Cytotoxicities and Topoisomerase I Inhibitory Activities of 2-[2-(2-Alkynylphenyl)ethynyl]benzonitriles, 1-Aryldec-3-ene-1,5-diynes, and Related Bis(enediynyl)arene Compounds

The activities of a series of acyclic enediynes, 2‐(6‐substituted hex‐3‐ene‐1,5‐diynyl)benzonitriles (1–5) and their derivatives 7–23 were evaluated against several solid tumor cell lines and topoisomerase I. Compounds 1–5 show selective cytotoxicity with Hepa cells, and 2‐[6‐phenylhex‐3‐ene‐1,5‐diynyl]benzonitrile (5) reveals the most‐potent activity. Analogues 8–10 and 13–22 also have the same effect with DLD cells; 1‐[(Z)‐dec‐3‐ene‐1,5‐diynyl)‐4‐nitrobenzene 21 shows the highest activity among them. Moreover, 1‐[(Z)‐dec‐3‐ene‐1,5‐diynyl]‐2‐(trifluoromethyl)benzene (20) exhibits the strongest inhibitory activity with the Hela cell line. Derivatives 9, 10, 18, and 23 display inhibitory activities with topoisomerase I at 87 μM. The cell‐cycle analysis of compound 5, which induces a significant blockage in S phase, indicates that these novel enediynes probably undergo other biological pathways leading to the cytotoxicity, except the inhibitory activity toward topoisomerase I.