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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-07, Vol.25 (15), p.3332
• Main Authors: Carramiñana, Victor, Ochoa de Retana, Ana M., Palacios, Francisco, de los Santos, Jesús M.
• Format: Article
• Language: English
• Subjects: 2H-azirines; Acetals; Adenocarcinoma; Alcohol; Alcohols; Aliphatic alcohols; Aliphatic compounds; allylic α-aminophosphorus compounds; antiproliferative effect; Antiproliferatives; aziridines; Chloride; Cytotoxicity; Drugs; Enzymes; Ethanol; Lung cancer; Lungs; Nitrogen; Oxides; Peptides; Phenols; Phosphonates; Phosphorus; Ring opening; Selectivity; Sulfur; α-aminophosphine oxide or phosphonate acetals
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25153332

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 2H-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 2H-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 O- or S-nucleophiles to the starting 2H-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.