Nucleophilic Addition of Organozinc Reagents to 2-Sulfonyl Cyclic Ethers: Stereoselective Synthesis of Manassantins A and B

Kim, Hyoungsu; Kasper, Amanda; Moon, Eui Jung; Park, Yongho; Wooten, Ceshea M.; Dewhirst, Mark W.; Hong, Jiyong

doi:10.1021/ol8024617

Cited by 43 publications

(46 citation statements)

References 25 publications

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“…In this analysis, the endogenous proteins in a yeast cell lysate were analyzed for binding to manassantin A, a natural product that has been shown to have anti-cancer activity in cell-based assays but that has an unknown mode-of-action (18–20). The LC-MS/MS data for this ligand-binding experiment were acquired on an orbitrap mass spectrometer with HCD.…”

Section: Resultsmentioning

confidence: 99%

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False-Positive Rate Determination of Protein Target Discovery using a Covalent Modification- and Mass Spectrometry-Based Proteomics Platform

Strickland

Geer

Hong

et al. 2013

J. Am. Soc. Mass Spectrom.

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Detection and quantitation of protein-ligand binding interactions is important in many areas of biological research. The Stability of Proteins from Rates of Oxidation (SPROX) technique is an energetics-based technique for identifying the proteins targets of ligands in complex biological mixtures. Knowing the false positive rate of protein target discovery in proteome-wide SPROX experiments is important for the correct interpretation of results. Reported here are the results of a control SPROX experiment in which chemical denaturation data is obtained on the proteins in two samples that originated from the same yeast lysate, as would be done in a typical SPROX experiment except that one sample would be spiked with the test ligand. False positive rates of 1.2–2.2% and <0.8% are calculated for SPROX experiments using Q-TOF and orbitrap mass spectrometer systems, respectively. Our results indicate that the false positive rate is largely determined by random errors associated with the mass spectral analysis of the isobaric mass tag (e.g., iTRAQ®) reporter ions used for peptide quantitation. Our results also suggest that technical replicates can be used to effectively eliminate such false positives that result from this random error, as is demonstrated in a SPROX experiment to identify yeast protein targets of the drug, manassantin A. The impact of ion purity in the tandem mass spectral analyses and of background oxidation on the false positive rate of protein target discovery using SPROX is also discussed.

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Section: Resultsmentioning

confidence: 99%

“…A 20X inhibitor cocktail was prepared in which stock solutions of the inhibitors were mixed to give a final concentration of 0.2 mM pepstatin A, 0.4 mM leupeptin, 0.3 mM E-64, 1 mM bestatin, and 20 mM AEBSF. Manassantin A was prepared by total chemical synthesis and purified as described elsewhere (18). …”

Section: Methodsmentioning

confidence: 99%

False-Positive Rate Determination of Protein Target Discovery using a Covalent Modification- and Mass Spectrometry-Based Proteomics Platform

Strickland

Geer

Hong

et al. 2013

J. Am. Soc. Mass Spectrom.

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“…Previously, we reported that 1 exhibited a highly potent level of HIF-1 inhibitory activity in a luciferase-reporter based assay (IC 50 = 1–10 nM) 17. Based on the luciferase assay data, we used Western blots to further confirm the HIF-1 inhibitory activity of 1 .…”

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confidence: 96%

“…In broad connection with our interest in the stereoselective synthesis of substituted tetrahydrofurans,15,16 we recently completed the synthesis of 1 and 2 via a direct nucleophilic addition of an organozinc reagent to a 2-benzenesulfonyl cyclic ether to synthesize the 2,3- cis -3,4- trans -4,5- cis -tetrahydrofuran moiety of 1 and 2 17. In addition, we also showed that the ( R )-configuration at C-7 and C-7‴ is not critical for HIF-1 inhibition and that the hydroxyl group at C-7 and C-7‴ can be replaced with carbonyl group without significant loss of activity.…”

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Analysis of HIF-1 inhibition by manassantin A and analogues with modified tetrahydrofuran configurations

Kasper

Moon

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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We have shown that manassantin A downregulated the HIF-1α expression and inhibited the secretion of VEGF. We have also demonstrated that the 2,3-cis-3,4-trans-4,5-cis-configuration of the tetrahydrofuran is critical to the HIF-1 inhibition of manassantin A.Molecular oxygen (O 2 ) is required for aerobic metabolism to maintain intracellular bioenergetics and to serve as an electron acceptor in many organic and inorganic reactions. 1 Hypoxia, usually defined as ≤ 2% of O 2 , occurs in a variety of pathological conditions, including stroke, tissue ischemia, inflammation, and tumor growth. 2 Mammalian tissues have developed a number of essential mechanisms to cope with the stress of hypoxia. Among these coping mechanisms is the response mediated by the hypoxia-inducible transcription factor 1 (HIF-1). It is a basic helix-loop-helix (bHLH)-PER-ARNT-SIM (PAS) family protein that forms a heterodimer with its α and β subunits and acts as a transcription factor. 3 There are two additional HIF-1α-related bHLH-PAS proteins: HIF-2α and HIF-3α. 4 Like HIF-1α, they also bind to HIF-1β (ARNT) for activation. HIF-1 is a main regulator of hypoxia since it activates more than 60 genes involved in angiogenesis (VEGF), glucose transport (GLUT1), glycolytic pathways (LDHA), ROS signals (iNOS), and erythropoiesis (EPO), as well as a number of other processes. 5Through HIF-1, tumors adapt to hypoxia by increasing angiogenesis and metastatic potential, altering apoptosis, and regulating metabolism. 6 These adaptations make tumors more aggressive and treatment-resistant resulting in poor patient prognosis. 7 Immunohistochemical analyses have revealed that HIF-1 is overexpressed in many human cancers. 8 HIF-1 overexpression is not only involved in tumor progression but also associated with resistance to radiation 9 and chemotherapy. 10 It has been shown that inhibition of HIF-1 activity suppresses tumor growth, destroys blood vessels, enhances tumor apoptosis, and increases radiosensitivity, 11 making HIF-1 a good potential target for anti-cancer treatment.Due to the importance of HIF-1 in tumor development and progression, a considerable amount of effort has been made to identify HIF-1 inhibitors for treatment of cancer. 12 A variety of anticancer drugs, most of which were not developed as HIF-1 inhibitors, have been reported Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. to inhibit HIF-1. However, these compounds possess relatively low HIF-1 inhibitory activity (≥ micromolar range). In addition, most of them lack the desired selectivity for the HIF-1 signaling pathway or toxicity profil...

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Design of Carborane‐Based Hypoxia‐Inducible Factor Inhibitors

Ban

Nakamura

2018

Boron‐Based Compounds

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Nucleophilic Addition of Organozinc Reagents to 2-Sulfonyl Cyclic Ethers: Stereoselective Synthesis of Manassantins A and B

Cited by 43 publications

References 25 publications

False-Positive Rate Determination of Protein Target Discovery using a Covalent Modification- and Mass Spectrometry-Based Proteomics Platform

False-Positive Rate Determination of Protein Target Discovery using a Covalent Modification- and Mass Spectrometry-Based Proteomics Platform

Analysis of HIF-1 inhibition by manassantin A and analogues with modified tetrahydrofuran configurations

Design of Carborane‐Based Hypoxia‐Inducible Factor Inhibitors

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