ABSTRACT
A series of novel N-substituted-ß-d-glucosamine derivatives that incorporate benzenesulfonamides were designed using a fragment-based drug design strategy. Each derivative was synthesized and evaluated in vitro for its inhibitory activity against human carbonic anhydrase (hCA) IX; several derivatives displayed desirable potency profiles against this enzyme. The molecular docking studies provided the design rationale and predicted potential binding modes for carbonic anhydrase (CA) IX and three target compounds, including the most potent inhibitor, compound 7f (IC50 = 10.01 nM). Moreover, the calculated Log P (cLog P) values showed that all the compounds tended to be hydrophilic. In addition, topological polar surface area (TPSA) value-based predictions highlighted the selectivity of these carbohydrate-based inhibitors for membrane-associated CA IX.
Subject(s)
Carbonic Anhydrase IX/antagonists & inhibitors , Carbonic Anhydrase Inhibitors/pharmacology , Galactosamine/analogs & derivatives , Glucosamine/analogs & derivatives , Sulfonamides/chemical synthesis , Antigens, Neoplasm/metabolism , Carbonic Anhydrase IX/metabolism , Drug Design , Galactosamine/chemical synthesis , Galactosamine/chemistry , Galactosamine/pharmacology , Humans , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , BenzenesulfonamidesABSTRACT
We synthesized a diosgenyl saponin bearing a unique disaccharide from the natural product ß-hederin, together with twelve glycosylated derivatives and determined their cytotoxicity against five different human cancer cell lines. Most of them showed weak cytotoxicity, with the exception of compound , diosgenyl α-L-rhamnopyranosyl-(1â2)-[α-L-arabinopyranosyl-(1â4)]-α-L-arabinopyranoside, which exhibited strong cytotoxicity against A549 cells. The cytotoxicity of was associated with apoptotic cell death, which was characterized by morphological changes, chromatin condensation, DNA fragmentation, and phosphatidylserine externalization. Compound 20 induced apoptosis of A549 cells through a caspase-8-mediated extrinsic pathway and a caspase-9-mediated intrinsic pathway. In addition, phosphorylation of JNK increased but the phosphorylation of ERK decreased after treatment with 20. These results provide a basic mechanism for the anticancer activity of 20.
