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.