Synthesis, characterization and biological activity of methotrexate-derived salts in lung cancer cells

Abstract

Lung cancer is one of the deadliest types of cancer, and is a public health problem worldwide. Methotrexate (MTX), a class IV drug in the biopharmaceutical classification system, is a folate antagonist that has demonstrated efficacy in cancer treatment. A suitable combination of MTX as a di-anion and biocompatible counter ions allowed the modulation of their physicochemical properties. In this work, twelve MTX salts were prepared and characterized by ¹H NMR, ¹³C NMR, and elemental analysis. The antiproliferative effects of MTX salts were studied in A459 and H1975 (lung cancer cell lines) with three promising results: [C₁₂mim]₂[MTX] (IC₅₀ = 0.55 ± 0.25) > [C₁₀-3-picoline]₂[MTX] (IC₅₀ = 0.94 ± 0.03) > [C₁₀mim]₂[MTX] (IC₅₀ = 1.71 ± 0.23) in A549. These three MTX salts also demonstrated intrinsic apoptosis, avoiding necrosis and the formation of reactive oxygen species.