Design, Synthesis and Biological Evaluation of 1,4-Benzenesulfonamide Derivatives as Glyoxalase I Inhibitors.

Background: 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.

Design, synthesis, and biologic evaluation of novel chrysin derivatives as cytotoxic agents and caspase-3/7 activators.

BACKGROUND: Chrysin (5,7-dihydroxyflavone) is a widely distributed natural flavonoid found in many plant extracts, honey and propolis. Several studies revealed that chrysin possesses multiple biological activities including anti-cancer effects. It has been established that activation of apoptosis is the key molecular mechanism responsible for the cytotoxic potential of chrysin. The objective of this study was to design and synthesize potent chrysin analogues as potential cytotoxic agents. METHODS: A series of chrysin derivatives (3a-m) bearing N'-alkylidene/arylideneacetohydrazide moiety were designed, synthesized, and evaluated for their antiproliferative activity against two human breast cancer cell lines, MDA-MB-231 and MCF-7 by applying the MTT colorimetric assay. Selected compounds were tested for their ability to induce apoptosis through caspase 3/7 activation in MDA-MB-231 cells only since MCF-7 cells lack procaspase 3. RESULTS: Compounds (3a-m) were obtained as geometrical isomers (E/Z isomers) in good yields upon treatment of hydrazide 5 with different aliphatic and aromatic aldehydes. Most of the synthesized compounds demonstrated moderate-to-good activity against both cell lines. The cytotoxicity results revealed the importance of lipophilic moieties at C-4 position of ring D in imparting the cytotoxic activities to the compounds. Compound 3e with 4-benzyloxy substituent was found to be the most active among the synthesized compounds with IC50 3.3 µM against MDA-MB-231 and 4.2 µM against MCF-7 cell lines. The cytotoxic potential of compound 3e is comparable to that of the well-known anti-cancer agent doxorubicin. In addition, compounds substituted with fluoro (3b), nitro (3h), and dimethylamino (3j) exhibited good cytotoxicity with IC50 <6.5 µM against MDA-MB-231 and <12 µM against MCF-7. Selected compounds were able to induce apoptosis in MDA-MB-231 cells as indicated by caspase-3 and/or -7 activation. CONCLUSION: Our results show that the newly designed chrysin derivatives exert anticancer activity in human breast cancer cell lines, MDA-MB-231 and MCF-7. Therefore, they can be considered as leads for further development of more potent and selective cytotoxic agents.