118-31-0Relevant articles and documents
CYP2C19 and 3A4 Dominate Metabolic Clearance and Bioactivation of Terbinafine Based on Computational and Experimental Approaches
Davis, Mary A.,Barnette, Dustyn A.,Flynn, Noah R.,Pidugu, Anirudh S.,Swamidass, S. Joshua,Boysen, Gunnar,Miller, Grover P.
, p. 1151 - 1164 (2019)
Lamisil (terbinafine) is an effective, widely prescribed antifungal drug that causes rare idiosyncratic hepatotoxicity. The proposed toxic mechanism involves a reactive metabolite, 6,6-dimethyl-2-hepten-4-ynal (TBF-A), formed through three N-dealkylation pathways. We were the first to characterize them using in vitro studies with human liver microsomes and modeling approaches, yet knowledge of the individual enzymes catalyzing reactions remained unknown. Herein, we employed experimental and computational tools to assess terbinafine metabolism by specific cytochrome P450 isozymes. In vitro inhibitor phenotyping studies revealed six isozymes were involved in one or more N-dealkylation pathways. CYP2C19 and 3A4 contributed to all pathways, and so, we targeted them for steady-state analyses with recombinant isozymes. N-Dealkylation yielding TBF-A directly was catalyzed by CYP2C19 and 3A4 similarly. Nevertheless, CYP2C19 was more efficient than CYP3A4 at N-demethylation and other steps leading to TBF-A. Unlike microsomal reactions, N-denaphthylation was surprisingly efficient for CYP2C19 and 3A4, which was validated by controls. CYP2C19 was the most efficient among all reactions. Nonetheless, CYP3A4 was more selective at steps leading to TBF-A, making it more effective in terbinafine bioactivation based on metabolic split ratios for competing pathways. Model predictions did not extrapolate to quantitative kinetic constants, yet some results for CYP3A4 and CYP2C19 agreed qualitatively with preferred reaction steps and pathways. Clinical data on drug interactions support the CYP3A4 role in terbinafine metabolism, while CYP2C19 remains understudied. Taken together, knowledge of P450s responsible for terbinafine metabolism and TBF-A formation provides a foundation for investigating and mitigating the impact of P450 variations in toxic risks posed to patients.
Exploring reversible reactions between CO2 and amines
Hampe, Erin M.,Rudkevich, Dmitry M.
, p. 9619 - 9625 (2003)
The 'old' chemistry between CO2 and primary alkylamines has been revisited. Amines 1 and 2, with appended aromatic fluorophores, reversibly reacted with CO2 in polar aprotic solvent (e.g. DMSO, DMF) with the formation of carbamic acids 3 and 4. As a result, strong fluorescence occurred, thus directly reporting on the CO2 entrapment. Carbamic acids were studied by 1H and 13C NMR spectroscopy in DMSO-d 6. The carbamate bond, despite being covalent, is reversible and can be broken upon heating or simply flashing solutions with inert gases. Synthesis and evaluation of a CO2-sensing amino acid-α-naphthylglycine 7 is also reported for potential CO2 monitoring under biorelevant conditions in aqueous solutions.
Mandell et al.
, p. 574 (1963)
Detoxification of the cruciferous phytoalexin brassinin in Sclerotinia sclerotiorum requires an inducible glucosyltransferase
Pedras, M. Soledade C.,Ahiahonu, Pearson W.K.,Hossain, Mohammad
, p. 2685 - 2694 (2004)
The phytoalexins, brassinin, 1-methoxybrassinin and cyclobrassinin, were metabolized by the stem rot fungus Sclerotinia sclerotiorum into their corresponding glucosyl derivatives displaying no detectable antifungal activity. Importantly, co-incubation of S. sclerotiorum with camalexins, various phytoalexin analogs, and brassinin indicated that a synthetic camalexin derivative could slow down substantially the rate of brassinin detoxification. Furthermore, inducible brassinin glucosyltransferase (BGT) activity was detected in crude cell-free extracts of S. sclerotiorum. BGT activity was induced by the phytoalexin camalexin, and the brassinin analogs methyl tryptamine dithiocarbamate and methyl 1-methyltryptamine dithiocarbamate. The overall results suggest that the fungus S. sclerotiorum in its continuous adaptation and co-evolution with brassinin producing plants, has acquired efficient glucosyltransferase(s) that can disarm some of the most active plant chemical defenses.
Polymer bound iminodicarbonate: A new ammonia equivalent for solid-phase synthesis of primary amines
Subramanyam
, p. 6537 - 6540 (2000)
A polymer bound iminodicarbonate has been designed and its use in solid-phase synthesis of primary amines is reported. (C) Elsevier Science Ltd.
Improved synthesis of (R)-glycine-d-15N
Walker, Joel R,Curley Jr., Robert W
, p. 6695 - 6701 (2001)
Previously, we have synthesized the title glycine to permit assignment of the prochiral α-protons of glycine residues in the NMR study of the protein FKBP. A key, and low yielding step in this synthesis occurs in the ruthenium tetraoxide mediated degradation of N-t-Boc-p-methoxybenzyl amine to N-t-Boc-glycine. Efforts to improve this key step by exploring different substrates and N-protecting groups were successful to render this synthesis amenable for the large scale production of (R)-glycine-d-15N.
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Rupe,Brentano
, p. 581,586 (1936)
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Hydroalkylation of Styrenes with Benzylamines by Potassium Hydride
Chiba, Shunsuke,Pang, Jia Hao,Takita, Ryo,Wang, Bin,Watanabe, Kohei
, (2021/09/25)
A method for the synthesis of 1,3-diarylpropylamines through hydroalkylation of styrenes with benzylamines by potassium hydride has been developed. The protocol is initiated by solvothermal treatment of benzylamines with KH at 100 °C to generate deprotonated anionic species, which undergo selective C-alkylation with arylalkenes at 0 °C to ambient temperature to afford 1,3-diarylpropylamines as the major product.
Dehydrogenation of Primary Alkyl Azides to Nitriles Catalyzed by Pincer Iridium/Ruthenium Complexes
Gan, Lan,Jia, Xiangqing,Fang, Huaquan,Liu, Guixia,Huang, Zheng
, p. 3661 - 3665 (2020/06/02)
Pincer metal complexes exhibit superior catalytic activity in the dehydrogenation of plain alkanes, but find limited application in the dehydrogenation of functionalized organic molecules. Starting from easily accessible primary alkyl azides, here we report an efficient dehydrogenation of azides to nitriles using pincer iridium or ruthenium complexes as the catalysts. This method offers a route to cyanide-free preparation of nitriles without carbon chain elongation and without the use of strong oxidants. Both benzyl and linear aliphatic azides can be dehydrogenated with tert-butylethylene as the hydrogen acceptor to afford nitriles in moderate to high yields. Various functional groups can be tolerated, and the H?C?C?H bond dehydrogenation does not occur for linear alkyl azide substrates. Furthermore, the pincer Ir catalytic system was found to catalyze the direct azide dehydrogenation without the use of a sacrificial hydrogen acceptor.