Structural diversity of nature

The structural diversity of natural products with antimalarial activity from marine and freshwater sources are stunning, ranging from isonitrile-containing derivatives to depsipeptides through peroxides and alkaloids. 

Considering the structural diversity of natural products, the structures of DNA and RNA are simple. All their components, called nucleotides, are polyfunctional, and it is one of the wonders of nature that evolution has eliminated all but a few specific combinations. Nucleic acids are polymers in which phosphate units link sugars, which bear various heterocyclic nitrogen bases (Figure 26-10). 

Replacement of coded L-amino acids with d-amino acids is a common strategy in peptide drugs. However, it must be stressed that D-amino acids are far from unknown in nature and can even be found in animal peptides, where they are usually formed from L-amino acids by a post-translational reaction [208], It appears that this mechanism increases the structural diversity of products that can be synthesized from one gene, thus increasing the scope of evolution by natural selection. In other words, the incorporation of D-amino acids into peptides is a strategy discovered by evolution and rediscovered by chemists. 

The structural modification of natural products is useful in several ways. The known pharmacology of bisindole alkaloids is enriched by the diversity of chemical structures that are made available by structure modification and total synthesis. These molecules have served as biochemical probes in several areas of biology, especially in those of microtubule assembly and drug resistance. The most elusive prize, however, has remained the discovery of new compounds with clinical activity. In recent years several compounds have been evaluated in clinical trials, but vinblastine and vincristine remain the only bisindole alkaloids approved for the treatment of cancer in the United States. These compounds are joined by vindesine in Europe, and at least two new derivatives are the subject of ongoing clinical trials. Considering the breadth of chemical research in this area, the overall yield as measured by new compounds with clinical activity has been relatively low, but this observation is not unique in history of analog development in cancer research. Nevertheless, the search continues, and this chapter details the chemical endeavors to discover a new bisindole alkaloid with clinical activity. 

The structural and biological diversity of naturally occurring endoperoxides is further illustrated by the antimalarial cardamom peroxide (7) containing a 7-membered ring cyclic peroxide moiety , and by the tremorgenic verruculogen (8) containing an 8-membered endoperoxide system (Chart 1) . 

---