Design and synthesis of novel 4'-demethyl-4-deoxypodophyllotoxin derivatives as potential anticancer agents

Bioorg Med Chem Lett. 2016 Feb 15;26(4):1360-4. doi: 10.1016/j.bmcl.2015.06.089.

Xiong Zhu ¹, Junjie Fu ², Yan Tang ¹, Yuan Gao ³, Shijin Zhang ¹, Qinglong Guo ⁴

Affiliations

1 Medicinal and Chemical Institute, China Pharmaceutical University, Nanjing 210009, PR China.
2 Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610, United States.
3 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, PR China.
4 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: anticancer_drug@163.com.

PMID: 26804229 DOI: 10.1016/j.bmcl.2015.06.089

Abstract

A group of podophyllotoxin (PPT) derivatives (7a-j) were synthesized by conjugating aryloxyacetanilide moieties to the 4'-hydroxyl of 4'-demethyl-4-deoxypodophyllotoxin (DDPT), and their Anticancer activity was evaluated. It was found that the most potent compound 7d inhibited the proliferation of three Cancer cell lines with sub to low micromolar IC50 values. Furthermore, it was demonstrated that 7d induced cell cycle arrest in G2/M phase in MGC-803 cells, and regulated the expression of cell cycle check point proteins, such as cyclin A, cyclin B, CDK1, cdc25c, and p21. Finally, 4 mg/kg of 7d reduced the weights and volumes of HepG2 xenografts in mice. Our findings suggest that 7d might be a potential Anticancer agent.

Keywords

Anticancer; Aryloxyacetanilide; Cell cycle; Cyclin; Podophyllotoxin.

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