| Autor: |
Cheng J; Hubei Key Laboratory of Industrial Microbiology, Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, China., Zhao W; State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China., Yao H; Hubei Key Laboratory of Industrial Microbiology, Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, China., Shen Y; State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China., Zhang Y; State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China., Li YZ; State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China., Qi Q; State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China., Wongprasert K; Department of Anatomy, Faculty of Science, Mahidol University, Rama Sixth Road, Bangkok 10400, Thailand., Tang YJ; State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China. |
| Abstrakt: |
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 IC 50 value of novel 4,6- O -thenylidene-β-d-glucopyranoside-(2″-acetamido, 3″-acetyl-di- S -5-fluorobenzothizole/5-fluorobenzoxazole)-4'-demethylepipodophyllotoxin (compounds 15 and 16 ) was 120.4-125.1 μM, which was significantly improved by around 10 times more than teniposide (11.5-22.3 μM) 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 (LD 50 values of 208.45 and 167.52 mg/kg), which was lower than that of teniposide (LD 50 = 46.12 mg/kg). Compounds 15 and 16 caused mild γH2AX phosphorylation for low DNA toxicity and less inhibition of PI3K/Akt. Compounds 15 and 16 might be potential antitumor drugs with low toxicity. |
