Synthesis, molecular properties prediction and cytotoxic screening of 3-(2-aryl-2-oxoethyl)isobenzofuran-1(3H)-ones. Issue 12 (15th June 2016)

• Record Type: Journal Article
• Authors: da Silva Maia, Angélica Faleiros; Siqueira, Raoni Pais; de Oliveira, Fabrício Marques; Ferreira, Joana Gasperazzo; da Silva, Silma Francielle; Caiuby, Clarice Alves Dale; de Oliveira, Leandro Licursi; de Paula, Sérgio Oliveira; Souza, Rafael Aparecido Carvalho; Guilardi, Silvana; Bressan, Gustavo Costa; Teixeira, Róbson Ricardo
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 12(2016)
• Page Start: 2810
• Page End: 2816
• Publication Date: 2016-06-15
• Subjects: Isobenzofuran-1(3H)-one -- Phthalides -- 3-(2-Aryl-2-oxoethyl)isobenzofuran-1(3H)-ones -- Cytotoxicity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.04.065
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: A series of nineteen 3-(2-aryl-2-oxoethyl)isobenzofuran-1(3 H )-ones was prepared. Isobenzofuranones were screened against HL-60, K562 and NALM6 cancer cell lines. The most active compound18 triggered early events of apoptosis on NALM6. Compounds did no present cytotoxicity against PBMC cells. Abstract: In the present investigation, a collection of nineteen 3-(2-aryl-2-oxoethyl)isobenzofuran-1(3 H )-ones was synthesized and screened for their cytotoxic activity against a panel of three leukemia cancer cell lines. The compounds were prepared via ZrOCl2 ·8H2 O catalyzed condensation reactions between phthalaldehydic acid and different acetophenones. The reactions were carried out free of solvent and the isobenzofuran-1(3 H )-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 compounds1, 4 and16 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 48 h of treatment, twelve derivatives were able to reduce cell viability and presented IC50 values equal to or below 20 μmol L −1 against at least one of the evaluated lineages. The most active compound corresponded to 3-(3-methylphenyl-2-oxoethyl)isobenzofuran-1(3 H )-one (18 ) (IC50 values obtained for HL-60, K562 and NALM6 were, respectively, 13.5 μmol L −1, 8.83 μmol L −1, and 5.24 μmol L −1 ). In addition, compound18 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.