Synthesis and In Vitro Evaluation of Tetrahydroquinoline Derivatives as Antiproliferative Compounds of Breast Cancer via Targeting the GPER

Author(s):

Oscar J. Zacarías-Lara, David Méndez-Luna, Gustavo Martínez-Ruíz, José R. García-Sanchéz, Manuel J. Fragoso-Vázquez*, Martiniano Bello, Elvia Becerra-Martínez, Juan B. García-Vázquez and José Correa-Basurto*   Pages 760 - 771 ( 12 )

Abstract:

<P>Background: Some reports have demonstrated the role of the G Protein-coupled Estrogen Receptor (GPER) in growth and proliferation of breast cancer cells. </P><P> Objective: In an effort to develop new therapeutic strategies against breast cancer, we employed an in silico study to explore the binding modes of tetrahydroquinoline 2 and 4 to be compared with the reported ligands G1 and G1PABA. </P><P> Methods: This study aimed to design and filter ligands by in silico studies determining their Lipinski&#039;s rule, toxicity and binding properties with GPER to achieve experimental assays as anti-proliferative compounds of breast cancer cell lines. </P><P> Results: In silico studies suggest as promissory two tetrahydroquinoline 2 and 4 which contain a carboxyl group instead of the acetyl group (as is needed for G1 synthesis), which add low (2) and high hindrance (4) chemical moieties to explore the polar, hydrophobic and hindrance effects. Docking and molecular dynamics simulations of the target compounds were performed with GPER to explore their binding mode and free energy values. In addition, the target small molecules were synthesized and assayed in vitro using breast cancer cells (MCF-7 and MDA-MB-231). Experimental assays showed that compound 2 decreased cell proliferation, showing IC50 values of 50&#181;M and 25&#181;M after 72h of treatment of MCF-7 and MDA-MB-231 cell lines, respectively. Importantly, compound 2 showed a similar inhibitory effect on proliferation as G1 compound in MDA-MB-231 cells, suggesting that both ligands reach the GPER-binding site in a similar way, as was demonstrated through in silico studies. </P><P> Conclusion: A concentration-dependent inhibition of cell proliferation occurred with compound 2 in the two cell lines regardless of GPER.</P>

Keywords:

Tetrahydroquinoline derivatives, GPER, breast cancer, virtual screening, molecular docking, cell growth inhibitor, antiproliferation, MCF-7, MDA-MB-231.

Affiliation:

Laboratorio de Diseno y Desarrollo de Nuevos Farmacos e Innovacion Biotecnologica (Laboratory for the Design and Development of New Drugs and Biotechnological Innovation), Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron, 11340 Mexico, CDMX, Laboratorio de Diseno y Desarrollo de Nuevos Farmacos e Innovacion Biotecnologica (Laboratory for the Design and Development of New Drugs and Biotechnological Innovation), Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron, 11340 Mexico, CDMX, Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de Mexico, Federico Gomez, Laboratorio de Oncologia Molecular y Estres Oxidativo, Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron, 11340 Mexico, CDMX, Laboratorio de Diseno y Desarrollo de Nuevos Farmacos e Innovacion Biotecnologica (Laboratory for the Design and Development of New Drugs and Biotechnological Innovation), Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron, 11340 Mexico, CDMX, Laboratorio de Diseno y Desarrollo de Nuevos Farmacos e Innovacion Biotecnologica (Laboratory for the Design and Development of New Drugs and Biotechnological Innovation), Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron, 11340 Mexico, CDMX, Laboratorio de RMN, Centro de Nanociencias y Micro y Nanotecnologias, Instituto Politecnico Nacional, Calle Luis Enrique Erro s/n, Unidad Profesional Adolfo Lopez Mateos, Gustavo A, Madero, 07738 Mexico, Ciudad de Mexico, Laboratorio de Diseno y Desarrollo de Nuevos Farmacos e Innovacion Biotecnologica (Laboratory for the Design and Development of New Drugs and Biotechnological Innovation), Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron, 11340 Mexico, CDMX, Laboratorio de Diseno y Desarrollo de Nuevos Farmacos e Innovacion Biotecnologica (Laboratory for the Design and Development of New Drugs and Biotechnological Innovation), Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron, 11340 Mexico, CDMX

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