Synthesis, modification, and evaluation of (R)-de-O-methyllasiodiplodin and analogs as nonsteroidal antagonists of mineralocorticoid receptor.
Macrolide (R)-de-O-methyllasiodiplodin (1), discovered to be a potent nonsteroidal antagonist of the mineralocorticoid receptor (MR), was synthesized via an efficient method and evaluated for MR antagonistic activity together with its analogs. Among all the tested compounds, compounds 18a, 18b and 18c, exhibited more potent antagonistic activity against MR with IC(50) values ranging from 0.58 to 1.11 μM. Generally, it was obviously demonstrated that acetylation at phenolic hydroxyl groups and the ring size in analogs of 1 were very important for MR antagonist activity.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
Cheng-Shi
CS
Jiang
Rong
R
Zhou
Jing-Xu
JX
Gong
Li-Li
LL
Chen
Tibor
T
Kurtán
Xu
X
Shen
Yue-Wei
YW
Guo
D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D020798:Two-Hybrid System Techniques
D047628:Estrogen Receptor alpha; D018942:Macrolides; D000451:Mineralocorticoid Receptor Antagonists; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D011980:Receptors, Progesterone; C558290:de-O-methyllasiodiplodin