underlying the inactivity of tumor-infiltrating CTLs is unk...

Despite the presence of CTLs in the tumor microenvironment, the majority of immunogenic human colon cancer does not respond to immune checkpoint inhibitor immunotherapy, and microsatellite instable (MSI) tumors are not naturally eliminated. The molecular mechanism underlying the inactivity of tumor-infiltrating CTLs is unknown. We report here that...

Novel species of fungi described in this study include those from various countries as follows: Angola, Gnomoniopsis angolensis and Pseudopithomyces angolensis on unknown host plants. Australia, Dothiora corym­ biae on Corymbia citriodora, Neoeucasphaeria eucalypti (incl. Neoeucasphaeria gen. nov.) on Eucalyptus sp., Fumagopsis stellae on Eucalyptu...

Verticillins are a group of epipolythiodioxopiperazine alkaloids that have displayed potent cytotoxicity. To evaluate their potential further, a larger supply of these compounds was needed for both in vivo studies and analogue development via semisynthesis. To optimize the biosynthesis of these secondary metabolites, their production was analyzed i...

Human colon cancer, except for the small subset of microsatellite instable (MSI) colon cancer, does not respond to anti-PD-L1/PD-1 immune checkpoint inhibitor (ICI) immunotherapy. A well-established notion is that MSI colon cancer harbors various mutations that serve as neoantigens to generate tumor-specific cytotoxic T lymphocytes (CTLs). Because...

Whole‐organism ex vivo assays that are key to the discovery process for new animal health ectoparasiticides and that form an essential bridge between in vitro target‐based screens and animal models are described. The purpose and basic principles of conducting whole‐organism assays are discussed. Typical workflows are outlined for the use of whole‐o...

Background: Pancreas ductal adenocarcinoma (PDAC) has the most dismal prognosis among all human cancers since it is highly resistant to chemotherapy, radiotherapy and immunotherapy. The anticipated consequence of all therapies is induction of tumor apoptosis. The highly resistance nature of PDACs to all therapies suggests that the intrinsic tumor...

Fungi are morphologically, ecologically, metabolically, and phylogenetically diverse. They are known to produce numerous bioactive molecules, which makes them very useful for natural products researchers in their pursuit of discovering new chemical diversity with agricultural, industrial, and pharmaceutical applications. Despite their importance in...

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 5 min liquid chromatographic run time employing heated electrospray ionization (HESI) was evaluated to determine whether...

Nanoparticle ( NP )‐based drug‐delivery systems are frequently employed to improve the intravenous administration of chemotherapy; however, few reports explore their application as an intraperitoneal therapy. We developed a pH ‐responsive expansile nanoparticle ( eNP ) specifically designed to leverage the intraperitoneal route of administration to...

Background: Pancreatic cancer is one of the cancers where anti-PD-L1/PD-1 immunotherapy has been unsuccessful. What confers pancreatic cancer resistance to checkpoint immunotherapy is unknown. The aim of this study is to elucidate the underlying mechanism of PD-L1 expression regulation in the context of pancreatic cancer immune evasion. Methods:...

Analysis of complex mixtures is a common challenge in natural products research. Quantitative nuclear magnetic resonance spectroscopy (qNMR) offers analysis of complex mixtures at early stages and with benefits that are orthogonal to more common methods of quantitation, including ultraviolet absorption spectroscopy (UV) and mass spectrometry (MS)....

Recent progress is described in an ongoing collaborative multidisciplinary research project directed towards the purification, structural characterization, chemical modification, and biological evaluation of new potential natural product anticancer agents obtained from a diverse group of organisms, comprising tropical plants, aquatic and terrestria...

Objective The heterogeneity of soft tissue sarcoma (STS) represents a major challenge for the development of effective therapeutics. Comprised of over 50 different histology subtypes of various etiologies, STS subsets are further characterized as either karyotypically simple or complex. Due to the number of genetic anomalies associated with genetic...

Aim: Fungi are valuable resources for bioactive secondary metabolites. However, the chemical space of fungal secondary metabolites has been studied only on a limited basis. Herein, we report a comprehensive chemoinformatic analysis of a unique set of 207 fungal metabolites isolated and characterized in a USA National Cancer Institute funded drug d...

Mevalocidin is a fungal secondary metabolite produced by Coniolariella sp. It is a unique phytotoxin that demonstrates broad spectrum post-emergent herbicidal properties. With limited options for weed control, the commercialization of a natural product pesticide would be beneficial to organic farming. In this study, two mevalocidin-producing fungal...

Spiroscytalin (1), a new tetramic acid that possesses an uncommon spiro-ring fusion between a polyketide-derived octalin ring system and a 2,4-pyrrolidinedione, along with two known compounds, leporin B (2) and purpactin A (3), were isolated from a solid phase culture of the fungus Scytalidium cuboideum (MSX 68345). The molecular connectivity of 1-...

(5Z)-7-Oxozeanol and related analogues were isolated and screened to explore their activity as TAK1 inhibitors. Seven analogues were synthesized and more than a score of natural products isolated that examined the role that different areas of the molecule contribute to TAK1 inhibition. A novel nonaromatic difluoro-derivative was synthesized that ha...

Ambient ionization mass spectrometry techniques have recently become prevalent in natural product research due to their ability to examine secondary metabolites in situ. These techniques retain invaluable spatial and temporal details that are lost through traditional extraction processes. However, most ambient ionization techniques do not collect m...

The Fas-FasL effector mechanism plays a key role in cancer immune surveillance by host T cells, but metastatic human colon carcinoma often uses silencing Fas expression as a mechanism of immune evasion. The molecular mechanism under FAS transcriptional silencing in human colon carcinoma is unknown. We performed genome-wide chromatin immunoprecipita...

Ambient ionization mass spectrometry techniques have recently become very prevalent in natural product research due to their ability to examine an organism in situ. Profiling a sample directly on an organism without the need for lengthy regrowth and extraction procedures is extremely attractive. However, direct ambient ionization techniques, such a...

NMR;1H NMR;13C NMR;diketopiperazine;fungi;secondary metabolites

The Fas-FasL effector mechanism plays a key role in cancer immune surveillance by host T cells, but metastatic human colorectal carcinoma (CRC) often uses silencing of Fas expression as a mechanism of immune evasion. The molecular mechanism of FAS transcriptional silencing in human CRC is unknown. We performed genome-wide ChIP-Sequencing analysis a...

##Assembly-Data-START## Assembly Method :: Sequencher v. 5.3 Sequencing Technology :: Sanger dideoxy sequencing ##Assembly-Data-END##

##Assembly-Data-START## Assembly Method :: Sequencher v. 5.3 Sequencing Technology :: Sanger dideoxy sequencing ##Assembly-Data-END##

Sixteen polyketides belonging to diverse structural classes, including monomeric/dimeric tetrahydroxanthones and resorcylic acid lactones, were isolated from an organic extract of a fungal culture Setophoma terrestris (MSX45109) by bioactivity-directed fractionation as part of a search for anticancer leads from filamentous fungi. Of these, six were...

The ongoing search for effective antiplasmodial agents remains essential in the fight against malaria worldwide. Emerging parasitic drug resistance places an urgent need to explore chemotherapies with novel structures and mechanisms of action. Natural products have historically provided effective antimalarial drug scaffolds. In an effort to search...

As part of an ongoing project to explore filamentous fungi for anticancer and antibiotic leads, 11 compounds were isolated and identified from an organic extract of the fungus Scytalidium album (MSX51631) using bioactivity-directed fractionation against human cancer cell lines. Of these, eight compounds were a series of sorbicillinoid analogs (1-8)...

Antimalarial screening of diverse fungal samples resulted in the isolation and identification of a new sesquiterpene, trichothecinol D (1), which exhibited potent in vitro activity against Plasmodium falciparum with a 200-fold selectivity for parasite versus mammalian cytotoxicity. Trichothecinol D was obtained by bioassay-guided fractionation of t...

The use of epigenetic modifiers, such as histone deacetylase inhibitors and DNA methyltransferase inhibitors, has been explored increasingly as a technique to induce the production of additional microbial secondary metabolites. The application of such molecules to microbial cultures has been shown to upregulate otherwise suppressed genes, and in se...

We conducted a screening campaign to investigate fungi as a source for new antimalarial compounds. A subset of our fungal collection comprising Chinese mangrove endophytes provided over 5000 lipophilic extracts. We developed an accelerated discovery program based on small-scale cultivation for crude extract screening and a high-throughput malaria a...

The γ-lactones (I) and (II) are tested against two cancer cell lines, whereas compound (I) displays moderate cytotoxic activity against the SW-620 cancer cell line, compound (II) shows no activity.

##Assembly-Data-START## Sequencing Technology :: Sanger dideoxy sequencing ##Assembly-Data-END##

##Assembly-Data-START## Sequencing Technology :: Sanger dideoxy sequencing ##Assembly-Data-END##

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 know...

Organic farming and organic produce have seen exponential growth over the past decade. There are few options available for weed control compatible with these products other than manual labor. Scientists at Mycosynthetix, Inc, in collaboration with colleagues from Dow AgroSciences co-discovered (Gerwick et al, 2013) and subsequently licensed mevaloc...

An extract of the filamentous fungus Bionectria sp. (MSX 47401) showed both promising cytotoxic activity (>90% inhibition of H460 cell growth at 20 μg/mL) and antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). A bioactivity-directed fractionation study yielded one new peptaibol (1) and one new tetramic acid derivativ...

An organic extract of a filamentous fungus (MSX 58801), identified as a Volutella sp. (Hypocreales, Ascomycota), displayed moderate cytotoxic activity against NCI-H460 human large cell lung carcinoma. Bioactivity-directed fractionation led to the isolation of three γ-lactones having the furo[3,4-b]pyran-5-one bicyclic ring system [waol A (1), trans...

A multiyear effort to identify new natural products was built on a hypothesis that both phytotoxins from plant pathogens and antimicrobial compounds might demonstrate herbicidal activity. The discovery of one such compound, mevalocidin, is described in the current report. Mevalocidin was discovered from static cultures of two unrelated fungal isola...

Three bioactive compounds were isolated from an organic extract of an ascomycete fungus of the order Chaetothyriales (MSX 47445) using bioactivity-directed fractionation as part of a search for anticancer leads from filamentous fungi. Of these, two were benzoquinones [betulinan A (1) and betulinan C (3)], and the third was a terphenyl compound, BTH...

The hollow fiber assay (HFA) is a drug discovery tool to aid investigators in the prioritization of lead compounds identified by in vitro testing for further development in animal models of disease. In the HFA, cells are cultured in hollow fibers containing pores of a diameter (500 kDa) large enough for proteins and other macromolecules to enter, b...

Enniatins are cyclohexadepsipeptides isolated largely from Fusarium species of fungi, although they have been isolated from other genera, such as Verticillium and Halosarpheia. They were first described over 60 years ago, and their range of biological activities, including antiinsectan, antifungal, antibiotic and cytotoxic, drives contemporary inte...

Bioactivity-directed fractionation of the organic extracts of two filamentous fungi of the Bionectriaceae, strains MSX 64546 and MSX 59553 from the Mycosynthetix library, led to the isolation of a new dimeric epipolythiodioxopiperazine alkaloid, verticillin H (1), along with six related analogs, Sch 52900 (2), verticillin A (3), gliocladicillin C (...

As part of an ongoing investigation of filamentous fungi for anticancer leads, an active culture was identified from the Mycosynthetix library (MSX 70741, of the order Hypocreales, Ascomycota). The fungal extract exhibited cytotoxic activity against the H460 (human nonsmall cell lung carcinoma) cell line, and bioactivity-directed fractionation yiel...

A collaborative project has been undertaken to explore filamentous fungi, cyanobacteria, and tropical plants for anti-cancer drug leads. Through principal component analysis, the chemical space covered by compounds isolated and characterized from these three sources over the last four years was compared to each other and to the chemical space of se...

(5Z)-7-Oxozeaenol was studied to reveal the path through which it exerts its effects on triple-negative MDA-MB-231 breast cancer cells. The apoptotic effect of (5Z)-7-oxozeaenol on MDA-MB-231 cancer cells was analyzed by cell flow cytometry. The effects of (5Z)-7-oxozeaenol on the expression of the nuclear factor kappa B (NF-κB) p65, p50, IκB kinas...

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. 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...

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 know...

In 2012, the Journal of Natural Products has reached a major milestone, through the publication of volume 75. The journal first appeared in 1938 under the title Lloydia, and was published by the Lloyd Library and Museum, Cincinnati, Ohio. The founding Editor of Lloydia was Theodor K. Just, who continued in this position until his death in 1960. The...

##Assembly-Data-START## Sequencing Technology :: Sanger dideoxy sequencing ##Assembly-Data-END##

##Assembly-Data-START## Sequencing Technology :: Sanger dideoxy sequencing ##Assembly-Data-END##

##Assembly-Data-START## Sequencing Technology :: Sanger dideoxy sequencing ##Assembly-Data-END##

Two new xanthone-anthraquinone heterodimers, acremoxanthone C (5) and acremoxanthone D (2), have been isolated from an extract of an unidentified fungus of the order Hypocreales (MSX 17022) by bioactivity-directed fractionation as part of a search for anticancer leads from filamentous fungi. Two known related compounds, acremonidin A (4) and acremo...