Synthesis and Biological Evaluation of 2-Heteroarylthioalkanoic Acid Analogues of Clofibric Acid as Peroxisome Proliferator-Activated Receptor alpha Agonists

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Seeking for Non-Zinc-Binding MMP-2 Inhibitors: Synthesis, Biological Evaluation and Molecular Modelling Studies

Matrix metalloproteinases (MMPs) are an important family of zinc-containing enzymes with a central role in many physiological and pathological processes. Although several MMP inhibitors have been synthesized over the years, none reached the market because of off-target effects, due to the presence of a zinc binding group in the inhibitor structure. To overcome this problem non-zinc-binding inhibitors (NZIs) have been recently designed. In a previous article, a virtual screening campaign identified some hydroxynaphtyridine and hydroxyquinoline as MMP-2 non-zinc-binding inhibitors. In the present work, simplified analogues of previously-identified hits have been synthesized and tested in enzyme inhibition assays. Docking and molecular dynamics studies were carried out to rationalize the activity data

Anticancer Inhibitors

Cancer is a multifactorial disorder caused by several aberrations in gene expression that generate a homeostatic imbalance between cell division and death [...

A Review of Strategies for the Development of Alkyl Prolines in Drug Discovery

Among all natural \u3b1-amino acids, proline represents a singularity. Due to the presence of the pyrrolidine ring, proline includes a secondary amino group, that does not contain a hydrogen atom when involved in an amide bond. A variety of synthetic analogues have been developed in the last years, based on ring substitutions, incorporation of heteroatoms into the ring, expansion or contraction of the pyrrolidine ring. The present review focuses on chemical synthesis of mono substituted derivatives of proline containing leucine, isoleucine, valine side chains, and other alkyls, including the contribution of literature from 2004 to 2015 or earlier where necessary

PPAR Ligands Induce Antiviral Effects Targeting Perturbed Lipid Metabolism during SARS-CoV-2, HCV, and HCMV Infection

The manipulation of host metabolisms by viral infections has been demonstrated by several studies, with a marked influence on the synthesis and utilization of glucose, nucleotides, fatty acids, and amino acids. The ability of virus to perturb the metabolic status of the infected organism is directly linked to the outcome of the viral infection. A great deal of research in recent years has been focusing on these metabolic aspects, pointing at modifications induced by virus, and suggesting novel strategies to counteract the perturbed host metabolism. In this review, our attention is turned on PPARs, nuclear receptors controlling multiple metabolic actions, and on the effects played by PPAR ligands during viral infections. The role of PPAR agonists and antagonists during SARS-CoV-2, HCV, and HCMV infections will be analyzed

Anticancer Activity of Natural Products and Related Compounds

Nature has always been a precious source of bioactive molecules which are used for the treatment of various diseases [...

Synthetic Strategies to Serine-Proline Chimeras: An Overview

This review focuses on synthetic strategies developed to obtain serine-proline chimeras. The conformational properties of proline, combined with functional groups typical of aminoacid side chains, represent an interesting approach to stabilize peptide secondary structures such as -turns. Different chemical pathways to synthesize 3-, 4-, and 5-hydroxyprolines, considered proline chimeras of aminoacid serine, will be presented and discussed

HDAC Inhibitors for the Therapy of Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) is an urgent as well as huge medical challenge, which is associated with poor prognosis and responsiveness to chemotherapies. Since epigenetic changes are highly implicated in TNBC tumorigenesis and development, inhibitors of histone deacetylases (HDACIs) could represent a promising therapeutic strategy. Although clinical trials involving single HDACIs showed disappointing results against TNBC, recent studies emphasize the high potential impact of HDACIs in controlling TNBC. In addition, encouraging results stem from new compounds designed to obtain isoform selectivity and/or polypharmacological HDAC approach. The present review provides a discussion of the HDACIs pharmacophoric models and of the structural modifications, leading to compounds with a potent activity against TNBC progression

Synthesis and structure-activity relationships of fibrate-based analogues inside PPARs

In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, new compounds based on a combination of clofibric acid, the active metabolite of clofibrate, and lipophilic groups derived from natural products chalcone and stilbene were synthesised. Some of them were found to be active at micromolar concentrations only on PPARα or PPARγ, while others were identified as dual agonists PPARα/γ