Ugi Reaction on α-Phosphorated Ketimines for the Synthesis of Tetrasubstituted α-Aminophosphonates and Their Applications as Antiproliferative Agents

Abstract

An Ugi three-component reaction using preformed α-phosphorated N-tosyl ketimines with different isocyanides in the presence of a carboxylic acid affords tetrasubstituted α-aminophosphonates. Due to the high steric hindrance, the expected acylated amines undergo a spontaneous elimination of the acyl group. The reaction is applicable to α-aryl ketimines bearing a number of substituents and several isocyanides. In addition, the densely substituted α-aminophosphonate substrates showed in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell line A549 (carcinomic human alveolar basal epithelial cell).

Relationship between Structure and Antibacterial Activity of α-Aminophosphonate Derivatives Obtained via Lipase-Catalyzed Kabachnik−Fields Reaction

“…α-Aminophosphonates appear to be a very important class of organic compounds because of their potential biological activities [ 1 , 2 , 3 , 4 ]. The distinctive character of bioactive organophosphorus compounds has established their wide applicability in agricultural and medicinal chemistry [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. α-Aminophosphonates ( Figure 1 ) play a crucial role as a platform to design new drugs [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ].…”

Hydroxy- and Amino-Phosphonates and -Bisphosphonates: Synthetic Methods and Their Biological Applications

“…The compound 8 derivatives with R 1 : Bn, R 2 : Ph, and R 3 : Cy, and R 1 : Me, R 2 : p -SCCl 3 Ph, and R 3 : Cy showed good cytotoxicity against the A549 cell line (carcinomic human alveolar basal epithelial cell). They presented an IC 50 Value of 16.14 ± 1.14 µM and 14.56 ± 2.53 µM, respectively ( López-Francés et al, 2021 ). The same group also reported antiproliferative effect on A549 cells of some novel a-aminophosphonic acid derivatives 9–11 synthesized through the addition of O- and S- nucleophiles to 2H-azirines ( Supplementary Scheme S8 ) ( Carrraminana et al, 2020 ).…”

Kabachnik–Fields reactions with stable nitroxide free radicals

“…There is tremendous interest in -amino phosphonic acids and their phosphonate esters, which are analogs of -amino carboxylic acids and amino acid esters, respectively. They exhibit various biological activities, such as enzyme inhibitory, 19 antibacterial, 20 antiviral, 21 and antiproliferative 22 activities, and can be used as building blocks for peptide mimetics. These results inspired us to adopt the Kabachnik-Fields reaction for carbonyl (aldehyde or ketone)-or amino-group-containing nitroxides to give paramagnetic -aminophosphonates, including a phosphonate ester-substituted pyrrolo [3,4-f][1,4]thiazepine scaffold and a biradical.…”