Development of the “Molecular Glue” Using Hybridization of Natural Products

<p>Natural product chemistry has entered a mature phase, where the total synthesis of a variety of natural products has been achieved and can then promote structure-activity relationship studies and chemical biology research. However, bioorganic and chemical biological researches on natural products that are challenging to synthesize because of the large sizes and the structural complexities, are currently at a standstill. We have been working on the mystery of aplyronine A for almost 30 years from its isolation in 1993 to the present day and have clarified the mechanism of actions to a certain extent. In this article, we introduce our research to create ‘useful molecules’ based on aplyronine A as medicinal chemistry and chemical biology tools, which evolve further aplyronine A. Thus, we designed and synthesized aplyronine A-swinholide A hybrid 5, which consists of the macrolactone part of aplyronine A (1) and the side chain part of swinholide A (4). Hybrid 5 retained not only a strong actin-depolymerizing activity but also a potent cytotoxicity, which is much stronger than that of aplyronine A-mycalolide B hybrid (3) reported previously. In addition, hybrid 5 induces protein-protein interactions between actin and tubulin in the same manner as aplyronine A. These results showed that the substitution patterns and configurations at C24-C26 positions in the side chain are essential for the strong cytotoxicity of aplyronine A-type compound. Furthermore, we conducted the structure-activity relationship studies about the amino acid moiety at C7 using hybrid 5 and found that the methoxy group of the trimethylserine ester group is important for potent cytotoxicity. In addition, comparing the side chain analogs of aplyronine A and swinholide A, we clarified that the side chain analog of swinholide A had a weaker actin-depolymerizing activity than that of aplyronine A. These studies have provided important findings into the mechanism of cytotoxicity of the “molecular glue” between two major cytoskeletons, actin and tubulin.</p>