Pan Weidong team, Key Laboratory of natural product chemistry, Chinese Academy of Sciences, Guizhou Province: design, synthesis and antitumor activity of tetrandrine A and B derivatives

The active molecules from natural sources have always been an important source of new anti-tumor drugs The structure of dibenzylisoquinoline alkaloids is diverse and their pharmacological activities are outstanding Therefore, the structural derivatization is undoubtedly one of the important ways to find new anti-tumor candidate drugs Tetrandrine A and tetrandrine B are 18 membered double ether linked double benzyl isoquinoline alkaloids derived from Stephania tetrandra S Moore They have attracted the attention of many teams due to their anti pulmonary fibrosis, reversal of multidrug resistance and other pharmacological effects Pan Weidong, a member of Pan Weidong's team from the Key Laboratory of natural product chemistry, Chinese Academy of Sciences, Guizhou Province (the National Key Laboratory of medicinal plant efficacy and utilization jointly established by the Ministry of Guizhou Province), has been studying the separation, purification and biological function of this alkaloid since 2007 Through cooperation with Professor Feng Yibin of the school of traditional Chinese medicine of Hong Kong University, it was found that tetrandrine B has good anti hepatoma cell activity, and It was found that it was different from tetrandrine in the mechanism of inducing apoptosis of hepatoma cells, but by inducing autophagic death of hepatoma cells to play an anti hepatoma activity The research results were published in British Journal of Pharmacology (BR J Pharmacol., 2011, 164, 731-742) In recent years, pan Weidong's team has been committed to the research on the follow-up structural modification, total synthesis, antitumor activity and mechanism of tetrandrine A and B, in order to obtain more selective and drug-resistant candidate drug molecules The related research results have been published in European Journal of Medical Chemistry (EUR J Med Chem 2017, 127, 554-566; EUR J Med Chem 2018, 143, 1968-1980) and molecules Pan Weidong team profile pan Weidong team has 7 fixed staff members, including 3 doctoral candidates Now there are 2 postdoctoral students, 2 doctoral students and 12 postgraduate students He is mainly engaged in the research of pharmaceutical chemistry and synthesis methodology based on natural products Researcher pan Weidong, male, 44 years old, doctoral supervisor, winner of Guizhou provincial government special allowance and Guizhou provincial management expert In October 2005, he graduated from the sixth University of Paris, France, majoring in molecular chemistry and received his Ph.D in science From 2005 to 2007, he was engaged in the postdoctoral research of bioorganic chemistry at Namur University, Belgium At present, he is a researcher in the Key Laboratory of natural product chemistry, Chinese Academy of Sciences, Guizhou Province (the Key Laboratory of natural product chemistry, Guizhou Medical University), deputy director and discipline leader of the State Key Laboratory of medicinal plant efficacy and utilization jointly established by the Ministry of Guizhou Province He has been selected into the "light of the west" talent plan of the Chinese Academy of Sciences, the "ten, one hundred and one thousand" talent training plan of Guizhou Province, and the excellent young scientific and technological talents of Guizhou Province It has successively won the 12th Youth Science and technology award of Guizhou Province, the first prize of science and technology progress of Guizhou Province and the third prize of natural science of Guizhou Province He is mainly engaged in the research of natural pharmaceutical chemistry, with the main research directions as follows: 1) the discovery, total synthesis and derivative synthesis of natural pharmaceutical active lead compounds; 2) the research of pesticide from plant (monomer or compound preparation) He has successively presided over more than 20 scientific research projects such as the major science and technology special project of "major new drug creation" of the Ministry of science and technology and the National Fund (5 projects) More than 80 papers have been published on relevant research results, including more than 50 SCI papers published by the first or corresponding author; 8 domestic and foreign patents have been applied, including 2 PCT international patents (1 patent authorized by the United States) Cutting edge research achievements: the design, synthesis and antitumor activity of tetrandrine A and B derivatives of tetrandrine by Pan Weidong, the Key Laboratory of natural product chemistry, Chinese Academy of Sciences, Guizhou Province In the early stage, pan Weidong's team carried out a large number of structural modifications on the 5, 7 and 14 positions of a (for specific structure and biological activity, please refer to the literature EUR J Med Chem 2017, 127, 554-566; EUR J Med Chem 2018, 143, 1968-1980; Med Chem Commun 2018, 9, 1131; m olecules 2017, 22, 1923) In particular, benzoyl group at 7-position and nitro group at 14-Position showed antitumor effects on five tumor cell lines (HEL, K562, MDA-MB-231, PC3 and wm9) Pan Weidong group applied molecular docking technology to screen the target, and determined AKT1 as its potential target On this basis, a series of tetrandrine 7-ester derivatives were designed and synthesized The design route is shown in Figure 1 Fig 1 The design route of tetrandrine 7-ester derivatives (source: EUR J Med Chem) a total of 25 tetrandrine derivatives were synthesized, and their anti proliferation activities on human leukemia cell lines hel and K562, breast cancer cell lines MDA-MB-231 and MCF-7 were detected by MTT method The results showed that 7-oh-h (compound 3e) substituted by 2-thiophene formyl chloride showed good anti proliferation activity on these cell beads, and the inhibition of cell growth of HEL cells by 3E compound was related to cell cycle arrest of G0 / G1 cells (Fig 2) and apoptosis induced by inhibition of PI3K / Akt and MAPK pathways (Fig 3) Fig 2 and Fig 3 E affect cell cycle and induce apoptosis of Hel cell line (source: EUR J Med Chem) Fig 3 and Fig 3E inhibit PI3K / Akt and MAPK signaling pathway of Hel cell line (source: EUR J Med Chem) In order to further explore the mechanism of Akt inhibition of this compound, we use the Akt kinase was measured in HEL cells Molecular docking analysis did show that the high affinity interaction between 3E and Akt resulted in kinase inactivation Figure 4 Prediction of the binding mode of 3E compound and protein KAT1: the binding structure of 3E and AKT1 is gray, and hanfanghexin is yellow; B 3E interacts with AKT1 plane; C interaction between hanfanghexin and AKT1 plane; D plane binding interaction of eutectic ligand g4k and AKT1 (source: EUR J Med Chem) This achievement was recently published in European Journal of Medical Chemistry (J Yang, S Hu, C W pan et al Fangchinoline derivatives induce cell cycle arrest and apoptosis in human leukemia cell lines via suppression of the PI3K / Akt and MAPK signaling pathway, European Journal of Medical Chemistry (2019), Doi: 10.1016/j.ejmech.2019.111898) Yang Jin and Hu Shengcao, graduate students, jointly wrote the paper Pan Weidong, Yaacov Ben David and fan Yanhua are co authors This research work was supported by the National Natural Science Foundation, Guizhou science and Technology Fund and Guizhou natural medicine engineering research center Nowadays, people and scientific research have been paid more and more attention in the economic life China has ushered in the "node of science and technology explosion" Behind the progress of science and technology is the work of countless scientists In the field of chemistry, in the context of the pursuit of innovation driven, international cooperation has been strengthened, the influence of Returned Scholars in the field of R & D has become increasingly prominent, and many excellent research groups have emerged in China For this reason, CBG information adopts the 1 + X reporting mechanism CBG information website, chembeangoapp, chembeango official micro blog, CBG information wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the representative research groups in China, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.