Structure–Activity Relationship of <i>N</i>-Phenylthieno[2,3-<i>b</i>]pyridine-2-carboxamide Derivatives Designed as Forkhead Box M1 Inhibitors: The Effect of Electron-Withdrawing and Donating Substituents on the Phenyl Ring
We report synthesis, characterization, biological evaluation, and molecular-docking studies of 18 thieno[2,3-<i>b</i>]pyridines with a phenylacetamide moiety at position 2, which is disubstituted with F, Cl, Br, or I at position 4, and with electron-withdrawing and electron-donating grou...
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| Format: | Article |
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MDPI AG
2022-02-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/3/283 |
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| author | César Sebastian Huerta-García David J. Pérez Carlos A. Velázquez-Martínez Seyed Amirhossein Tabatabaei Dakhili Antonio Romo-Mancillas Rafael Castillo Alicia Hernández-Campos |
| author_facet | César Sebastian Huerta-García David J. Pérez Carlos A. Velázquez-Martínez Seyed Amirhossein Tabatabaei Dakhili Antonio Romo-Mancillas Rafael Castillo Alicia Hernández-Campos |
| author_sort | César Sebastian Huerta-García |
| collection | DOAJ |
| description | We report synthesis, characterization, biological evaluation, and molecular-docking studies of 18 thieno[2,3-<i>b</i>]pyridines with a phenylacetamide moiety at position 2, which is disubstituted with F, Cl, Br, or I at position 4, and with electron-withdrawing and electron-donating groups (-CN, -NO<sub>2</sub>, -CF<sub>3</sub>, and -CH<sub>3</sub>) at position 2, to study how the electronic properties of the substituents affected the FOXM1-inhibitory activity. Among compounds <b>1</b>–<b>18</b>, only those bearing a -CN (regardless of the halogen) decreased FOXM1 expression in a triple-negative breast cancer cell line (MDA-MB-231), as shown by Western blotting. However, only compounds <b>6</b> and <b>16</b> decreased the relative expression of FOXM1 to a level lower than 50%, and hence, we determined their anti-proliferative activity (IC<sub>50</sub>) in MDA-MB-231 cells using the MTT assay, which was comparable to that observed with <b>FDI-6</b>, in contrast to compound <b>1</b>, which was inactive according to both Western blot and MTT assays. We employed molecular docking to calculate the binding interactions of compounds <b>1</b>–<b>18</b> in the FOXM1 DNA-binding site. The results suggest a key role for residues Val296 and Leu289 in this binding. Furthermore, we used molecular electrostatic potential maps showing the effects of different substituents on the overall electron density. |
| first_indexed | 2024-03-09T13:01:53Z |
| format | Article |
| id | doaj.art-9b1f37ab697c41fdbe4b1250007097b7 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T13:01:53Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-9b1f37ab697c41fdbe4b1250007097b72023-11-30T21:53:57ZengMDPI AGPharmaceuticals1424-82472022-02-0115328310.3390/ph15030283Structure–Activity Relationship of <i>N</i>-Phenylthieno[2,3-<i>b</i>]pyridine-2-carboxamide Derivatives Designed as Forkhead Box M1 Inhibitors: The Effect of Electron-Withdrawing and Donating Substituents on the Phenyl RingCésar Sebastian Huerta-García0David J. Pérez1Carlos A. Velázquez-Martínez2Seyed Amirhossein Tabatabaei Dakhili3Antonio Romo-Mancillas4Rafael Castillo5Alicia Hernández-Campos6Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, MexicoFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6E 2E1, CanadaFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6E 2E1, CanadaFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6E 2E1, CanadaLaboratorio de Diseño Asistido por Computadora y Síntesis de Fármacos, Facultad de Química, Universidad Autónoma de Querétaro, Centro Universitario, Querétaro 76010, MexicoDepartamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, MexicoDepartamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, MexicoWe report synthesis, characterization, biological evaluation, and molecular-docking studies of 18 thieno[2,3-<i>b</i>]pyridines with a phenylacetamide moiety at position 2, which is disubstituted with F, Cl, Br, or I at position 4, and with electron-withdrawing and electron-donating groups (-CN, -NO<sub>2</sub>, -CF<sub>3</sub>, and -CH<sub>3</sub>) at position 2, to study how the electronic properties of the substituents affected the FOXM1-inhibitory activity. Among compounds <b>1</b>–<b>18</b>, only those bearing a -CN (regardless of the halogen) decreased FOXM1 expression in a triple-negative breast cancer cell line (MDA-MB-231), as shown by Western blotting. However, only compounds <b>6</b> and <b>16</b> decreased the relative expression of FOXM1 to a level lower than 50%, and hence, we determined their anti-proliferative activity (IC<sub>50</sub>) in MDA-MB-231 cells using the MTT assay, which was comparable to that observed with <b>FDI-6</b>, in contrast to compound <b>1</b>, which was inactive according to both Western blot and MTT assays. We employed molecular docking to calculate the binding interactions of compounds <b>1</b>–<b>18</b> in the FOXM1 DNA-binding site. The results suggest a key role for residues Val296 and Leu289 in this binding. Furthermore, we used molecular electrostatic potential maps showing the effects of different substituents on the overall electron density.https://www.mdpi.com/1424-8247/15/3/283thieno[2,3-<i>b</i>]pyridinesFOXM1transcription factorcancer |
| spellingShingle | César Sebastian Huerta-García David J. Pérez Carlos A. Velázquez-Martínez Seyed Amirhossein Tabatabaei Dakhili Antonio Romo-Mancillas Rafael Castillo Alicia Hernández-Campos Structure–Activity Relationship of <i>N</i>-Phenylthieno[2,3-<i>b</i>]pyridine-2-carboxamide Derivatives Designed as Forkhead Box M1 Inhibitors: The Effect of Electron-Withdrawing and Donating Substituents on the Phenyl Ring Pharmaceuticals thieno[2,3-<i>b</i>]pyridines FOXM1 transcription factor cancer |
| title | Structure–Activity Relationship of <i>N</i>-Phenylthieno[2,3-<i>b</i>]pyridine-2-carboxamide Derivatives Designed as Forkhead Box M1 Inhibitors: The Effect of Electron-Withdrawing and Donating Substituents on the Phenyl Ring |
| title_full | Structure–Activity Relationship of <i>N</i>-Phenylthieno[2,3-<i>b</i>]pyridine-2-carboxamide Derivatives Designed as Forkhead Box M1 Inhibitors: The Effect of Electron-Withdrawing and Donating Substituents on the Phenyl Ring |
| title_fullStr | Structure–Activity Relationship of <i>N</i>-Phenylthieno[2,3-<i>b</i>]pyridine-2-carboxamide Derivatives Designed as Forkhead Box M1 Inhibitors: The Effect of Electron-Withdrawing and Donating Substituents on the Phenyl Ring |
| title_full_unstemmed | Structure–Activity Relationship of <i>N</i>-Phenylthieno[2,3-<i>b</i>]pyridine-2-carboxamide Derivatives Designed as Forkhead Box M1 Inhibitors: The Effect of Electron-Withdrawing and Donating Substituents on the Phenyl Ring |
| title_short | Structure–Activity Relationship of <i>N</i>-Phenylthieno[2,3-<i>b</i>]pyridine-2-carboxamide Derivatives Designed as Forkhead Box M1 Inhibitors: The Effect of Electron-Withdrawing and Donating Substituents on the Phenyl Ring |
| title_sort | structure activity relationship of i n i phenylthieno 2 3 i b i pyridine 2 carboxamide derivatives designed as forkhead box m1 inhibitors the effect of electron withdrawing and donating substituents on the phenyl ring |
| topic | thieno[2,3-<i>b</i>]pyridines FOXM1 transcription factor cancer |
| url | https://www.mdpi.com/1424-8247/15/3/283 |
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