- Inhibition of thyroid peroxidase by dietary flavonoids
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Flavonoids are widely distributed in plant-derived foods and possess a variety of biological activities including antithyroid effects in experimental animals and humans. A structure-activity study of 13 commonly consumed flavonoids was conducted to evaluate inhibition of thyroid peroxidase (TPO), the enzyme that catalyzes thyroid hormone biosynthesis. Most flavonoids tested were potent inhibitors of TPO, with IC50 values ranging from 0.6 to 41 μM. Inhibition by the more potent compounds, fisetin, kaempferol, naringenin, and quercetin, which contain a resorcinol moiety, was consistent with mechanism-based inactivation of TPO as previously observed for resorcinol and derivatives. Other flavonoids inhibited TPO by different mechanisms, such as myricetin and naringin, showed noncompetitive inhibition of tyrosine iodination with respect to iodine ion and linear mixed-type inhibition with respect to hydrogen peroxide. In contrast, biochanin A was found to be an alternate substrate for iodination. The major product, 6,8- diiodo-biochanin A, was characterized by electrospray mass spectrometry and 1H-NMR. These inhibitory mechanisms for flavonoids are consistent with the antithyroid effects observed in experimental animals and, further, predict differences in hazards for antithyroid effects in humans consuming dietary flavonoids. In vivo, suicide substrate inhibition, which could be reversed only by de novo protein synthesis, would be long-lasting. However, the effects of reversible binding inhibitors and alternate substrates would be temporary due to attenuation by metabolism and excretion. The central role of hormonal regulation in growth and proliferation of thyroid tissue suggests that chronic consumption of flavonoids, especially suicide substrates, could play a role in the etiology of thyroid cancer.
- Divi, Rao L.,Doerge, Daniel R.
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- Synthesis of the Rubiyunnanin B Core Aglycon
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Rubiyunnanin B possesses an intriguing anticancer profile whose activity is dependent on the glycosylation of a fused tyrosinyl residue. We have developed a rapid synthesis of the rubiyunnanin B dityrosine core using a Suzuki coupling. Furthermore, the atropisomeric and isomeric products obtained were identified and their distribution controlled. The two major products obtained from the dityrosine coupling were discovered to be locked cis/trans isomers of the internal amide with atropisomerization quantifiable on the NMR timescale.
- Moschitto, Matthew J.,Lewis, Chad A.
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Read Online
- Stereocontrolled Synthesis of Arylomycin-Based Gram-Negative Antibiotic GDC-5338
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We report herein an efficient, stereocontrolled, and chromatography-free synthesis of the novel broad spectrum antibiotic GDC-5338. The route features the construction of a functionalized tripeptide backbone, a high-yielding macrocyclization via a Pd-catalyzed Suzuki-Miyaura reaction, and the late-stage elaboration of key amide bonds with minimal stereochemical erosion. Through extensive reaction development and analytical understanding, these key advancements allowed the preparation of GDC-5338 in 17 steps, 15% overall yield, >99 A % HPLC, and >99:1 dr.
- Wong, Nicholas,Petronijevi?, Filip,Hong, Allen Y.,Linghu, Xin,Kelly, Sean M.,Hou, Haiyun,Cravillion, Theresa,Lim, Ngiap-Kie,Robinson, Sarah J.,Han, Chong,Molinaro, Carmela,Sowell, C. Gregory,Gosselin, Francis
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supporting information
p. 9099 - 9103
(2019/11/14)
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- PROCESS FOR MAKING ARYLOMYIN RING ANALOGS
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Methods for making an arylomycin ring of formula t or salts or solvates thereof, wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R5, R10 and Pg1 are as defined herein.
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Page/Page column 32; 36-38
(2018/10/25)
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- Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors
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Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei (T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors (Ki 50 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys-SOH) during crystallization. The P-glycoprotein efflux ratio was measured and the in vivo brain penetration in rats determined. When tested in vivo in acute HAT model, the compounds permitted up to 16.25 (vs 13.0 for untreated controls) mean days of survival.
- Giroud, Maude,Dietzel, Uwe,Anselm, Lilli,Banner, David,Kuglstatter, Andreas,Benz, J?rg,Blanc, Jean-Baptiste,Gaufreteau, Delphine,Liu, Haixia,Lin, Xianfeng,Stich, August,Kuhn, Bernd,Schuler, Franz,Kaiser, Marcel,Brun, Reto,Schirmeister, Tanja,Kisker, Caroline,Diederich, Fran?ois,Haap, Wolfgang
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supporting information
p. 3350 - 3369
(2018/05/01)
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- Remarkable Effect of Chalcogen Substitution on an Enzyme Mimetic for Deiodination of Thyroid Hormones
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Iodothyronine deiodinases are selenoenzymes which regulate the thyroid hormone homeostasis by catalyzing the regioselective deiodination of thyroxine (T4). Synthetic deiodinase mimetics are important not only to understand the mechanism of enzyme catalysis, but also to develop therapeutic agents as abnormal thyroid hormone levels have implications in different diseases, such as hypoxia, myocardial infarction, critical illness, neuronal ischemia, tissue injury, and cancer. Described herein is that the replacement of sulfur/selenium atoms in a series of deiodinase mimetics by tellurium remarkably alters the reactivity as well as regioselectivity toward T4. The tellurium compounds reported in this paper represent the first examples of deiodinase mimetics which mediate sequential deiodination of T4 to produce all the hormone derivatives including T0 under physiologically relevant conditions.
- Raja, Karuppusamy,Mugesh, Govindasamy
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p. 7674 - 7678
(2015/06/25)
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- Total synthesis of mycocyclosin
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The first total synthesis of mycocyclosin, a diketopiperazine natural product isolated from M. tuberculosis, is described. While direct oxidative coupling of tyrosine phenolic groups was unsuccessful, construction of the highly strained bicyclic framework was successfully accomplished through an intramolecular Miyaura-Suzuki cross-coupling to generate the biaryl linkage.
- Cochrane, James R.,White, Jonathan M.,Wille, Uta,Hutton, Craig A.
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supporting information; experimental part
p. 2402 - 2405
(2012/06/18)
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- Proton-coupled electron transfer from tyrosine: A strong rate dependence on intramolecular proton transfer distance
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Proton-coupled electron transfer (PCET) was examined in a series of biomimetic, covalently linked RuII(bpy)3-tyrosine complexes where the phenolic proton was H-bonded to an internal base (a benzimidazyl or pyridyl group). Photooxidation in laser flash/quench experiments generated the RuIII species, which triggered long-range electron transfer from the tyrosine group concerted with short-range proton transfer to the base. The results give an experimental demonstration of the strong dependence of the rate constant and kinetic isotope effect for this intramolecular PCET reaction on the effective proton transfer distance, as reflected by the experimentally determined proton donor-acceptor distance.
- Zhang, Ming-Tian,Irebo, Tania,Johansson, Olof,Hammarstroem, Leif
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supporting information; experimental part
p. 13224 - 13227
(2011/10/10)
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- Intramolecular suzuki-miyaura reaction for the total synthesis of signal peptidase inhibitors, arylomycins A2and B2
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Development of the total syntheses of arylomycins A1 and B 2 is detailed. Key features of our approach include 1) formation of 14-membered meta, meta-cyclophane by an intramolecular Suzuki-Miyaura reaction; 2) incorporation of N-Me-4-hydroxyphenylglycine into the cyclization precursor, which avoids the late-stage low-yielding N-methylation step; 3) segment coupling of a fully elaborated peptide side chain to the macrocycle, which makes the synthesis highly convergent. Overall, arylomycin A2 was obtained in 13 steps from L-Tyr for the longest linear sequence, in 13% overall yield. Arylomycin B2 was synthesized in 10 steps from L-3-nitro-Tyr, in 10% overall yield.
- Dufour, Jeremy,Neuville, Luc,Zhu, Jieping
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scheme or table
p. 10523 - 10534
(2010/11/04)
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- Thieme Chemistry Journal awardees - Where are they now? Scope of tyrosine O-arylations with boronic acids: Optimized synthesis of an orthogonally protected isodityrosine
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The Evans-Chan-Lam variant of the Ullman condensation has been explored to deliver O-arylated tyrosines and tyrosinyl peptides. Key modifications for success were the slow addition of boronic acids to the phenol-catalyst mixture. Selectivity and scope are investigated. Georg Thieme Verlag Stuttgart.
- Kilitoglu, Bahar,Arndt, Hans-Dieter
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scheme or table
p. 720 - 723
(2009/08/07)
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- Interaction of anti-thyroid drugs with iodine: The isolation of two unusual ionic compounds derived from Se-methimazole
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The inhibition of lactoperoxidase (LPO)-catalyzed iodination of l-tyrosine by the anti-thyroid drug methimazole (MMI) and its selenium analogue (MSeI) is described. MSeI inhibits LPO with an IC50 value of 12.4 M, and this inhibition could be completely reversed by increasing the peroxide concentration. In addition to the inhibition, MSeI reacts with molecular iodine to produce novel ionic diselenides, and the nature of the species formed in this reaction appear to be solvent-dependent. The formation of ionic species in the reaction is confirmed by single-crystal X-ray studies, FT-IR and FT-Raman spectroscopic investigations. This study provides the first experimental evidence that MSeI not only effectively inhibits the LPO-catalyzed iodination of tyrosine, but also reacts with I2 to produce novel ionic diselenides. These results also suggest that MSeI reacts with iodine, even in its oxidized form, to form ionic diselenides containing iodide or polyiodide anions, which might be effective intermediates in the inhibition of thyroid hormones. The Royal Society of Chemistry 2006.
- Roy, Gouriprasanna,Nethaji, Munirathinam,Mugesh
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p. 2883 - 2887
(2008/02/08)
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- Electrophilic radioiodination of tyrosine derivatives
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A comparative study on the electrophilic radioiodination of L-tyrosine, L-α-methyl tyrosine and L-tyrosine methyl ester has been carried out using chloramine-T (CAT) and iodogen as oxidizing agents to generate electrophilic radioiodine. Optimization of the radioiodination conditions has been performed resulting in high labelling yields within short reaction times at room temperature. Radiochromatograms also revealed side product impurities at longer reaction time and higher oxidizing agent concentration. Maximum yields of 93%, 90% and 78% were obtained in case of CAT, while 87%, 88% and 53% were obtained in case of iodogen for L-3-[131I] iodotyrosine, L-3-[131I] iodo-a-methyl tyrosine and L-3-[131I] iodotyrosine methyl ester respectively.
- Farah,Farouk
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p. 255 - 259
(2007/10/03)
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- Ratios of Iodination Rates of Tyrosine and Diiodo-Thyronine
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Ratios of the iodination rates of tyrosine and diiodothyronine were determined by measuring the quantity of reacted thyroninine in a mixture of both components.It was found that tyrosine reacts faster, namely, the ratios of rate constants are 4.9 and 2.6 at 20 and 40 deg C, respectively.A comparison between these results and the data for the electron densities, calculated for carbon atom in both compounds, at which the reaction of iodination takes place, indicates a clear correlation.For both compounds, and for the transition state complex heats of formation and bond energies were also calculated.All the calculations were performed by MNDO semiempirical quantum mechanical method.
- Juznic, K.,Hodoscek, M.
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p. 223 - 226
(2007/10/02)
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- Differential Spectrophotometry of Solutions of Iodoaminoacids and Iodinated Proteins Containing Poly(ethylene glycol) as a Perturbing Agent
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We have measured the difference absorption spectra of solutions of monoiodotyrosine, di-iodotyrosine and thyroxine with 20percent poly(ethylene glycol) (molecular weight 400) as a perturbing agent.These spectra have been used to develop a method for determining the number of iodoaminoacid residues accessible to poly(ethylene glycol) in iodinated proteins.The number of such residues has been determined in iodinated ox serum albumen.
- Gussakovskii, E. E.,Akhmedzhanov, I. G.,Babaev, T. A.
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p. 373 - 375
(2007/10/02)
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- Prevention of Tryptophan Oxidation During Iodination of Tyrosyl Residues in Peptides
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Studies on model systems clearly revealed oxidative degradation of tryptophan under the usual conditions of iodination of tyrosine residues in peptides, whereby the rate of former reaction was found to be faster than the iodination itself.Nin-formylation of tryptophan brings about an efficient indole protection against this oxidative degradation. - Keywords: Iodination of Tyrosyl Residues, Oxidative Degradation of Tryptophan, Nin-Formyl Tryptophan
- Mourier, G.,Moroder, L.,Previero, A.
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p. 101 - 104
(2007/10/02)
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