ABSTRACT
Steroids are highly prevalent structures in small-molecule therapeutics, with the level of oxidation being key to their biological activity and physicochemical properties. These C(sp3 )-rich tetracycles contain many stereocentres, which are important for creating specific vectors and protein binding orientations. Therefore, the ability to hydroxylate steroids with a high degree of regio-, chemo- and stereoselectivity is essential for researchers working in this field. This review will cover three main methods for the hydroxylation of steroidal C(sp3 )-H bonds: biocatalysis, metal-catalysed C-H hydroxylation and organic oxidants, such as dioxiranes and oxaziridines.
Subject(s)
Oxidants , Steroids , Hydroxylation , Oxidation-Reduction , Oxidants/chemistry , Steroids/metabolism , BiocatalysisABSTRACT
As part of a program to develop a small molecule inhibitor of LIMK, a series of aminothiazole inhibitors were discovered by high throughput screening. Scaffold hopping and subsequent SAR directed development led to a series of low nanomolar inhibitors of LIMK1 and LIMK2 that also inhibited the direct biomarker p-cofilin in cells and inhibited the invasion of MDA MB-231-luc cells in a matrigel inverse invasion assay.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Lim Kinases/antagonists & inhibitors , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Actin Depolymerizing Factors/metabolism , Animals , Biotransformation , Drug Design , High-Throughput Screening Assays , Humans , Microsomes, Liver/metabolism , Neoplasm Invasiveness , Structure-Activity RelationshipABSTRACT
A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target.