TY - JOUR
T1 - Insights on pregnane-X-receptor modulation. Natural and semisynthetic steroids from Theonella marine sponges
AU - Sepe, Valentina
AU - D'Amore, Claudio
AU - Ummarino, Raffella
AU - Renga, Barbara
AU - D'Auria, Maria Valeria
AU - Novellino, Ettore
AU - Sinisi, Annamaria
AU - Taglialatela-Scafati, Orazio
AU - Nakao, Yoichi
AU - Limongelli, Vittorio
AU - Zampella, Angela
AU - Fiorucci, Stefano
PY - 2014/2/12
Y1 - 2014/2/12
N2 - Pregnane-X-receptor (PXR) is a member of nuclear receptors superfamily that activates gene transcription by binding to responsive elements in the promoter of target genes. PXR is a master gene orchestrating the expression/activity of genes involved in the metabolism of endobiotics including bilirubin, bile acids, glucose and lipid. In addition PXR oversights the metabolism of the large majority of xenobiotics including a large amount of prescribing drugs. Thus, developing PXR ligands represents a great opportunity for a therapeutic intervention on human diseases including diabetes, obesity, dyslipidemias and liver disorders. To this end, natural compounds represent an arsenal of new chemical scaffolds useful for the identification of novel PXR ligands. Here, we report a series of 4-methylenesteroid derivatives isolated from Theonella marine sponges as novel PXR modulators. In addition, combining medicinal chemistry, pharmacological experiments and computational studies, we have investigated the effects of different modifications on ring A and on the side chain of 4-methylenesteroid derivatives toward PXR modulation. This study provides the molecular bases of ligand/PXR interaction useful for designing novel PXR modulators.
AB - Pregnane-X-receptor (PXR) is a member of nuclear receptors superfamily that activates gene transcription by binding to responsive elements in the promoter of target genes. PXR is a master gene orchestrating the expression/activity of genes involved in the metabolism of endobiotics including bilirubin, bile acids, glucose and lipid. In addition PXR oversights the metabolism of the large majority of xenobiotics including a large amount of prescribing drugs. Thus, developing PXR ligands represents a great opportunity for a therapeutic intervention on human diseases including diabetes, obesity, dyslipidemias and liver disorders. To this end, natural compounds represent an arsenal of new chemical scaffolds useful for the identification of novel PXR ligands. Here, we report a series of 4-methylenesteroid derivatives isolated from Theonella marine sponges as novel PXR modulators. In addition, combining medicinal chemistry, pharmacological experiments and computational studies, we have investigated the effects of different modifications on ring A and on the side chain of 4-methylenesteroid derivatives toward PXR modulation. This study provides the molecular bases of ligand/PXR interaction useful for designing novel PXR modulators.
KW - 4-Methylenesteroids
KW - Conicasterol
KW - Molecular docking
KW - Pregnane-X-receptor
KW - Structure-activity relationship
KW - Theonella marine sponges
UR - http://www.scopus.com/inward/record.url?scp=84891693245&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84891693245&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2013.12.005
DO - 10.1016/j.ejmech.2013.12.005
M3 - Article
C2 - 24388834
AN - SCOPUS:84891693245
SN - 0223-5234
VL - 73
SP - 126
EP - 134
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -