ABSTRACT
Inspired by a rhodanine-based dual inhibitor of Bcl-xL and Mcl-1, a focused library of analogues was prepared wherein the rhodanine core was replaced with a less promiscuous thiazolidine-2,4-dione scaffold. Compounds were initially evaluated for their abilities to inhibit Mcl-1. The most potent compound 12b inhibited Mcl-1 with a Ki of 155â¯nM. Further investigation revealed comparable inhibition of Bcl-xL (Kiâ¯=â¯90â¯nM), indicating that the dual inhibitory profile of the initial rhodanine lead had been retained upon switching the heterocycle core.
Subject(s)
Drug Discovery , Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors , Thiazolidinediones/pharmacology , Dose-Response Relationship, Drug , Humans , Molecular Structure , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Structure-Activity Relationship , Thiazolidinediones/chemical synthesis , Thiazolidinediones/chemistryABSTRACT
Structure-based drug design was utilized to develop novel, 1-hydroxy-2-naphthoate-based small-molecule inhibitors of Mcl-1. Ligand design was driven by exploiting a salt bridge with R263 and interactions with the p2 pocket of the protein. Significantly, target molecules were accessed in just two synthetic steps, suggesting further optimization will require minimal synthetic effort. Molecular modeling using the Site-Identification by Ligand Competitive Saturation (SILCS) approach was used to qualitatively direct ligand design as well as develop quantitative models for inhibitor binding affinity to Mcl-1 and the Bcl-2 relative Bcl-xL as well as for the specificity of binding to the two proteins. Results indicated hydrophobic interactions in the p2 pocket dominated affinity of the most favourable binding ligand (3bl: Ki = 31 nM). Compounds were up to 19-fold selective for Mcl-1 over Bcl-xL. Selectivity of the inhibitors was driven by interactions with the deeper p2 pocket in Mcl-1 versus Bcl-xL. The SILCS-based SAR of the present compounds represents the foundation for the development of Mcl-1 specific inhibitors with the potential to treat a wide range of solid tumours and hematological cancers, including acute myeloid leukemia.
Subject(s)
Carboxylic Acids/pharmacology , Drug Design , Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors , Naphthalenes/pharmacology , Carboxylic Acids/chemical synthesis , Carboxylic Acids/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Hydrophobic and Hydrophilic Interactions , Models, Molecular , Molecular Structure , Naphthalenes/chemical synthesis , Naphthalenes/chemistry , Structure-Activity RelationshipABSTRACT
A mild and efficient one-pot procedure is described to transform salicylaldoximes into salicylonitriles using Mitsunobu chemistry. The reactions proceed through the corresponding 1,2-benzisoxazoles that undergo the Kemp elimination in situ to generate the target salicylonitriles in excellent yields. The chemistry exhibits a broad scope, and the salicylonitriles can be readily isolated by a simple acid-base workup. In addition to functioning as useful synthetic precursors, salicylonitriles may serve as more cell penetrable bioisosteres of carboxylic acids.
