Antitumor agents. 111. New 4-hydroxylated and 4-halogenated anilino derivatives of 4'-demethylepipodophyllotoxin as potent inhibitors of human DNA topoisomerase II

Abstract

A series of C-4 hydroxylated and halogenated anilino derivatives of epipodophyllotoxin or 4'-demethylepipodophyllotoxin have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. Compounds 11-17 and 22 are more potent than etoposide in causing DNA breakage, while compounds 11-13, 15, 16, and 20 are as active or more active than etoposide in their inhibition of the human DNA topoisomerase II. The cytotoxicity in KB cells appears to have no direct correlation with their ability to inhibit DNA topoisomerase II and to cause protein-linked DNA breaks in cells.

HJC, a New Arylnaphthalene Lignan Isolated From Justicia procumbens, Causes Apoptosis and Caspase Activation in K562 Leukemia Cells

“…Deoxypodophyllotoxin and podophyllotoxin (POD) are two well-known naturally occurring aryltetralin lignans. Both compounds are cytotoxic (1), and their derivatives such as etoposide (ETO) (2,3), teniposide (4), and etopophos have potential clinical use as antitumor agents (5,6). However, due to the drug resistance developed by cancer cells as well as side effects associated with the use of these agents in the clinic (including myelosuppression, neutropenia, and nausea), the search for new effective anticancer analogs remains an intense area of research (7,8).…”

Development of Predictive Quantitative Structure-Activity Relationship Models of Epipodophyllotoxin Derivatives

“…[5][6][7][8] To generate statistically robust and, most important, validated models, all compounds in the original data set were divided randomly into 100 molecules in the training set and 30 molecules in the test set. All compounds in this study were evaluated for their ability to form intracellular covalent topoisomerase II-DNA complexes using human TP-IIα at similar laboratory conditions and experimental setup.…”

“…Efforts for further improving their clinical efficacy by overcoming drug resistance, myelosuppression, and poor bioavailability problems 4 associated with them have continued to be challenging. Over the years, a number of laboratories throughout the world have engaged in the synthesis and testing of epipodophyllotoxin derivatives [5][6][7][8] to prepare new more potent and less toxic analogues, that is, with better therapeutic indices. The proposed mechanism of epipodophyllotoxins' antitopoisomerase II activity is to inhibit the catalytic activity of the target enzyme by stabilizing the covalent topoisomerase II (TP-II)-DNA cleavable complex.…”

The binding modes and binding affinities of epipodophyllotoxin derivatives with human topoisomerase IIα

“…Efforts for improving their clinical efficacy further by overcoming the drug resistance, myelosuppresion and poor bioavailability problems [15] associated with them, were continued to be challenging. Over the years a number of laboratories throughout the world engaged in the synthesis and testing of epipodophyllotoxin derivatives [16][17][18][19][20][21][22][23][24][25][26][27] to prepare new more potent and less toxic analogues, that is, with better therapeutic indices. The mechanism of action of any drug is very important in drug development.…”