title: Synthesis, molecular properties prediction and cytotoxic screening of 3-(2-aryl-2-oxoethyl)isobenzofuran-1(3H)-ones.
abstract: In the present investigation, a collection of nineteen 3-(2-aryl-2-oxoethyl)isobenzofuran-1(3H)-ones was synthesized and screened for their cytotoxic activity against a panel of three leukemia cancer cell lines. The compounds were prepared via ZrOCl2·8H2O catalyzed condensation reactions between phthalaldehydic acid and different acetophenones. The reactions were carried out free of solvent and the isobenzofuran-1(3H)-ones were obtained in good yields (80-92%). The identities of the synthesized compounds were confirmed upon IR and NMR ((1)H and (13)C) spectroscopy as well as high resolution mass spectrometry analyses. Structures of compounds 1, 4 and 16 were also investigated by X-ray analysis. The synthesized compounds were submitted to in vitro bioassays against HL-60, K562 and NALM6 cancer cell lines using MTT cytotoxicity assay. After 48h of treatment, twelve derivatives were able to reduce cell viability and presented IC50 values equal to or below 20μmolL(-1) against at least one of the evaluated lineages. The most active compound corresponded to 3-(3-methylphenyl-2-oxoethyl)isobenzofuran-1(3H)-one (18) (IC50 values obtained for HL-60, K562 and NALM6 were, respectively, 13.5μmolL(-1), 8.83μmolL(-1), and 5.24μmolL(-1)). In addition, compound 18 was capable of triggering apoptosis on NALM6 cells. All isobenzofuranones herein evaluated did not present cytotoxicity on peripheral blood mononuclear cells (PBMC), suggesting selective cytotoxic effect on leukemic cells. A computational study allowed prediction of pharmacokinetics and drug-likeness properties of the synthesized compounds. DFT calculations were performed to obtain the energy values of HOMO, LUMO, and dipole moments of isobenzofuranones.
authors.affiliation: Departamento de Química, Universidade Federal de Viçosa, Av. P.H. Rolfs, S/N, Viçosa, MG 36570-900, Brazil.
authors.forename: Angélica Faleiros
authors.initials: AF
authors.lastname: da Silva Maia
authors.affiliation: Departmento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Av. P.H. Rolfs, S/N, Viçosa, MG 36570-900, Brazil.
authors.forename: Raoni Pais
authors.initials: RP
authors.lastname: Siqueira
authors.affiliation: Instituto Federal de Minas Gerais (IFMG), Campus Ouro Branco, Rua Afonso Sardinha, 90, Ouro Branco, MG 36420-000, Brazil.
authors.forename: Fabrício Marques
authors.initials: FM
authors.lastname: de Oliveira
authors.affiliation: Departmento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Av. P.H. Rolfs, S/N, Viçosa, MG 36570-900, Brazil.
authors.forename: Joana Gasperazzo
authors.initials: JG
authors.lastname: Ferreira
authors.affiliation: Departamento de Química, Universidade Federal de Viçosa, Av. P.H. Rolfs, S/N, Viçosa, MG 36570-900, Brazil.
authors.forename: Silma Francielle
authors.initials: SF
authors.lastname: da Silva
authors.affiliation: Departamento de Química, Universidade Federal de Viçosa, Av. P.H. Rolfs, S/N, Viçosa, MG 36570-900, Brazil.
authors.forename: Clarice Alves Dale
authors.initials: CAD
authors.lastname: Caiuby
authors.affiliation: Departamento de Biologia Celular, Universidade Federal de Viçosa, Av. P.H. Rolfs, S/N, Viçosa, MG 36570-900, Brazil.
authors.forename: Leandro Licursi
authors.initials: LL
authors.lastname: de Oliveira
authors.affiliation: Departamento de Biologia Celular, Universidade Federal de Viçosa, Av. P.H. Rolfs, S/N, Viçosa, MG 36570-900, Brazil.
authors.forename: Sérgio Oliveira
authors.initials: SO
authors.lastname: de Paula
authors.affiliation: Instituto de Química, Universidade Federal de Uberlândia, Av. João Naves de Ávila, 2160-Bloco 1D, Santa Mônica, Uberlândia, MG 39400-902, Brazil.
authors.forename: Rafael Aparecido Carvalho
authors.initials: RAC
authors.lastname: Souza
authors.affiliation: Instituto de Química, Universidade Federal de Uberlândia, Av. João Naves de Ávila, 2160-Bloco 1D, Santa Mônica, Uberlândia, MG 39400-902, Brazil.
authors.forename: Silvana
authors.initials: S
authors.lastname: Guilardi
authors.affiliation: Departmento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Av. P.H. Rolfs, S/N, Viçosa, MG 36570-900, Brazil. Electronic address: gustavo.bressan@ufv.br.
authors.forename: Gustavo Costa
authors.initials: GC
authors.lastname: Bressan
authors.affiliation: Departamento de Química, Universidade Federal de Viçosa, Av. P.H. Rolfs, S/N, Viçosa, MG 36570-900, Brazil. Electronic address: robsonr.teixeira@ufv.br.
authors.forename: Róbson Ricardo
authors.initials: RR
authors.lastname: Teixeira
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D011789:Quantum Theory; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans
keywords: 3-(2-Aryl-2-oxoethyl)isobenzofuran-1(3H)-ones; Cytotoxicity; Isobenzofuran-1(3H)-one; Phthalides