Biocatalysis at Work: Applications in the Development of Sagopilone

Area of Science:

• Pharmaceutical Chemistry
• Biocatalysis
• Process Development

Background:

• Sagopilone, an epothilone analogue, requires large-scale synthesis for clinical trials.
• Key chiral building blocks (A and C) needed improved synthesis with high optical purity and yield.
• A human metabolite of sagopilone was required for clinical development.

Purpose of the Study:

• To develop scalable, high-yield, and high-optical purity syntheses for sagopilone intermediates.
• To establish a rapid synthesis for a sagopilone human metabolite.
• To integrate enzymatic and microbial processes for efficient pharmaceutical intermediate production.

Main Methods:

• Novel enzymatic hydrolysis for building block A synthesis.
• Microbial process replacement for chemical catalysis in building block C synthesis.
• Genetically engineered E. coli expressing human cytochrome P450 enzyme 2C19 for metabolite synthesis.

Main Results:

• Improved synthesis of building blocks A and C with higher yields and optical purity.
• Successful multi-gram scale, single-step synthesis of the sagopilone human metabolite.
• Demonstrated feasibility of integrating biocatalysis for complex molecule synthesis.

Conclusions:

• Enzymatic and microbial processes offer efficient and scalable routes for pharmaceutical intermediates and metabolites.
• Biocatalysis accelerates drug development by simplifying synthesis pathways.
• This approach provides valuable tools for producing highly functionalized molecules.