Modifications on the Tetrahydroquinoline Scaffold Targeting a Phenylalanine Cluster on GPER as Antiproliferative Compounds against Renal, Liver and Pancreatic Cancer Cells

Pharmaceuticals

ManuelJonathan Fragoso-Vázquez¹  JoséAntonio Gómez-Vidal²  Nuria De Pedro³  Alfonso Dueñas González⁴  HumbertoLubriel Mendoza-Figueroa⁵  José Correa-Basurto⁵  David Méndez-Luna⁵  JuanBenjamín García-Vázquez⁵  Martiniano Bello⁵  LoreleyAraceli Morelos-Garnica⁵  ItziaIrene Padilla-Martínez⁶ 

[1] Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional Prolongación de Carpio y Plan de Ayala S/N. Col. Casco de Santo Tomas, Ciudad de México 11340, Mexico;Facultad de Farmacia, Departamento de Química Farmacéutica y Orgánica, Universidad de Granada, 18071 Granada, Spain;Fundación MEDINA, Parque Tecnológico Ciencias de la Salud, Avenida del Conocimiento 34, 18016 Granada, Spain;Genomic Medicine and Environmental Toxicology, Biomedical Research Institute, UNAM, National Cancer Institute, Av San Fernando 22, Tlalpan, Mexico City 14080, Mexico;Laboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica (Laboratory for the Design and Development of New Drugs and Biotechnological Innovation), Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, s/n, Col. Casco de Santo Tomas, Ciudad de México 11340, Mexico;Laboratorio de Química Supramolecular y Nanociencias, Unidad Profesional Interdisciplinaria de Biotecnología, Instituto Politécnico Nacional, Av. Acueducto s/n., Barrio La Laguna Ticomán, Ciudad de México 07340, Mexico;

关键词: GPER;    docking;    molecular dynamics simulations;    Suzuki–Miyaura cross-coupling;    tetrahydroquinoline scaffold;    antiproliferative;   

DOI  :  10.3390/ph14010049

来源: DOAJ

【 摘 要 】

The implementation of chemo- and bioinformatics tools is a crucial step in the design of structure-based drugs, enabling the identification of more specific and effective molecules against cancer without side effects. In this study, three new compounds were designed and synthesized with suitable absorption, distribution, metabolism, excretion and toxicity (ADME-tox) properties and high affinity for the G protein-coupled estrogen receptor (GPER) binding site by in silico methods, which correlated with the growth inhibitory activity tested in a cluster of cancer cell lines. Docking and molecular dynamics (MD) simulations accompanied by a molecular mechanics/generalized Born surface area (MMGBSA) approach yielded the binding modes and energetic features of the proposed compounds on GPER. These in silico studies showed that the compounds reached the GPER binding site, establishing interactions with a phenylalanine cluster (F206, F208 and F278) required for GPER molecular recognition of its agonist and antagonist ligands. Finally, a 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay showed growth inhibitory activity of compounds 4, 5 and 7 in three different cancer cell lines—MIA Paca-2, RCC4-VA and Hep G2—at micromolar concentrations. These new molecules with specific chemical modifications of the GPER pharmacophore open up the possibility of generating new compounds capable of reaching the GPER binding site with potential growth inhibitory activities against nonconventional GPER cell models.

【 授权许可】

Unknown