1. Academic Validation
  2. 5-methyl-2-carboxamidepyrrole-based novel dual mPGES-1/sEH inhibitors as promising anticancer candidates

5-methyl-2-carboxamidepyrrole-based novel dual mPGES-1/sEH inhibitors as promising anticancer candidates

  • Arch Pharm (Weinheim). 2025 Jan;358(1):e2400708. doi: 10.1002/ardp.202400708.
Ester Colarusso 1 Gianluigi Lauro 1 Marianna Potenza 1 2 Paola Galatello 1 Maria Luisa d'Aulisio Garigliota 1 Maria Grazia Ferraro 3 Marialuisa Piccolo 4 Maria Giovanna Chini 5 Carlo Irace 4 Pietro Campiglia 1 Robert Klaus Hoffstetter 2 Oliver Werz 2 Anna Ramunno 1 Giuseppe Bifulco 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Salerno, Fisciano, Italy.
  • 2 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Jena, Germany.
  • 3 Department of Molecular Medicine and Medical Biotechnologies, School of Medicine and Surgery, University of Naples, Naples, Italy.
  • 4 BioChem Lab, Department of Pharmacy, School of Medicine and Surgery, University of Naples, Naples, Italy.
  • 5 Department of Biosciences and Territory, University of Molise, Pesche, Italy.
Abstract

Inhibiting microsomal prostaglandin E2 synthase-1 (mPGES-1), an inducible Enzyme involved in prostaglandin E2 (PGE2) biosynthesis and tumor microenvironment (TME) homeostasis, is a valuable strategy for treating inflammation and Cancer. In this work, 5-methylcarboxamidepyrrole-based molecules were designed and synthesized as new compounds targeting mPGES-1. Remarkably, compounds 1f, 2b, 2c, and 2d were able to significantly reduce the activity of the isolated Enzyme, showing IC50 values in the low micromolar range. With the aim of further profiling the synthesized molecules, their ability to interfere with the activity of soluble Epoxide Hydrolase (sEH), whose inhibition blocks the loss of the anti-inflammatory mediators epoxyeicosatrienoic acids (EETs or epoxyicosatrienoic acids), was investigated in silico and by employing specific biological assays. Among the set of tested compounds, 1f, 2b, 2c, and 2d emerged as mPGES-1/sEH dual inhibitors. Moreover, given that overexpression of mPGES-1 has been observed in many human tumors, we finally explored the biological effect of our compounds in an in vitro model of human colorectal Cancer (CRC). The obtained outcomes pave the way for future investigation to optimize and further characterize Anticancer pharmacological profile of the carboxamidepyrrole-based molecules.

Keywords

5‐methyl‐2‐carboxamidepyrrole‐based compounds; cancer; docking experiments; mPGES‐1; sEH.

Figures
Products