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1.
SLAS Discov ; 22(9): 1093-1105, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28697309

ABSTRACT

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme crucial for cleavage of the covalent topoisomerase 1-DNA complex, an intermediate in DNA repair. TDP1 plays a role in reversing inhibition of topoisomerase I by camptothecins, a series of potent and effective inhibitors used in the treatment of colorectal, ovarian, and small-cell lung cancers. It is hypothesized that inhibition of TDP1 activity may enhance camptothecin sensitivity in tumors. Here, we describe the design, development, and execution of a novel assay to identify inhibitors of TDP1 present in natural product extracts. The assay was designed to address issues with fluorescent "nuisance" molecules and to minimize the detection of false-positives caused by polyphenolic molecules known to nonspecifically inhibit enzyme activity. A total of 227,905 purified molecules, prefractionated extracts, and crude natural product extracts were screened. This yielded 534 initial positives (0.23%). Secondary prioritization reduced this number to 117 (0.05% final hit rate). Several novel inhibitors have been identified showing micromolar affinity for human TDP1, including halenaquinol sulfate, a pentacyclic hydroquinone from the sponge Xestospongia sp.

2.
J Nat Prod ; 75(9): 1632-6, 2012 Sep 28.
Article in English | MEDLINE | ID: mdl-22928967

ABSTRACT

Renal or kidney cancer accounts for about 3% of all cancer cases reported each year in the U.S. Molecular signatures that define the cancer, such as the loss of functional VHL, are found in both sporadic and familial cases of cancer. In clear cell renal cancer, the transcription factor HIF-2α has been shown to have a distinct role in tumorigenesis. Our laboratories developed a cell-based screen to identify modulators of HIF-2α. Screening of the NCI's Natural Product Extract Repository resulted in the identification of 10 sponge extracts, from which 12 compounds were isolated. The biological evaluation of these compounds will be discussed including evaluation of HIF-1α vs HIF-2α selectivity and the isolated compounds' effects on mRNA from several pathways regulated by HIF.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors , Biological Products/isolation & purification , Biological Products/pharmacology , Porifera/chemistry , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Biological Products/chemistry , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Marine Biology , Molecular Structure , RNA, Messenger/genetics
3.
J Nat Prod ; 75(3): 394-9, 2012 Mar 23.
Article in English | MEDLINE | ID: mdl-22313254

ABSTRACT

Barleria alluaudii and Diospyros maritima were both investigated as part of an ongoing search for synergistic TRAIL (tumor necrosis factor-α-related apoptosis-inducing ligand) sensitizers. As a result of this study, two naphthoquinone epoxides, 2,3-epoxy-2,3-dihydrolapachol (1) and 2,3-epoxy-2,3-dihydro-8-hydroxylapachol (2), both not previously isolated from natural sources, and the known 2-methylanthraquinone (3) were identified from B. alluaudii. Time-dependent density functional theory (TD-DFT) calculations of electronic circular dichroism (ECD) spectra were utilized to establish the absolute configuration of 1 and 2. Additionally, five known naphthoquinone derivatives, maritinone (4), elliptinone (5), plumbagin (6), (+)-cis-isoshinanolone (7), and ethylidene-6,6'-biplumbagin (8), were isolated from D. maritima. Compounds 1, 2, and 4-6 showed varying levels of synergy with TRAIL. Maritinone (4) and elliptinone (5) showed the highest synergistic effect, with more than a 3-fold increase in activity observed with TRAIL than with compound alone.


Subject(s)
Acanthaceae/chemistry , Anthraquinones/isolation & purification , Diospyros/chemistry , Naphthoquinones/isolation & purification , TNF-Related Apoptosis-Inducing Ligand/drug effects , Anthraquinones/chemistry , Anthraquinones/pharmacology , Madagascar , Molecular Structure , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , TNF-Related Apoptosis-Inducing Ligand/metabolism , Tumor Necrosis Factor-alpha
4.
J Am Chem Soc ; 133(37): 14629-36, 2011 Sep 21.
Article in English | MEDLINE | ID: mdl-21776994

ABSTRACT

Fibrosterol sulfate A is a polysulfated bis-steroid with an atypical side chain. Due to the flexibility of the linker, large-scale motions that change dramatically the shape of the entire molecule are expected. Such motions pose major challenges to the structure elucidation and the correct determination of configuration. In this study, we will describe the determination of the relative configuration of fibrosterol sulfate A through a residual dipolar coupling based multiple alignment tensor analysis complemented by molecular dynamics. For completeness, we applied also the single tensor approach which is unreliable due to the large-scale motions and compare the results.


Subject(s)
Molecular Dynamics Simulation , Sterols/chemistry , Magnetic Resonance Spectroscopy , Molecular Conformation , Motion
5.
Org Lett ; 13(13): 3518-21, 2011 Jul 01.
Article in English | MEDLINE | ID: mdl-21644548

ABSTRACT

Extracts of the sponge genus Candidaspongia showed selective cytotoxicity toward melanoma cells in the NCI 60-cell-line screen. Continued investigation of the Candidaspongia sp. extracts led to the isolation of three new tedanolide analogues, precandidaspongiolides A (1) and B (2) and candidaspongiolide B (4), as well as candidaspongiolide A (3) and tedanolide (5). Semisynthetic derivatives were also generated to develop SAR. Candidaspongiolides A/B were the most potent and showed low nanomolar activity against several melanoma cell lines.


Subject(s)
Cell Proliferation/drug effects , Macrolides/chemistry , Macrolides/chemical synthesis , Melanoma/pathology , Cell Line, Tumor , Humans , Macrolides/pharmacology , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 21(7): 2113-5, 2011 Apr 01.
Article in English | MEDLINE | ID: mdl-21353547

ABSTRACT

Kidney cancer was the cause of almost 13,000 deaths in the United States in 2009. Loss of function of the VHL tumor suppressor gene (von Hippel-Lindau disease) dramatically increases the risk of developing clear cell kidney cancer. The VHL protein is best understood for its regulation of hypoxia inducible factor (HIF). HIF responds to changes in oxygen levels in the cell and is responsible for mediating the transcriptional response to hypoxia. Of the three known HIFα gene products, HIF-2α appears to play a fundamental role in renal carcinoma. A high throughput screen was developed to identify small molecule inhibitors of HIF-2 gene expression. The screen was performed and yielded 153 confirmed active natural product extracts. Three of the active extracts were from marine soft corals of the order Alcyonacea: Sarcophyton sp., Lobophytum sarcophytoides and Asterospicularia laurae. Bioassay-guided fractionation led to the isolation of two new cembrane diterpenes, (4Z,8S*,9R*,12E,14E)-9-hydroxy-1-(prop-1-en-2-yl)-8,12-dimethyl-oxabicyclo[9.3.2]-hexadeca-4,12,14-trien-18-one (1), and (1E,3E,7R*,8R*,11E)-1-(2-methoxypropan-2-yl)-4,8,12-trimethyloxabicyclo[12.1.0]-pentadeca-1,3,11-triene (7), as well as eight known compounds, 2-6 and 8-10.


Subject(s)
Anthozoa/chemistry , Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors , Diterpenes/analysis , Animals , Basic Helix-Loop-Helix Transcription Factors/physiology , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray Ionization
7.
J Nat Prod ; 73(12): 2013-8, 2010 Dec 27.
Article in English | MEDLINE | ID: mdl-21067210

ABSTRACT

Casearia arguta was investigated as part of the ongoing search for synergistic TRAIL (tumor necrosis factor-α-related apoptosis-inducing ligand) sensitizers. As a result of this study, argutins A-H, eight new highly oxygenated clerodane diterpenes, were isolated from the plant Casearia arguta collected in Guatemala. The modified Mosher ester method was utilized to establish the absolute configuration of argutins A and F. Each of the argutins showed varying levels of synergy with TRAIL. Argutin B showed the highest TRAIL sensitization; the synergistic effect of argutin B and TRAIL together was 3-fold greater than argutin B alone.


Subject(s)
Casearia/chemistry , Diterpenes, Clerodane/isolation & purification , Diterpenes, Clerodane/pharmacology , Plants, Medicinal/chemistry , TNF-Related Apoptosis-Inducing Ligand/drug effects , Diterpenes, Clerodane/chemistry , Guatemala , Molecular Structure , Plant Leaves/chemistry
8.
J Org Chem ; 74(3): 1156-62, 2009 Feb 06.
Article in English | MEDLINE | ID: mdl-19053188

ABSTRACT

Eudistomides A (1) and B (2), two new cyclic peptides, were isolated from a Fijian ascidian Eudistoma sp. These five-residue cystine-linked cyclic peptides are flanked by a C-terminal methyl ester and a 12-oxo- or 12-hydroxy-tetradecanoyl moiety. The complete structures of the eudistomides were determined using a combination of spectroscopic and chemical methods. Chiral HPLC analysis revealed that all five amino acid residues in 1 and 2 had the L-configuration. Total synthesis of eudistomides A (1) and B (2) confirmed the proposed structures. Enantioselective lipase-catalyzed hydrolysis of a mixture of C-35 acetoxy epimers indicated a 35R absolute configuration for 2.


Subject(s)
Lipopeptides/chemistry , Peptides, Cyclic/chemistry , Urochordata/chemistry , Animals , Chromatography, High Pressure Liquid , Lipopeptides/isolation & purification , Nuclear Magnetic Resonance, Biomolecular , Peptides, Cyclic/isolation & purification , Sequence Analysis, Protein , Tandem Mass Spectrometry
9.
J Org Chem ; 74(16): 5902-8, 2009 Aug 21.
Article in English | MEDLINE | ID: mdl-20560563

ABSTRACT

Three new sulfated sterol dimers, fibrosterol sulfates A-C (1-3), have been isolated from the sponge Lissodendoryx (Acanthodoryx) fibrosa, collected in the Philippines. The structures were assigned on the basis of extensive 1D and 2D NMR studies as well as analysis by HRESIMS. Compounds 1 and 2 inhibited PKCzeta with IC(50) values of 16.4 and 5.6 microM, respectively.


Subject(s)
Dimerization , Porifera/chemistry , Protein Kinase C/antagonists & inhibitors , Sterols/chemistry , Sterols/pharmacology , Sulfates/chemistry , Animals , Complex Mixtures/chemistry , Drug Evaluation, Preclinical , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Methanol/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/isolation & purification , Protein Kinase Inhibitors/pharmacology , Sterols/isolation & purification
10.
J Nat Prod ; 71(7): 1213-7, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18558742

ABSTRACT

Three new sterol sulfates, spheciosterol sulfates A-C (1-3), and the known sterol sulfate topsentiasterol sulfate E (4) have been isolated from the sponge Spheciospongia sp., collected in the Philippines. Structures were assigned on the basis of extensive 1D and 2D NMR studies as well as analysis by HRESIMS. Compounds 1-4 inhibited PKCzeta with IC50 values of 1.59, 0.53, 0.11, and 1.21 microM, respectively. In a cell-based assay, 1-4 also inhibited NF-kappaB activation with EC50 values of 12-64 microM.


Subject(s)
NF-kappa B/drug effects , Porifera/chemistry , Protein Kinase C/antagonists & inhibitors , Sterols/isolation & purification , Sterols/pharmacology , Sulfuric Acid Esters/isolation & purification , Sulfuric Acid Esters/pharmacology , Animals , Cartilage/drug effects , Cartilage/metabolism , Dose-Response Relationship, Drug , Humans , Isoenzymes , Philippines , Sterols/chemistry , Sulfuric Acid Esters/chemistry
11.
J Nat Prod ; 69(12): 1833-5, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17190474

ABSTRACT

Two new sesquiterpene pyridine alkaloids, oppositines A (1) and B (2), have been isolated from the plant Pleurostylia opposita, collected in Sri Lanka. The compounds were isolated and purified by solvent/solvent partitioning, column chromatography, and HPLC. Their structures were assigned on the basis of extensive 1D and 2D NMR studies as well as analysis by HRESIMS. Oppositines A (1) and B (2) showed moderate cytotoxicity against HCT116 cell lines with EC50 values of 27 +/- 2 and 26 +/- 3 microM, respectively.


Subject(s)
Alkaloids/isolation & purification , Antineoplastic Agents, Phytogenic/isolation & purification , Celastraceae/chemistry , Plants, Medicinal/chemistry , Sesquiterpenes/isolation & purification , Alkaloids/chemistry , Alkaloids/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacology , Sri Lanka
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