- Coumarin Derivatives as Substrate Probes of Mammalian Cytochromes P450 2B4 and 2B6: Assessing the Importance of 7-Alkoxy Chain Length, Halogen Substitution, and Non-Active Site Mutations
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Using a combined structural and biochemical approach, the functional importance of a recently described peripheral pocket bounded by the E-, F-, G-, and I-helices in CYP2B4 and 2B6 was probed. Three series of 4-substituted-7-alkoxycoumarin derivatives with -H, -CH3, or -CF3 at the 4 position of the coumarin core were used initially to monitor functional differences between CYP2B4 and 2B6. 7-Ethoxy-4-(trifluoromethyl)coumarin (7-EFC) displayed the highest catalytic efficiency among these substrates. Mutants were made to alter side-chain polarity (V/E194Q) or bulk (F/Y244W) to alter access to the peripheral pocket. Modest increases in catalytic efficiency of 7-EFC O-deethylation by the mutants were magnified considerably by chlorination or bromination of the substrate ethoxy chain. A structure of CYP2B6 Y244W in complex with (+)-α-pinene was solved at 2.2 ? and showed no CYMAL-5 in the peripheral pocket. A ligand free structure of CYP2B4 F244W was solved at 3.0 ? with CYMAL-5 in the peripheral pocket. In both instances, comparison of the respective wild-type and mutant CYP2B enzymes revealed that CYMAL-5 occupancy of the peripheral pocket had little effect on the topology of active site residue side-chains, despite the fact that the peripheral pocket and active site are located on opposite sides of the I-helix. Analysis of available CYP2B structures suggest that the effect of the amino acid substitutions within the peripheral pocket derive from altered interactions between the F and G helices.
- Liu, Jingbao,Shah, Manish B.,Zhang, Qinghai,Stout, C. David,Halpert, James R.,Wilderman, P. Ross
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Read Online
- Synthesis of 6- and 7-alkoxy-4-methylcoumarins from corresponding hydroxy coumarins and their conversion into 6- and 7-alkoxy-4-formylcoumarin derivatives
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Hydroxy derivatives of 4-methyl-2H-chromen-2-one were prepared from hydroquinone and resorcinol through their reaction with ethyl acetoacetate. These hydroxy coumarins were then converted into corresponding alkoxy derivatives by reaction with alkyl halides. The yields of 6- and 7-alkoxy-4-methylcoumarins 3a–i and 4a–i were 55?95%. Oxidation of these compounds by selenium dioxide under conventional and microwave-assisted heating conditions produced corresponding 4-formyl compounds 5b–h and 6b–h with yields of 40?67% and 90?93%, respectively. Several 6- and 7-alkoxy-4-methylcoumarins 3a–i, 4a–i and nearly all 6- and 7-alkoxy-4-formylcoumarins 5b–h, 6b–h are novel compounds.
- Ngoc Toan, Vu,Dinh Thanh, Nguyen
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p. 3603 - 3615
(2020/08/21)
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- Synthesis, characterisation and photophysical studies of oxadiazolyl coumarin: A new class of blue light emitting fluorescent dyes
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A library of novel 1, 2, 4-oxadiazole linked coumarin dyes have been synthesised via condensation of corresponding acid 6 and N’-hydroxybenzimidamide 8. This new class of organic compounds were examined for their fluorescent properties and found to emit blue light in the visible region of the spectrum with very high Stoke's shift values. Most of these compounds demonstrated high quantum yields and fluorescence life time in nano-second range which makes them quite lucrative to be used as new fluorescent probes. The highest quantum yield of 0.68 was shown by compound 9j which also shows high Stoke's shift value. The electronic structure of these coumarin-based donor–π–acceptor (D–π–A)-type organic dyes have been examined by Density Functional Theory (DFT). TGA analysis of few of the compounds show that they are stable up to temperature range of 0–245?°C. The synthesised compounds were characterised by NMR and mass spectrometry and the structure of two of these compounds have been confirmed by X-ray crystallography.
- Matta, Akanksha,Bahadur, Vijay,Taniike, Toshiaki,Van der Eycken, Johan,Singh, Brajendra K.
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p. 250 - 260
(2017/02/05)
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- Synthesis, spectral characterization and α-chymotrypsin activity of 7-O-substituted derivatives of 7-hydroxy-4-methyl-1-benzopyran-2-one
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In this work, a series of O-alkyl/arenyl/acyl substituted derivatives of 7-hydorxy-4-methyl-1-benzenpyran-2-one (3a-l) was synthesized. The parent compound 7-hydroxy-4-methyl-1-benzenpyran-2-one (1) was geared up by the coupling of resorcinol (a) with ethylacetoacetate (b) in the presence of conc. sulphuric acid. Further, O-substituted derivatives of parent compound were prepared by treating with different electrophiles (2a-l) using sodium hydride as base and DMF as a solvent. The structure of these synthesized compounds were characterized by IR, EI-MS and 1H NMR. These derivatives were also screened against α-chymotrypsin enzyme to check their enzyme inhibition activity. All the compounds displayed a-chymotrypsin activity to varying degree.
- Aziz-Ur-Rehman,Ilyas, Tehseen,Abbasi, Muhammad Athar,Nafeesa, Khadija,Khaliq, Shaista,Rubab, Kaniz,Hussain, Ghulam,Khurshid, Shazia,Ahmad, Irshad
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p. 326 - 330
(2014/06/09)
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- Semisynthesis, ex vivo evaluation, and SAR studies of coumarin derivatives as potential antiasthmatic drugs
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Asthma is a chronic inflammatory disorder that causes contraction in the smooth muscle of the airway and blocking of airflow. Reversal the contractile process is a strategy for the search of new drugs that could be used for the treatment of asthma. This work reports the semisynthesis, ex vivo relaxing evaluation and SAR studies of a series of 18 coumarins. The results pointed that the ether derivatives 1-3, 7-9 and 13-15 showed the best activity (E max = 100%), where compound 2 (42 μM) was the most potent, being 4-times more active than theophylline (positive control). The ether homologation (methyl, ethyl and propyl) in position 7 or positions 6 and 7 of coumarins lead to relaxing effect, meanwhile formation of esters generated less active compounds than ethers. The SAR analysis showed that it is necessary the presence of two small ether groups and the methyl group at position 4 (site 3) encourage biological activity through soft hydrophobic changes in the molecule, without drastically affecting the cLogP.
- Sánchez-Recillas, Amanda,Navarrete-Vázquez, Gabriel,Hidalgo-Figueroa, Sergio,Rios, María Yolanda,Ibarra-Barajas, Maximiliano,Estrada-Soto, Samuel
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p. 400 - 408
(2014/04/17)
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- Synthesis of some peracetylated glucopyranosyl thiosemicarbazones of substituted 4-formylcoumarins
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Some substituted 4-formylcoumarins were prepared by oxidation of 4-corresponding formylcoumarins using SeO2. These aldehydes were converted to thiosemicarbazones by condensation reaction with tetra-O-acetyl-β-D-glucopyranosyl thiosemicarbazide usingmicrowave-assisted heating method. The synthesized compounds were characterized by FT-IR and 1H NMR, 13C NMR and mass spectral studies.
- Thanh, Nguyen Dinh,Toan, Vu Ngoc
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p. 6609 - 6611
(2013/07/26)
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- Ultrasound-assisted one-pot synthesis of substituted coumarins catalyzed by poly(4-vinylpyridinium) hydrogen sulfate as an efficient and reusable solid acid catalyst
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Poly(4-vinylpyridinium) hydrogen sulfate solid acid was found to be efficient catalyst for synthesis of substituted coumarins via Pechmann reaction using ultrasound irradiation at room temperature and neat condition in high yields with short reaction times. This methodology offers momentous improvements over various options for the synthesis of coumarins with regard to yield of products, simplicity in operation and green aspects by avoiding toxic catalysts and solvents. Further, the catalyst can be reused and recovered for several times.
- Khaligh, Nader Ghaffari
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p. 1062 - 1068
(2013/04/24)
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- Xanthan sulfuric acid: An efficient and recyclable solid acid catalyst for Pechmann condensation
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In this report, substituted coumarins are formed via Pechmann condensation using various substituted phenols and ethyl acetoacetates in the presence of xanthan sulfuric acid as a solid acid catalyst under solvent-free conditions. This method is very simple, costeffective, and has shorter reaction times, and the catalyst could be reused. Copyright Taylor & Francis Group, LLC.
- Kuarm, B. Suresh,Madhav, J. Venu,Rajitha
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experimental part
p. 1770 - 1777
(2012/04/23)
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- Expeditious Pechmann condensation by using biodegradable cellulose sulfuric acid as a solid acid catalyst
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A facile synthesis of coumarins was performed in excellent yields via Pechmann condensation by using different type of phenols and ethylacetoacetates under solvent-free media using both conventional method and microwave irradiation in short reaction times is described. The reaction workup is very simple, and the catalyst can be easily separated from the reaction mixture and reused several times in subsequent reactions. Copyright
- Kuarm, B. Suresh,Madhav, J. Venu,Laxmi, S. Vijaya,Rajitha,Reddy, Y. Thirupathi,Reddy, P. Narsimha,Crooks, Peter A.
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experimental part
p. 3358 - 3364
(2010/12/25)
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- Pechmann Reaction Promoted by Boron Trifluoride Dihydrate
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The Pechmann reaction of substituted phenols 1a-e with methyl acetoacetate (2) can be activated by boron trifluoride dihydrate (3) to give the corresponding 4-methylcoumarin derivatives 4a-e in excellent yield (98-99 percent).
- Stoyanov, Edmont V.,Mezger, Jochen
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p. 720 - 724
(2007/10/03)
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- Selective methylation of coumarins and naphthoquinones using dimethyl sulfoxide
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On UV irradiation, coumarins 1-6 and 1,4-naphthoquinones 7-11 with dimethyl sulfoxide in tertiary butyl alcohol under nitrogen atmosphere give corresponding 4-methylcoumarins 12-17 and 2-methyl-1,4-naphthoquinones 18-22 selectively in a single step facile reaction with good yields.
- Thapliyal, Prakash Chander
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p. 726 - 727
(2007/10/03)
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- PHOTOCHEMISTRY OF PESTICIDES, 13. SOME PHOTOREACTIONS OF O,O-DIETHYL-O-(4-METHYL-2-OXO-2H-1-BENZOPYRAN-7-YL)-PHOSPHOROTHIOATE (POTASAN)
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UV-irradiation (λ>313 nm) of O,O-diethyl-O-(4-methyl-2-oxo-2H-1-benzopyran-7-yl)-phosphorothioate (Potasan) 1a in chloroform and/or methanol with and without singlet oxygen results in the formation of the 2-oxo-2H-1-benzopyran-phosphate 2 the 3,3'-bipotasan dehydrodimer 3, and 7-ethoxy-4-methyl-2-oxo-2H-1-benzopyran 4; the mechanisms of formation, especially for 4 are discussed.
- Abdou, Wafaa M.,Mahran, M. Refat,Sidky, Mahmoud M.,Wamhoff, Heinrich
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p. 199 - 204
(2007/10/02)
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