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Open AccessArticle

Pyridine-Containing Macrocycles Display MMP-2/9 Inhibitory Activity and Distinct Effects on Migration and Invasion of 2D and 3D Breast Cancer Models

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
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(20), 5109; https://doi.org/10.3390/ijms20205109
Received: 13 September 2019 / Revised: 1 October 2019 / Accepted: 9 October 2019 / Published: 15 October 2019
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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. View Full-Text
Keywords: pyridine-containing macrocyclic; molecular docking studies; 3D models; breast cancer; MMP inhibitors; migration and invasion pyridine-containing macrocyclic; molecular docking studies; 3D models; breast cancer; MMP inhibitors; migration and invasion
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Proença, S.; Antunes, B.; Guedes, R.C.; Ramilo-Gomes, F.; Cabral, M.F.; Costa, J.; Fernandes, A.S.; Castro, M.; Oliveira, N.G.; Miranda, J.P. Pyridine-Containing Macrocycles Display MMP-2/9 Inhibitory Activity and Distinct Effects on Migration and Invasion of 2D and 3D Breast Cancer Models. Int. J. Mol. Sci. 2019, 20, 5109.

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