标题：Discovery of 4,6-O-Thenylidene-beta-D-glucopyranoside-(2 ''-acetamido, 3 ''-acetyl-di-S-5-fluorobenzothizole/5-fluorobenzoxazole)-4 '-demethylepipodophyllotoxin as Potential Less Toxic Antitumor Candidate Drugs by Reducing DNA Damage and Less Inhibition of PI3K
作者：Cheng, Jie; Zhao, Wei; Yao, Hui; Shen, Yuemao; Zhang, Youming; Li, Yue-zhong; Qi, Qingsheng; Wongprasert, Kanokpan; Tang, Ya-Jie
作者机构：[Zhao, Wei; Shen, Yuemao; Zhang, Youming; Li, Yue-zhong; Qi, Qingsheng; Tang, Ya-Jie] Shandong Univ, State Key Lab Microbial Technol, Qingdao 266237, 更多
通讯作者地址：Tang, YJ (corresponding author), Shandong Univ, State Key Lab Microbial Technol, Qingdao 266237, Peoples R China.
来源：JOURNAL OF MEDICINAL CHEMISTRY
摘要：As an FDA-approved drug, teniposide, was utilized in cancer treatment but was accompanied by a strong side effect in long-term clinical trials. This work discovered potential candidate drugs with low toxicity by modifying the molecule structure of teniposide through a structure-guided drug design approach. The IC50 value of novel 4,6-O-thenylidene-beta-D-glucopyranoside-(2 ''-acetamido, 3 ''-acetyl-di-S-5-fluorobenzothizole/5-fluorobenzoxazole)-4'-demethylepipodophyllotoxin (compounds 15 and 16) was 120.4-125.1 mu M, which was significantly improved by around 10 times more than teniposide (11.5-22.3 mu M) against healthy human cells (i.e., HL-7702, H8, MRC-5, and HMEC). In vivo studies demonstrated compounds 15 and 16 significantly suppressed the tumor growth in the HepG2 cell xenograft model without exhibiting obvious toxicity (LD50 values of 208.45 and 167.52 mg/kg), which was lower than that of teniposide (LD50 = 46.12 mg/kg). Compounds 15 and 16 caused mild gamma H2AX phosphorylation for low DNA toxicity and less inhibition of PI3K/Akt. Compounds 15 and 16 might be potential antitumor drugs with low toxicity.