Cyclization kinetics and biological evaluation of an anticancer 1,2-dialkynylimidazole.
1,2-Dialkynylimidazoles have been reported to undergo thermal cyclization/rearrangement to diradical and carbene intermediates. Optimization of the synthesis of the 1,2-dialkynylimidazole has provided sufficient material for kinetic and biological studies. The 1,2-dialkynylimidazole is cytotoxic against a wide range of cancer cells and induces apoptosis in A549 cells. Experimentally-determined kinetics of the thermolysis of (E(a) = 30.0 kcal mol(-1)) are in excellent agreement with DFT calculations of the cyclization/rearrangement to diradical and cyclopentapyrazine carbene intermediates (E(a) = 29.7 kcal mol(-1)). Commensurate with the relatively high barrier for cyclization of , no evidence for cleavage of supercoiled DNA under physiological conditions was found; however, under aqueous conditions at 70 degrees C formed a covalent adduct with a model peptide. These studies indicate that if cyclization of is involved in its anticancer activity, the cyclization must be facilitated, perhaps through initial protein binding, which could lead to covalent protein modification.
Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA.
Christophe
C
Laroche
Jing
J
Li
Cristina
C
Gonzales
Wendi M
WM
David
Sean M
SM
Kerwin
D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003500:Cyclization; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D013816:Thermodynamics
D000480:Alkynes; D000970:Antineoplastic Agents; D007093:Imidazoles