Synthesis and biological evaluation of cyanoaziridine phosphine oxides and phosphonates with antiproliferative activity

This work reports an efficient diastereoselective synthetic methodology for the preparation of phosphorus substituted cyanoaziridines through the nucleophilic addition of TMSCN, as cyanide source, to the C–N double bond of 2H-azirine derivatives. The aziridine ring, in these novel cyanoaziridines, c...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2019-02, Vol.163, p.736-746
Main Authors: Carramiñana, Victor, Ochoa de Retana, Ana M., Vélez del Burgo, Ander, de los Santos, Jesús M., Palacios, Francisco
Format: Article
Language:English
Subjects:
2H-azirine
A549 Cells
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Antiproliferative effect
Aziridines - chemical synthesis
Aziridines - pharmacology
Cell Proliferation - drug effects
Cyanides
HEK293 Cells
Humans
Organophosphonates - chemical synthesis
Organophosphonates - pharmacology
Oxides - chemical synthesis
Oxides - pharmacology
Phosphorus substituted cyanoaziridines
Structure-Activity Relationship
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Summary:This work reports an efficient diastereoselective synthetic methodology for the preparation of phosphorus substituted cyanoaziridines through the nucleophilic addition of TMSCN, as cyanide source, to the C–N double bond of 2H-azirine derivatives. The aziridine ring, in these novel cyanoaziridines, can be activated by simple N-tosylation or N-acylation. In addition, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549) and human embryonic kidney (HEK293) was also screened. N-H and N-Substituted cyanoaziridines showed excellent activity against the A549 cell line in vitro. Moreover, selectivity towards cancer cell (A549) over (HEK293), and non-malignant cells (MCR-5) has been observed. [Display omitted] •A diastereoselective approach to phosphorated cyanoaziridines have been developed.•Activation of aziridine ring can be performed by acylation or tosylation of the nitrogen atom of cyanoaziridines.•Cyanoaziridines showed very good in vitro cytotoxic effect against A549 cell line.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2018.12.002