In addition to known compounds, the aerial parts of E. semiperfoliata afforded an abietanolide (3), 13 jatrophane polyesters (4-9, 12, 14-19), two 4-deoxyphorbol diesters (23, 24), and a pair of epimeric diterpenes (21, 22) with a novel carbon skeleton, which was named euphoperfoliane. Structures were determined by spectroscopic analysis, and the main conformational features of jatropha-6(17),11-dienes are discussed in detail. The obtained isolation yield of several jatrophanes was unprecedented within the spurges (Euphorbia spp.), making E. semiperfoliata a unique source of macrocyclic diterpenoids.
Protein phosphatases have recently emerged as important targets for research in chemical biology and medicinal chemistry, and new classes of phosphatase inhibitors are in high demand. BIOS (biology-oriented synthesis) employs the criteria of relevance to nature and biological prevalidation for the design and synthesis of compound collections. In an application of the BIOS principle, an efficient solid-phase synthesis of highly substituted indolo[2,3-a]quinolizidines by using a vinylogous Mannich-Michael reaction in combination with phosgene- or acid-mediated ring closure was developed. Screening of this library for phosphatase inhibitors yielded a new inhibitor class for the Mycobacterium tuberculosis phosphatase MptpB.
Recently, we developed a concept known as biology-oriented synthesis (BIOS), which targets the design and synthesis of small- to medium-sized compound libraries on the basis of genuine natural product templates to provide screening compounds with high biological relevance. We herein describe the parallel solution phase synthesis of two BIOS-based libraries starting from alpha-santonin (1). Modification of the sesquiterpene lactone 1 by introduction of a thiazole moiety followed by a Lewis-acid-mediated lactone opening yielded a first library of natural product analogues. An acid-mediated dienone-phenol rearrangement of 1 and a subsequent etherification/amidation sequence led to a second natural product-based library. After application of a fingerprint-based virtual screening on these compounds, the biological screening of 23 selected library members against 5-lipoxygenase resulted in the discovery of four potent novel inhibitors of this enzyme.
For the first time, the in silico design, screening and in vitro validation of potent GSK-3β type-II inhibitors is presented. In the absence of crystallographic evidence for DFGout GSK-3β activation loop conformation, computational models were designed using an adapted DOLPHIN approach and a method consisting of Prime loop refinement, induced-fit docking and molecular dynamics. Virtual screening of the Biogenics subset from the ZINC database led to an initial selection of 20 Phase I compounds revealing two low micromolar inhibitors in an isolated enzyme assay. 20 more analogues (Phase II compounds) related to the hit [pyrmidin-2-yl]amino-furo[3,2-b]furyl-urea scaffold were selected for structure activity relationship analysis. The Phase II studies lead to five highly potent nanomolar inhibitors, with compound 23 (IC50 =0.087 µM) >100 times more potent than the best Phase I inhibitor, and selectivity for GSK-3β inhibition compared to homologous kinases observed. Ex-vivo experiments (SH-SY5Y cell lines) for tau hyperphosphorylation revealed promising neuroprotective effects at low micromolar concentrations. Type-II inhibitor design has been unraveled as a potential route towards more clinically effective GSK-3β inhibitors.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.