ABSTRACT
Leukotriene B4 (LTB4) is a potent chemoattractant that can recruit and activate immune cells such as neutrophils, eosinophils, and monocytes to sites of inflammation. Excessive production of LTB4 has been linked to acute and chronic inflammatory diseases, including asthma, rheumatoid arthritis, and psoriasis. Inhibiting the binding of LTB4 to its receptors, BLT1 and BLT2, is a potential strategy for treating these conditions. While several BLT1 antagonists have been developed for clinical trials, most have failed due to efficacy and safety issues. Therefore, discovering selective BLT2 antagonists could improve our understanding of the distinct functions of BLT1 and BLT2 receptors and their pharmacological implications. In this study, we aimed to discover novel BLT2 antagonists by synthesizing a series of biphenyl analogues based on a BLT2 selective agonist, CAY10583. Among the synthesized compounds, 15b was found to selectively inhibit the chemotaxis of CHO-BLT2 cells with an IC50 value of 224 nM without inhibiting the chemotaxis of CHO-BLT1 cells. 15b also inhibited the binding of LTB4 and BLT2 with a Ki value of 132 nM. Furthermore, 15b had good metabolic stability in liver microsomes and moderate bioavailability (F = 34%) in in vivo PK studies. 15b also showed in vivo efficacy in a mouse model of asthma, reducing airway hyperresponsiveness by 59% and decreasing Th2 cytokines by up to 46%. Our study provides a promising lead for the development of selective BLT2 antagonists as potential therapeutics for inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease.
Subject(s)
Arthritis, Rheumatoid , Asthma , Mice , Cricetinae , Animals , Leukotriene B4 , Asthma/drug therapy , Inflammation , CHO Cells , Receptors, Leukotriene B4/metabolismABSTRACT
A series of isosteric surrogates of the 4-phenyl group in luminespib were investigated as new scaffolds of the Hsp90 inhibitor for the discovery of novel antitumor agents. Among the synthesized surrogates of isoxazole and pyrazole, compounds 4a, 5e and 12b exhibited potent Hsp90 inhibition in ATPase activity and Her2 degradation assays and significant antitumor activity in A2780 and HCT116 cell lines. Animal studies indicated that compared to luminespib, their activities were superior in A2780 or NCI-H1975 tumor xenograft models. A molecular modeling study demonstrated that compound 4a could fit nicely into the N-terminal ATP binding pocket.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Isoxazoles/pharmacology , Resorcinols/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HSP90 Heat-Shock Proteins/metabolism , Humans , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Resorcinols/chemical synthesis , Resorcinols/chemistry , Structure-Activity RelationshipABSTRACT
When intracellular reactive oxygen species (ROS) increase, cancer cells are more vulnerable to oxidative stress compared to normal cells; thus, the collapse of redox homeostasis can lead to selective death of cancer cells. Indeed, recent studies have shown that inhibition of sulfiredoxin (Srx), which participates in antioxidant mechanisms, induces ROS-mediated cancer cell death. In this paper, we describe how an Srx inhibitor, J14 (4-[[[4-[4-(2-chlor-ophenyl)-1-piperazinyl]-6-phenyl-2-pyrimidinyl]thio]methyl]-benzoic acid), interferes with the antioxidant activity of Srx at the molecular level. We searched for possible binding sites of Srx using a binding site prediction method and uncovered two possible inhibition mechanisms of Srx by J14. Using molecular dynamics simulations and binding free energy calculations, we confirmed that J14 binds to the ATP binding site; therefore, J14 acts as a competitive inhibitor of ATP, settling the question of the two mechanisms. Based on the inhibition mechanism revealed at the atomic level, we designed several derivatives of J14, which led to LMT-328 (4-(((4-(4-(2-Chlorophenyl)piperazin-1-yl)-6-(2,4-dihydroxy-5-isopropylphenyl)pyrimidin-2-yl)thio)methyl)benzoic acid), which is possibly an even more potent inhibitor than J14.
Subject(s)
Antioxidants/chemistry , Enzyme Inhibitors/chemistry , Models, Molecular , Oxidoreductases Acting on Sulfur Group Donors/chemistry , Adenosine Triphosphate/chemistry , Antioxidants/pharmacology , Binding Sites , Catalysis , Enzyme Inhibitors/pharmacology , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Oxidoreductases Acting on Sulfur Group Donors/antagonists & inhibitors , Protein Binding , Reactive Oxygen Species/chemistry , Structure-Activity RelationshipABSTRACT
A series of novel (1S)-(-)-verbenone derivatives was synthesized bearing a 4-styryl scaffold. The synthesized compounds were tested for their anti-oxidant, anti-excitotoxic, and anti-ischemic activities. These derivatives significantly reduced oxygen-glucose deprivation-induced neuronal injury and N-methyl-D-aspartic acid-evoked excitotoxicity in cortical neurons. Furthermore, compound 3f was identified as a potent anti-ischemic agent in an in vitro ischemic model, potentially due to the inhibition of N-methyl-D-aspartic acid-evoked excitotoxicity and oxidative/nitrosative stress.
