Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids
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 (...
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| Format: | Article |
| Language: | English |
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MDPI AG
2018-02-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/23/2/340 |
| _version_ | 1818997054852038656 |
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| author | Blanca Colín-Lozano Samuel Estrada-Soto Fabiola Chávez-Silva Abraham Gutiérrez-Hernández Litzia Cerón-Romero Abraham Giacoman-Martínez Julio Cesar Almanza-Pérez Emanuel Hernández-Núñez Zhilong Wang Xin Xie Mario Cappiello Francesco Balestri Umberto Mura Gabriel Navarrete-Vazquez |
| author_facet | Blanca Colín-Lozano Samuel Estrada-Soto Fabiola Chávez-Silva Abraham Gutiérrez-Hernández Litzia Cerón-Romero Abraham Giacoman-Martínez Julio Cesar Almanza-Pérez Emanuel Hernández-Núñez Zhilong Wang Xin Xie Mario Cappiello Francesco Balestri Umberto Mura Gabriel Navarrete-Vazquez |
| author_sort | Blanca Colín-Lozano |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T21:39:32Z |
| format | Article |
| id | doaj.art-b0e09c58c78344f4a3cdad112d654b73 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-20T21:39:32Z |
| publishDate | 2018-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-b0e09c58c78344f4a3cdad112d654b732022-12-21T19:25:51ZengMDPI AGMolecules1420-30492018-02-0123234010.3390/molecules23020340molecules23020340Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic AcidsBlanca Colín-Lozano0Samuel Estrada-Soto1Fabiola Chávez-Silva2Abraham Gutiérrez-Hernández3Litzia Cerón-Romero4Abraham Giacoman-Martínez5Julio Cesar Almanza-Pérez6Emanuel Hernández-Núñez7Zhilong Wang8Xin Xie9Mario Cappiello10Francesco Balestri11Umberto Mura12Gabriel Navarrete-Vazquez13Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, MexicoFacultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, MexicoFacultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, MexicoFacultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, MexicoFacultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, MexicoLaboratorio de Farmacología, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana Iztapalapa, Ciudad de México 09340, MexicoLaboratorio de Farmacología, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana Iztapalapa, Ciudad de México 09340, MexicoCátedra CONACyT, Departamento de Recursos del Mar, Centro de Investigación y de Estudios Avanzados del IPN, Unidad Mérida, Yucatán 97310, MexicoCAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China, <email>endlesslily@hotmail.com</email> (Z.W.)CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China, <email>endlesslily@hotmail.com</email> (Z.W.)Dipartimento di Biologia, Unità di Biochimica, University of Pisa, 56126 Pisa, ItalyDipartimento di Biologia, Unità di Biochimica, University of Pisa, 56126 Pisa, ItalyDipartimento di Biologia, Unità di Biochimica, University of Pisa, 56126 Pisa, ItalyFacultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, MexicoWe 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.http://www.mdpi.com/1420-3049/23/2/340diabetesGPR40AKRB1PPARγ, GLUT-4 |
| spellingShingle | Blanca Colín-Lozano Samuel Estrada-Soto Fabiola Chávez-Silva Abraham Gutiérrez-Hernández Litzia Cerón-Romero Abraham Giacoman-Martínez Julio Cesar Almanza-Pérez Emanuel Hernández-Núñez Zhilong Wang Xin Xie Mario Cappiello Francesco Balestri Umberto Mura Gabriel Navarrete-Vazquez Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids Molecules diabetes GPR40 AKRB1 PPARγ, GLUT-4 |
| title | Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids |
| title_full | Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids |
| title_fullStr | Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids |
| title_full_unstemmed | Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids |
| title_short | Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids |
| title_sort | design synthesis and in combo antidiabetic bioevaluation of multitarget phenylpropanoic acids |
| topic | diabetes GPR40 AKRB1 PPARγ, GLUT-4 |
| url | http://www.mdpi.com/1420-3049/23/2/340 |
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