Diversity-Oriented Syntheses of Natural Products and Natural Product-Like Compounds

Natural products have proven to be valuable sources for the identification of new drug candidates, and also as tools for chemical biology and medicinal chemistry research [1]. In fact, if we trace back human history, many natural products have also long been used to treat various human disorders and distinguished by their drug-like properties [2]. To date, tens of thousands of bioactive compounds have been isolated from plants, microbes, marine invertebrates, and other sources [3]. Consequently, these chemical structures have been employed by chemists as references to scan the diversity space for drug discovery efforts [4]. It is estimated that 50–70% of launched drugs in the marketplace are either natural products themselves or natural product-derived molecules [5]. So, what features of natural products make them effective drug candidates? Natural products play important roles in biomedical research and drug discovery largely attributable to their structural complexity and diversity, which Nature has engineered to facilitate optimal functions of living systems. Structural complexity and diversity enable natural products to modulate biological targets of human diseases. The drug-likeness of natural products often possesses common factors including molecular complexity, ability to bind to proteins, structural rigidity, and three-dimensionality [6]. Comparedwith synthetic molecules, the chemical structures of natural products are more constrained, which allows the accumulation of reliable structure–activity relationship (SAR) data for studying protein target–chemical ligand interactions [7]. Recently, much attention has been devoted to the natural products which are an obvious violation of ‘‘Rule-of-Five’’ [8], but still possess reasonable biopharmaceutical and pharmacokinetic properties, for example, ciclosporin A. Thus, exploitation of such types of natural products could not only significantly broaden the chemical space beyond the ‘‘Rule-of-Five’’ domain for the purpose of drug discovery, but also give us the opportunity to appreciate and investigate how Nature selects and optimizes natural products which are able to bind to and disrupt the function of biological targets through evolution. We should also recognize that natural products were optimized in living systems presumably not for the same purpose as is desired to serve in a biomedical research