Discovery of aziridine-triazole conjugates as selective MMP-2 inhibitors

Kreituss, Imants; Rozenberga, Elīna; Zemītis, Jānis; Trapencieris, Pēteris; Romanchikova, Nadezhda; Turks, Māris

doi:10.1007/s10593-013-1351-9

Cited by 9 publications

(6 citation statements)

References 27 publications

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Section: Matrix Metalloprotease-2 (Mmp-2)mentioning

confidence: 99%

“…According to Kreituss et al, a series of (aryl triazolyl) methyl aziridines compounds was synthesized and evaluated for their selective inhibition of MMP-2 [ 102 ]. Compound 18 is made up of a hydrophilic aziridine, a lipophilic part, and a triazole fragment that connects the two [ 102 ]. Among all the synthesized inhibitors that were tested against melanoma and PT-67 fibroblast cell lines, compounds 19 and 20 showed the best inhibition of MMP-2, with a concentration of 20 and 10 µM, respectively [ 102 ].…”

Section: Matrix Metalloprotease-2 (Mmp-2)mentioning

confidence: 99%

“…Compound 18 is made up of a hydrophilic aziridine, a lipophilic part, and a triazole fragment that connects the two [ 102 ]. Among all the synthesized inhibitors that were tested against melanoma and PT-67 fibroblast cell lines, compounds 19 and 20 showed the best inhibition of MMP-2, with a concentration of 20 and 10 µM, respectively [ 102 ].…”

Section: Matrix Metalloprotease-2 (Mmp-2)mentioning

confidence: 99%

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Matrix Metalloproteinases Inhibitors in Cancer Treatment: An Updated Review (2013–2023)

Almutairi,

Kalloush,

Manoon

et al. 2023

Molecules

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Matrix metalloproteinases (MMPs) are identifiable members of proteolytic enzymes that can degrade a wide range of proteins in the extracellular matrix (ECM). MMPs can be categorized into six groups based on their substrate specificity and structural differences: collagenases, gelatinases, stromelysins, matrilysins, metalloelastase, and membrane-type MMPs. MMPs have been linked to a wide variety of biological processes, such as cell transformation and carcinogenesis. Over time, MMPs have been evaluated for their role in cancer progression, migration, and metastasis. Accordingly, various MMPs have become attractive therapeutic targets for anticancer drug development. The first generations of broad-spectrum MMP inhibitors displayed effective inhibitory activities but failed in clinical trials due to poor selectivity. Thanks to the evolution of X-ray crystallography, NMR analysis, and homology modeling studies, it has been possible to characterize the active sites of various MMPs and, consequently, to develop more selective, second-generation MMP inhibitors. In this review, we summarize the computational and synthesis approaches used in the development of MMP inhibitors and their evaluation as potential anticancer agents.

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Section: Matrix Metalloprotease-2 (Mmp-2)mentioning

confidence: 99%

Section: Matrix Metalloprotease-2 (Mmp-2)mentioning

confidence: 99%

Section: Matrix Metalloprotease-2 (Mmp-2)mentioning

confidence: 99%

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Matrix Metalloproteinases Inhibitors in Cancer Treatment: An Updated Review (2013–2023)

Almutairi,

Kalloush,

Manoon

et al. 2023

Molecules

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“…The design protocol utilized the isomeric triazoles as privileged motifs of many reported lead MMP-2/9 inhibitors [ 49 , 50 , 51 , 52 , 53 , 54 , 55 ] ( Figure 1 ). Besides its unique chemical and biological properties, 1,2,3-triazole was rationalized as a non-classical amide isostere [ 56 ].…”

Section: Design Rationalementioning

confidence: 99%

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

Albelwi

Teleb

Abu‐Serie

et al. 2021

IJMS

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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.

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“…We have recently discovered a novel type of selective MMP-2 inhibitors 30 with general structure 1, presented in Figure 1. Their structures combine an aziridine moiety and a lipophilic side chain via triazole linker.…”

Section: Synthesis Of a Novel Class Of Mmp-2 Inhibitorsmentioning

confidence: 99%

A novel matrix metalloproteinase-2 inhibitor triazolylmethyl aziridine reduces melanoma cell invasion, angiogenesis and targets ERK1/2 phosphorylation

Romanchikova

Trapencieris

Zemītis

et al. 2013

Journal of Enzyme Inhibition and Medicinal Chemistry

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A novel matrix metalloproteinase-2 (MMP-2) inhibitor JaZ-30, which belongs to the class of C(2)-monosubstituted aziridine -aryl-1,2,3-triazole conjugates, was developed. MTT and crystal violet assays were used to determine cytotoxicity-IC(50) values of compound JaZ-30 on melanoma cell line B16 4A5. Our study proves the anti-cancer properties of JaZ-30 with a wide spectrum of activities. JaZ-30 was revealed as selective inhibitor of matrix metalloproteinase-2. JaZ-30-mediated decrease of Vascular Endothelial Growth Factor (VEGF) secretion results in inhibition of angiogenesis, performed with the human umbilical vein endothelial cell line (HUVEC-2) on Matrigel. A novel inhibitor decreases invasive properties of melanoma cells measured in Matrigel chambers assay. JaZ-30 downregulates phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in melanoma cells stimulated by phorbol-12-myristate-13-acetate (PMA). Our findings propose a novel MMP-2 inhibitor JaZ-30 as an attractive potential agent for melanoma treatment.

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Discovery of aziridine-triazole conjugates as selective MMP-2 inhibitors

Cited by 9 publications

References 27 publications

Matrix Metalloproteinases Inhibitors in Cancer Treatment: An Updated Review (2013–2023)

Matrix Metalloproteinases Inhibitors in Cancer Treatment: An Updated Review (2013–2023)

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

A novel matrix metalloproteinase-2 inhibitor triazolylmethyl aziridine reduces melanoma cell invasion, angiogenesis and targets ERK1/2 phosphorylation

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