Antitumor agents. 124. New 4.beta.-substituted aniline derivatives of 6,7-O,O-demethylene-4'-O-demethylpodophyllotoxin and related compounds as potent inhibitors of human DNA topoisomerase II

Abstract

A series of 6,7-O,O-demethylene-4'-O-demethyl-4 beta-(substituted anilino)-4-desoxypodophyllotoxins (18-23), 6,7-O,O-demethylene-6,7-O,O-dimethyl-4'-O-demethyl-4 beta-(substituted anilino)-4-desoxypodophyllotoxins (28-31), and their corresponding 4'-O-methyl analogues (12-17 and 24-27) 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 18-23 are 2-fold more potent than etoposide and compounds 12, 16, 17, 30, and 31 are as active as etoposide in their inhibition of the human DNA topoisomerase II. Compounds 19 and 20 and 29-31 are as active or more active than etoposide in causing protein-linked DNA breakage. These results indicate that a free C-4' hydroxy group is essential for the DNA breakage activity, and that the hydroxyl groups at C-6 and -7 positions may be involved in an interaction which is responsible for the inhibitory activity of DNA topoisomerase II. The maintenance of an intact methylene dioxy-type ring-A system would contribute to enhanced activity. In addition, the sterically less hindered substitution at C-6 and C-7 positions may be important for optimal interactions with DNA topoisomerase II. There is no correlation between the ability of these compounds to inhibit DNA topoisomerase II and their ability to cause protein-linked DNA breaks in cells. This may relate to the difference in uptake of these compounds. The better correlation was observed between the protein-linked DNA breaks and the cytotoxicity in KB cells of these compounds.

Podophyllotoxin Derivatives: Current Synthetic Approaches for New Anticancer Agents

“…Cho et al [72] and Bertounesque et al [73] synthesized several ring A-expanded derivatives as phenazine and pyridazine analogues. Wang et al [74] and Kamal et al [75] made a series of 6, 7-O, O-demethylene-4β-substituted podophyllotoxins and their 4'-O-demethyl analogues and evaluated their ability to inhibit human topo II. However, all of them were less potent than the methylenedioxy-bearing analogues.…”

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

“…A total of 143 epipodophyllotoxin analogues (Tables 1 and 2 ) were used in the study, which were collected from different published articles [16][17][18][19][20][21][22][23][24][25][26][27]. These compounds were tested for their ability to form intracellular covalent topoisomerase II-DNA complexes.…”

“…Their potencies and chemical structures were obtained from literature [23]. Experimentally determined biological activity of the drugs based on in vitro study is also provided in order to evaluate the accuracy of predictions.…”

“…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.…”

Antitumor Agents. 213. Modeling of Epipodophyllotoxin Derivatives Using Variable SelectionkNearest Neighbor QSAR Method

“…2,3 To improve their clinical efficacy and overcome the problems of drug resistance, myelosuppression, and poor oral availability, [4][5][6] we have been engaged for years in the synthesis and testing of epipodophyllotoxin derivatives. [7][8][9][10][11][12][13][14][15][16][17][18] Interestingly, although podophyllotoxin is known as an antimicrotubule agent, the epipodophyllotoxins, its 4 -congeners, are potent inhibitors of DNA topoisomerase II. The proposed mechanism of epipodophyllotoxins' antitopoisomerase II activity is to inhibit the catalytic activity of the target enzyme by stabilizing the covalent topoisomerase II-DNA cleavable complex.…”