Halting Tumor Progression via Novel Non-Hydroxamate Triazole-Based Mannich Bases MMP-2/9 Inhibitors; Design, Microwave-Assisted Synthesis, and Biological Evaluation.

Fawzia Faleh Albelwi,Mai S Alsubaie,Mohamed Reda Aouad,Mohamed Teleb,Marwa M Abu-Serie,Mohamed Hagar,Yeldez El Kilany,Mohamed A Zakaria,Nadjet Rezki,Mohamed Nabil Abd Al Moaty

doi:10.3390/ijms221910324

Abstract

Matrix metalloproteinases (MMPs) are key signaling modulators in the tumor microenvironment. Among MMPs, MMP-2 and MMP-9 are receiving renewed interest as validated druggable targets for halting different tumor progression events. Over the last decades, a diverse range of MMP-2/9 inhibitors has been identified starting from the early hydroxamic acid-based peptidomimetics to the next generation non-hydroxamates. Herein, focused 1,2,4-triazole-1,2,3-triazole molecular hybrids with varying lengths and decorations, mimicking the thematic features of non-hydroxamate inhibitors, were designed and synthesized using efficient protocols and were alkylated with pharmacophoric amines to develop new Mannich bases. After full spectroscopic characterization the newly synthesized triazoles tethering Mannich bases were subjected to safety assessment via MTT assay against normal human fibroblasts, then evaluated for their potential anticancer activities against colon (Caco-2) and breast (MDA-MB 231) cancers. The relatively lengthy bis-Mannich bases 15 and 16 were safer and more potent than 5-fluorouracil with sub-micromolar IC50 and promising selectivity to the screened cancer cell lines rather than normal cells. Both compounds upregulated p53 (2–5.6-fold) and suppressed cyclin D expression (0.8–0.2-fold) in the studied cancers, and thus, induced apoptosis. 15 was superior to 16 in terms of cytotoxic activities, p53 induction, and cyclin D suppression. Mechanistically, both were efficient MMP-2/9 inhibitors with comparable potencies to the reference prototype hydroxamate-based MMP inhibitor NNGH at their anticancer IC50 concentrations. 15 (IC50 = 0.143 µM) was 4-fold more potent than NNGH against MMP-9 with promising selectivity (3.27-fold) over MMP-2, whereas 16 was comparable to NNGH. Concerning MMP-2, 16 (IC50 = 0.376 µM) was 1.2-fold more active than 15. Docking simulations predicted their possible binding modes and highlighted the possible structural determinants of MMP-2/9 inhibitory activities. Computational prediction of their physicochemical properties, ADMET, and drug-likeness metrics revealed acceptable drug-like criteria.

Highlights

Medicinal chemistry research is always focusing on modulating the tumor microenvironment, its extracellular matrix, which innately confers cancer growth and metastasis [1,2]
The synthetic approach adopted for the synthesis of the targeted 1,2,3-triazole-1,2,4triazole molecular hybrids is depicted in Schemes 1–3
When the click reaction was carried out under microwave irradiation, the click adduct 3 was obtained in 3 min and 98%

Summary

Introduction

Medicinal chemistry research is always focusing on modulating the tumor microenvironment, its extracellular matrix, which innately confers cancer growth and metastasis [1,2]. Various crucial cancer progression signaling pathways are dependent on a plethora of proteases released into the tumor extracellular matrix [3]. Matrix metalloproteinases (MMPs) are among the most studied proteases given the fact that most of them have been found dysregulated in most human malignancies [4,5,6]. Twenty-six MMPs have been characterized and correlated as a family of zinc-dependent endopeptidase [7]. All the MMPs family members share nearly the same catalytic domain structure with three a-helixes and five ß-sheets. The domain is characterized by critical active-site zinc coordinated by three histidine residues and five calcium ions

Methods

Results

Conclusion