Design and synthesis of potent hydroxamate inhibitors with increased selectivity within the gelatinase family.

MMP-2 is a validated target for the development of anticancer agents. Herein we describe the synthesis of a new series of potent phenylalanine derived hydroxamates, with increased MMP-2/MMP-9 selectivity compared to analogous hydroxamates described previously. Docking and molecular dynamics experiments have been used to account for this selectivity, and to clarify the role of the triazole ring in the binding process.

Human protein kinase CK2 phosphorylates matrix metalloproteinase 2 and inhibits its activity.

Matrix metalloproteinase 2 (MMP-2) is involved in cancer development and is overexpressed in a variety of malignant tumors. MMP-2 activity is controlled mainly by transcription, proteolytic activation, and inhibition by endogenous inhibitors. It had previously been demonstrated that MMP-2 activity is also regulated by phosphorylation at several sites by protein kinase C.

An integrated computational and experimental approach to gaining selectivity for MMP-2 within the gelatinase subfamily.

Looking for water-soluble inhibitors of matrix metalloproteinase-2 (MMP-2 or gelatinase A), we have previously reported compound 1, a potent MMP-2 inhibitor with a promising selectivity over the structurally homologous MMP-9 (gelatinase B). Here we report the results of Molecular Dynamics (MD) simulations for both gelatinases (MMP-2 and MMP-9), and for the corresponding MMP/1 complexes, in an attempt to shed light on the observed selectivity between the two enzymes. These studies indicated a higher plasticity of MMP-2 at the S1' pocket and suggested an induced-fit effect at the "back door" of this pocket.

Dietary gallic acid and anthocyanin cytotoxicity on human fibrosarcoma HT1080 cells. A study on the mode of action.

Gallic acid and anthocyanins are abundant plant food bioactives present in many fruits and vegetables, being especially important in the composition of berries. Gallic acid has been shown to possess cytotoxic properties in several cancer cell lines and to inhibit carcinogenesis in animal models. However, its mechanism of action is not yet fully understood.

Progress towards water-soluble triazole-based selective MMP-2 inhibitors.

Water solubility is a key aspect that needs to be addressed to obtain drug-like compounds. In an effort to improve the water solubility of our recently reported nanomolar matrix metalloproteinase type 2 (MMP-2) inhibitors based on triazole-substituted hydroxamates, we synthesized a new series of α-sulfone, α-tetrahydropyran and α-piperidine, α-sulfone clicked hydroxamates and determined their inhibitory activities against both MMP-2 and MMP-9. The best results were found for 13e, a water-soluble compound that displays a low nanomolar activity against MMP-2 and is 26-fold less active against MMP-9.

Towards β-selectivity in functional estrogen receptor antagonists.

Based on the benzo[b]naphtho[1,2-d]furan and benzo[b]naphtho[1,2-d]thiophene frameworks, a series of ligands with different basic side chains (BSCs) has been synthesized and pharmacologically evaluated. Also, their binding modes have been modelled using docking techniques. It was found that the introduction of a BSC in these systems brings about a decrease of affinity for both estrogen receptors α and β in an in vitro competitive binding assay.

Potent "clicked" MMP2 inhibitors: synthesis, molecular modeling and biological exploration.

A new series of MMP2 inhibitors is described, following a fragment-based drug design approach. One fragment containing an azide group and a well known hydroxamate Zinc Binding Group in a α-sulfone, α-tetrahydropyrane scaffold, has been synthesized. Water-LOGSY, STD and competition-STD experiments indicate that this fragment binds to the active site of the enzyme.