Toward High-Throughput Synthesis of Complex Natural Product-Like Compounds in the Genomics and Proteomics Age

Abstract

In the age of high-throughput biology, novel genes and proteins are emerging quickly. The need for developing organic synthesis-derived methods that allow rapid access to polyfunctional, complex natural product-like compounds is growing constantly, largely because these small-molecule-based compounds serve as smart, powerful tools both in understanding the roles and functions of emerging biological targets and in validating their biological responses. Developing asymmetric synthesis-derived organic reactions on solid phase allows the synthesis of complex natural product-like compounds in a high-throughput manner. Solid phase organic synthesis is now commonly utilized in the library synthesis of rather simple compounds (i.e., compounds with no multiple stereogenic centers). With few exceptions, the synthesis of complex natural product-like derivatives is still in its infancy. Some recent efforts made in this area indicate opportunities yet to be explored.

The evolution of gene collectives: How natural selection drives chemical innovation

“…To perform this task efficiently, we will have to know the rules that govern gene cluster evolution in the real world. By further developing our knowledge of the rules Nature uses to diversify its small molecules, we can facilitate the efforts of chemists to synthesize libraries of small molecules that are ''natural product-like'' and therefore, more likely to have useful biological activities (31). In what follows, we look forward by considering two fundamental questions: How do gene clusters propagate by horizontal transfer?…”

The Role of Natural Product Chemistry in Drug Discovery

“…In an interesting development, some groups and companies have begun to synthesize more complex structures to match the chemical space occupied by NPs, and this has been described as "diversity orientated synthesis" (DOS) by Schreiber. 75, 76 NPs have been used also as starting templates in the synthesis of combinatorial libraries. 73,77-81 NP pharmacophores are well represented in lists of "privileged structures", which makes them ideal candidates for building blocks for biologically relevant chemical libraries.…”

Advances in Solution- and Solid-Phase Synthesis toward the Generation of Natural Product-like Libraries

“…Parallel to this approach, the goal of DOS is to populate the unexplored chemical space by developing methods that allow rapid access to natural product-like compounds having three-dimensionally complex architectures. 1,[70][71][72][73][74][75][76][77][78][79][80][81][82][83] In addition to generating the libraries of natural product derivatives, interest is also growing in developing methods for obtaining bioactive natural product-inspired scaffolds. These scaffolds could then be utilized in the library generation protocols.…”