- Correlation of Carbon-13 Substituent-Induced Chemical Shifts: meta- and para-Substituted Methyl Benzoates
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Carbon-13 NMR spectra are reported for 69 substituted methyl benzoates in deuteriochloroform or in its mixture with dimethyl sulphoxide-d6.The substituent-induced chemical shifts (SCS) of the CO carbon correlate poorly with dual substituent parameters (DSP) in all possible modifications, and for meta derivatives in particular this correlation is both overparameterized and imprecise.A much better correlation was obtained with parameters (designated Bm, Bp and Cp) derived previously by principal component analysis (PCA) from a larger set.The SCS of the CH3 carbon correlate very well with the original simple Hammett equation, and no DSP treatment is needed.The clustering of substituents is not consequential in such a large set.KEY WORDS Methyl benzoates 13C NMR Substituent effects
- Budesinsky, Milos,Exner, Otto
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- Design, synthesis, and biological studies of novel 3-benzamidobenzoic acid derivatives as farnesoid X receptor partial agonist
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Farnesoid X receptor (FXR), a bile acid-activated nuclear receptor, regulates the metabolism of bile acid and lipids as well as maintains the stability of internal environment. FXR was considered as a therapeutic target of liver disorders, such as drug-induced liver injury, fatty liver and cholestasis. The previous reported FXR partial agonist 6 was a suitable lead compound in terms of its high potent and low molecular size, while the docking study of compound 6 suggested a large unoccupied hydrophobic pocket, which might be provided more possibility of structure-activity relationship (SAR) study. In this study, we have performed comprehensive SAR and molecular modeling studies based on lead compound 6. All of these efforts resulted in the identification of a novel series of FXR partial agonists. In this series, compound 41 revealed the best activity and strong interaction with binding pocket of FXR. Moreover, compound 41 protected mice against acetaminophen-induced hepatotoxicity by the regulation of FXR-related gene expression and improving antioxidant capacity. In summary, these results suggest that compound 41 is a promising FXR partial agonist suitable for further investigation.
- Hu, Lijun,Ren, Qiang,Deng, Liming,Zhou, Zongtao,Cai, Zongyu,Wang, Bin,Li, Zheng
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supporting information
(2020/12/25)
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- Discovery of acylsulfonohydrazide-derived inhibitors of the lysine acetyltransferase, kat6a, as potent senescence-inducing anti-cancer agents
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A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 μM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 μM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.
- Priebbenow, Daniel L.,Leaver, David J.,Nguyen, Nghi,Cleary, Benjamin,Lagiakos, H. Rachel,Sanchez, Julie,Xue, Lian,Huang, Fei,Sun, Yuxin,Mujumdar, Prashant,Mudududdla, Ramesh,Varghese, Swapna,Teguh, Silvia,Charman, Susan A.,White, Karen L.,Shackleford, David M.,Katneni, Kasiram,Cuellar, Matthew,Strasser, Jessica M.,Dahlin, Jayme L.,Walters, Michael A.,Street, Ian P.,Monahan, Brendon J.,Jarman, Kate E.,Jousset Sabroux, Helene,Falk, Hendrik,Chung, Matthew C.,Hermans, Stefan J.,Downer, Natalie L.,Parker, Michael W.,Voss, Anne K.,Thomas, Tim,Baell, Jonathan B.
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p. 4655 - 4684
(2020/06/08)
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- Loss of benzene to generate an enolate anion by a site-specific double-hydrogen transfer during CID fragmentation of o-alkyl ethers of ortho-hydroxybenzoic acids
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Collision-induced dissociation of anions derived from orffco- alkyloxybenzoic acids provides a facile way of producing gaseous enolate anions. The alkyloxyphenyl anion produced after an initial loss of CO2 undergoes elimination of a benzene molecule by a double-hydrogen transfer mechanism, unique to the ortho isomer, to form an enolate anion. Deuterium labeling studies confirmed that the two hydrogen atoms transferred in the benzene loss originate from positions 1 and 2 of the alkyl chain. An initial transfer of a hydrogen atom from the C-l position forms a phenyl anion and a carbonyl compound, both of which remain closely associated as an ion/neutral complex. The complex breaks either directly to give the phenyl anion by eliminating the neutral carbonyl compound, or to form an enolate anion by transferring a hydrogen atom from the C-2 position and eliminating a benzene molecule in the process. The pronounced primary kinetic isotope effect observed when a deuterium atom is transferred from the C-l position, compared to the weak effect seen for the transfer from the C-2 position, indicates that the first transfer is the rate determining step. Quantum mechanical calculations showed that the neutral loss of benzene is a thermodynamically favorable process. Under the conditions used, only the spectra from ortho isomers showed peaks at mlz 77 for the phenyl anion and mlz 93 for the phenoxyl anion, in addition to that for the ortho-specific enolate anion. Under high collision energy, the ortho isomers also produce a peak at mlz 137 for an alkene loss. The spectra of meta and para compounds show a peak at mlz 92 for the distonic anion produced by the homolysis of the O-C bond. Moreover, a small peak at mlz 136 for a distonic anion originating from an alkyl radical loss allows the differentiation of para compounds from meta isomers. Copyright
- Attygalle, Athula B.,Bialecki, Jason B.,Nishshanka, Upul,Weisbecker, Carl S.,Ruzicka, Josef
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experimental part
p. 1224 - 1234
(2009/09/29)
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- Diels-Alder Reactions with 2H-Pyran-2-ones: Reactivity and Selectivity
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2H-Pyran-2-ones 1 react with maleic anhydride (2) in a double Diels-Alder reaction to give bicyclooct-2-ene-5,6:7,8-tetracarboxylic dianhydrides 5; the syn/syn structure was established.As expected, the reactivity of 1 was increased by electron donor substituents (OR, alkyl) and diminished by electron withdrawing substituents (CO2R).The steric influence of substituents at C-6 also decrease the reactivity of 1. - Methyl propiolate (6) and phenylacetylene (9) react with 1 to form the Diels-Alder products 7 which suffer CO2 elimination to yield methyl benzoates 8 with low and biphenyls 10 with high regioselectivity, respectively.
- Effenberger, Franz,Ziegler, Thomas
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p. 1339 - 1346
(2007/10/02)
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