Catalytic Enantioselective Synthesis of Meta Benzene Isosteres for Improved Pharmaceutical Properties

Konsep Inti

Catalytic enantioselective synthesis of chiral boron-containing nortricyclanes as isosteric replacements for meta-disubstituted aromatic rings in pharmaceuticals, offering improved biophysical properties and stereochemistry-dependent activity.

Abstrak

The article discusses the limitations of aromatic rings in pharmaceutical compounds and the potential benefits of replacing them with non-aromatic isosteric motifs. Aromatic rings can lead to suboptimal potency, metabolic stability, solubility, and lipophilicity, while their planar and achiral nature may not fit well with the chiral binding pockets of many pharmaceutical targets.

The authors present a novel palladium-catalyzed reaction that converts hydrocarbon-derived precursors into chiral boron-containing nortricyclanes, which they propose as plausible isosteres for meta-disubstituted aromatic rings. This catalytic enantioselective reaction provides access to a broad array of nortricyclane structures, which can then be further transformed.

The authors demonstrate that incorporating nortricyclanes into pharmaceutical motifs can result in improved biophysical properties, as well as stereochemistry-dependent activity. They anticipate that the simple and inexpensive synthesis of the functionalized nortricyclane scaffold will make this platform a useful foundation for the assembly of new biologically active agents.

Statistik

Aromatic rings in pharmaceuticals can lead to suboptimal potency, metabolic stability, solubility, and lipophilicity.
Aromatic rings are planar and lack three-dimensionality, while most pharmaceutical targets have chiral binding pockets.
The catalytic enantioselective reaction converts hydrocarbon-derived precursors into chiral boron-containing nortricyclanes.
Incorporating nortricyclanes into pharmaceutical motifs can result in improved biophysical properties and stereochemistry-dependent activity.

Kutipan

"A notable impediment to this approach is the lack of simple and scalable catalytic enantioselective syntheses of candidate isosteres from readily available precursors."
"We also show that the incorporation of nortricyclanes into pharmaceutical motifs can result in improved biophysical properties along with stereochemistry-dependent activity."

Wawasan Utama Disaring Dari

Catalytic asymmetric synthesis of meta benzene isosteres - Nature

by Mingkai Zhan... pada www.nature.com 08-21-2024

https://www.nature.com/articles/s41586-024-07865-4

Pertanyaan yang Lebih Dalam

How can the catalytic enantioselective synthesis of nortricyclanes be further optimized and scaled up for industrial applications?

The optimization and scaling up of the catalytic enantioselective synthesis of nortricyclanes for industrial applications can be achieved through several strategies. Firstly, the development of more efficient chiral catalysts that can enhance the enantioselectivity of the reaction is crucial. This can involve exploring different ligands, tuning reaction conditions, and conducting extensive screening to identify the most effective catalysts. Additionally, process optimization to increase the reaction yield and reduce by-products is essential for industrial scalability. This may involve fine-tuning reaction parameters such as temperature, pressure, and solvent choice. Furthermore, the development of continuous flow processes can streamline the synthesis and improve productivity. Continuous flow systems offer better control over reaction conditions, higher throughput, and easier scale-up compared to batch processes. Lastly, collaboration with chemical engineering experts to design efficient reactor systems and purification methods can further optimize the synthesis of nortricyclanes for large-scale production.

What are the potential limitations or drawbacks of using nortricyclanes as isosteric replacements for aromatic rings in pharmaceutical compounds?

While nortricyclanes show promise as isosteric replacements for aromatic rings in pharmaceutical compounds, there are potential limitations and drawbacks to consider. One major concern is the novelty and unfamiliarity of nortricyclanes in drug design, which may lead to challenges in regulatory approval and acceptance in the pharmaceutical industry. Additionally, the synthesis of chiral nortricyclanes may be complex and costly, especially on an industrial scale, which could impact the overall cost-effectiveness of drug development. Another limitation is the limited structural diversity of nortricyclanes compared to aromatic rings, which may restrict their applicability in a wide range of drug targets. Furthermore, the biotransformation and metabolic stability of nortricyclanes in vivo need to be thoroughly evaluated to ensure their safety and efficacy as drug candidates. Overall, while nortricyclanes offer exciting opportunities as isosteric replacements, their limitations in terms of synthesis, structural diversity, and regulatory considerations should be carefully addressed.

What other types of non-aromatic isosteric motifs could be explored as alternatives to aromatic rings in drug design, and how do they compare to the nortricyclane platform?

In drug design, several non-aromatic isosteric motifs can be explored as alternatives to aromatic rings, offering diverse options for optimizing drug properties. One such motif is the bioisostere sulfur, which can replace oxygen in heterocyclic rings to enhance metabolic stability and binding affinity. Sulfur-containing compounds like thiazoles and thiophenes have shown promising pharmacological activities and are widely used in drug discovery. Another isosteric replacement is the spirocyclic motif, which introduces three-dimensionality and rigidity into the molecule, potentially improving receptor binding and selectivity. Spirocyclic compounds have been utilized in drug design to enhance potency and pharmacokinetic properties. Moreover, the use of cyclic sulfonamides as isosteres for amides has gained attention due to their improved stability and bioavailability. These motifs offer unique advantages in drug design, complementing the nortricyclane platform by providing alternative strategies to modulate drug-receptor interactions and optimize pharmacological properties.