Exploring a unique path for hybrid molecules

In recent years, extensive research has demonstrated the ability of natural products to modulate protein-protein interactions (PPI), either by activating or inhibiting them. These natural products exhibit remarkable complexity, possessing intricate three-dimensional architectures with multiple chiral centers, and a diverse array of protein-binding elements. In Figure 1, we present three bioactive natural products that have been identified for their interference with protein-protein interactions. Analogues of these compounds have been found to bind to the β-subunit of the tubulin heterodimer, thereby stabilizing the heterodimer. This interaction enhances tubulin polymerization into microtubules and induces cell cycle arrest, ultimately leading to programmed cell death. Other natural products, such as epothilones, discodermolide, and laulimalide (structures not shown), have also been discovered in recent years for their microtubule-stabilizing properties. Similar to taxol, these natural products serve as promising lead compounds for the development of novel antitumor agents.

Rapamycin (F1.2) interacts with a protein called FKBP12, forming a small molecule-protein complex that can associate with FRAP, a critical downstream signaling component of the PI3K/Akt pathway. Therefore, rapamycin acts as a chemical inducer of dimerization (CID). Rapamycin and its derivatives have proven valuable as tools for modulating protein-protein interactions and have significantly contributed to our understanding of the pathways involved in these interactions.

Chlorofusin (F1.3), a novel fungal metabolite, was identified as an inhibitor of the binding between p53 and MDM2 during a screening of 5300 microbial extracts. The p53 tumor suppressor protein has a short lifespan due to rapid proteasomal degradation. Upon exposure to various stress stimuli, p53 levels increase, leading to the activation of gene expression programs that inhibit cell growth or induce apoptosis. MDM2 plays a crucial role in regulating the stability of p53 by directly interacting with it and promoting its ubiquitination and neddylation. By targeting a hydrophobic cleft in MDM2, which serves as a critical site for MDM2-p53 interaction, small-molecule interventions can disrupt this interaction. Since tumors often overexpress MDM2, it was hypothesized that small molecules could be used to interfere with p53-MDM2 interactions in tumor cells, leading to cell cycle arrest or apoptosis. Chlorofusin, despite its complex nature, has been identified as an antagonist of MDM2 and shows promising potential as a lead compound in this regard.

The examples discussed above clearly highlight the ability of natural products to interfere with biomacromolecular interactions, particularly protein-protein interactions. Such characteristics are vital for investigating protein functions using small molecules. Small-molecule chemical probes have immense potential for selective and reversible modulation of proteins. Consequently, the interest in developing novel chemical approaches to create architecturally complex compounds, similar to natural products, has grown significantly. These compounds could greatly aid in understanding cellular signaling pathways based on protein-protein interactions. To contribute to this goal, our research group has embarked on a program aimed at developing a synthesis method for enantioenriched tetrahydroquinoline scaffolds inspired by natural products.