19165-63-0Relevant articles and documents
Pigments of fungi. LXIX.* Total synthesis of (R)-ochratoxin α and the formal total synthesis of ochratoxin A
Donner, Christopher D.,Gill, Melvyn
, p. 213 - 217 (2002)
(R)-Ochratoxin α, the monochiral carboxylic acid component of the biologically active dipeptide ochratoxin A, is synthesized for the first time over nine steps from (R)-propylene oxide. The method constitutes a versatile and general route to functionalized dihydroisocoumarins.
Synthesis and Structural Elucidation of Analogs of Ochratoxin A
Xiao, Hao,Marquardt, Ronald R.,Frohlich, Andrew A.,Ling, Yang Z.
, p. 524 - 530 (1995)
Five analogs of ochratoxin A (OA) including the ethylamide of OA (OE-OA), the D-phenylalanine form of OA (d-OA), the decarboxylated OA (DC-OA), the O-methyl ether of OA (OM-OA), and the methyl ester of ochratoxin α (M-Oα) were synthesized using OA or ochratoxin α (Oα) as the starting material.The reactions involved activation of OA to the N-hydroxysuccinimide ester (OA-NHS) and of Oα to acyl chloride (Oα-Cl) followed by nucleophilic substitution with primary amines, amino acids, and alcohols to form corresponding amides and esters.All analogs were obtained in pure forms, and all but OM-OA were crystallized.A simplified procedure for the isolation and crystallization of Oα was also developed.The chemical structures of all analogs were elucidated and/or confirmed using EI-MS and 1H NMR.Other physicochemical parameters such as melting point, UV-vis absorption, fluorescence, and HPLC elution pattern for each analog are presented.The procedures that have been developed for the synthesis of the analogs of OA from OA or Oα are simple and efficient.The reactions generally result in high yields of the desired compounds.The overall yields of final products range approximately from 85 to 90percent of the starting materials.The analogs synthesized together with the natural analogs of OA can be used to establish the structure-activity relationship of OA and for metabolic and immunological studies.Keywords: Ochratoxin A; synthetic analogs; synthesis; structure
Identification and in vitro cytotoxicity of ochratoxin A degradation products formed during coffee roasting
Cramer, Benedikt,Koenigs, Maika,Humpf, Hans-Ulrich
, p. 5673 - 5681 (2008)
The mycotoxin ochratoxin A is degraded by up to 90% during coffee roasting. In order to investigate this degradation, model heating experiments with ochratoxin A were carried out, and the reaction products were analyzed by HPLC-DAD and HPLC-MS/MS. Two ochratoxin A degradation products were identified, and their structure and absolute configuration were determined. As degradation reactions, the isomerization to 14-(R)-ochratoxin A and the decarboxylation to 14-decarboxy-ochratoxin A were identified. Subsequently, an analytical method for the determination of these compounds in roasted coffee was developed. Quantification was carried out by HPLC-MS/MS and the use of stable isotope dilution analysis. By using this method for the analysis of 15 coffee samples from the German market, it could be shown that, during coffee roasting, the ochratoxin A diastereomer 14-(R)-ochratoxin A was formed in amounts of up to 25.6% relative to ochratoxin A. The decarboxylation product was formed only in traces. For toxicity evaluations, first preliminary cell culture assays were performed with the two new substances. Both degradation products exhibited higher IC50 values and caused apoptotic effects with higher concentrations than ochratoxin A in cultured human kidney epithelial cells. Thus, these cell culture data suggest that the degradation products are less cytotoxic than ochratoxin A.
Metabolism of ochratoxin A: Absence of formation of genotoxic derivatives by human and rat enzymes
Gautier, Jean-Charles,Richoz, Janique,Welti, Dieter H.,Markovic, Jovanka,Gremaud, Eric,Peter Guengerich,Turesky, Robert J.
, p. 34 - 45 (2001)
Ochratoxin A (OTA) is a potent renal carcinogen in male rats, although its mode of carcinogenicity is not known. The metabolism and covalent binding of OTA to DNA were investigated in vitro with cytochromes P450, glutathione S-transferases, prostaglandin H-synthase, and horseradish peroxidase. Incubation of OTA with rat or human liver microsomes fortified with NADPH resulted in formation of 4-(R)-hydroxyochratoxin A at low rates [10-25 pmol min-1 (mg of protein)-1]. There was no evidence of OTA metabolism and glutathione conjugate formation with rat, mouse, or human kidney microsomes or postmitochondrial supernatants (S-9) [-1 (mg of protein)-1]. Recombinant human cytochromes P450 (P450) 1A1 and 3A4 formed 4-(R)-hydroxyochratoxin A at low rates [0.08 and 0.06 pmol min-1 (pmol of P450)-1, respectively]; no oxidation products of OTA were detected with recombinant human P450 1A2 or 2E1 or rat P450 1A2 or 2Cll [-1 (pmol of P450)-1]. Prostaglandin H-synthase produced small amounts of an apolar product [33 pmol min-1 (mg of protein)-1], and OTA products were not formed with horseradish peroxidase. There was no evidence of DNA adduct formation when [3H]OTA was incubated with these enzyme systems in the presence of calf thymus DNA (9 DNA bases); however, these enzymes catalyzed DNA adduct formation with the genotoxins aflatoxin B1, 2-amino-3-methylimidazo-[4,5-f]quinoline, benzo[a]pyrene, and pentachlorophenol. There was also no detectable [3H]-OTA bound in vivo to kidney DNA of male Fischer-344 rats treated orally with [3H]OTA (1 mg/kg, 100 mCi/mmol, 24 h exposure, 9 DNA bases), based upon liquid scintillation counting. However, 32P-postlabeling experiments did show evidence of DNA lesions with total adduct levels ranging from 31 to 71 adducts/109 DNA bases, while adducts in untreated rat kidney ranged from 6 to 24 adducts/109 DNA bases. These results do not support the premise that OTA or metabolically activated species covalently bind to DNA and suggest that the 32P-postlabeled lesions are due to products derived from OTA-mediated cytotoxicity.
A kinetic study into the hydrolysis of the ochratoxins and analogues by carboxypeptidase A
Stander,Steyn,Van der Westhuizen,Payne
, p. 302 - 304 (2001)
The hydrolyses of the ochratoxins and analogues by carboxypeptidase A were assessed. This was done by measuring the amount of phenylalanine formed with liquid chromatography coupled to tandem electrospray mass spectrometry. The kinetic data of ochratoxin A, ochratoxin B, and the synthetic bromo-ochratoxin B were compared to the values of a number of synthesized structure analogues, namely, ochratoxin A methyl ester, ochratoxin B methyl ester, N-(2-hydroxybenzoyl)phenylalanine, N-(5-chloro-2-hydroxybenzoyl)phenylalanine, N-(5-bromo-2-hydroxybenzoyl)phenylalanine, and N-(5-fluoro-2-hydroxybenzoyl)phenylalanine. The halogen-containing analogues had lower turnovers than their des-halo analogues. There are no substantial differences in the kinetic data between the different halogen-containing analogues.
Microbial degradation of amino acid-containing compounds using the microcystin-degrading bacterial strain B-9
Jin, Haiyan,Hiraoka, Yoshiko,Okuma, Yurie,Hashimoto, Elisabete Hiromi,Kurita, Miki,Anas, Andrea Roxanne J.,Uemura, Hitoshi,Tsuji, Kiyomi,Harada, Ken-Ichi
, (2018)
Strain B-9, which has a 99% similarity to Sphingosinicella microcystinivorans strain Y2, is a Gram-negative bacterium with potential for use in the degradation of microcystin-related compounds and nodularin. We attempted to extend the application area of strain B-9 and applied it to mycotoxins produced by fungi. Among the tested mycotoxins, only ochratoxin A was completely hydrolyzed to provide the constituents ochratoxin α and L-phenylalanine, and levels of fumonisin B1 gradually decreased after 96 h. However, although drugs including antibiotics released into the aquatic environment were applied for microbial degradation using strain B-9, no degradation occurred. These results suggest that strain B-9 can only degrade amino acid-containing compounds. As expected, the tested compounds with amide and ester bonds, such as 3,4-dimethyl hippuric acid and 4-benzyl aspartate, were readily hydrolyzed by strain B-9, although the sulfonamides remained unchanged. The ester compounds were characteristically and rapidly hydrolyzed as soon as they came into contact with strain B-9. Furthermore, the degradation of amide and ester compounds with amino acids was not inhibited by the addition of ethylenediaminetetraacetic acid (EDTA), indicating that the responsible enzyme was not MlrC. These results suggest that strain B-9 possesses an additional hydrolytic enzyme that should be designated as MlrE, as well as an esterase.
Structural and functional characterization of ochratoxinase, a novel mycotoxin-Degrading enzyme
Dobritzsch, Doreen,Wang, Huaming,Schneider, Gunter,Yu, Shukun
, p. 441 - 452 (2014)
Ochratoxin, with ochratoxin A as the dominant form, is one of the five major mycotoxins most harmful to humans and animals. It is produced by Aspergillus and Penicillium species and occurs in a wide range of agricultural products. Detoxification of contaminated food is a challenging health issue. In the present paper we report the identification, characterization and crystal structure (at 2.2 A) of a novel microbial ochratoxinase from Aspergillus niger. A putative amidase gene encoding a 480 amino acid polypeptide was cloned and homologously expressed in A. niger. The recombinant protein is N-terminally truncated, thermostable, has optimal activity at pH ~6 and 66°C, and is more efficient in ochratoxin A hydrolysis than carboxypeptidase A and Y, the two previously known enzymes capable of degrading this mycotoxin. The subunit of the homo-octameric enzyme folds into a two-domain structure characteristic of a metal dependent amidohydrolase, with a twisted TIM (triosephosphateisomerase)- barrel and a smaller β-sandwich domain. The active site contains an aspartate residue for acid-base catalysis, and a carboxylated lysine and four histidine residues for binding of a binuclear metal centre.
Ruthenium-NHC-Diamine Catalyzed Enantioselective Hydrogenation of Isocoumarins
Li, Wei,Wiesenfeldt, Mario P.,Glorius, Frank
, p. 2585 - 2588 (2017/03/08)
A novel and practical chiral ruthenium-NHC-diamine system is disclosed for the enantioselective hydrogenation of isocoumarins, which provides a new concept to apply (chiral) NHC ligands in asymmetric catalysis. A variety of optically active 3-substituted 3,4-dihydroisocoumarins were obtained in excellent enantioselectivities (up to 99% ee). Moreover, this methodology was utilized in the synthesis of O-methylmellein, mellein, and ochratoxin A.
Efficient synthesis of (R)-ochratoxin alpha, the key precursor to the mycotoxin ochratoxin A
Lenz, Cesar Antonio,Rychlik, Michael
, p. 883 - 886 (2013/02/25)
Two new routes for the synthesis of enantiomerically pure ochratoxin alpha ((3R)-OTα) are presented, which is the key intermediate for the synthesis of ochratoxin A (OTA) by coupling reaction with the amino acid l-phenylalanine. The key step of both routes is the one pot directed ortho-metalation/alkylation/ lactonization of unprotected and suitably functionalized aromatic carboxylic acids, using lithium tetramethylpiperidide (LTMP) and (R)-propylene oxide.
Crystal Structures and Conformational Analysis of Ochratoxin A and B: Probing the Chemical Structure causing Toxicity
Bredenkamp, Martin W.,Dillen, Jan L. M.,Rooyen, Petrus H. van,Steyn, Pieter S.
, p. 1835 - 1840 (2007/10/02)
Studies performed on two metabolites from Aspergillus ochraceus, ochratoxin A (1) and B (2), have yielded information related to the steric, conformational, and electric considerations that could contribute to the different toxicities of these metabolites
