title: Synthesis of 1H-1,2,3-triazole linked aryl(arylamidomethyl) - dihydrofurocoumarin hybrids and analysis of their cytotoxicity.
abstract: A series of 2-(4-R-triazolyl)substituted 3-oxo-2,3-dihydrofurocoumarins have been synthesized by a regioselective cycloaddition of 2-azidooreoselone 1 or 2-azido-9-[(4-methylpiperazin-1-yl)methyl]oreoselone 2 with various alkynes in the presence of Cu(II)/ascorbate in water/methylene chloride reaction medium. The structure of 2-azidooreoselone was established by X-ray structure analysis. The cytotoxicity of 2-substituted dihydrofurocoumarins was determined against three cancer cell lines (CEM-13, MT-4, U-937) using the conventional MTT assays. Among the tested molecules, most of the analogs displayed better cytotoxic activity then the parent natural furocoumarin peucedanin 3. The activity and selectivity to the cell line increased even further in the series of 2-(4-{2,3-dihydrobenzo[b][1,4]dioxine}triazolyl)-3-oxo-2,3-dihydrofurocoumarins and 2-(4-aryltriazolyl)-3-oxo-2,3-dihydrofurocoumarins having the (4-methylpiperazin-1-ylmethyl) substituent in the 9-th position. The most active compound 20 contain the 4-hydroxy-3-methoxybenzamidomethyl substituent in the 4-th position at the triazole ring of 2-(triazol-1-yl)dihydrofurocoumarins. The obtained 2-triazolyl substituted dihydrofurocoumarins were studied as inhibitors of phosphodiesterase (PDE-4B) using docking experiments. As a result of virtual screening 3 compounds are selected based on minimum binding energy. The interactions of the most active compound and amino acid residues in the binding site were studied.
authors.affiliation: Laboratory of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentyev Avenue 9, 630090 Novosibirsk, Russia.
authors.forename: Alla V
authors.initials: AV
authors.lastname: Lipeeva
authors.affiliation: Medicinal Department of Novosibirsk State University, Pirogov St. 2, Novosibirsk 630090, Russia.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Pokrovsky
authors.affiliation: Laboratory of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentyev Avenue 9, 630090 Novosibirsk, Russia.
authors.forename: Dmitry S
authors.initials: DS
authors.lastname: Baev
authors.affiliation: Laboratory of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentyev Avenue 9, 630090 Novosibirsk, Russia.
authors.forename: Makhmut M
authors.initials: MM
authors.lastname: Shakirov
authors.affiliation: Laboratory of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentyev Avenue 9, 630090 Novosibirsk, Russia; Medicinal Department of Novosibirsk State University, Pirogov St. 2, Novosibirsk 630090, Russia.
authors.forename: Irina Y
authors.initials: IY
authors.lastname: Bagryanskaya
authors.affiliation: Laboratory of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentyev Avenue 9, 630090 Novosibirsk, Russia; Medicinal Department of Novosibirsk State University, Pirogov St. 2, Novosibirsk 630090, Russia.
authors.forename: Tatijana G
authors.initials: TG
authors.lastname: Tolstikova
authors.affiliation: Medicinal Department of Novosibirsk State University, Pirogov St. 2, Novosibirsk 630090, Russia.
authors.forename: Andrey G
authors.initials: AG
authors.lastname: Pokrovsky
authors.affiliation: Laboratory of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentyev Avenue 9, 630090 Novosibirsk, Russia; Medicinal Department of Novosibirsk State University, Pirogov St. 2, Novosibirsk 630090, Russia. Electronic address: schultz@nioch.nsc.ru.
authors.forename: Elvira E
authors.initials: EE
authors.lastname: Shults
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D011564:Furocoumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011564:Furocoumarins; D014230:Triazoles
keywords: 1,2,3-Triazoles; Alkynes; Azides; Click chemistry; Cytotoxicity