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Suaad Abdallah Audat,1 Qosay Ali Al-Balas,2 Buthina Abdallah Al-Oudat,2 Mo’ad Jamil Athamneh,1 Amanda Bryant-Friedrich3 1Department of Chemistry, College of Science and Arts, Jordan University of Science and Technology, Irbid, 22110, Jordan; 2Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, 22110, Jordan; 3Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, 48202, USACorrespondence: Suaad Abdallah Audat, Department of Chemistry, College of Science and Arts, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan, Tel +962 2 720 1000, Fax +962 2 720 1071, Email saaudat@just.edu.joBackground: Glyoxalase system is one of the defense cellular mechanisms that protect cells against endogenous harmful metabolites, mainly methylglyoxal (MG), through conversion of cytotoxic methylglyoxal into the non-toxic lactic acid. Glyoxalase system comprises of two enzymes glyoxalase I, glyoxalase II, and a catalytic amount of reduced glutathione. Cancerous cells overexpress glyoxalase I, making it a target for cancer therapy. Many studies have been conducted to identify potent Glx-I inhibitors.Methods: Aiming to discover and develop novel Glx-I inhibitors, a series of 1,4-benzenesulfonamide derivatives were designed, synthesized, and biologically evaluated in vitro against human Glx-I enzyme. Seventeen compounds were designed based on the hit compound that was obtained from searching the National Cancer Institute (NCI) database. The synthesis of the target compounds ( 13– 29) was accomplished utilizing an azo coupling reaction of aniline derivatives and activated substituted aromatic compounds. To understand the binding mode of the active compounds at the active site of Glx-I, docking studies were performed.Results: Structure activity relationship (SAR) studies were accomplished which led to the identification of several compounds that showed potent inhibitory activity with IC50 values below 10 μM. Among the compounds tested, compounds (E)-2-hydroxy-5-((4-sulfamoylphenyl)diazenyl)benzoic acid ( 26) and (E)-4-((8-hydroxyquinolin-5-yl)diazenyl) benzenesulfonamide ( 28) displayed potent Glx-I inhibitory activity with IC50 values of 0.39 μM and 1.36 μM, respectively. Docking studies of compounds 26 and 28 were carried out to illustrate the binding mode of the molecules into the Glx-I active site.Conclusion: Our results show that compounds 26 and 28 displayed potent Glx-I inhibitory activity and can bind the Glx-I well. These findings should lead us to discover new classes of compounds with better Glx-I inhibition.Graphical Abstract: Keywords: anticancer agents, glyoxalase I, structure activity relationship, SAR, molecular docking

Leukotriene B4 (LTB4) is a potent, proinflammatory lipid mediator implicated in the pathologies of an array of inflammatory diseases and cancer. The biosynthesis of LTB4 is regulated by the leukotriene A4 hydrolase (LTA4H). Compounds capable of limiting the formation of LTB4, through selective inhibition of LTA4H, are expected to provide potent anti-inflammatory and anti-cancer agents. The aim of the current study is to obtain potential LTA4H inhibitors using computer-aided drug design. A hybrid 3D structure-based pharmacophore model was generated based on the crystal structure of LTA4H in complex with bestatin. The generated pharmacophore was used in a virtual screen of the Maybridge database. The retrieved hits were extensively filtered, then docked into the active site of the enzyme. Finally, they were consensually scored to yield five hits as potential LTA4H inhibitors. Consequently, the selected hits were purchased and their biological activity assessed in vitro against the epoxide hydrolase activity of LTA4H. The results were very promising, with the most active compound showing 73.6% inhibition of the basal epoxide hydrolase activity of LTA4H. The results from this exploratory study provide valuable information for the design and development of more potent and selective inhibitors.

In a previous report, we described the discovery of (E)-5-((8-hydroxyquinolin-5-yl)diazenyl)-2-methylbenzenesulfonamide as a potent inhibitor of GLO-I enzyme with IC

DNA damage pathways induced by low-energy electrons (LEEs) are believed to involve the formation of 2-deoxyribose radicals. These radicals, formed at the C3' and C5' positions of nucleotides, are the result of cleavage of the C-O phosphodiester bond through transfer of LEEs to the phosphate group of DNA oligomers from the nucleobases. A considerable amount of information has been obtained to illuminate the identity of the unmodified oligonucleotide products formed through this process. There exists, however, a paucity of information as to the nature of the modified lesions formed from degradation of these sugar radicals. To determine the identity of the damage products formed via the 2',3'-dideoxy-C3'-thymidinyl radical (C3'(dephos) sugar radical), phenyl selenide and acyl modified sugar and nucleoside derivatives have been synthesized, and their suitability as photochemical precursors of the radical of interest has been evaluated. Upon photochemical activation of C3'-derivatized nucleosides in the presence of the hydrogen atom donor tributyltin hydride, 2',3'-dideoxythymidine is formed indicating the selective generation of the C3'(dephos) sugar radical. These precursors will make the identification and quantification of products of DNA damage derived from radicals generated by LEEs possible.