Discovery of 4,6--Thenylidene-β-d-glucopyranoside-(2″-acetamido, 3″-acetyl-di--5-fluorobenzothizole/5-fluorobenzoxazole)-4'-demethylepipodophyllotoxin as Potential Less Toxic Antitumor Candidate Drugs by Reducing DNA Damage and Less Inhibition of PI3K
Authors: Yuemao Shen
Youming Zhang
Wei Zhao
Hui Yao
Yue-Zhong Li
Qingsheng Qi
Ya-Jie Tang
Jie Cheng
Kanokpan Wongprasert
Journal: Journal of medicinal chemistry (2020)
Discipline: CHEMISTRY
Keywords: teniposide; drug design; toxicity; cancer treatment; IC50 value
Affiliations: 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., State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China., State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China, Department of Anatomy, Faculty of Science, Mahidol University, Rama Sixth Road, Bangkok 10400, Thailand.

Abstract:  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. 

Retracted: No

PubPeer comments:
 The strange, almost featureless yet perfectly rectangular western blots within this ASAP paper could do with some examination. Fig 6b,c and Fig10 ![file] ![file] Or perhaps not: ![file] , 
 These images are from ProteinSimple Western immunoassay systems. Each lane is a separate capillary tube. The lanes can be combined in any order. https: www.proteinsimple.com simple_western_overview.html While the technology is great, the digital imaging opens the door for possible band modifications duplications . , 
 The article states  Equivalent amounts of protein (0.2 u03bcg) were analyzed by Simple Western... Proteinsimple WES assays may be presented as a virtual gel image. The authors may as well submit the raw assay file to the reviewers that cannot be modified one the assay is run, making this assaymuch more transparent and reliable for peer reviewing. The capillary assay may as well be presented as a signal graph. I have been using proteinsimple assays in my lab since a year and am very pleased that I may share my results objectively. Please see below proteinsimple WES assay. 150 kDa protein construct expressing C-term myc-tag is transfected into mouse (C2C12) and human iPS cells. Despite satisfactory immunostaining results, no specific signal was detected in western immunoassays. a 50kDa band (endogenous) myc protein band was detected in protein extracts from human iPS cells. We used the rabbit polyclonal Anti-Myc tag antibody from Abcam (ab9106). These results show that myc-tag antibodies may not be appropriate for western blots but are good for detecting endogenous proteins. ![file] ,