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Discover the leading compound of 4β-S-(5-fluorobenzoxazole)-4-deoxy-4'-demethylepipodophyllotoxin with millimolar-potency toxicity by modifying the molecule structure of 4'-demethylepipodophyllotoxin. | LitMetric
4'-Demethylepipodophyllotoxin (DMEP) derivatives are broad-spectrum and potent antitumor leading compound. Because of their unacceptable toxicity, DMEP derivatives often failed in the development of new drug. Until now, there was no report on the millimolar-potency toxicity of DMEP derivatives by modifying the molecule structure of DMEP. For the first time, this work discovered leading compounds with millimolar-potency toxicity by modifying the molecule structure of DMEP. The IC value of 4β-S-(5-fluorobenzoxazole-2-)-4-deoxy-4'-demethylepipodophyllotoxin (Compound 2) was around 323.4-2000.9 μM on human healthy cells (i.e., HL-7702, H8, MRC-5 and HMEC), which was significantly reduced by 171-1999 times than podophyllotoxin (1.0-2.6 μM) and 9-80 times than etoposide (21.5-75.4 μM). Compared with the treatment of etoposide, DNA repair proteins HMGB1 and PARK7 were specifically activated and the expression of anti-apoptotic proteins were up-regulated in HL-7702 cells after the treatment of Compound 2. These indicated the toxicity of Compound 2 was synergistically reduced by DNA repair and anti-apoptosis pathway.
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