title: Selective COX-1 inhibition as a target of theranostic novel diarylisoxazoles.
abstract: Cyclooxygenase(COX)-1 role in some diseases is increasingly studied. 3-(5-Chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6), a highly selective cyclooxygenase-1 inhibitor, was used as a "lead" to design new isoxazoles (2a-m), differently selective towards COX-1. Those isoxazoles might be useful as novel theranostic agents and also to better clarify COX-1 role in the human physiology and diseases. 2a-m were prepared in fair to good yields developing suitable synthetic strategies. They were evaluated in vitro for their COX-inhibitory activity and selectivity. Structure-activity relationship studies of the novel set of diarylisoxazoles allowed to identify new key determinants for COX-1 selectivity, and to uncover compounds appropriate for a deep pharmacokinetic and pharmacodynamic investigation. 3-(5-Chlorofuran-2yl)-4-phenylisoxazol-5-amine (2f) was the most active compound of the series, its inhibitory activity was assessed in purified enzyme (COX-1 IC₅₀ = 1.1 μM; COX-2 IC₅₀ > 50 μM) and in the ovarian cancer cell line (OVCAR-3) expressing only COX-1 (IC₅₀ = 0.58 μM). Furthermore, the high inhibitory potency of 2f was rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-1 binding site. We found critical interactions between the inhibitor and constriction residues R120 and Y355 at the base of the active site, as well as with S530 at the top of the side pocket.
authors: Department of Pharmacy & Pharmaceutical Sciences, University of Bari "A. Moro", Via Orabona 4, 70125 Bari, Italy.
authors: Paola
authors: P
authors: Vitale
authors: Department of Pharmacy & Pharmaceutical Sciences, University of Bari "A. Moro", Via Orabona 4, 70125 Bari, Italy.
authors: Maria Grazia
authors: MG
authors: Perrone
authors: Department of Pharmacy & Pharmaceutical Sciences, University of Bari "A. Moro", Via Orabona 4, 70125 Bari, Italy.
authors: Paola
authors: P
authors: Malerba
authors: Department of Pharmacy, "Drug Discovery" Laboratory, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy. Electronic address: lavecchi@unina.it.
authors: Antonio
authors: A
authors: Lavecchia
authors: Department of Pharmacy & Pharmaceutical Sciences, University of Bari "A. Moro", Via Orabona 4, 70125 Bari, Italy. Electronic address: antonio.scilimati@uniba.it.
authors: Antonio
authors: A
authors: Scilimati
mesh_terms: D045744:Cell Line, Tumor; D051545:Cyclooxygenase 1 / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
chemical_list: D016861:Cyclooxygenase Inhibitors; D007555:Isoxazoles; D051545:Cyclooxygenase 1
keywords: Cyclooxygenase(COX)-1 inhibitors; Diagnostic probes; Diarylisoxazole scaffold; Docking; OVCAR-3 cell line; Ovarian cancer