A5067388546- Natural product bioactivities and synthesis
- Protein Degradation and Inhibitors
- Cancer, Hypoxia, and Metabolism
- Marine Sponges and Natural Products
- Sarcoma Diagnosis and Treatment
- Mitochondrial Function and Pathology
- Metalloenzymes and iron-sulfur proteins
- Microbial Natural Products and Biosynthesis
- Ubiquitin and proteasome pathways
- Endoplasmic Reticulum Stress and Disease
- FOXO transcription factor regulation
- Cancer Research and Treatments
- Botanical Research and Chemistry
- Photosynthetic Processes and Mechanisms
- Chemical synthesis and alkaloids
- Genomics and Chromatin Dynamics
- Synthetic Organic Chemistry Methods
- Cancer Genomics and Diagnostics
- Lung Cancer Treatments and Mutations
- Protein Kinase Regulation and GTPase Signaling
- RNA Research and Splicing
- Fungal Biology and Applications
- Cancer-related molecular mechanisms research
- RNA modifications and cancer
- Phytochemistry and Biological Activities
Frederick National Laboratory for Cancer Research
2011-2024
Leidos (United States)
2016-2024
Yangzhou University
2024
Target (United States)
2006-2022
National Cancer Institute
2006-2022
Center for Cancer Research
2006-2022
Wachemo University
2022
Leidos Biomedical Research Inc. (United States)
2016-2018
Science Applications International Corporation (United States)
2011-2012
Molecular Oncology (United States)
2011
At least 16 saponins were detected in the seeds of Chenopodium quinoa. The 5 previously isolated major saponins, 3-O-β-d-glucuronopyranosyl oleanolic acid 28-O-β-d-glucopyranosyl ester, 3-O-α-l-arabinopyranosyl hederagenin 3-O-β-d-glucopyranosyl-(1→3)-α-l-arabinopyranosyl phytolaccagenic and new saponin characterized using mainly NMR spectroscopy, mass spectrometry, chemical methods. antifungal activity against Candida albicans hemolytic on erythrocytes these compounds derived monodesmosides...
Chromosomal translocations generating oncogenic transcription factors are the hallmark of a variety tumors, including many sarcomas. Ewing sarcoma family tumors (ESFTs) characterized by t(11;22)(q24;q12) translocation that generates breakpoint region 1 and Friend leukemia virus integration (EWS-FLI1) fusion factor responsible for highly malignant phenotype this tumor. Although continued expression EWS-FLI1 is believed to be critical ESFT cell survival, clinically effective small-molecule...
Abstract Identity determining transcription factors (TFs), or core regulatory (CR) TFs, are governed by cell-type specific super enhancers (SEs). Drugs to selectively inhibit CR circuitry of high interest for cancer treatment. In alveolar rhabdomyosarcoma, PAX3-FOXO1 activates SEs induce the expression other providing a model system studying cell addiction transcription. Using chemical genetics, systematic screening matter biological outcome, here we report on screen epigenetic probes able...
Abstract Purpose: The goal of this study was to identify second-generation mithramycin analogues that better target the EWS-FLI1 transcription factor for Ewing sarcoma. We previously established as an inhibitor, but compound's toxicity prevented its use at effective concentrations in patients. Experimental Design: screened a panel mithralogs establish their ability inhibit compared IC50 with MTD mice determine relationship between efficacy and toxicity. confirmed suppression promoter, mRNA,...
Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting are lacking. Here, we screen 62,643 compounds using engineered cell line that monitors transcriptional activity identifying a hitherto uncharacterized compound, P3FI-63. RNA-seq, ATAC-seq, and docking analyses implicate histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirm inhibition of multiple KDMs with highest...
Seven new arylpyrrole alkaloids (1–7), along with four known compounds, were isolated from an extract of a Dactylia sp. nov. marine sponge, and their structures elucidated by interpretation NMR MS spectroscopic data. Denigrins D–G (1–4) have highly substituted pyrrole or pyrrolone rings in core structures, while dactylpyrroles A–C (5–7) tricyclic phenanthrene cores. Due to the proton-deficient nature these scaffolds, key heteronuclear correlations 1H–15N HMBC LR-HSQMBC experiments used...
The Argentinean legume Caesalpinia paraguariensis Burk. (Fabaceae) was selected for further fractionation work based on the strong antimicrobial activity of its CH 2 Cl -MeOH (1:1 v/v) extract against a host clinically significant microorganisms, including antibiotic resistant strains. 1D and 2D NMR enabled identification novel benzoxecin derivative caesalpinol along with known compounds bilobetin, stigma-5-en-3-O-β-6′-stearoyl-glucopyranoside, stigma-5-en-3-β-6′-palmitoylglucopyranoside,...
A series of novel madecassic acid (1) derivatives was synthesized, and their cytotoxicity evaluated against the NCI-60 panel cancer cell lines. Several analogues exhibited broad-spectrum cytotoxic activities over all nine tumor types represented in panel, with more potent antiproliferative observed selected lines, including multidrug-resistant phenotypes. Among them, compound 29 showed GI50 (50% growth inhibition) values ranging from 0.3 to 0.9 μM 26 different lines selectivity for one colon...
Two new isopimaranes, 19-methylmalonyloxy-ent-isopimara-8(9),15-diene (5) and 19-malonyloxy-ent-isopimara-8(9),15-diene (6), were isolated using bioassay-guided fractionation of the CH2Cl2−MeOH (1:1) extract aerial part Calceolaria pinifolia along with eight other diterpenes (1−4, 7−10) two triterpenes (11, 12). All compounds assayed against Staphylococcus aureus (SA), methicillin-resistant S. (MRSA), Bacillus subtilis (BS), Escherichia coli (EC). 4-Epi-dehydroabietinol (2)...
Bioactivity-guided fractionation of the CH2Cl2/MeOH extract aerial part Ruprechtia triflora Griseb. led to identification several sterols and a triterpene as active components against Mycobacterium tuberculosis. This is first report chemical investigation member genus Ruprechtia. The novel acylated sterol, 5α,8α-epidioxyergosta-6,22-dien-3β-yl stearate, was isolated its structure determined on basis spectral evidence including NMR (especially selective 1D NOE, TOCSY, HSQC, HMBC) MS (HR-FAB)....
Four novel compounds consisting of two new pimaranes, lecheronol A (1) and B (2), an acylated cycloartane, 3-O-beta-lauroyl-cycloart-(23E)-en-25-ol (10), a highly oxygenated chalconoid, alpha,beta,3,4,5,2',4',6'-octahydroxydihydrochalcone (12), were isolated along with seven known triterpene derivatives three flavonol glucosides from Mycobacterium tuberculosis growth-inhibiting fractions the CH(2)Cl(2)/MeOH (1:1) extract aerial parts Sapium haematospermum. Compounds 1, 3 (3...
Bioassay guided isolation of an antibacterial extract prepared from the fermentation broth a Micromonospora sp. P1068 led to eight compounds identified as (3R) 3,4',7-trihydroxy-isoflavanone (1), 3-hydroxydehydrodaidzein, daidzein (2), 3-methyl-1H-indole-2-carboxylic acid (3), 1H-indole-3-carboxaldehyde (4), 3-(p-hydroxyphenyl)-N-methylpropionamide, N-methylphloretamide (5), phenyl acetic (6), 2-hydroxy (7) and 4-hydroxy-5-methoxy-benzoic (8). Compounds 1 5 were found be novel chemical...
Fractionation of cytotoxic extracts specimens a newly described sponge genus, Candidaspongia, has yielded the candidaspongiolides (3), complex mixture acyl esters macrolide related to tedanolide. The general structure was determined by analyses various 2D NMR and MS data sets. ester components were identified GC-MS analysis derived fatty acid methyl esters. could be selectively converted deacylated core (4) enzymolysis with immobilized porcine lipase, candidaspongiolide then secured...
Verrucarin A (VA) is a small molecule derived from the fungal plant pathogen Myrothecium verrucaria and was identified as selective inhibitor of clear cell renal carcinoma (CCRCC) proliferation in high-throughput screen library naturally occurring molecules. CCRCC arises result loss-of-function mutations von Hippel-Lindau (VHL) gene. Here we show that VA inhibits protein translation initiation culminating apoptosis through extrinsic signaling pathway. Reintroduction VHL gene cells afforded...
Neopetrotaurines A–C (1–3), unusual alkaloids possessing two isoquinoline-derived moieties that are linked via a unique taurine bridge, were isolated from Neopetrosia sp. marine sponge. These new compounds have proton-deficient structural scaffolds difficult to unambiguously assign using only conventional 2- and 3-bond 1H–13C 1H–15N heteronuclear correlation data. Thus, the application of LR-HSQMBC HMBC NMR experiments optimized detect 4- 5-bond long-range correlations facilitated structure...
In a search for natural product inhibitors of hypoxia inducible factor-1 (HIF-1) function, crinamine (1), crinane type alkaloid, showed potent dose dependent inhibition (IC50 = 2.7 microM) HIF-1alpha in cell-based reporter gene assay. Crinamine (1) was isolated from the aerial parts Crinum asiaticum var. japonicum together with lycorine (2), norgalanthamine (3) and epinorgalanthamine (4). The other components (2-4) no significant induced transcriptional activity.
Spirodactylone (1), a hexacyclic indolizidone alkaloid possessing novel spiro ring system, was isolated from the marine sponge Dactylia sp. The structure elucidated by extensive spectroscopic methods including application of LR-HSQMBC NMR pulse sequence. Oxidative cyclization denigrin B (2), an aryl-substituted 2-oxo-pyrroline derivative that also extract, provided material identical to spirodactylone (1). This confirmed assigned and provides insight into probable biogenesis 1.
Neopetrothiazide (1), a pentacyclic isoquinoline quinone, was isolated from Neopetrosia sp. sponge. The structure elucidation facilitated by utilizing long-range heteronuclear single quantum multiple bond correlation (LR-HSQMBC) and (HMBC) nuclear magnetic resonance (NMR) pulse sequences optimized to detect four- five-bond 1H–13C correlations. These NMR experiments can help assign proton-deficient structural motifs like neopetrothiazide which has 14 contiguous nonprotonated centers (C, N,...
Reporter cell lines have been developed for the identification of inhibitors gene expression enhanced by hypoxia-inducible factor 2, which has implicated as a transcription involved in tumorigenesis clear renal carcinoma. Stably transformed reporter clones human carcinoma line 786-O were generated transfection or retroviral infection. Luciferase vectors used was driven either natural vascular endothelial growth (VEGF) promoter-enhancer VEGF and nitric oxide synthase enhancers modulating...
Clear cell renal carcinoma (CCRCC) evolves due to mutations in the Von Hippel-Lindau (VHL) tumor suppressor gene. Although loss of VHL enables survival and proliferation CCRCC cells, it is also expected introduce vulnerabilities that may be exploited for therapeutics discovery. To this end, we developed a high-throughput screen identify small molecules derived from plants, microorganisms, marine organisms which cells are sensitive. Screening over 8,000 compounds using approach, report here...
Bioassay-guided fractionation of the antibacterial CH2Cl2−MeOH extract obtained from aerial parts Argentinean plant Caiophora coronata led to isolation a new triterpene, 1β,3β-dihydroxyurs-12-en-27-oic acid, 1, and iridoid, 1α-methoxy-6α,10-dihydroxyisoepiiridomyrmecin (caiophoraenin), 2, along with known iridoid isoboonein 3. Their structures were established by spectroscopic techniques (1D 2D NMR, HRFABMS, FTIR). The MIC values isolated compounds determined against methicillin-sensitive...