Amino alcohol acrylonitriles as broad spectrum and tumour selective cytotoxic agents

Abstract

We have identified specific dichlorophenylacrylonitriles as lead compounds in the development of novel anticancer compounds, notably, (Z)-N-(4-(2-cyano-2-(3,4-dichlorophenyl)vinyl)phenyl)acetamide (1) and ANI-7 (2). Herein we specifically probe the SAR associated with the terminal aromatic ring and associated cytoxicity in a broad range of human cancer cell lines. Synthesis of three focused libraries revealed a poor tolerance for electron withdrawing and donating moieties (Library A). A clear preference for hydrophobic substituents on a terminal piperazine moiety (Library B) with good levels of broad spectrum cytotoxicity, e.g.13a (GI₅₀ 2.5–6.0 μM), as did the introduction of a methylene spacer with 13i (4-CH₃PhCH₂; GI₅₀ 1.5–4.5 μM). Removal of the aromatic moiety and installation of simple hydrophobic groups (Library C), in particular an adamantyl moiety, afforded highly active broad spectrum cytotoxic agents with GI₅₀ values ranging from 1.7 μM (14k; 1-adamantyl) to 5.6 μM (14i; pyrrolidine). Within these libraries we note lung cancer selectivity, relative to normal cells, of 13h (fluoro substituted acrylonitrile, GI₅₀ 1.6 μM, 9.3-fold selective); the colorectal selectivity of 14h (methylpiperidine analogue, GI₅₀ 0.36 μM, 6.9-fold selective) and the breast cancer selectivity of 13f (nitrile substituted acrylonitrile, GI₅₀ 2.3–6.0 μM, up to 20-fold selective). The latter was confirmed as a novel AhR ligand and a CYP1A1 activating compound, that likely induces cell death following bioactivation; a phenomenon previously described in breast cancer cell populations.