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ABSTRACT

(5Z,9Z)-11-Phenylundeca-5,9-dienoic acid was stereoselectively synthesized, based on original cross-cyclomagnesiation of 2-(hepta-5,6-dien-1-yloxy)tetrahydro-2H-pyran and buta-2,3-dien-1-ylbenzene with EtMgBr in the presence of the Cp2TiCl2 catalyst giving 2,5-dialkylydenemagnesacyclopentane in 86% yield. The acid hydrolysis of the product and Jones oxidation of the resulting 2-{[(5Z,9Z)-11-phenylundeca-5,9-dien-1-yl]oxy}tetrahydro-2Ð-pyran afforded (5Z,9Z)-11-phenylundeca-5,9-dienoic acid in an overall yield of 75%. A high inhibitory activity of the synthesized acid with respect to human topoisomerase I (hTop1) and II (hTop2α) was detected. Resorting to the data of molecular docking, a mechanism of inhibition was proposed.

Subject(s)

DNA-Binding Proteins/antagonists & inhibitors , Drug Design , Fatty Acids, Unsaturated/chemical synthesis , Fatty Acids, Unsaturated/pharmacology , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/pharmacology , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacology , Antigens, Neoplasm/chemistry , Antigens, Neoplasm/metabolism , Binding Sites , Catalytic Domain , DNA Topoisomerases, Type I/chemistry , DNA Topoisomerases, Type I/metabolism , DNA Topoisomerases, Type II/chemistry , DNA Topoisomerases, Type II/metabolism , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , Fatty Acids, Unsaturated/metabolism , Humans , Molecular Docking Simulation , Protein Binding , Protein Conformation , Structure-Activity Relationship , Topoisomerase I Inhibitors/metabolism , Topoisomerase II Inhibitors/metabolism

ABSTRACT

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