Isolation of Nocuolin A and Synthesis of New Oxadiazine Derivatives. Design, Synthesis, Molecular Docking, Apoptotic Evaluation, and Cathepsin B Inhibition
Víctor Tena Pérez,
Luis Apaza Ticona,
Alfredo H. Cabanillas,
Santiago Maderuelo Corral,
Diego Fernando Rosero Valencia,
Antera Martel Quintana,
Montserrat Ortega Domenech,
Ángel Rumbero Sánchez
Affiliations
Víctor Tena Pérez
Department of Organic Chemistry, Faculty of Sciences, University Autónoma of Madrid, Cantoblanco, 28049 Madrid, Spain
Luis Apaza Ticona
Department of Organic Chemistry, Faculty of Sciences, University Autónoma of Madrid, Cantoblanco, 28049 Madrid, Spain
Alfredo H. Cabanillas
Department of Organic Chemistry, Faculty of Sciences, University Autónoma of Madrid, Cantoblanco, 28049 Madrid, Spain
Santiago Maderuelo Corral
VALORALIA I MÁS D, SL, Tres Cantos, 28760 Madrid, Spain
Diego Fernando Rosero Valencia
VALORALIA I MÁS D, SL, Tres Cantos, 28760 Madrid, Spain
Antera Martel Quintana
Spanish Bank of Algas, Institute of Oceanography and Global Change (IOCAG) University of Las Palmas de Gran Canarias, Muelle de Taliarte s/n, 35214 Telde, Canary Islands, Spain
Montserrat Ortega Domenech
VALORALIA I MÁS D, SL, Tres Cantos, 28760 Madrid, Spain
Ángel Rumbero Sánchez
Department of Organic Chemistry, Faculty of Sciences, University Autónoma of Madrid, Cantoblanco, 28049 Madrid, Spain
Nocuolin A (1), an oxadiazine, was isolated from the cyanobacterium Nostoc sp. Its chemical structure was elucidated using NMR and mass spectroscopic data. From this compound, two new oxadiazines, 3-[(6R)-5,6-dihydro-4,6-dipentyl-2H-1,2,3-oxadiazin-2-yl]-3-oxopropyl acetate (2) and 4-{3-[(6R)-5,6-dihydro-4,6-dipentyl-2H-1,2,3-oxadiazin-2-yl]-3-oxopropoxy}-4-oxobutanoic acid (3), were synthesised. The chemical structures of these two compounds were elucidated by a combination of NMR and MS analysis. Compound 3 showed cytotoxicity against the ACHN (0.73 ± 0.10 μM) and Hepa-1c1c7 (0.91 ± 0.08 μM) tumour cell lines. Similarly, compound 3 significantly decreased cathepsin B activity in ACHN and Hepa-1c1c7 tumour cell lines at concentrations of 1.52 ± 0.13 nM and 1.76 ± 0.24 nM, respectively. In addition, compound 3 showed no in vivo toxicity in a murine model treated with a dose of 4 mg/kg body weight.
