TY - JOUR
T1 - Design, synthesis, and docking of highly hypolipidemic agents
T2 - Schizosaccharomyces pombe as a new model for evaluating α-asarone-based HMG-CoA reductase inhibitors
AU - Argüelles, Nancy
AU - Sánchez-Sandoval, Eugenia
AU - Mendieta, Aarón
AU - Villa-Tanaca, Lourdes
AU - Garduño-Siciliano, Leticia
AU - Jiménez, Fabiola
AU - Cruz, María del Carmen
AU - Medina-Franco, José L.
AU - Chamorro-Cevallos, Germán
AU - Tamariz, Joaquín
PY - 2010/6/15
Y1 - 2010/6/15
N2 - A series of α-asarone-based analogues was designed by conducting docking experiments with published crystal structures of human HMG-CoA reductase. Indeed, synthesis and evaluation of this series showed a highly hypocholesterolemic in vivo activity in a murine model, as predicted by previous docking studies. In agreement with this model, the polar groups attached to the benzene ring could play a key role in the enzyme binding and probably also in its biological activity, mimicking the HMG-moiety of the natural substrate. The hypolipidemic action mechanism of these compounds was investigated by developing a simple, efficient, and novel model for determining HMG-CoA reductase inhibition. The partial purification of the enzyme from Schizosaccharomyces pombe allowed for testing of α-asarone- and fibrate-based analogues, resulting in positive and significant inhibitory activity.
AB - A series of α-asarone-based analogues was designed by conducting docking experiments with published crystal structures of human HMG-CoA reductase. Indeed, synthesis and evaluation of this series showed a highly hypocholesterolemic in vivo activity in a murine model, as predicted by previous docking studies. In agreement with this model, the polar groups attached to the benzene ring could play a key role in the enzyme binding and probably also in its biological activity, mimicking the HMG-moiety of the natural substrate. The hypolipidemic action mechanism of these compounds was investigated by developing a simple, efficient, and novel model for determining HMG-CoA reductase inhibition. The partial purification of the enzyme from Schizosaccharomyces pombe allowed for testing of α-asarone- and fibrate-based analogues, resulting in positive and significant inhibitory activity.
KW - Alpha-asarone
KW - Docking
KW - HMG-CoA reductase
KW - Hypocholesterolemic activity
KW - Schizosaccharomyces pombe
UR - http://www.scopus.com/inward/record.url?scp=77953126688&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2010.04.096
DO - 10.1016/j.bmc.2010.04.096
M3 - Artículo
C2 - 20576575
SN - 0968-0896
VL - 18
SP - 4238
EP - 4248
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 12
ER -