Abstract
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.
Highlights
Some of their varied applications include antitumor agents [5,6,7], potent antibiotics [8,9], as antibacterial agents [10,11], antiviral [12], and enzyme inhibitors [13,14,15] such as renin [14,16], or HIV protease [17,18], among others. Joined with their structural similarity to natural carboxylic acids, the intriguing properties of α-aminophosphonic acids stem from the fact that the tetrahedral geometry of phosphonic acid functionality resembles in a stable manner the high-energy transition state of peptide bond hydrolysis [19]
(1-amino-2-propenyl)phosphonic acid (IV) inhibit alanine racemase and D-alanine:D-alanine ligase [30,31], while α-aminophosphonic acid analogue (V) of the natural phenylalanine bearing a methylidene at the β-position acts as an inhibitor of phenylalanine ammonia-lyases (PAL) [32] (Figure 1)
We explored the N-functionalization of α-aminophosphine oxide and phosphonate acetals 4 using the tosyl group as protecting group
Summary
Aminophosphonic acids are structural bioisosteres of amino acids displaying a wide range of biological properties and applications in many areas ranging from agrochemistry to medicine [1,2,3,4] Some of their varied applications include antitumor agents [5,6,7], potent antibiotics [8,9], as antibacterial agents [10,11], antiviral [12], and enzyme inhibitors [13,14,15] such as renin [14,16], or HIV protease [17,18], among others. (1-amino-2-propenyl)phosphonic acid (IV) inhibit alanine racemase and D-alanine:D-alanine ligase [30,31], while α-aminophosphonic acid analogue (V) of the natural phenylalanine bearing a methylidene at the β-position acts as an inhibitor of phenylalanine ammonia-lyases (PAL) [32] (Figure 1)
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