Biocatalysis at Work: Applications in the Development of Sagopilone.
For the antitumour agent sagopilone, an epothilone analogue, a large-scale synthesis was developed to synthesise the active pharmaceutical ingredient for clinical trials, exploring enzymatic and microbial methods to produce chiral building blocks on a multi-kilogram scale. The three building blocks were identified as key intermediates in the synthesis and needed to be produced with high optical purity in yields higher than those previously published. The improved syntheses of two of these building blocks are detailed herein. For building block A, the chemical research synthesis was abandoned, and a novel chemical route was developed leading to building block A via an enzymatic hydrolysis process. For building blocks C, replacement of a chemical catalytic procedure by a microbial process meant that the development of a new starting material could be avoided, thereby accelerating the development process. For the clinical development process, a human metabolite of sagopilone was required as a reference. To accelerate the synthesis of the metabolite, no chemical synthesis was investigated; rather, we relied solely on oxidoreductases. The human metabolite of sagopilone was synthesised on a multi-gram scale in a single-step process using genetically engineered E. coli expressing human cytochrome P450 enzyme 2C19. The integration of enzymatic and microbial processes provided tools that enable the synthesis of highly functionalised intermediates and metabolites.
['Gottfried|Kathrin|K|', 'Klar|Ulrich|U|', 'Platzek|Johannes|J|', 'Zorn|Ludwig|L|']
D052160:Benzothiazoles D055162:Biocatalysis D065731:Cytochrome P-450 CYP2C19 D034261:Epothilones D005818:Genetic Engineering D006801:Humans D010088:Oxidoreductases
biocatalysis oxidoreductases enzymes antitumor agents gene expression