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A Breakthrough Method to Accomplish Total Synthesis of Palhinines, Leading to the Potential of Natural Product-Type Drugs

Under the support by Ministry of Science and Technology (MOST) and National Health Research Institutes (NHRI), Dr. Hsing-Pang Hsieh’s research group recently developed a breakthrough method to accomplish the first total synthesis of isopalhinine A, and improve the synthetic efficiency of palhinine A and palhinine D by biomimetic synthetic strategy. The method not only provides shortest synthesis steps with highest synthetic yields, but also will help further biological studies and the potential of novel natural product-type drugs.

 

Natural products are an important source of new structures for drug discovery, more than 50% of approved small molecular drugs are derived from natural products or their pharmacophore groups mimicking natural products. However, due to the difficulty of isolation with a large of quantity, chemical synthesis not only provides critical solution to solve the limitation of accessing, but also aids structure-activity relationship of synthetic analogs to discover natural product-type drugs.

 

The Chinese herbal medicine, Lycopodii Herba, contain many effective components, which Lycopodium alkaloids showed some bioactivities against cancer, infection and diabetes. However, the total synthesis of Lycopodium alkaloids is a big challenge for synthetic chemists due to the complexity of polycyclic structures. Since 2010, five new-type Lycopodium alkaloids, palhinines A-D and isopalhinine A, were isolated and possessed unique 5/6/6/9 tetracyclic or 5/6/6/6/7 pentacyclic structures with the conformationally rigid isotwistane framework.

 

Associate Director Dr. Hsing-Pang Hsieh of NHRI and Prof. Uang, Biing-Jiun of National Tsing Hua University (NTHU) guide PhD student Chih-Ming Chen to FIRST complete the total synthesis of isopalhinine A, and improve the synthetic efficiency of palhinine A and palhinine D by biomimetic synthetic strategy. With the design “bioinspired intermediate” mimicking the biogenetic pathway of palhinine alkaloid to design a “bioinspired intermediate”, isopalhinine A, palhinine A and palhinine D were synthesized less than 20 synthetic steps with the highest yields (5-fold significant improvement) as compared to previous method (nearly 30 synthetic steps). Currently, our research team continues to pursue the first total synthesis of palhinine B and palhinine C, and explore the potential of all synthetic palhinines as natural product-like leads in the areas of anticancer, anti-infection or diabetes.

 

The paper of biomimetic synthesis of isopalhinine A palhinine A, palhinine D was published one of the best chemistry, “Angewandte Chemie International Edition” in November, 2018 (Angew. Chem. Int. Ed. 2018, 57, 15572-15576). The impact factor is over 12. It is also worthy to note that this paper was selected as Synfact of the Month (Synfacts 2019, 15, 1) by Thieme Medical Publishers, Germany.

 

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Last Modified : 2021/08/09