Fernando Hernández-Borja1, Itzel Mercado-Sánchez1, Yolanda Alcaraz2, Marco A García-Revilla1, Clarisa Villegas Gómez1, David Ordaz-Rosado3, Nancy Santos-Martínez3, Rocío García-Becerra4, Miguel A Vazquez5. 1. Departamento de Química, Universidad de Guanajuato, Guanajuato, Gto, 36050, México. 2. Departamento de Farmacia, Universidad de Guanajuato, Guanajuato, Gto, 36050, México. 3. Departamento de Biología de la Reproducción Dr. Carlos Gual Castro, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, 14080, México. 4. Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, 04510, México. 5. Departamento de Química, Universidad de Guanajuato, Guanajuato, Gto, 36050, México. mvazquez@ugto.mx.
Abstract
PURPOSE: Histone deacetylases (HDACs) play a vital role in the epigenetic regulation of gene expression due to their overexpression in several cancer forms. Therefore, these enzymes are considered as a potential anticancer drug target. Different synthetic and natural structures have been studied as HDACs inhibitors; based on available structural design information, the capping group is important for the biological activity due to the different interactions in the active site entrance. The present study aimed to analyze high substituted pyridine as a capping group, which included carrying out the synthesis, antiproliferative activity analysis, and docking studies of these novel compounds. METHODS: To achieve the synthesis of these derivatives, four reaction steps were performed, generating desired products 15a-k. Their effects on cell proliferation and gene expression of p21, cyclin D1, and p53 were determined using the sulphorhodamine B (SRB) method and quantitative real-time polymerase chain reaction. The HDAC1, HDAC6, and HDAC8 isoforms were used for performing docking experiments with our 15a-k products. RESULT: The products 15a-k were obtained in overall yields of 40-71%. Compounds 15j and 15k showed the highest antiproliferative activity in the breast (BT-474 and MDA-MB-231) and prostate (PC3) cancer cell lines at a concentration of 10 µM. These compounds increased p21 mRNA levels and decreased cyclin D1 and p53 gene expression. The docking study showed an increment in the strength, and in the number of interactions performed by the capping moiety of the tested molecules compared with SAHA; interactions displayed are mainly van der Waals, π-stacking, and hydrogen bond. CONCLUSION: The synthesized compounds 2-thiophene (15j) and 2-furan (15k) pyridine displayed cell growth inhibition, regulation of genes related to cell cycle progression in highly metastatic cancer cell lines. The molecular coupling analysis performed with HDAC1, HDAC6 and HDAC8 showed an increment in the number of interactions performed by the capping moiety and consequently in the strength of the capping group interaction.
PURPOSE: Histone deacetylases (HDACs) play a vital role in the epigenetic regulation of gene expression due to their overexpression in several cancer forms. Therefore, these enzymes are considered as a potential anticancer drug target. Different synthetic and natural structures have been studied as HDACs inhibitors; based on available structural design information, the capping group is important for the biological activity due to the different interactions in the active site entrance. The present study aimed to analyze high substituted pyridine as a capping group, which included carrying out the synthesis, antiproliferative activity analysis, and docking studies of these novel compounds. METHODS: To achieve the synthesis of these derivatives, four reaction steps were performed, generating desired products 15a-k. Their effects on cell proliferation and gene expression of p21, cyclin D1, and p53 were determined using the sulphorhodamine B (SRB) method and quantitative real-time polymerase chain reaction. The HDAC1, HDAC6, and HDAC8 isoforms were used for performing docking experiments with our 15a-k products. RESULT: The products 15a-k were obtained in overall yields of 40-71%. Compounds 15j and 15k showed the highest antiproliferative activity in the breast (BT-474 and MDA-MB-231) and prostate (PC3) cancer cell lines at a concentration of 10 µM. These compounds increased p21 mRNA levels and decreased cyclin D1 and p53 gene expression. The docking study showed an increment in the strength, and in the number of interactions performed by the capping moiety of the tested molecules compared with SAHA; interactions displayed are mainly van der Waals, π-stacking, and hydrogen bond. CONCLUSION: The synthesized compounds 2-thiophene (15j) and 2-furan (15k) pyridine displayed cell growth inhibition, regulation of genes related to cell cycle progression in highly metastatic cancer cell lines. The molecular coupling analysis performed with HDAC1, HDAC6 and HDAC8 showed an increment in the number of interactions performed by the capping moiety and consequently in the strength of the capping group interaction.
Authors: Fernando Hernández; Arturo Sánchez; Priscila Rendón-Vallejo; César Millán-Pacheco; Yolanda Alcaraz; Francisco Delgado; Miguel A Vázquez; Samuel Estrada-Soto Journal: Eur J Med Chem Date: 2013-10-14 Impact factor: 6.514
Authors: Nabanita Patra; Umasankar De; Tae Hyung Kim; Young Ju Lee; Mee Young Ahn; Nam Deuk Kim; Jung Hyun Yoon; Wahn Soo Choi; Hyung Ryong Moon; Byung Mu Lee; Hyung Sik Kim Journal: Biomed Pharmacother Date: 2013-02-16 Impact factor: 6.529