Xi:Irritant;
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.
Conformational Effects in Fluorescent Excited Charge-transfer Complex Formation
Luo, Xiu-Jin,Beddard, Godfrey S.,Porter, George,Davidson, R. Stephen,Whelan, Terence D.
, p. 3467 - 3476 (1982)
From a study if the variation in fluorescence quantum yield and lifetime with change in solvent polarity for some ω-(1-naphthyl)-N-alkylpyrroles it is concluded that the conformation of the excited complex has little effect upon the wavelength of fluorescence but does have an effect upon the relative efficiencies of the radiative and non-radiative decay processes.
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.
Synthesis of primary amines via nucleophilic addition of organometallic reagents to aldimines on solid support
Katritzky, Alan R.,Xie, Linghong,Zhang, Guifen,Griffith, Michael,Watson, Karen,Kiely, John S.
, p. 7011 - 7014 (1997)
Resin-immobilized aldimines 5, derived from the condensation of amine-functionalized Rink polystyrene resin with aldehydes, react with Grignard reagents, lithium reagents or LiBH4 to afford a wide variety of primary amines in good to excellent yields upon trifluoroacetic acid cleavage. In this amine synthesis, Rink resin functions both as a solid support and as a NH protecting group.
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.
Beyond the BET Family: Targeting CBP/p300 with 4-Acyl Pyrroles
Hügle, Martin,Lucas, Xavier,Ostrovskyi, Dmytro,Regenass, Pierre,Gerhardt, Stefan,Einsle, Oliver,Hau, Mirjam,Jung, Manfred,Breit, Bernhard,Günther, Stefan,Wohlwend, Daniel
, p. 12476 - 12480 (2017)
Bromodomain and extra-terminal domain (BET) inhibitors are widely used both as chemical tools to study the biological role of their targets in living organisms and as candidates for drug development against several cancer variants and human disorders. However, non-BET bromodomains such as those in p300 and CBP are less studied. XDM-CBP is a highly potent and selective inhibitor for the bromodomains of CBP and p300 derived from a pan-selective BET BRD-binding fragment. Along with X-ray crystal-structure analysis and thermodynamic profiling, XDM-CBP was used in screenings of several cancer cell lines in vitro to study its inhibitory potential on cancer cell proliferation. XDM-CBP is demonstrated to be a potent and selective CBP/p300 inhibitor that acts on specific cancer cell lines, in particular malignant melanoma, breast cancer, and leukemia.
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.
Recreating the natural evolutionary trend in key microdomains provides an effective strategy for engineering of a thermomicrobial N-demethylase
Gu, Zhenghua,Guo, Zitao,Shao, Jun,Shen, Chen,Shi, Yi,Tang, Mengwei,Xin, Yu,Zhang, Liang
, (2022/03/09)
N-demethylases have been reported to remove the methyl groups on primary or secondary amines, which could further affect the properties and functions of biomacromolecules or chemical compounds; however, the substrate scope and the robustness of N-demethylases have not been systematically investigated. Here we report the recreation of natural evolution in key microdomains of the Thermomicrobium roseum sarcosine oxidase (TrSOX), an N-demethylase with marked stability (melting temperature over 100 C) and enantioselectivity, for enhanced substrate scope and catalytic efficiency on -C-N-bonds. We obtained the structure of TrSOX by crystallization and X-ray diffraction (XRD) for the initial framework. The natural evolution in the nonconserved residues of key microdomains—including the catalytic loop, coenzyme pocket, substrate pocket, and entrance site—was then identified using ancestral sequence reconstruction (ASR), and the substitutions that accrued during natural evolution were recreated by site-directed mutagenesis. The single and double substitution variants catalyzed the N-demethylation of N-methyl-L-amino acids up to 1800- and 6000-fold faster than the wild type, respectively. Additionally, these single substitution variants catalyzed the terminal N-demethylation of non-amino-acid compounds and the oxidation of the main chain -C-N- bond to a -C=N- bond in the nitrogen-containing heterocycle. Notably, these variants retained the enantioselectivity and stability of the initial framework. We conclude that the variants of TrSOX are of great potential use in N-methyl enantiomer resolution, main-chain Schiff base synthesis, and alkaloid modification or degradation.
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.
