Synthesis and Biological Evaluation of Novel Allobetulon/Allobetulin–Nucleoside Conjugates as AntitumorAgents
Yanli Wang,
Xiaowan Huang,
Xiao Zhang,
Jingchen Wang,
Keyan Li,
Guotao Liu,
Kexin Lu,
Xiang Zhang,
Chengping Xie,
Teresa Zheng,
Yung-Yi Cheng,
Qiang Wang
Affiliations
Yanli Wang
School of Medicine, Huanghe Science and Technology College, Zhengzhou 450063, China
Xiaowan Huang
High & New Technology Research Center, Henan Academy of Science, Zhengzhou 450002, China
Xiao Zhang
BGI College & Henan Institute of Medical and Pharmaceutical Science, Zhengzhou University, Zhengzhou 450052, China
Jingchen Wang
BGI College & Henan Institute of Medical and Pharmaceutical Science, Zhengzhou University, Zhengzhou 450052, China
Keyan Li
National Health Commission Key Laboratory of Birth Defect Prevention, Henan Institute of Reproductive Health Science and Technology, Zhengzhou 450002, China
Guotao Liu
National Health Commission Key Laboratory of Birth Defect Prevention, Henan Institute of Reproductive Health Science and Technology, Zhengzhou 450002, China
Kexin Lu
BGI College & Henan Institute of Medical and Pharmaceutical Science, Zhengzhou University, Zhengzhou 450052, China
Xiang Zhang
High & New Technology Research Center, Henan Academy of Science, Zhengzhou 450002, China
Chengping Xie
High & New Technology Research Center, Henan Academy of Science, Zhengzhou 450002, China
Teresa Zheng
Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7568, USA
Yung-Yi Cheng
Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7568, USA
Qiang Wang
School of Medicine, Huanghe Science and Technology College, Zhengzhou 450063, China
Allobetulin is structurally similar tobetulinic acid, inducing the apoptosis of cancer cells with low toxicity. However, both of them exhibited weak antiproliferation against several tumor cell lines. Therefore, the new series of allobetulon/allobetulin–nucleoside conjugates 9a–10i were designed and synthesized for potency improvement. Compounds 9b, 9e, 10a, and 10d showed promising antiproliferative activity toward six tested cell lines, compared to zidovudine, cisplatin, and oxaliplatin based on their antitumor activity results. Among them, compound 10d exhibited much more potent antiproliferative activity against SMMC-7721, HepG2, MNK-45, SW620, and A549 human cancer cell lines than cisplatin and oxaliplatin. In the preliminary study for the mechanism of action, compound 10d induced cell apoptosis and autophagy in SMMC cells, resulting in antiproliferation and G0/G1 cell cycle arrest by regulating protein expression levels of Bax, Bcl-2, and LC3. Consequently, the nucleoside-conjugated allobetulin (10d) evidenced that nucleoside substitution was a viable strategy to improve allobetulin/allobetulon’s antitumor activity based on our present study.
