Diverted total synthesis

Ixabepilone

Epothilone A B

Carfilzomib structure

Epoxomicin

Eravacycline structure

Diverted Total Synthesis (DTS) is a strategy in organic chemistry and medicinal chemistry that involves modifying the route of a total synthesis of a complex organic molecule to create analogs of the target molecule. This approach is particularly useful in the development of pharmaceuticals, as it allows chemists to explore the structure-activity relationship (SAR) of a compound more efficiently. By understanding how changes in the molecule's structure affect its biological activity, researchers can optimize its properties for use as a drug.

Overview

The concept of diverted total synthesis builds upon the principles of total synthesis, which is the complete chemical synthesis of complex organic molecules from simpler, commercially available precursors. In DTS, once the synthesis route of the target molecule is established, chemists divert the synthesis pathway at strategic points to introduce variations into the molecule's structure. This method is advantageous for generating libraries of analogs, which are crucial for drug discovery and development processes.

Applications in Drug Discovery

Diverted total synthesis has become a valuable tool in drug discovery and development. By generating analogs of a biologically active compound, researchers can investigate the effects of structural changes on the compound's pharmacological properties. This information is vital for identifying the most promising candidates for further development into therapeutic agents. DTS is particularly useful for optimizing the potency, selectivity, and pharmacokinetic properties of compounds.

Advantages

The primary advantage of diverted total synthesis is its efficiency in exploring chemical space around a molecule of interest. Traditional methods of analog generation, such as parallel synthesis, can be time-consuming and resource-intensive. DTS, on the other hand, allows for the rapid synthesis of analogs by leveraging the existing synthetic route. This approach can significantly accelerate the drug discovery process, reducing the time and cost associated with bringing a new drug to market.

Challenges

Despite its advantages, diverted total synthesis also presents several challenges. The success of a DTS approach depends heavily on the flexibility of the synthetic route to the target molecule. Some routes may not easily allow for diversification, limiting the range of analogs that can be synthesized. Additionally, the complexity of the synthetic route can impact the overall efficiency of the DTS process, as more complex routes may require more steps to introduce variations.

Future Directions

As the field of organic and medicinal chemistry continues to evolve, diverted total synthesis is likely to play an increasingly important role in drug discovery and development. Advances in synthetic methodology, such as the development of new catalytic reactions and the application of computational chemistry for route planning, are expected to overcome some of the current limitations of DTS. Furthermore, the integration of DTS with other drug discovery technologies, such as high-throughput screening and machine learning, holds the potential to further enhance the efficiency and effectiveness of this approach.