Macrociclos contendo piridina inibem as MMP- 2/9 e apresentam efeitos distintos na migração e invasão celular em modelos 2D e 3D de cancro de mama

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Macrociclos contendo piridina inibem as MMP- 2/9 e apresentam efeitos distintos na migração e invasão celular em modelos 2D e 3D de cancro de mama

Segunda, 06.01.2020

O papel das metaloproteinases de matriz (MMPs) na migração e invasão de células de cancro tem sido correlacionado com a agressividade tumoral, destacando-se entre outras, as MMP-2/9. Neste trabalho, dois macrociclos contendo grupos piridina ([15]pyN5 e [16]pyN5) foram sintetizados, caracterizados quimicamente e testados como potenciais inibidores destas enzimas no âmbito da terapêutica do cancro de mama, utilizando modelos celulares 2D e 3D desenvolvidos no nosso laboratório. Em geral, [15]pyN5 e [16]pyN5 comprometeram a migração de células tumorais e revelaram ser potenciais inibidores de MMP-2 e 9, tendo sido demonstrada também a importância do recurso a modelos fisiologicamente mais relevantes no contexto de estudos in vitro.

 

Autores e Afiliações:

Susana Proença1,2,† Bernardo Antunes1,† Rita C. Guedes1 Filipa Ramilo-Gomes1,3 M. Fátima Cabral1 Judite Costa1 Ana S. Fernandes4 Matilde Castro1 Nuno G. Oliveira1 and Joana P. Miranda1,†*

1 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal

2 Institute for Risk Assessment Sciences, Utrecht University, P.O. Box 80177, 3508TD Utrecht, The Netherlands

3 Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisbon, Portugal

4 CBIOS, University Lusófona, 1749-024 Lisbon, Portugal

These authors contributed equally to this work

 

Abstract:

The role of metalloproteinases (MMPs) on the migration and invasion of cancer cells has been correlated with tumor aggressiveness, namely with the up-regulation of MMP-2 and 9. Herein, two pyridine-containing macrocyclic compounds, [15]pyN5 and [16]pyN5, were synthesized, chemically characterized and evaluated as potential MMP inhibitors for breast cancer therapy using 3D and 2D cellular models. [15]pyN5 and [16]pyN5 (5-20 µM) showed a marked inhibition of MMPs activity (100% at concentrations ≥ 7.5 μM) when compared to ARP-100, a known MMP inhibitor. The inhibitory activity of [15]pyN5 and [16]pyN5 was further supported through in silico docking studies using Goldscore and ChemPLP scoring functions. Moreover, although no significant differences were observed in the invasion studies in the presence of all MMPs inhibitors, cell migration was significantly inhibited by both pyridine-containing macrocycles at concentrations above 5 μM in 2D cells (p < 0.05). In spheroids, the same effect was observed, but only with [16]pyN5 at 20 μM and ARP-100 at 40 μM. Overall, [15]pyN5 and [16]pyN5 led to impaired breast cancer cell migration and revealed to be potential inhibitors of MMPs 2 and 9.

 

Revista: International Journal of Molecular Sciences

 

Link: https://www.mdpi.com/1422-0067/20/20/5109