Journal of medicinal chemistry p. 446 - 452 (1994)
Update date:2022-08-05
Topics:
Zhang
Guo
Cheng
Lee
A series of novel 4 beta-amino derivatives of etoposide (1), which can form water-soluble salts and demonstrate excellent activity against mdr- and topo II-resistant cell lines, have been synthesized. Compared with etoposide, compounds 5-6, 8, and 10-16 show comparable or greater inhibition of human DNA topo II. In a cellular protein-DNA complex formation assay, compounds 5-6, 8, 10-14, and 16 are more potent than 1. A dose-response study of 8 shows that it is 20 times more active in formation of protein-linked DNA breaks than etoposide. Furthermore, both 8 and its free base 7 were found to be highly active toward etoposide-resistant KB cell lines. All compounds were also evaluated in vitro against a total of 56 human tumor cell lines derived from seven cancer types. Comparison of the log10 GI50 mean graph midpoints of 5-19 (-4.89 to -7.30) with that of 1 (-4.08) shows these new analogs to be 6-1659-fold more active than 1.
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