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Pharmacological Study On The Antitumor Activity And Mechanism Of 6-Hydroxylphenanthrozinaridin Alkaloid Derivatives
- Feb 23, 2018 -

Professor Wang Qingmin from Nankai University collaborated with Professor Meng Linghua from Shanghai Institute of Materia Medica, Chinese Academy of Sciences to study the anticancer activity and mechanism of 6-hydroxy-phenanthrozirdine alkaloid derivatives. The compounds were found to have very good anti-cancer activity. Among them, the research on the mechanism of the representative compounds shows that the compounds can block the S-cycle process, inhibit the cell proliferation and exert anti-tumor effect.
Natural products are one of the important sources of antineoplastic drugs. Tylophorine is an alkaloid isolated from Indian vines in 1935. Studies have shown that such alkaloids with phenanthroindolizidine skeleton have strong antitumor, anti-inflammatory and anti-viral effects . Among them, the average growth inhibition IC50 (GI50) of 59 representative tumor cells in NCI anti-tumor candidate compound screening platform DCC-3503 (NSC-716802, 1) was about 10-8 M Inhibit the proliferation of multi-drug resistant tumor cells. Tylocrebrine, a candidate antineoplastic candidate, was once in clinical Phase I studies but was discontinued due to severe neurotoxicity. Although the anti-tumor mechanism of these compounds has been reported more and more at home and abroad, its exact target is still not clear enough.
Professor Wang Qingmin from Nankai University conducted a long-term cooperation with the team of Professor Meng Linghua from Shanghai Institute of Materia Medica, Chinese Academy of Sciences to study the mechanism of the synthesis, anti-cancer structure-activity relationship, Find more effective derivatives, and reveal its new anti-tumor targets.
The previous collaborative study found that the phenanthroindolizidine alkylamine 6-O-desmethylanthofen (6-O-Desmethylantofine) has more antitumor activity than Antofine (Antofine) Quinolidine compounds are structural analogs of phenanthroindolizidine compounds, and the representative compound, Cryptopleurine, shows a higher anticancer activity than the phenanthroindolizidine compounds (Eur J. Med. Chem., 2012, 51, 250-258). Therefore, the authors hypothesized that 6-O-Desmethylcryptopleurine may exhibit higher activity.


The authors designed and synthesized a 6-O-demethyl side of the posaconitine (2) and 6-O-acylation, alkylation products were used to study the position of the substituent on the anti-cancer activity. In order to simultaneously study the effect of compound chirality on activity, the authors also designed a synthetic route for the synthesis of chiral 6-O-demethyl side caustic soda.


The authors screened the target compounds and their intermediates, and found that most of the compounds showed excellent antiproliferative ability against A549 (human lung adenocarcinoma cells) and BEL-7402 (Xiao Chaihu decoction reversed human hepatoma cells), among which The IC50 values for optically pure 2-R and 21-R (median inhibit concentration) are as low as 1 nM.


The authors selected the most active non-natural optical pure 2-R as a representative compound, detected its anti-tumor effect on tumor spectrum and found that 2-R can significantly inhibit the growth of hematological tumors and solid tumor cells, including three multidrug resistance cells , Has a broad spectrum of cytostatic activity. The average IC50 for 30 human tumor cell lines was 2.1 nM, which was significantly better than that of control compound 1 (mean IC50 = 165.4 nM).


In-depth mechanism studies show that 2-R can significantly inhibit the growth and cloning ability of BEL-7402 cells, block cell cycle progression, lead to cell S phase arrest, significantly inhibit DNA synthesis, but can not cause DNA double-stranded Broken. The compound can not induce autophagy in cells, and its high dose and prolonged action on cells can not significantly induce cell apoptosis or death. 2-R also has anti-multidrug resistance effect, and the proliferation inhibitory activity of drug-resistant cells is similar to that of the parental cells, and the RF value is about 1, thereby blocking the cycle progression of drug-resistant cells.
 In summary, the non-natural phenanthridine quinolinyl alkaloid 2-R has broad spectrum anti-tumor activity and is more active than the control compound DCB-3503 (1). Mechanistic studies have shown that 2-R can inhibit the synthesis of DNA, block the S-cycle progression, inhibit cell proliferation, and thus play an antitumor effect. This result is published in Journal of Medicinal Chemistry. Liu Yuxiu, an associate researcher at Nankai University, and Qing Lihua, a master's graduate student at Shanghai Institute of Materia Medica, and Meng Shousong, a master's graduate student at Nankai University, were co-authors. Professor Wang Qingmin and Professor Meng Linghua were co-authors.
 The author of this paper is: Yuxiu Liu, Lihua Qing, Chuisong Meng, Jiajie Shi, Yan Yang, Ziwen Wang, Guifang Han, Yi Wang, Jian Ding, Ling-hua Meng and Qingmin Wang
6-OH-Phenanthroquinolizidine Alkaloid and Its Derivatives Exert Potent Anticancer Activity by Delaying S Phase Progression
J. Med. Chem., 2017, 60, 2764, DOI: 10.1021 / acs.jmedchem.6b01502
Liu Yuxiu, Institute of Elemental Organic Chemistry, Nankai University, associate professor and master tutor. In 1997, he received a master's degree from Nankai University and stayed in the school. In 2003, he received his Ph.D. from Nankai University. In 2008, he was a visiting scholar at the University of West Virginia in the United States .
His research interests include molecular design, organic synthesis, structure-activity relationship and mechanism study of bioactive compounds. He is the author of more than 60 papers on SCI published in relevant fields, including the first author Or more than 30 correspondence authors.

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