The Experts below are selected from a list of 294 Experts worldwide ranked by ideXlab platform
Trevor C Mcmorris - One of the best experts on this subject based on the ideXlab platform.
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Hydroxyurea derivatives of irofulven with improved antitumor efficacy
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Michael D. Staake, Trevor C Mcmorris, Leita A. Estes, Alisala Kashinatham, Michael J KelnerAbstract:Irofulven is a semi-synthetic derivative of Illudin S, a toxic sesquiterpene isolated from the mushroom Omphalotus illudens. Irofulven has displayed significant antitumor activity in various clinical trials but displayed a limited therapeutic index. A new derivative of irofulven was prepared by reacting hydroxyurea with irofulven under acidic conditions. Acetylation of this new compound with acetic anhydride produced a second derivative. Both of these new derivatives displayed significant antitumor activity in vitro and in vivo comparable to or exceeding that of irofulven.
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Structure-activity studies of urea, carbamate, and sulfonamide derivatives of acylfulvene.
Journal of Medicinal Chemistry, 2010Co-Authors: Trevor C Mcmorris, Michael D. Staake, Ramesh Chimmani, Kashinatham Alisala, Gangadasu Banda, Michael J KelnerAbstract:Illudin S and M (1, 2) are highly toxic sesquiterpenes found in the basidiomycete Omphalotus illudens. Illudins have a low therapeutic index, but acylfulvene derivatives display potent in vivo antitumor activity against a variety of multidrug resistant tumors. The lead acylfulvene (4), irofulven (5), in a randomized phase IIB clinical trial significantly increased overall survival in patients with metastatic hormone-refractory prostate cancer who failed prior treatment with two different standard chemotherapeutic regimens. Irofulven is unique, as the primary allylic hydroxyl group can undergo displacement with a variety of nucleophiles to produce analogues that retain key functional groups required for biological activity including the reactive cyclopropylmethyl carbinol and α,β-unsaturated ketone. As described here, we synthesized a variety of urea, carbamate, and sulfonamide derivatives that retain key functional groups and display potent biological activity toward target solid tumor cells in vitro but ...
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Synergy of irofulven in combination with other DNA damaging agents: synergistic interaction with altretamine, alkylating, and platinum-derived agents in the MV522 lung tumor model
Cancer Chemotherapy and Pharmacology, 2008Co-Authors: Michael J Kelner, Trevor C Mcmorris, Leita A. Estes, Rafael J. Rojas, Pharnuk SuthipinijthamAbstract:Purpose Irofulven (MGI 114, NSC 683863) is a semisynthetic derivative of illudin S, a natural product present in the Omphalotus illudins (Jack O’Lantern) mushroom. This novel agent produces DNA damage, that in contrast to other agents, is predominately ignored by the global genome repair pathway of the nucleotide excision repair (NER)^2 system. The aim of this study was to determine the antitumor activity of irofulven when administered in combination with 44 different DNA damaging agents, whose damage is in general detected and repaired by the genome repair pathway. Methods The human lung carcinoma MV522 cell line and its corresponding xenograft model were used to evaluate the activity of irofulven in combination with different DNA damaging agents. Results Two main classes of DNA damaging agents, platinum-derived agents, and select bifunctional alkylating agents, demonstrated in vivo synergistic or super-additive interaction with irofulven. DNA helicase inhibiting agents also demonstrated synergy in vitro, but an enhanced interaction with irofulven could not be demonstrated in vivo. There was no detectable synergistic activity between irofulven and agents capable of inducing DNA cleavage or intercalating into DNA. Conclusion These results indicate that the antitumor activity of irofulven is enhanced when combined with platinum-derived agents, altretamine, and select alkylating agents such as melphalan or chlorambucil. A common factor between these agents appears to be the production of intrastrand DNA crosslinks. The synergistic interaction between irofulven and other agents may stem from the nucleotide excision repair system being selectively overwhelmed at two distinct points in the pathway, resulting in prolonged stalling of transcription forks, and subsequent initiation of apoptosis.
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Synergy of irofulven in combination with other DNA damaging agents: synergistic interaction with altretamine, alkylating, and platinum-derived agents in the MV522 lung tumor model
Cancer Chemotherapy and Pharmacology, 2008Co-Authors: Michael J Kelner, Trevor C Mcmorris, Leita A. Estes, Rafael Rojas, Pharnuk SuthipinijthamAbstract:Purpose Irofulven (MGI 114, NSC 683863) is a semisynthetic derivative of illudin S, a natural product present in the Omphalotus illudins (Jack O’Lantern) mushroom. This novel agent produces DNA damage, that in contrast to other agents, is predominately ignored by the global genome repair pathway of the nucleotide excision repair (NER)2 system. The aim of this study was to determine the antitumor activity of irofulven when administered in combination with 44 different DNA damaging agents, whose damage is in general detected and repaired by the genome repair pathway.
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Ab Initio Structure/Reactivity Investigations of Illudin‐Based Antitumor Agents: A Model for Reaction in vivo
Helvetica Chimica Acta, 2003Co-Authors: Laura N. Gregerson, Trevor C Mcmorris, Jay S. Siegel, Kim K. BaldridgeAbstract:(Hydroxymethyl)acylfulvene (HMAF, irofulven; 4), a third-generation derivative of a natural product extracted from the mushroom Omphalotus illudens, is selectively toxic towards certain forms of malignant tumors. Conversion of HMAF and cognates to stable aromatic derivatives is triggered by thiol attack in vitro and in vivo. Quantum-chemical methods predict well the structure for several functionalized derivatives of irofulven as compared to known X-ray crystallographic structures. Computational reaction profiles for thiol attack and aromatic rearrangement of irofulven and illudin S, a toxin from which irofulven is derived, provide insight into HMAF's selectivity and toxicity. Methods used include hybrid density-functional theory (HDFT), HartreeFock (HF), and MollerPlesset second-order perturbation theory (MP2). Solvent effects have been explored by means of the new continuum-solvation method, COSab, presented in an accompanying paper.
Michael J Kelner - One of the best experts on this subject based on the ideXlab platform.
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Hydroxyurea derivatives of irofulven with improved antitumor efficacy
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Michael D. Staake, Trevor C Mcmorris, Leita A. Estes, Alisala Kashinatham, Michael J KelnerAbstract:Irofulven is a semi-synthetic derivative of Illudin S, a toxic sesquiterpene isolated from the mushroom Omphalotus illudens. Irofulven has displayed significant antitumor activity in various clinical trials but displayed a limited therapeutic index. A new derivative of irofulven was prepared by reacting hydroxyurea with irofulven under acidic conditions. Acetylation of this new compound with acetic anhydride produced a second derivative. Both of these new derivatives displayed significant antitumor activity in vitro and in vivo comparable to or exceeding that of irofulven.
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Structure-activity studies of urea, carbamate, and sulfonamide derivatives of acylfulvene.
Journal of Medicinal Chemistry, 2010Co-Authors: Trevor C Mcmorris, Michael D. Staake, Ramesh Chimmani, Kashinatham Alisala, Gangadasu Banda, Michael J KelnerAbstract:Illudin S and M (1, 2) are highly toxic sesquiterpenes found in the basidiomycete Omphalotus illudens. Illudins have a low therapeutic index, but acylfulvene derivatives display potent in vivo antitumor activity against a variety of multidrug resistant tumors. The lead acylfulvene (4), irofulven (5), in a randomized phase IIB clinical trial significantly increased overall survival in patients with metastatic hormone-refractory prostate cancer who failed prior treatment with two different standard chemotherapeutic regimens. Irofulven is unique, as the primary allylic hydroxyl group can undergo displacement with a variety of nucleophiles to produce analogues that retain key functional groups required for biological activity including the reactive cyclopropylmethyl carbinol and α,β-unsaturated ketone. As described here, we synthesized a variety of urea, carbamate, and sulfonamide derivatives that retain key functional groups and display potent biological activity toward target solid tumor cells in vitro but ...
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Synergy of irofulven in combination with other DNA damaging agents: synergistic interaction with altretamine, alkylating, and platinum-derived agents in the MV522 lung tumor model
Cancer Chemotherapy and Pharmacology, 2008Co-Authors: Michael J Kelner, Trevor C Mcmorris, Leita A. Estes, Rafael J. Rojas, Pharnuk SuthipinijthamAbstract:Purpose Irofulven (MGI 114, NSC 683863) is a semisynthetic derivative of illudin S, a natural product present in the Omphalotus illudins (Jack O’Lantern) mushroom. This novel agent produces DNA damage, that in contrast to other agents, is predominately ignored by the global genome repair pathway of the nucleotide excision repair (NER)^2 system. The aim of this study was to determine the antitumor activity of irofulven when administered in combination with 44 different DNA damaging agents, whose damage is in general detected and repaired by the genome repair pathway. Methods The human lung carcinoma MV522 cell line and its corresponding xenograft model were used to evaluate the activity of irofulven in combination with different DNA damaging agents. Results Two main classes of DNA damaging agents, platinum-derived agents, and select bifunctional alkylating agents, demonstrated in vivo synergistic or super-additive interaction with irofulven. DNA helicase inhibiting agents also demonstrated synergy in vitro, but an enhanced interaction with irofulven could not be demonstrated in vivo. There was no detectable synergistic activity between irofulven and agents capable of inducing DNA cleavage or intercalating into DNA. Conclusion These results indicate that the antitumor activity of irofulven is enhanced when combined with platinum-derived agents, altretamine, and select alkylating agents such as melphalan or chlorambucil. A common factor between these agents appears to be the production of intrastrand DNA crosslinks. The synergistic interaction between irofulven and other agents may stem from the nucleotide excision repair system being selectively overwhelmed at two distinct points in the pathway, resulting in prolonged stalling of transcription forks, and subsequent initiation of apoptosis.
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Synergy of irofulven in combination with other DNA damaging agents: synergistic interaction with altretamine, alkylating, and platinum-derived agents in the MV522 lung tumor model
Cancer Chemotherapy and Pharmacology, 2008Co-Authors: Michael J Kelner, Trevor C Mcmorris, Leita A. Estes, Rafael Rojas, Pharnuk SuthipinijthamAbstract:Purpose Irofulven (MGI 114, NSC 683863) is a semisynthetic derivative of illudin S, a natural product present in the Omphalotus illudins (Jack O’Lantern) mushroom. This novel agent produces DNA damage, that in contrast to other agents, is predominately ignored by the global genome repair pathway of the nucleotide excision repair (NER)2 system. The aim of this study was to determine the antitumor activity of irofulven when administered in combination with 44 different DNA damaging agents, whose damage is in general detected and repaired by the genome repair pathway.
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sesquiterpenes from Omphalotus illudens
Phytochemistry, 2002Co-Authors: Trevor C Mcmorris, Ricardo Lira, Peter Gantzel, Michael J Kelner, A Kashinatham, Henrik Rundgren, Robin DaweAbstract:Three sesquiterpenes, illudosone hemiacetal (1a), isoomphadione (2) and illudiolone (3) were isolated from the liquid culture extract of Omphalotus illudens. Their structures were elucidated by spectroscopic techniques as well as by X-ray crystallographic analysis.
Martin Kirchmair - One of the best experts on this subject based on the ideXlab platform.
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phylogeny of the genus Omphalotus based on nuclear ribosomal dna sequences
Mycologia, 2004Co-Authors: Martin Kirchmair, Reinhold Poder, Sandra Morandell, Daniela Stolz, Christian SturmbauerAbstract:The evolutionary history of the genus Om- phalotus was inferred from DNA sequences of the ITS1-5.8S-ITS2 rDNA region. We analyzed 32 collec- tions from different geographical areas: O. olearius (Europe), O. illudens (Europe, North America), O. subilludens (North America), O. olivascens var. olivas- cens (North America) and var. indigo (Mexico), O. mexicanus (Middle America), O. nidiformis (Austra- lia), and O. japonicus ( Japan). Phylogenetic analysis was performed declaring Nothopanus eugrammus as outgroup. Our analyses show that the genus Omphal- otus is split into two major clades, the first consisting of O. illudens and O. mexicanus and the second com- prising O. olearius, O. olivascens, O. japonicus, O. ni- diformis and O. subilludens. Moreover, the often dis- cussed synonymy of O. illudens and O. olearius is re- jected. Omphalotus japonicus, a species formerly placed in the genus Lampteromyces Sing. for morpho- logical reasons, clustered as the sister group of O. olearius.
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chemotaxonomical and morphological observations in the genus Omphalotus omphalotaceae
Persoonia, 2002Co-Authors: Martin Kirchmair, Reinhold Poder, Christian G Huber, Orson K MillerAbstract:Comparative thin-layer chromatography – for the first time applied to Omphalotus olivascens var. olivascens, O. olivascens var. indigo, O. nidiformis, and to O. mexicanus – revealed strikingly similar pigment patterns for all Omphalotus species except O. mexicanus. Atromentin, thelephoric acid and pulvinic acid derivates were found in dried material and/or culture extracts of all species. Illudin S and illudin M were detected in O. mexicanus by high-performance liquid chromatography-atmospheric pressure chemical ionisation mass spectrometry. Data on morphological features of all described Omphalotus and Lampteromyces species are listed, illustrated, and summarized in a key. New combinations in the genus Omphalotus are proposed for Lampteromyces japonicus and L. mangensis.
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why Omphalotus illudens schwein bresinsky et besl i an independent species
Revista Catalana de Micologia, 2002Co-Authors: Martin Kirchmair, Reinhold PoderAbstract:Per que Omphalotus illudens (Schwein.) Bresinsky et Besi es una especie independent. El genere Omphalotus viu des de la zona tropical a la temperada de tot el mon. Actualment, hi ha vuit especies descrites. Dues, O. Olearius i O. Illudens viuen a Europa. Tenint en compte que aquestes dues especies son morfologicament molt semblants, el seu estatus taxonomic es encara materia de controversia. Aquest estudi es basa en una revisio detallada d'aquest problema: s' hi evaluen dades morfol ogiques, quimiotaxonomiques, moleculars, i tambe experiments d'encreuament. Els resultats ens porten a la conclusio que O. olearius i O. Illudens son dues especies diferents.
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identification of illudins in Omphalotus nidiformis and Omphalotus olivascens var indigo by column liquid chromatography atmospheric pressure chemical ionization tandem mass spectrometry
Journal of Chromatography A, 1999Co-Authors: Martin Kirchmair, Reinhold Poder, Christian G HuberAbstract:Reversed-phase liquid chromatography was used to separate toxins in mushrooms of the genus Omphalotus. Crude ethyl acetate extracts of cultures were injected directly onto a 150×2 mm I.D. column packed with 3 μm octadecylsilica and eluted with a gradient of acetonitrile in 0.1% aqueous acetic acid at a flow-rate of 200 μl/min. Monitoring of the column effluate by atmospheric pressure ionization tandem mass spectrometry allowed the identification of the toxins. The fungal toxins illudin M and illudin S were detected and identified for the first time in cultures of the Australian Omphalotus nidiformis and the North American Omphalotus olivascens var. indigo (Boletales, Basidiomycetes) and confirmed the valuable taxonomic character of illudins for the genus Omphalotus.
Heidrun Anke - One of the best experts on this subject based on the ideXlab platform.
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the fatty acid synthase of the basidiomycete Omphalotus olearius is a single polypeptide
Zeitschrift für Naturforschung C, 2009Co-Authors: Luis Antelo, Katrin Eisfeld, Angela Schlipp, Holger Berg, Till Hornbogen, Rainer Zocher, Heidrun AnkeAbstract:: Fatty acids are essential components of almost all biological membranes. Additionally, they are important in energy storage, as second messengers during signal transduction, and in post-translational protein modification. De novo synthesis of fatty acids is essential for almost all organisms, and entails the iterative elongation of the growing fatty acid chain through a set of reactions conserved in all kingdoms. During our work on the biosynthesis of secondary metabolites, a 450-kDa protein was detected by SDS-PAGE of enriched fractions from mycelial lysates from the basidiomycete Omphalotus olearius. Protein sequencing of this protein band revealed the presence of peptides with homology to both alpha and beta subunits of the ascomycete fatty acid synthase (FAS) family. The FAS encoding gene of O. olearius was sequenced. The positions of its predicted 21 introns were verified. The gene encodes a 3931 amino acids single protein, with an equivalent of the ascomycetous beta subunit at the N-terminus and the a subunit at the C-terminus. This is the first report on an FAS protein from a homobasidiomycete and also the first fungal FAS which is comprised of a single polypeptide.
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omphalotins e i five oxidatively modified nematicidal cyclopeptides from Omphalotus olearius
European Journal of Organic Chemistry, 2009Co-Authors: Johannes C Liermann, Till Opatz, Heinz Kolshorn, Luis Antelo, Heidrun AnkeAbstract:Omphalotins E–I, oxidatively modified cyclic dodecapeptides, were isolated from mycelial extracts of the basidiomycete Omphalotus olearius, and their structures were determined by NMR spectroscopic and MS methods. Four of the five omphalotins contained an unprecedented N-hydroxylated tricyclic tryptophan derivative. All compounds exhibited strong and selective nematicidal activity against the plant pathogen Meloidogyne incognita with LD90 values between 2 and 5 μg mL–1. Cytotoxic activities were not detected up to 50 μg mL–1. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
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Omphalotins E–I, Five Oxidatively Modified Nematicidal Cyclopeptides from Omphalotus olearius
European Journal of Organic Chemistry, 2009Co-Authors: Johannes C Liermann, Till Opatz, Heinz Kolshorn, Luis Antelo, Heidrun AnkeAbstract:Omphalotins E–I, oxidatively modified cyclic dodecapeptides, were isolated from mycelial extracts of the basidiomycete Omphalotus olearius, and their structures were determined by NMR spectroscopic and MS methods. Four of the five omphalotins contained an unprecedented N-hydroxylated tricyclic tryptophan derivative. All compounds exhibited strong and selective nematicidal activity against the plant pathogen Meloidogyne incognita with LD90 values between 2 and 5 μg mL–1. Cytotoxic activities were not detected up to 50 μg mL–1. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
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characterization of the ferrichrome a biosynthetic gene cluster in the homobasidiomycete Omphalotus olearius
Fems Microbiology Letters, 2005Co-Authors: Kai Welzel, Timm Anke, Luis Antelo, Katrin Eisfeld, Heidrun AnkeAbstract:Under iron deprivation Omphalotus olearius was found to produce the hydroxamate siderophore ferrichrome A. A gene cluster consisting of three genes: fso1, a nonribosomal peptide synthetase whose expression is enhanced in the absence of iron; omo1, a l-ornithine-N5-monooxygenase; and ato1, an acyltransferase probably involved in the transfer of the methylglutaconyl residue to N5-hydroxyorinithine was identified. The fso1 sequence is interrupted by 48 introns and its derived protein sequence has a similar structure to the homologous genes of Ustilago maydis and Aspergillus nidulans. This is the first report of a nonribosomal peptide synthetase gene and a biosynthetic gene cluster in homobasidiomycetes.
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In-vitro and in-vivo nematicidal activities of the cyclic dodecapeptide omphalotin A
Pesticide Science, 1999Co-Authors: Anke Mayer, Olov Sterner, Michael Kilian, Birgit Hoster, Heidrun AnkeAbstract:Omphalotin A, a cyclic dodecapeptide produced by submerged cultures of the basidiomycete Omphalotus olearius, exhibited in-vitro and in-vivo nematicidal activity. Meloidogyne incognita was the most sensitive nematode. At 2.0 mg litre -1 , 50% of the nematodes were dead after one hour. Heterodera schachtii, Radopholus similis and Pratylenchus penetrans were affected at higher concentrations. Incorporated into agar, the compound prevented infection of cucumber seedlings by M. incognita at concentrations of 1 mg litre -1 and higher. In glasshouse tests, complete protection of cucumbers and lettuce was achieved between 2.5 and 10 mg litre -1 . No insecticidal activity was observed when Plutella xylostella, Phaedon cochleariae or Spodoptera frugiperda were fed material containing 4 g kg -1 of omphalotin A.
Christian G Huber - One of the best experts on this subject based on the ideXlab platform.
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chemotaxonomical and morphological observations in the genus Omphalotus omphalotaceae
Persoonia, 2002Co-Authors: Martin Kirchmair, Reinhold Poder, Christian G Huber, Orson K MillerAbstract:Comparative thin-layer chromatography – for the first time applied to Omphalotus olivascens var. olivascens, O. olivascens var. indigo, O. nidiformis, and to O. mexicanus – revealed strikingly similar pigment patterns for all Omphalotus species except O. mexicanus. Atromentin, thelephoric acid and pulvinic acid derivates were found in dried material and/or culture extracts of all species. Illudin S and illudin M were detected in O. mexicanus by high-performance liquid chromatography-atmospheric pressure chemical ionisation mass spectrometry. Data on morphological features of all described Omphalotus and Lampteromyces species are listed, illustrated, and summarized in a key. New combinations in the genus Omphalotus are proposed for Lampteromyces japonicus and L. mangensis.
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identification of illudins in Omphalotus nidiformis and Omphalotus olivascens var indigo by column liquid chromatography atmospheric pressure chemical ionization tandem mass spectrometry
Journal of Chromatography A, 1999Co-Authors: Martin Kirchmair, Reinhold Poder, Christian G HuberAbstract:Reversed-phase liquid chromatography was used to separate toxins in mushrooms of the genus Omphalotus. Crude ethyl acetate extracts of cultures were injected directly onto a 150×2 mm I.D. column packed with 3 μm octadecylsilica and eluted with a gradient of acetonitrile in 0.1% aqueous acetic acid at a flow-rate of 200 μl/min. Monitoring of the column effluate by atmospheric pressure ionization tandem mass spectrometry allowed the identification of the toxins. The fungal toxins illudin M and illudin S were detected and identified for the first time in cultures of the Australian Omphalotus nidiformis and the North American Omphalotus olivascens var. indigo (Boletales, Basidiomycetes) and confirmed the valuable taxonomic character of illudins for the genus Omphalotus.
