Identification of dehydroxy isoquine and isotebuquine as promising anticancer agents targeting K+channel

A small series of dehydroxi isoquine and isotebuquines were identified as potential anticancer agents against a panel of five cancer cell, exhibiting from submicromolar ranges of IC₅₀, as well as low relative toxicities on human fibroblast cells; pharmacologic profile superior to Adriamycin reference drug in most of studied cases. Mechanistic studies suggested that the most active quinolines act as voltage‐gated K+channel activator.

Abstract

Traditional antimalarial drugs based on 4‐aminoquinolines have exhibited good antiproliferative activities against human tumor cells; however, their low relative efficacy has limited their corresponding clinical uses. In order to identify new potent anticancer agents based on 4‐aminoquinoline, we evaluated the antiproliferative activity of a series of dehydroxy isoquines and isotebuquines against five human cancer lines. HeLa and SKBr3 were significantly more sensitive to the action of tested quinolines than the A549, MCF‐7 and PC‐3 cancer lines. Compound 2h was by far the most potent derivative against four of the tested lines (except to PC3 line), exhibiting low micromolar or nanomolar IC₅₀ values superior to adriamycin reference, low toxicities on dermis human fibroblasts (LD₅₀>250 μM) and excellent selectivity indexes against the mentioned cancer cells. A structure‐activity relationship analysis putted in evidence that a pyrrolidine or morpholine moiety as N‐alkyl terminal substitution as well as the incorporation of the extra phenyl attached to aniline ring are pharmacophore essentials for improvement the anticancer activity of the studied dehydroxy isoquines and isotebuquines. From the results, compound 2h emerged as a promising anticancer candidate for further in vitro assays against resistant‐strain and in vivo studies as well as pharmacokinetic and genotoxicity studies. Mechanistic assays suggested that the most active quinoline 2h act as IKCa1 activator.

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