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37 results on '"Challinor, Victoria L."'

2. Carbon-Carbon Bond Cleavage in Activation of the Prodrug Nabumetone

Author

Varfaj, Fatbardha, Zulkifli, Siti NA, Park, Hyoung-Goo, Challinor, Victoria L, De Voss, James J, and de Montellano, Paul R Ortiz

Subjects
Biotechnology, Biocatalysis, Biotransformation, Butanones, Chromatography, High Pressure Liquid, Cyclooxygenase 2 Inhibitors, Cytochrome P-450 CYP1A2, Escherichia coli, Humans, In Vitro Techniques, Microsomes, Nabumetone, Naphthaleneacetic Acids, Oxidation-Reduction, Prodrugs, Substrate Specificity, Transfection, Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy
Abstract

Carbon-carbon bond cleavage reactions are catalyzed by, among others, lanosterol 14-demethylase (CYP51), cholesterol side-chain cleavage enzyme (CYP11), sterol 17β-lyase (CYP17), and aromatase (CYP19). Because of the high substrate specificities of these enzymes and the complex nature of their substrates, these reactions have been difficult to characterize. A CYP1A2-catalyzed carbon-carbon bond cleavage reaction is required for conversion of the prodrug nabumetone to its active form, 6-methoxy-2-naphthylacetic acid (6-MNA). Despite worldwide use of nabumetone as an anti-inflammatory agent, the mechanism of its carbon-carbon bond cleavage reaction remains obscure. With the help of authentic synthetic standards, we report here that the reaction involves 3-hydroxylation, carbon-carbon cleavage to the aldehyde, and oxidation of the aldehyde to the acid, all catalyzed by CYP1A2 or, less effectively, by other P450 enzymes. The data indicate that the carbon-carbon bond cleavage is mediated by the ferric peroxo anion rather than the ferryl species in the P450 catalytic cycle. CYP1A2 also catalyzes O-demethylation and alcohol to ketone transformations of nabumetone and its analogs.

Published
2014

10. Biosynthetic insights provided by unusual sesterterpenes from the medicinal herb Aletris farinosa † †Dedicated to Prof. Sir Alan Battersby on the occasion of his 90th birthday. ‡ ‡Electronic supplementary information (ESI) available: Full computational details, 1H and 13C NMR spectra for 2–6 and experimental procedures Click here for additional data file. Click here for additional data file

Author

Challinor, Victoria L., Johnston, Ryne C., Bernhardt, Paul V., Lehmann, Reginald P., Krenske, Elizabeth H., and De Voss, James J.

Subjects
Chemistry
Abstract

Configuration of a single stereocenter determines if a key carbocation in sesterterpene biosynthesis undergoes simple elimination or a cascade of seven 1,2-methyl and hydride migrations., A series of novel sesterterpenes (2–6) have been isolated from the roots of Aletris farinosa and structurally characterized by MS, NMR, and X-ray crystallography in conjunction with computational modeling. Their structures provide new insights into the mechanisms of sesterterpene biosynthesis. Specifically, we propose with support from density functional theory computations that the configuration at a single stereocenter determines the fate of a key tetracyclic carbocationic intermediate, derived from an oxidogeranylfarnesol precursor. Whereas one epimer of the carbocation undergoes H+ elimination to give 6, the other undergoes a spectacular cascade of seven 1,2-methyl and hydride migrations leading to the previously unreported carbon skeleton of 5. Theoretical calculations suggest that the cascade is triggered by substrate preorganization in the enzyme active site.

Published
2015

11. Data from: Disease-free monoculture farming by fungus-growing termites

Author

Otani, Saria, Challinor, Victoria L., Kreuzenbeck, Nina B., Kildgaard, Sara, Christensen, Søren Krath, Larsen, Louise Lee Munk, Aanen, Duur, Rasmussen, Silas Anselm, Beemelmanns, Christine, Poulsen, Michael, Otani, Saria, Challinor, Victoria L., Kreuzenbeck, Nina B., Kildgaard, Sara, Christensen, Søren Krath, Larsen, Louise Lee Munk, Aanen, Duur, Rasmussen, Silas Anselm, Beemelmanns, Christine, and Poulsen, Michael

Abstract

Fungus-growing termites engage in an obligate mutualistic relationship with Termitomyces fungi, which they maintain in monocultures on specialised fungus comb structures, without apparent problems with infectious diseases. While other fungi have been reported in the symbiosis, detailed comb fungal community analyses have been lacking. Here we use culture-dependent and -independent methods to characterise fungus comb mycobiotas from three fungus-growing termite species (two genera). Internal Transcribed Spacer (ITS) gene analyses using 454 pyrosequencing and Illumina MiSeq showed that non-Termitomyces fungi were essentially absent in fungus combs, and that Termitomyces fungal crops are maintained in monocultures as heterokaryons with two or three abundant ITS variants in a single fungal strain. To explore whether the essential absence of other fungi within fungus combs is potentially due to the production of antifungal metabolites by Termitomyces or comb bacteria, we performed in vitro assays and found that both Termitomyces and chemical extracts of fungus comb material can inhibit potential fungal antagonists. Chemical analyses of fungus comb material point to a highly complex metabolome, including compounds with the potential to play roles in mediating these contaminant-free farming conditions in the termite symbiosis.

Published
2019

15. Structure and Absolute Configuration of Methyl (3R)-Malonyl-(13S)-hydroxycheilanth-17-en-19-oate, a Sesterterpene Derivative from the Roots of Aletris farinosa

Author

Challinor, Victoria L., Chap, Sonet, Lehmann, Reginald P., Bernhardt, Paul V., and De Voss, James J.

Abstract

We report the isolation and structure elucidation of a new cheilanthane sesterterpene from the roots of Aletris farinosathat possesses an unusual malonate half-ester functional group. The structure of 1was determined via mass spectrometry and 1D and 2D NMR spectroscopy, while its absolute configuration was determined via X-ray crystallographic analysis performed on its methyl ester derivative 2.

Published
2024
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22. Biosynthesis of the Antibiotic Nematophin and Its Elongated Derivatives in Entomopathogenic Bacteria.

Author

Xiaofeng Cai, Challinor, Victoria L., Lei Zhao, Reimer, Daniela, Adihou, Hélène, Grün, Peter, Kaiser, Marcel, and Bode, Helge B.

Subjects
*BIOSYNTHESIS, *ANTIBIOTICS, *CHEMICAL derivatives, *XENORHABDUS nematophilus, *STAPHYLOCOCCUS aureus
Abstract

Nematophin, a known antibiotic natural product against Staphylococcus aureus for almost 20 years, is produced by all strains of Xenorhabdus nematophila. Despite its simple structure, its biosynthesis was unknown. Its biosynthetic pathway is reported using heterologous production in Escherichia coli. Additionally, the identification, structure elucidation, and biosynthesis of six extended nematophin derivatives from Xenorhabdus PB62.4 carrying an additional valine are reported. Preliminary bioactivity studies suggest a biological role of these compounds in the bacteria-nematode-insect symbiosis. [ABSTRACT FROM AUTHOR]

Published
2017
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34. Structure and Bioactivity of Steroidal Saponins Isolated from the Roots of Chamaelirium luteum(False Unicorn)

Author

Challinor, Victoria L., Stuthe, Julia M. U., Parsons, Peter G., Lambert, Lynette K., Lehmann, Reginald P., Kitching, William, and De Voss, James J.

Abstract

Phytochemical investigation of Chamaelirium luteum(“false unicorn”) resulted in the isolation of 15 steroidal glycosides. Twelve of these (1, 2, 4–9, 11–13, and 15) are apparently unique to this species, and eight of these (6–9, 11–13, and 15) are previously unreported compounds; one (15) possesses a new steroidal aglycone. In addition, the absolute configuration of (23R,24S)-chiograsterol A (10) was defined, and its full spectroscopic characterization is reported for the first time. The structures and configurations of the saponins were determined using a combination of multistage mass spectrometry (MSn), 1D and 2D NMR experiments, and chemical degradation. The antiproliferative activity of nine compounds obtained in the present work, and eight related compounds generated in previous work, was compared in six human tumor cell lines, with aglycones 3and 10and related derivatives 16, 17, 19, and 20all displaying significant antiproliferative activity.

Published
2012
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35. Contribution of Siderophore Systems to Growth and Urinary Tract Colonization of Asymptomatic Bacteriuria Escherichia coli

Author

Watts, Rebecca E., Totsika, Makrina, Challinor, Victoria L., Mabbett, Amanda N., Ulett, Glen C., De Voss, James J., and Schembri, Mark A.

Abstract

ABSTRACTThe molecular mechanisms that define asymptomatic bacteriuria (ABU) Escherichia colicolonization of the human urinary tract remain to be properly elucidated. Here, we utilize ABU E. colistrain 83972 as a model to dissect the contribution of siderophores to iron acquisition, growth, fitness, and colonization of the urinary tract. We show that E. coli83972 produces enterobactin, salmochelin, aerobactin, and yersiniabactin and examine the role of these systems using mutants defective in siderophore biosynthesis and uptake. Enterobactin and aerobactin contributed most to total siderophore activity and growth in defined iron-deficient medium. No siderophores were detected in an 83972 quadruple mutant deficient in all four siderophore biosynthesis pathways; this mutant did not grow in defined iron-deficient medium but grew in iron-limited pooled human urine due to iron uptake via the FecA ferric citrate receptor. In a mixed 1:1 growth assay with strain 83972, there was no fitness disadvantage of the 83972 quadruple biosynthetic mutant, demonstrating its capacity to act as a “cheater” and utilize siderophores produced by the wild-type strain for iron uptake. An 83972 enterobactin/salmochelin double receptor mutant was outcompeted by 83972 in human urine and the mouse urinary tract, indicating a role for catecholate receptors in urinary tract colonization.

Published
2011
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36. Synthesis and determination of the absolute configuration of (-)-(5R,6Z)-dendrolasin-5-acetate from the nudibranch Hypselodoris jacksoni.

Author

Mudianta IW, Challinor VL, Winters AE, Cheney KL, De Voss JJ, and Garson MJ

Abstract

A small sample of (-)-(5R,6Z)-dendrolasin-5-acetate, which was fully characterized by 2D NMR studies, was isolated from the nudibranch Hypselodoris jacksoni, along with the sesquiterpenes (+)-agassizin, (-)-furodysinin, (-)-euryfuran, (-)-dehydroherbadysidolide and (+)-pallescensone. A synthetic sample ([α]D -8.7) of the new metabolite was prepared by [1,2]-Wittig rearrangement of a geranylfuryl ether followed by acetylation of purified alcohol isomers. The absolute configuration at C-5 was established as R by the analysis of MPA ester derivatives of (Z)-5-hydroxydendrolasin obtained by preparative enantioselective HPLC.

Published
2013
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37. The truth about false unicorn (Chamaelirium luteum): total synthesis of 23R,24S-chiograsterol B defines the structure and stereochemistry of the major saponins from this medicinal herb.

Author

Matovic NJ, Stuthe JM, Challinor VL, Bernhardt PV, Lehmann RP, Kitching W, and De Voss JJ

Subjects
Crystallography, X-Ray, Models, Molecular, Molecular Conformation, Phytosterols chemistry, Plant Extracts chemistry, Plant Extracts isolation & purification, Saponins isolation & purification, Stereoisomerism, Phytosterols chemical synthesis, Plants, Medicinal chemistry, Saponins chemistry
Abstract

Chamaelirium luteum is used in traditional medicine systems and commercial botanical dietary supplements for the treatment of female reproductive health problems. Despite the wide use of this herb, only very limited phytochemical characterisation is available. Our investigation of C. luteum roots led to the isolation of two new steroidal saponins 1 and 2 that contain an unusual aglycone 3. The absolute configurations of these molecules were unable to be determined spectroscopically and thus the total synthesis of 3 was undertaken and achieved in 16 steps and 1.6 % overall yield from pregnenolone. The key step in the synthesis was the stereoselective installation of the side chain at C-17 and C-20, which employed anion-accelerated oxy-Cope methodology. The relative configuration of aglycone 3 was determined by X-ray crystallography of an advanced synthetic intermediate. The absolute configuration was based upon that of the pregnenolone-derived steroidal skeleton and determined to be 23R,24S., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2011
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