ABSTRACT
Inspired by the previously reported neuroprotective activity of hederacolchiside E (1), we synthesized hederacolchiside E for the first time along with eleven of its derivatives. The neuroprotective effects of these compounds were further evaluated against H2O2- and Aß1-42-induced injury using cell-based assays. The derivatives showed obvious differences in activity due to structural variations, and two of them exhibited better neuroprotective effects than 1 in the Aß1-42-induced injury model. Compound 7 was the most active derivative and had a relatively simple chemical structure. Moreover, 1 and 7 can significantly reduce the release of lactate dehydrogenase (LDH), level of intracellular reactive oxygen species (ROS) and extent of malondialdehyde (MDA) increase resulting from Aß1-42 treatment, which demonstrated that these kinds of compounds show neuroprotective effects in Alzheimer's disease (AD) models via modulating oxidative stress. Compound 7 could be used as promising lead for the development of a new type of neuroprotective agent against AD.
Subject(s)
Alzheimer Disease/drug therapy , Neuroprotective Agents/pharmacology , Saponins/pharmacology , Alzheimer Disease/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Cell Survival/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Hydrogen Peroxide/antagonists & inhibitors , Hydrogen Peroxide/pharmacology , L-Lactate Dehydrogenase/antagonists & inhibitors , L-Lactate Dehydrogenase/metabolism , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , PC12 Cells , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Rats , Reactive Oxygen Species/analysis , Reactive Oxygen Species/metabolism , Saponins/chemical synthesis , Saponins/chemistry , Structure-Activity RelationshipABSTRACT
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
Carbonic anhydrase IX (CA IX) is a tumor associated protein which is able to be a potent anticancer target, since it is highly expressed in a multitude of carcinomas, while it is present in a limited number of normal tissues. This review focuses on its role in tumor physiology, the most recent three dimensional structure features of this enzyme which has recently been elucidated. In addition, we present recent advances in the development of small inhibitors able to target CA IX for therapeutic applications.
