ABSTRACT
Kv1.3, the voltage-gated potassium channel in human T cells, represents a new target for treating immunosuppression and autoimmune diseases. Correolide (1), a pentacyclic natural product, is a potent and selective Kv1.3 channel blocker. Simplification of correolide via removal of its E-ring generates enone 4, whose modification produced a new series of tetracyclic Kv1.3 blockers. The structure-activity relationship for this class of compounds in two functional assays, Rb_Kv and human T cell proliferation, is presented herein. The most potent analog 43 is 15-fold more potent than correolide as inhibitor of human T cell proliferation.
Subject(s)
Cell Proliferation/drug effects , Ion Channel Gating/drug effects , Potassium Channel Blockers/pharmacology , Potassium Channels, Voltage-Gated/antagonists & inhibitors , Triterpenes/pharmacology , Biological Assay , Humans , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacology , Kv1.3 Potassium Channel , Models, Molecular , Potassium Channel Blockers/chemistry , Structure-Activity Relationship , T-Lymphocytes , Triterpenes/chemistryABSTRACT
The voltage-gated potassium channel, Kv1.3, is present in human T-lymphocytes. Blockade of Kv1.3 results in T-cell depolarization, inhibition of T-cell activation, and attenuation of immune responses in vivo. A class of benzamide Kv1.3 channel inhibitors has been identified. The structure-activity relationship within this class of compounds in two functional assays, Rb_Kv and T-cell proliferation, is presented. In in vitro assays, trans isomers display moderate selectivity for binding to Kv1.3 over other Kv1.x channels present in human brain.
Subject(s)
Benzamides/chemical synthesis , Benzamides/pharmacology , Potassium Channel Blockers/chemical synthesis , Potassium Channel Blockers/pharmacology , Potassium Channels, Voltage-Gated , Potassium Channels/drug effects , Brain Chemistry/drug effects , Cell Division/drug effects , Humans , In Vitro Techniques , Kv1.3 Potassium Channel , Rubidium Radioisotopes , Stereoisomerism , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/metabolismABSTRACT
[reaction: see text] Pentacyclic triterpenoid natural product correolide (1) was converted to ketone 2 via ozonolysis. An unusual fragmentation reaction of ketone 2 with LiCl was discovered. This reaction is general among several similar substrates examined and appears to be specific for the correolide-type E-ring structure (ketone). A mechanism involving a retroaldol reaction, a nucleophilic opening of the epoxide, and a subsequent acetoxy elimination reaction was proposed.