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

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.