Hunting the Targets of Natural Product-Inspired Compounds

Abstract

In evolution, nature has created a variety of secondary metabolites with high chemical and structural diversity. These natural products (NPs) were evolved by nature to exert particular biological functions and to bind to different proteins as substrates and targets. Therefore, it is not surprising that a major fraction of the current drugs on the market are derived from or based on NPs and that NPs are valuable tools for the elucidation of biological processes [1]. Although NPs for decades have served as promising starting points for the discovery of new drugs and biological tools, isolation from their original sources and characterization in medium- and high-throughput approaches is severely hampered by limited amounts and insufficient purity. The total synthesis of NPs in principle offers an alternative route for getting access to pure and well-characterized compounds. In many cases, however, the complexity of NPs is prohibitive to fuel subsequent chemical biology or medicinal chemistry research. A systematic structural classification of natural products (SCONP) reveals that NPs embody only a limited number of different structural scaffolds that can be regarded as privileged [2]. SCONP therefore can serve to inspire new synthetic routes combining classical organic chemistry approaches with combinatorial chemistry methods for the synthesis of NP-inspired compound collections that can be regarded as biologically relevant and prevalidated [3, 4]. The synthesis of NP-like compound collections might provide new compounds with biological properties similar to the guiding NPs. The availability of such compounds and efficient methods for their synthesis allows establishing structure–activity correlations and the synthesis of suitable probes for isolation of target proteins and thereby lays the chemical foundation for subsequent identification of target proteins. Such information is crucial and very valuable because the lack of information about the cellular targets of most NPs hampers drug discovery: it defines a bottleneck in the quest for new drugs and in chemical biology research [5]. Furthermore, the missing information about so-called off-targets that may account for side effects complicates subsequent pharmacological and chemical research [5].