National Key Laboratory of Agricultural Microbiology, College of Life Science and Technology, Huazhong Agricultural University, 1 Shizishan Street, Wuhan, 430070, P.R. China.
College of Chemistry, Huazhong Agricultural University, 1 Shizishan Street, Wuhan, 430070, P.R. China.
Chemistry. 2024 Jun 6;30(32):e202400454. doi: 10.1002/chem.202400454. Epub 2024 Apr 30.
Rivastigmine is one of the several pharmaceuticals widely prescribed for the treatment of Alzheimer's disease. However, its practical synthesis still faces many issues, such as the involvement of toxic metals and harsh reaction conditions. Herein, we report a chemo-enzymatic synthesis of Rivastigmine. The key chiral intermediate was synthesized by an engineered alcohol dehydrogenase from Lactobacillus brevis (LbADH). A semi-rational approach was employed to improve its catalytic activity and thermal stability. Several LbADH variants were obtained with a remarkable increase in activity and melting temperature. Exploration of the substrate scope of these variants demonstrated improved activities toward various ketones, especially acetophenone analogs. To further recycle and reuse the biocatalyst, one LbADH variant and glucose dehydrogenase were co-immobilized on nanoparticles. By integrating enzymatic and chemical steps, Rivastigmine was successfully synthesized with an overall yield of 66 %. This study offers an efficient chemo-enzymatic route for Rivastigmine and provides several efficient LbADH variants with a broad range of potential applications.
重酒石酸卡巴拉汀是广泛用于治疗阿尔茨海默病的几种药物之一。然而，其实际合成仍面临许多问题，如涉及有毒金属和苛刻的反应条件。在此，我们报告了重酒石酸卡巴拉汀的化学酶法合成。关键的手性中间体是通过短乳杆菌（LbADH）工程化的醇脱氢酶合成的。采用半理性方法提高其催化活性和热稳定性。获得了几个 LbADH 变体，其活性和熔点有显著提高。对这些变体的底物范围的探索表明，它们对各种酮，特别是苯乙酮类似物的活性提高。为了进一步回收和再利用生物催化剂，将一种 LbADH 变体和葡萄糖脱氢酶共固定在纳米颗粒上。通过整合酶促和化学步骤，成功地以 66%的总收率合成了重酒石酸卡巴拉汀。本研究为重酒石酸卡巴拉汀提供了一种有效的化学酶法合成路线，并提供了几种具有广泛潜在应用的高效 LbADH 变体。
