title: Cytotoxic 1,2-dialkynylimidazole-based aza-enediynes: aza-Bergman rearrangement rates do not predict cytotoxicity.
abstract: A new class of potential antitumor agents inspired by the enediyne antitumor antibiotics has been synthesized: the 1,2-dialkynylimidazoles. The aza-Bergman rearrangement of these 1,2-dialkynylimidazoles has been investigated theoretically at the B3LYP/6-31G(d,p) level and experimentally by measuring the kinetics of rearrangement in 1,4-cyclohexadiene. There is a good correlation between the theoretical and experimental results; subtle substituent effects on the initial aza-Bergman cyclization barrier predicted by theory are confirmed by experiment. Yet, despite the ability of these 1,2-dialkynylimidazoles to undergo Bergman rearrangement to diradical/carbene intermediates under relatively mild conditions, there is no correlation between the rate of Bergman cyclization and cytotoxicity to A459 cells. In addition, cytotoxic 1,2-dialkynylimidazoles do not cause nicking of supercoiled plasmid DNA or cleavage of bovine serum albumin. An alternative mechanism for cytotoxicity involving the unexpected selective thiol addition to the N-ethynyl group of certain 1,2-dialkynylimidazoles is proposed.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Texas 78712, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Laroche
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Sean M
authors.initials: SM
authors.lastname: Kerwin
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002417:Cattle; D045744:Cell Line, Tumor; D003500:Cyclization; D053837:DNA Cleavage; D004278:DNA, Superhelical / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D006358:Hot Temperature; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D012710:Serum Albumin, Bovine / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000480:Alkynes; D000970:Antineoplastic Agents; D004278:DNA, Superhelical; D007093:Imidazoles; D012710:Serum Albumin, Bovine