Inspection of the NP structures indicated that the inhibitory activity is influenced by the stereochemistry of the D–E ring linkage and the substitution pattern of the E ring. Surprisingly, from seven investigated yohimbane-type alkaloids, three NPs proved to be weak inhibitors for the phosphatase Cdc25A ( Fig. The phosphatase inhibition screen of the isolated NPs led to the discovery of further classes of unprecedented phosphatase inhibitors. We refer to synthesis efforts based on these criteria as biology-oriented synthesis (BIOS). It permits the selection of library scaffolds based on relevance to and prevalidation by nature. Based on this reasoning, we have introduced a structural classification of natural products (SCONP) in a tree-like arrangement as an idea- and hypothesis-generating tool for the design and synthesis of compound collections ( 8). Consequently, it is to be expected that compound collections designed on the basis of NP structure will be enriched in biochemical and biological activity. The underlying frameworks of natural products (NPs) provide evolutionarily selected chemical structures encoding the properties required for binding to proteins, and their structural scaffolds represent the biologically relevant and prevalidated fractions of chemical space explored by nature so far ( 7– 9). Relevance to nature is one of the most important criteria to be met by compound classes for chemical biology and medicinal chemistry research. These results demonstrate that biology-oriented synthesis is an efficient approach to the discovery of new compound classes for medicinal chemistry and chemical biology research that opens up new opportunities for the study of phosphatases, which may lead to the development of new drug candidates. For VE-PTP and MptpB the first inhibitors were discovered. The screen yielded four unprecedented and selective phosphatase inhibitor classes for four phosphatases with high hit rates. For the discovery of phosphatase inhibitor classes by means of this approach, four natural product-derived or -inspired medium-sized compound collections were synthesized and investigated for inhibition of the tyrosine phosphatases VE-PTP, Shp-2, PTP1B, MptpA, and MptpB and the dual-specificity phosphatases Cdc25A and VHR. We refer to synthesis efforts and compound collection development based on these criteria as biology-oriented synthesis. The underlying frameworks of natural products represent the evolutionarily selected fractions of chemical space explored by nature so far and meet the criteria of relevance to nature and biological prevalidation most crucial to inhibitor development. Protein phosphatases have very recently emerged as important targets for chemical biology and medicinal chemistry research, and new phosphatase inhibitor classes are in high demand.
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