Artículo
Design of new quinolin-2-one-pyrimidine hybrids as sphingosine kinases inhibitors
Vettorazzi, Marcela Cristina
; Insuasty, Daniel; Lima, Santiago; Gutierrez, Lucas Joel
; Nogueras, Manuel; Marchal, Antonio; Abonia, Rodrigo; Andujar, Sebastian Antonio
; Spiegel, Sarah; Cobo, Justo; Enriz, Ricardo Daniel
Fecha de publicación:
01/2020
Editorial:
Academic Press Inc Elsevier Science
Revista:
Bioorganic Chemistry
ISSN:
0045-2068
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
Sphingosine-1-phosphate is now emerging as an important player in cancer, inflammation, autoimmune, neurological and cardiovascular disorders. Abundance evidence in animal and humans cancer models has shown that SphK1 is linked to cancer. Thus, there is a great interest in the development new SphK1 inhibitors as a potential new treatment for cancer. In a search for new SphK1 inhibitors we selected the well-known SKI-II inhibitor as the starting structure and we synthesized a new inhibitor structurally related to SKI-II with a significant but moderate inhibitory effect. In a second approach, based on our molecular modeling results, we designed new structures based on the structure of PF-543, the most potent known SphK1 inhibitor. Using this approach, we report the design, synthesis and biological evaluation of a new series of compounds with inhibitory activity against both SphK1 and SphK2. These new inhibitors were obtained incorporating new connecting chains between their polar heads and hydrophobic tails. On the other hand, the combined techniques of molecular dynamics simulations and QTAIM calculations provided complete and detailed information about the molecular interactions that stabilize the different complexes of these new inhibitors with the active sites of the SphK1. This information will be useful in the design of new SphK inhibitors.
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Articulos(IMIBIO-SL)
Articulos de INST. MULTIDICIPLINARIO DE INV. BIO. DE SAN LUIS
Articulos de INST. MULTIDICIPLINARIO DE INV. BIO. DE SAN LUIS
Citación
Vettorazzi, Marcela Cristina; Insuasty, Daniel; Lima, Santiago; Gutierrez, Lucas Joel; Nogueras, Manuel; et al.; Design of new quinolin-2-one-pyrimidine hybrids as sphingosine kinases inhibitors; Academic Press Inc Elsevier Science; Bioorganic Chemistry; 94; 103414; 1-2020; 1-20
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