- Calreticulin transacetylase: A novel enzyme-mediated protein acetylation by acetoxy derivatives of 3-alkyl-4-methylcoumarins
-
Our earlier investigations culminated in the discovery of a unique membrane-bound enzyme Calreticulin transacetylase (CRTAase) in mammalian cells catalyzing the transfer of acetyl group from polyphenolic acetates (PAs) to certain functional proteins viz. Glutathione S-transferase (GST), NADPH Cytochrome c reductase and Nitric oxide synthase (NOS) resulting in the modulation of their biological activities. In order to develop SAR study, herein, we studied the influence of alkyl group at C-3 position of acetoxy coumarins on the CRTAase activity. The alkylated acetoxy coumarins lead to inhibition of catalytic activity of GST, and ADP induced platelet aggregation by the way of activation of platelet Nitric oxide synthase (NOS). Furthermore, the increase in size of the coumarin C-3 alkyl group was found to decrease the CRTAase activity.
- Jalal, Sarah,Chand, Karam,Kathuria, Abha,Singh, Prabhjot,Priya, Nivedita,Gupta, Bhavna,Raj, Hanumantharao G.,Sharma, Sunil K.
-
-
Read Online
- Asymmetric Aza-Wacker-Type Cyclization of N-Ts Hydrazine-Tethered Tetrasubstituted Olefins: Synthesis of Pyrazolines Bearing One Quaternary or Two Vicinal Stereocenters
-
We have developed an asymmetric aza-Wacker-type cyclization of N-Ts hydrazine-tethered tetrasubstituted olefins, affording optically active pyrazolines bearing chiral tetrasubstituted carbon stereocenters. This reaction is tolerant to a broad range of substrates under mild reaction conditions, giving the desired chiral products with high enantioselectivities. Generation of two vicinal stereocenters on the C=C double bonds was also achieved with high selectivities, a process which has been rarely studied for Wacker-type reactions. A mechanistic study revealed that this aza-Wacker-type cyclization undergoes a syn-aminopalladation process. It was also found that for substrates bearing two linear alkyl substituents on the outer carbon atom of the olefin, both of which are larger than a methyl group, the alkyl substituent that is cis to the intranucleophilic group participates more readily in β-hydride elimination. When one of the two alkyl substituents on the outer carbon atom of the olefin is a methyl group, β-hydride elimination proceeds selectively at the methylene side, thus both diastereomers can be prepared via switching the configuration of the olefin. Furthermore, the product can be converted to a pharmaceutical compound in high yields over three steps.
- Kou, Xuezhen,Shao, Qihang,Ye, Chenghao,Yang, Guoqiang,Zhang, Wanbin
-
supporting information
p. 7587 - 7597
(2018/06/04)
-
- Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s)
-
Undesirable side effects associated with orthosteric agonists/antagonists of cannabinoid 1 receptor (CB1R), a tractable target for treating several pathologies affecting humans, have greatly limited their translational potential. Recent discovery of CB1R negative allosteric modulators (NAMs) has renewed interest in CB1R by offering a potentially safer therapeutic avenue. To elucidate the CB1R allosteric binding motif and thereby facilitate rational drug discovery, we report the synthesis and biochemical characterization of first covalent ligands designed to bind irreversibly to the CB1R allosteric site. Either an electrophilic or a photoactivatable group was introduced at key positions of two classical CB1R NAMs: Org27569 (1) and PSNCBAM-1 (2). Among these, 20 (GAT100) emerged as the most potent NAM in functional assays, did not exhibit inverse agonism, and behaved as a robust positive allosteric modulator of binding of orthosteric agonist CP55,940. This novel covalent probe can serve as a useful tool for characterizing CB1R allosteric ligand-binding motifs.
- Kulkarni, Pushkar M.,Kulkarni, Abhijit R.,Korde, Anisha,Tichkule, Ritesh B.,Laprairie, Robert B.,Denovan-Wright, Eileen M.,Zhou, Han,Janero, David R.,Zvonok, Nikolai,Makriyannis, Alexandros,Cascio, Maria G.,Pertwee, Roger G.,Thakur, Ganesh A.
-
-
- ALLOSTERIC MODULATORS OF THE CANNIBINOID 1 RECEPTOR
-
The present technology relates to compounds and compositions of Formulas I, II, VII, and VIII, and methods using such compounds. The compounds and compositions described herein may be used in the treatment or prophylaxis of addiction, metabolic syndrome, obesity, and/or a CB1 receptor-medited disorder.
- -
-
Paragraph 0269
(2015/03/13)
-
- Theoretical investigation of the reaction of dialkylzincs with α-alkoxycarbonyl radicals. Evaluation of α-bromoacrylates as radical acceptors in radical-polar crossover processes
-
The evaluation of ethyl α-bromoacrylate as radical acceptor in dialkylzinc radical-polar cascades addresses the question of the parameters controlling homolytic substitution at zinc by α-alcoxycarbonyl radicals. Under non-degassed medium ethyl α-bromoacrylate reacts with diethylzinc to give a bromocyclopropane. The reaction involves successively radical addition, SH2 at zinc, conjugate addition of the resulting enolate to the electrophilic substrate and ring closure. Theoretical calculations were performed to get a better insight into the detailed mechanism. They highlight the impact of zinc(II) chelation on the formal SH2 step. Additional experiments performed in the presence of other electrophiles-aldehydes and acylsilanes-are discussed.
- Vibert, Fran?ois,Maury, Julien,Lingua, Hugo,Besson, Eric,Siri, Didier,Bertrand, Michèle P.,Feray, Laurence
-
p. 8991 - 9002
(2015/11/02)
-
- Indole-2-carboxamides as allosteric modulators of the cannabinoid CB 1 receptor
-
We synthesized new N-phenylethyl-1H-indole-2-carboxamides as the first SAR study of allosteric modulators of the CB1 receptor. The presence of the carboxamide functionality was required in order to obtain a stimulatory effect. The maximum stimulatory activity on CB1 was exerted by carboxamides 13 (EC50 = 50 nM) and 21 (EC50 = 90 nM) bearing a dimethylamino or piperidinyl group, respectively, at position 4 of the phenethyl moiety and a chlorine atom at position 5 of the indole.
- Piscitelli, Francesco,Ligresti, Alessia,La Regina, Giuseppe,Coluccia, Antonio,Morera, Ludovica,Allarà, Marco,Novellino, Ettore,Di Marzo, Vincenzo,Silvestri, Romano
-
supporting information; experimental part
p. 5627 - 5631
(2012/08/28)
-
- Catalytic asymmetric synthesis of trisubstituted aziridines
-
A method is described which provides for the direct asymmetric catalytic synthesis of trisubstituted aziridines from imines and diazo compounds. While unactivated imines were not reactive to α-diazo carbonyl compounds in which the diazo carbon was disubstituted, N-Boc imines react with both α-diazo esters and α-diazo-N-acyloxazolidinones to give trisubstituted aziridines with excellent diastereo- and enantioselectivities.
- Huang, Li,Wulff, William D.
-
supporting information; experimental part
p. 8892 - 8895
(2011/08/04)
-
- Coumarins as novel 17β-hydroxysteroid dehydrogenase type 3 inhibitors for potential treatment of prostate cancer
-
The synthesis and SAR studies of 3- and 4-substituted 7-hydroxycoumarins as novel 17β-HSD3 inhibitors are discussed. The most potent compounds from this series exhibited low nanomolar inhibitory activity with acceptable selectivity versus other 17β-HSD isoenzymes and nuclear receptors.
- Harada, Koichiro,Kubo, Hideki,Tomigahara, Yoshitaka,Nishioka, Kazuhiko,Takahashi, Junya,Momose, Mio,Inoue, Shinichi,Kojima, Atsuyuki
-
scheme or table
p. 272 - 275
(2010/04/06)
-
- Asymmetric synthesis of 2-substituted butane-1,4-diols by hydrogenation of homochiral fumaramide derivatives
-
Diastereoselective hydrogenation of homochiral fumaramides 1 derived from (2R)-Oppolzer's sultam was observed by analysis of the 1H NMR spectra of the succinamide mixtures with de's of 77-88%. Reduction of these succinamides using LiAlH4 gave the corresponding (2S)-butane-1,4- diols and established that addition of hydrogen takes place selectively on the re-face of fumaramides 1. The stereoselectivity was confirmed by estimating the ee's from the 19F NMR spectra of the Mosher's diesters of the diols. This methodology was applied to the synthesis of selected pyrrolidine natural products in homochiral form.
- Jawaid, Samaila,Farrugia, Louis J.,Robins, David J.
-
p. 3979 - 3988
(2007/10/03)
-
- Polylithiumorganic compounds. Part 28. The reaction of allene and alkyl substituted allenes with lithium metal
-
The reaction of allene (3a) and alkyl substituted allenes 1,2-hexadiene (3b), cyclopropylallene (3c), and vinylidene cyclopropane (3d) with lithium metal was investigated in order to access 2,3-dilithioalkenes 4a-d. These dilithioalkenes 4a-d are very reactive in polar solvents like THF and act as strong bases, either metalation of the starting allene 3a-d, the solvent, or sufficiently acidic intermediates like 8 a-d is observed. The metalation products 5-7 show follow-up reactions like 1,3-H shift to the corresponding 1-lithio-1-alkynes 8 and subsequent metalation to the dilithioalkynes 9. Additionally, lithium hydride elimination and ring-chain rearrangement (for 5c) are observed. 1,2-Hexadiene (3b) can be brought to reaction with lithium metal in the apolar solvent pentane, here the follow-up reactions are much slower due to the insolubility of 4b. In all cases the elucidation of the reaction pathways is hampered by the formation of complex mixtures of, amongst others, regio- and stereoisomeric products upon quenching with simple electrophiles.
- Maercker, Adalbert,Tatai, Andrea,Grebe, Burkhard,Girreser, Ulrich
-
-
- Reduction of Diethyl Alkylidenemalonates and Ethyl Propylideneacetoacetate with Complex Metal Hydrides
-
Reduction of diethyl alkylidenemalonates and ethyl propylideneacetoacetate with complex metal hydrides occurs at the olefinic moiety. The reduction with NaBH4 in t-BuOH-MeOH yields saturated 1,3-diols; LiAlH4 as reducing agent gives rise to corresponding saturated esters. With NaAlH4 in THF, a mixture of products is formed, which contains considerable amounts of the initial ester and low-boiling compounds; ethyl propylideneacetoacetate is also reduced to ethyl propylacetoacetate. The system NaBH4-AlBr3 in THF almost does not reduce diethyl isopropylidenemalonate, whereas under the same conditions ethyl propylideneacetoacetate is converted into ethyl 2-(1-hydroxyethyl)pentanoate.
- Kuznetsov,Alekseeva,Gren'
-
p. 396 - 399
(2007/10/03)
-
- 3-Arylcyclohex-2-en-1-ones and 2,6-Diarylcyclohex-2-en-1-ones. New Liquid Crystalline Compounds
-
The cyclohex-2-en-1-one unit flanked by one or more aryl rings is shown to provide a new system which can exhibit liquid crystal properties; these new mesogens contain a chiral centre which is both adjacent to a lateral dipolar carbonyl group and its also located in the central core.
- Brettle, Roger,Dunmur, David A.,Farrand, Louise D.,Hindley, Nigel J.,Marson, Charles M.
-
p. 1663 - 1666
(2007/10/02)
-
- SELECTIVE C-ALKYLATION OF 1,3-DICARBONYL COMPOUNDS
-
Lithium hydroxide-mediated alkylation of 1,3-dicarbonyl compounds proves to proceed with high efficiency and selectivity.
- Antonioletti, Roberto,Bonadies, Francesco,Orelli, Liliana Raquel,Scettri, Arrigo
-
p. 237 - 238
(2007/10/02)
-
- Chemo-enzymatic alkylation of active methylene compounds
-
Active methylene compounds undergo chemical condensation in water with aldehydes derived from yeast oxidation of the corresponding alcohols. Unsaturated compounds so obtained are then further reduced by yeast.
- Fuganti,Pedrocchi-Fantoni,Servi
-
p. 4195 - 4198
(2007/10/02)
-
- Stereochemical Control in Microbial Reduction. 9. Diastereoselective Reduction of 2-Alkyl-3-oxobutanoate with Bakers' Yeast
-
Bakers' yeast reduces esters of 2-alkyl-3-oxobutanoic acid (CH3COCHRCO2R'; R=methyl, ethyl, propyl, propargyl, and allyl) into the corresponding (S)-hydroxy esters with exclusive stereoselectivity, while the configuration at the 2-position of the hydroxy esters is either S (anti) or R (syn) depending on the structure of the alkoxyl group in the carboalkoxyl moeity of the ester.Oftently, the stereoselectivity with respect to the 2-position is not satisfactory.In general, the reduction of t-butyl esters exerts predominancy in the products, whereas that of 1,1-dimethylpropyl esters exerts the syn predominancy.A marked difference between these two esters in diastereoselectivity is dicussed from the view point of plausible conformations of the esters.
- Nakamura, Kaoru,Miyai, Takehiko,Nagar, Ashish,Oka, Shinzaburo,Ohno, Atsuyoshi
-
p. 1179 - 1187
(2007/10/02)
-
- Stereospecific and Stereoselective Reactions. V. Alkylation of Active Methylene Compounds by the Use of Alcohols, Diethyl Azodicarboxylate, and Triphenylphosphine
-
The reagent formed by the reaction of diethyl azodicarboxylate (1) and triphenylphosphine (2) reacted with alcohols and ethyl cyanoacetate (6) to give alkylated products in 30 - 80percent yields.When ethyl acetoacetate, 1,3-1,3-coclopentanedione, or 1,3-cyclohexanedione was used in place of 6, the corresponding O-alkylated products were obtained.The reaction of either (S)-(-)-ethyl lactate or (S)-(-)-ethyl 2-hydroxy-3-phenylpropionate with 1, 2, and 6, followed by hydrolysis resulted in the formation of (S)-(-)-methylsuccinic acid or (S)-(-)-benzylsuccinic acid.The results indicate that nearly complete inversion of the configuration takes place in the alkylation step.
- Kurihara, Toshio,Sugizaki, Masaru,Kime, Itaru,Wada, Makoto,Mitsunobu, Oyo
-
p. 2107 - 2112
(2007/10/02)
-