| dc.description.abstract | Microsomal prostaglandin E2 synthase-1 (mPGES-1) is the enzyme responsible for the conversion of the cyclooxygenase (COX)-derived prostaglandins (PG)H2 into PGE2. This enzyme is deeply involved in different pathologies; in fact it is over-expressed in several inflammatory disorders[1] as well as in some human tumours.[2;3] Hence, the inhibition of mPGES-1 has been proposed as a promising approach for the development of safer drugs in inflammatory disorders, devoid of classical NSAID side effects.[4] Indeed, this enzyme is responsible for the biosynthesis of inducible PGE2 as a response to inflammatory stimuli[5] whereas it doesn’t affect constitutive PGE2 involved in crucial physiological functions. Today two are the main approaches employed in the inhibition of mPGES-1 activity.[6] The first consists in the negative modulation of its expression, while the second one concerns the direct and selective inhibition of the enzyme.
In order to identify novel molecules able to block mPGES-1, in the first part of this project we focused our attention on the design and synthesis of molecules able to inhibit the expression of our target enzyme. Specifically, as first task we decided to undertake the structural optimization of a γ-hydroxybutenolide related to petrosaspongiolide M (PM) 5, compound 6, that showed to be a potent negative modulator of mPGES-1 expression (IC50 = 1.80 μM).[7;8] In the course of our investigation we identified two new hits that revealed an increased activity compared to the parent molecule 6, compounds 30 (IC50 = 0.79 μM) and 31e (IC50 = 0.85 μM).[9] Encouraged by these results, in order to amplify the chemical diversity of the γ-hydroxybutenolide scaffold and identify new lead structures able to inhibit mPGES-1 expression, we decided to develop a new collection of PM-derivatives featuring amido-aromatic portions linked to the γ-hydroxybutenolide scaffold. These compounds are currently under biological investigations whose
outcomes could suggest new guidelines useful in the discovery of more effective agents.
As second task, we concentrated our efforts on the development of molecules able to directly interfere with mPGES-1. Owing to the lack of its crystallographic structure in protein data bank (PDB), we decided to choose, as model for our investigations, microsomal glutathione transferase 1 (MGST-1), an enzyme belonging to membrane associated proteins in eicosanoid and gluthatione metabolism (MAPEG) family and showing a high homology sequence with our selected target.[10] On the basis of virtual screening outcomes, we designed and synthesized a collection of potential mPGES-1 inhibitors based on 1,4-disubstituted triazole moiety, a scaffold extensively employed in drug discovery that can be obtained through click chemistry approach, a powerful tool for the rapid exploration of the chemical universe based on practical and reliable chemical reactions. The biological evaluation of these compounds allowed us to individuate three new potential anti-inflammatory agents: (I) compound 54 displaying selectivity for mPGES-1 with an IC50 value of 3.2 μM, (II) compound 70 that dually inhibits 5-lipoxygenase (5-LO) and mPGES-1 and (III) compound 57 acting as 5-lipoxygenase-activating protein (FLAP) inhibitor (IC50 = 0.4 μM).[11]
On the basis of these results, as last task of this project, we directed our attention on the new hit 54, emerged as a selective inhibitor of mPGES-1. In more details, on the basis of the suggestions coming from both the biological screening and the 3D model of interaction with MGST-1, aiming at improving its biological activity, we decided to rely on some well-reasoned structural changes of the basic molecule in order to enhance the binding affinity for the target enzyme. In this perspective, a new collection of triazole derivatives has been efficiently synthesized and their biological profile is currently under investigation. [edited by author] | en_US |
