Synthesis of α-Aminophosphonic Acid Derivatives Through the Addition of <i>O</i>- and <i>S</i>-Nucleophiles to 2<i>H</i>-Azirines and Their Antiproliferative Effect on A549 Human Lung Adenocarcinoma Cells

• Main Authors: Victor Carramiñana, Ana M. Ochoa de Retana, Francisco Palacios, Jesús M. de los Santos
• Format: Article
• Language: English
• Published: MDPI AG 2020-07-01
• Series: Molecules
• Subjects: allylic α-aminophosphorus compounds; α-aminophosphine oxide or phosphonate acetals; antiproliferative effect; aziridines; 2<i>H</i>-azirines
• Online Access: https://www.mdpi.com/1420-3049/25/15/3332

This work reports a straightforward regioselective synthetic methodology to prepare α-aminophosphine oxides and phosphonates through the addition of oxygen and sulfur nucleophiles to the C–N double bond of 2<i>H</i>-azirine derivatives. Determined by the nature of the nucleophile, different α-aminophosphorus compounds may be obtained. For instance, aliphatic alcohols such as methanol or ethanol afford α-aminophosphine oxide and phosphonate acetals after N–C3 ring opening of the intermediate aziridine. However, addition of 2,2,2-trifluoroethanol, phenols, substituted benzenthiols or ethanethiol to 2<i>H</i>-azirine phosphine oxides or phosphonates yields allylic α-aminophosphine oxides and phosphonates in good to high general yields. In some cases, the intermediate aziridine attained by the nucleophilic addition of <i>O</i>- or <i>S</i>-nucleophiles to the starting 2<i>H</i>-azirine may be isolated and characterized before ring opening. Additionally, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549) and non-malignant cells (MCR-5) was also screened. Some α-aminophosphorus derivatives exhibited very good activity against the A549 cell line in vitro. Furthermore, selectivity towards cancer cell (A549) over non-malignant cells (MCR-5) has been detected in almost all compounds tested.