Publication: Discovery of 4,6- O-Thenylidene-β- 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
Issued Date
2020-03-26
Resource Type
ISSN
15204804
00222623
00222623
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2-s2.0-85082542705
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Mahidol University
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SCOPUS
Bibliographic Citation
Journal of Medicinal Chemistry. Vol.63, No.6 (2020), 2877-2893
Suggested Citation
Jie Cheng, Wei Zhao, Hui Yao, Yuemao Shen, Youming Zhang, Yue Zhong Li, Qingsheng Qi, Kanokpan Wongprasert, Ya Jie Tang Discovery of 4,6- O-Thenylidene-β- 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. Journal of Medicinal Chemistry. Vol.63, No.6 (2020), 2877-2893. doi:10.1021/acs.jmedchem.9b01354 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/54467
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Title
Discovery of 4,6- O-Thenylidene-β- 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
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Abstract
Copyright © 2020 American Chemical Society. 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-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 (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 γH2AX phosphorylation for low DNA toxicity and less inhibition of PI3K/Akt. Compounds 15 and 16 might be potential antitumor drugs with low toxicity.