Synthesis, Characterization, Antiproliferative Activity of Galloyl Derivatives
and Investigation of Cytotoxic Properties in HepG2/C3A Cells

Rafael    Claudino    dos Santos; Raquel    Oliveira Nascimento    de Freitas; Mary    Ann    Foglio; João    Ernesto    de Carvalho; Ana    Lucia Tasca Góes    Ruiz; Lucas    Roberto    Pessatto; Rodrigo    Juliano    Oliveira; Adrivanio       Baranoski; Bruna    Isabela    Biazi; Mário    Sérgio    Mantovani; Candida    Aparecida Leite    Kassuya; Pedro    Cruz    de Oliveira Junior; Anelise    Samara Nazari    Formagio

doi:10.2174/1389201023666211217150837

Abstract

Background: Appropriate substituents in the galloyl group could lead to significant biological properties.

Objectives: Novel galloyl-substituted compounds bearing 2-substituted-1, 3, 4-oxadiazol-5-yl, 5- substituted-1,2,4-triazol-3-yl, and carboxamide groups were synthesized and evaluated for their antiproliferative activity. Additionally, galloyl hydrazide (2) was evaluated by performing cytotoxicity, membrane integrity, cell cycle, and apoptosis assays in HepG2/C3A cells.

Methods: General procedure was used for the synthesis of galloyl-substituted (3-9, 11) and characterized by their spectroscopic data (1H and 13C NMR). The antiproliferative activity of all novel galloyl derivatives was evaluated against nine human tumors and one nontumoral cell line. Three response parameters (GI50, TGI, and LC50) were calculated. The cytotoxicity test was performed for the resazurin assay. The membrane integrity, cell cycle, and apoptosis assays were performed by flow cytometry.

Results: The substitution of the methoxy group of the galloyl ring system for a carboxamide group (3, 4, 5, and 6) produced compounds with moderate antitumoral activity, particularly 6, against six human cancer cell lines, K-562, PC-3, NCI-ADR/RES, OVCAR, 786-0 and NCI-H460, with GI50 values ≤ 9.45 μg/mL. Triazole derivatives 7 and 8 exhibited higher antitumoral activity toward OVCAR, MCF-7 and leukemia K-562 cell lines, exhibiting GI50 values less than 10 μg/mL. Compound 11 displayed significant activity against PC-3 (GI50 = 4.31 μg/mL), OVCAR (GI50 = 8.84 μg/mL) and K-562 (GI50 = 8.80 μg/mL) cell lines. Galloyl hydrazide (2) had cytotoxic activity in HepG2/C3A cells (IC50 = 153.7 μg/mL). In membrane permeability, cell count, cell cycle, and apoptosis assays, as determined using the IC50 of compound (2) in HepG2/C3A cells, increased membrane permeability, decreased cell count, altered cell cycle, and initial apoptosis was observed compared to the control group.

Conclusion: Thus, our results showed for the first time the synthesis, antiproliferative activity, and cytotoxicity of galloyl-substituted compounds. Galloyl-substitution does not have a very strong synergistic effect in the inhibition of cancer cell proliferation compared with galloyl hydrazide (2). Compound 2 demonstrated promising activity in HepG2/C3A hepatocarcinoma cells.

Keywords: Galloyl, hydrazide, oxadiazole, triazole, antitumoral activity, hepatocarcinoma.

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DOI https://dx.doi.org/10.2174/1389201023666211217150837	Print ISSN 1389-2010
Publisher Name Bentham Science Publisher	Online ISSN 1873-4316

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Synthesis, Characterization, Antiproliferative Activity of Galloyl Derivatives and Investigation of Cytotoxic Properties in HepG2/C3A Cells

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