Identification of Novel 4′-O-Demethyl-epipodophyllotoxin Derivatives as Antitumor Agents Targeting Topoisomerase II

C4 variation of 4′-O-demethyl-epipodophyllotoxin (DMEP) is an effective approach to optimize the antitumor spectra of this compound class. Accordingly, two series of novel DMEP derivatives were synthesized, and as expected, the antitumor spectra of these derivatives varied with different C4 substitu...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2022-08, Vol.27 (15), p.5029
Main Authors: Xi, Wenli, Sun, Hua, Bastow, Kenneth F., Xiao, Zhiyan, Lee, Kuo-Hsiung
Format: Article
Language:English
Subjects:
4′-O-demethyl-epipodophyllotoxin
Antitumor activity
antitumor agent
Binding sites
Breast cancer
Cancer therapies
Chemotherapy
Clinical trials
DNA damage
DNA topoisomerase (ATP-hydrolysing)
Drug resistance
Etoposide
Hepatoma
Hydrogenation
Pharmacodynamics
Pharmacokinetics
Poisons
Spectra
topoisomerase II
Tumor cells
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Summary:C4 variation of 4′-O-demethyl-epipodophyllotoxin (DMEP) is an effective approach to optimize the antitumor spectra of this compound class. Accordingly, two series of novel DMEP derivatives were synthesized, and as expected, the antitumor spectra of these derivatives varied with different C4 substituents. Notably, most compounds showed significant inhibition against the etoposide (2)-resistant KBvin cells. Four of the compounds (11, 18, 27 and 28) induced protein-linked DNA break (PLDB) levels higher than those of GL-331 (6) and 2, and are assumed to be topoisomerase II (topo II) poisons more potent than 6 and 2. Compound 28, a potent topo II poison highly effective against KBvin cells, was further evaluated with a panel of tumor cells and was most active against HepG2. This compound also exhibited apparent in vivo antitumor efficacy in hepatoma 22 (H22) mouse model. The results indicated that C4 derivation of DMEP is a feasible approach to identify potent topo II inhibitors with optimized antitumor profiles.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules27155029