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

Abstract

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.

Inhibition of MMPs and ADAM/ADAMTS

“…The MMP superfamily is comprised of the classical types of MMPs. These include MMP-1 (collagenase-1), MMP-8 (neutrophil collagenase), MMP-13 (collagenase-3), and gelatinases (MMP-2) [29] and (MMP-9), the stromelysins exemplified by MMP-3, MMP-10, MMP-11, the matrilysins (MMP-7/PUMP-1 and MMP-26), the membrane-type MMPs (MMP-14, MMP-17, MMP-24/−25), [30][31][32], the ADAMs, also referred to as adamlysins, including, ADAM-2, −7, −−10, −11, −17, −18, −19, −22, −23, −29, −32, 33 [33][34][35][36], ADAM soluble variants, 9-S, 12-S, 28-S and DEC-1 [31] and the ADAMTS, most notably, ADAMTS-2, −3, 4, −5, −7, −10, −12, −13, −17, −20, SL-2 and SL-4 [37][38][39][40] As such, these enzymes have been of considerable interest for developing agents that curtail MMP gene expression and/or MMP production using classical medicinal chemistry paradigms designed to inhibit enzymes [41][42][43][44][45][46][47], blocking signal transduction pathways, initiated by TNF-α [48][49][50] after anti-TNF-α receptor blockade in Crohn's patients [51] and in experimentally-induced arthritis with Type II collagen [52], IL-17 [53], and IL-6 [54,55], by exploiting epigenetic mechanisms [56], by preventing enzyme-protein interactions [57], and by employing microRNA (miRNA) technology [58,59] or small interfering RNAs [60] or by using viral vectors [61] or glycosylated and non-glycosylate substrates [62].…”

A matrix metalloproteinase inhibitor enhances anti-cytotoxic T lymphocyte antigen-4 antibody immunotherapy in breast cancer by reprogramming the tumor microenvironment

“…Vascular remodeling can improve the abnormal state of tumor blood vessels, enhance vascular perfusion, and increase drug delivery. In addition to MMP-14, MMP-2 plays an important role in promoting tumor vascular remodeling ( 45 ). Moreover, MMPI has been shown to enhance the therapeutic effects of chemotherapy drugs on tumors by promoting remodeling of the tumor vasculature and increasing drug delivery ( 46 ).…”

Transition metal-free one-pot synthesis of nitrogen-containing heterocycles

“…Aziridines represent a key structural motif in a large number of compounds used as pharmaceuticals, agrochemicals, and dyes [20]. They are also useful building blocks in the synthesis of nitrogen-containing compounds due to their highly regio-and stereo-selective ring-opening reactions with nucleophiles [21].…”