Synthesis, crystal structure and effect of indeno[1,2-b]indole derivatives on prostate cancer in vitro. Potential effect against MMP-9

Gricela Lobo; Melina Monasterios; Juan Rodrigues; Neira Gamboa; Mario V Capparelli; Javier Martínez-Cuevas; Michael Lein; Klaus Jung; Claudia Abramjuk; Jaime Charris

doi:10.1016/j.ejmech.2015.04.023

Synthesis, crystal structure and effect of indeno[1,2-b]indole derivatives on prostate cancer in vitro. Potential effect against MMP-9

Eur J Med Chem. 2015:96:281-95. doi: 10.1016/j.ejmech.2015.04.023. Epub 2015 Apr 10.

Authors

Affiliations

¹ Laboratorio de Síntesis Orgánica, Unidad de Bioquímica, Facultad de Farmacia, Universidad Central de Venezuela, Apartado 47206, Los Chaguaramos, 1041-A Caracas, Venezuela.
² Unidad de Estructura Molecular, Fundación Instituto de Estudios Avanzados (IDEA), Apartado 17606, Caracas 1015-A, Venezuela.
³ Servicio de Difracción de Rayos X, Universidad Autónoma de Barcelona, 08193 Barcelona, Spain.
⁴ Department of Urology, University Hospital Charité, Campus Mitte, Schumannstrasse 20/21, 10117 Berlin, Germany; Berlin Institute for Urologic Research, Schumannstrasse 22/21, 10117 Berlin, Germany.
⁵ Department of Urology, University Hospital Charité, Campus Mitte, Schumannstrasse 20/21, 10117 Berlin, Germany; Department of Experimental Medicine (FEM), University Hospital Charité, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany.
⁶ Laboratorio de Síntesis Orgánica, Unidad de Bioquímica, Facultad de Farmacia, Universidad Central de Venezuela, Apartado 47206, Los Chaguaramos, 1041-A Caracas, Venezuela. Electronic address: jaime.charris@ucv.ve.

PMID: 25899333
DOI: 10.1016/j.ejmech.2015.04.023

Abstract

A highly regiospecific synthesis of a series of indenoindoles is reported, together with X-ray studies and their activity against human prostate cancer cells PC-3 and LNCaP in vitro. The most effective compound 7,7-dimethyl-5-[(3,4-dichlorophenyl)]-(4bRS,9bRS)-dihydroxy-4b,5,6,7,8,9bhexahydro-indeno[1,2-b]indole-9,10-dione 7q reduced the viability in both cell lines in a time and dose-dependent manner. Inhibitory effects were also observed on the adhesion, migration, and invasion of the prostate cancer cells as well as on clonogenic possibly by inhibition of MMP-9 activity. Molecular docking of 7q and 6k into MMP-9 human active site was also performed to determine the probable binding mode.

Keywords: Cancer; Crystal; Indeno; MMP-9; Prostate; Regiospecif.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Cells, Cultured
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Indenes / chemical synthesis
Indenes / chemistry
Indenes / pharmacology*
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Male
Matrix Metalloproteinase 9 / metabolism*
Matrix Metalloproteinase Inhibitors / chemical synthesis
Matrix Metalloproteinase Inhibitors / chemistry
Matrix Metalloproteinase Inhibitors / pharmacology*
Molecular Docking Simulation
Molecular Structure
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / enzymology*
Prostatic Neoplasms / pathology
Structure-Activity Relationship

Substances

Antineoplastic Agents
Indenes
Indoles
Matrix Metalloproteinase Inhibitors
indeno(1,2-b)indole
Matrix Metalloproteinase 9