- Design, synthesis and in combo antidiabetic bioevaluation of multitarget phenylpropanoic acids
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We have synthesized a small series of five 3-[4-arylmethoxy)phenyl]propanoic acids employing an easy and short synthetic pathway. The compounds were tested in vitro against a set of four protein targets identified as key elements in diabetes: G protein-coupled receptor 40 (GPR40), aldose reductase (AKR1B1), peroxisome proliferator-activated receptor gama (PPARγ) and solute carrier family 2 (facilitated glucose transporter), member 4 (GLUT-4). Compound 1 displayed an EC50 value of 0.075 μM against GPR40 and was an AKR1B1 inhibitor, showing IC50 = 7.4 μM. Compounds 2 and 3 act as slightly AKR1B1 inhibitors, potent GPR40 agonists and showed an increase of 2 to 4-times in the mRNA expression of PPARγ, as well as the GLUT-4 levels. Docking studies were conducted in order to explain the polypharmacological mode of action and the interaction binding mode of the most active molecules on these targets, showing several coincidences with co-crystal ligands. Compounds 1–3 were tested in vivo at an explorative 100 mg/kg dose, being 2 and 3 orally actives, reducing glucose levels in a non-insulin-dependent diabetes mice model. Compounds 2 and 3 displayed robust in vitro potency and in vivo efficacy, and could be considered as promising multitarget antidiabetic candidates. This is the first report of a single molecule with these four polypharmacological target action.
- Colín-Lozano, Blanca,Estrada-Soto, Samuel,Chávez-Silva, Fabiola,Gutiérrez-Hernández, Abraham,Cerón-Romero, Litzia,Giacoman-Martínez, Abraham,Almanza-Pérez, Julio Cesar,Hernández-Nú?ez, Emanuel,Wang, Zhilong,Xie, Xin,Cappiello, Mario,Balestri, Francesco,Mura, Umberto,Navarrete-Vazquez, Gabriel
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- Ruthenium-catalyzed intramolecular arene C(sp2)-H amidation for synthesis of 3,4-dihydroquinolin-2(1 H)-ones
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We report the [Ru(p-cymene)(l-proline)Cl] ([Ru1])-catalyzed cyclization of 1,4,2-dioxazol-5-ones to form dihydroquinoline-2-ones in excellent yields with excellent regioselectivity via a formal intramolecular arene C(sp2)-H amidation. The reactions of the 2- and 4-substituted aryl dioxazolones proceeds initially through spirolactamization via electrophilic amidation at the arene site, which is para or ortho to the substituent. A Hammett correlation study showed that the spirolactamization is likely to occur by electrophilic nitrenoid attack at the arene, which is characterized by a negative ρ value of -0.73.
- Au, Chi-Ming,Ling, Cho-Hon,Sun, Wenlong,Yu, Wing-Yiu
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supporting information
p. 3310 - 3314
(2021/05/29)
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- One-Pot, Tandem Wittig Hydrogenation: Formal C(sp3)-C(sp3) Bond Formation with Extensive Scope
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A one-pot, tandem Wittig hydrogenation of aldehydes with stabilized ylides is reported, representing a formal C(sp3)-C(sp3) bond construction. The tandem reaction operates under mild conditions, is high yielding, and is broad in scope. Chemoselectivity for olefin reduction is observed, and the methodology is demonstrated in the synthesis of lapatinib analogues and a formal synthesis of (±)-cuspareine. Early insights suggest that the chemoselectivity observed in the reduction step is due to partial poisoning of the catalyst, after step one, thus adding to the power of the one-pot procedure.
- Devlin, Rory,Jones, David J.,Mcglacken, Gerard P.
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supporting information
p. 5223 - 5228
(2020/07/14)
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- Ipomoeassin F Binds Sec61α to Inhibit Protein Translocation
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Ipomoeassin F is a potent natural cytotoxin that inhibits growth of many tumor cell lines with single-digit nanomolar potency. However, its biological and pharmacological properties have remained largely unexplored. Building upon our earlier achievements
- Zong, Guanghui,Hu, Zhijian,O'Keefe, Sarah,Tranter, Dale,Iannotti, Michael J.,Baron, Ludivine,Hall, Belinda,Corfield, Katherine,Paatero, Anja O.,Henderson, Mark J.,Roboti, Peristera,Zhou, Jianhong,Sun, Xianwei,Govindarajan, Mugunthan,Rohde, Jason M.,Blanchard, Nicolas,Simmonds, Rachel,Inglese, James,Du, Yuchun,Demangel, Caroline,High, Stephen,Paavilainen, Ville O.,Shi, Wei Q.
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p. 8450 - 8461
(2019/06/04)
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- Exploration of phenylpropanoic acids as agonists of the free fatty acid receptor 4 (FFA4): Identification of an orally efficacious FFA4 agonist
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The long chain free fatty acid receptor 4 (FFA4/GPR120) has recently been recognized as lipid sensor playing important roles in nutrient sensing and inflammation and thus holds potential as a therapeutic target for type 2 diabetes and metabolic syndrome. To explore the effects of stimulating this receptor in animal models of metabolic disease, we initiated work to identify agonists with appropriate pharmacokinetic properties to support progression into in vivo studies. Extensive SAR studies of a series of phenylpropanoic acids led to the identification of compound 29, a FFA4 agonist which lowers plasma glucose in two preclinical models of type 2 diabetes.
- Sparks, Steven M.,Aquino, Christopher,Banker, Pierette,Collins, Jon L.,Cowan, David,Diaz, Caroline,Dock, Steven T.,Hertzog, Donald L.,Liang, Xi,Swiger, Erin D.,Yuen, Josephine,Chen, Grace,Jayawickreme, Channa,Moncol, David,Nystrom, Christopher,Rash, Vincent,Rimele, Thomas,Roller, Shane,Ross, Sean
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p. 1278 - 1283
(2017/06/19)
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- Synthesis of tetrahydropyranyl diarylheptanoids from Dioscorea villosa
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Concise syntheses of four tetrahydropyranyl diarylheptanoids isolated from Dioscorea villosa have been described. The key features include Prins cyclization to construct the tetrahydropyran cores, Keck asymmetric allylation, and Mitsunobu inversion. Optimization of the Prins cyclization conditions in order to minimize racemization has been described. Our syntheses also confirmed the absolute stereochemistry of the natural products.
- Kantee, Kawalee,Rukachaisirikul, Vatcharin,Tadpetch, Kwanruthai
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supporting information
p. 3505 - 3509
(2016/07/15)
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- Palladium-Catalyzed Directed para C?H Functionalization of Phenols
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Various practical methods for the selective C?H functionalization of the ortho and recently also of the meta position of an arene have already been developed. Following our recent development of the directing-group-assisted para C?H functionalization of toluene derivatives, we herein report the first remote para C?H functionalization of phenol derivatives by using a recyclable silicon-containing biphenyl-based template. The effectiveness of this strategy was illustrated with different synthetic elaborations and by the synthesis of various phenol-based natural products.
- Patra, Tuhin,Bag, Sukdev,Kancherla, Rajesh,Mondal, Anirban,Dey, Aniruddha,Pimparkar, Sandeep,Agasti, Soumitra,Modak, Atanu,Maiti, Debabrata
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supporting information
p. 7751 - 7755
(2016/07/07)
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- REDUCTION OF C-0 BONDS BY CATALYTIC TRANSFER HYDROGENOLYSIS
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The present invention relates to a method of reducing a C-O bond to the corresponding C-H bond in a substrate which could be a benzylic alcohol, allylic alcohol, ester,or ether or an ether bond beta to a hydroxyl group or alpha to a carbonyl group.
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Page/Page column 14-15
(2012/09/22)
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- AMG 837: A potent, orally bioavailable GPR40 agonist
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The discovery that certain long chain fatty acids potentiate glucose stimulated insulin secretion through the previously orphan receptor GPR40 sparked interest in GPR40 agonists as potential antidiabetic agents. Optimization of a series of β-substituted p
- Houze, Jonathan B.,Zhu, Liusheng,Sun, Ying,Akerman, Michelle,Qiu, Wei,Zhang, Alex J.,Sharma, Rajiv,Schmitt, Michael,Wang, Yingcai,Liu, Jiwen,Liu, Jinqian,Medina, Julio C.,Reagan, Jeff D.,Luo, Jian,Tonn, George,Zhang, Jane,Lu, Jenny Ying-Lin,Chen, Michael,Lopez, Edwin,Nguyen, Kathy,Yang, Li,Tang, Liang,Tian, Hui,Shuttleworth, Steven J.,Lin, Daniel C.-H.
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p. 1267 - 1270
(2012/03/26)
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- Polymerizable liquid crystal composition and polymer thereof
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A polymerizable liquid crystal composition containing compounds represented by the formula (1-1) and the formula (1-2), compounds represented by the formula (2-1) and the formula (2-2), and a compound represented by the formula (3-1): the polymerizabl
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- Novel compounds, their preparation and use
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Novel compounds of the general formula (I), the use of these compounds as pharmaceutical compositions, pharmaceutical compositions comprising the compounds and methods of treatment employing these compounds and compositions. The present compounds may be u
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- Studies on antihyperlipidemic agents. II. Synthesis and biological activities of 2-chloro-3-arylpropionic acids
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α-Substituted-β-arylpropionic acid derivatives were prepared and examined for hypolipidemic activity. The structure-activity relationship study showed that a chloro substituent at the α-position and an aryloxy or aralkyloxy substituent on the β-aryl moiet
- Kawamatsu,Asakawa,Saraie,Imamiya,Nishikawa,Hamuro
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p. 585 - 589
(2007/10/02)
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