130273-69-7Relevant articles and documents
Synthesis and evaluation of 11β-(4-Substituted phenyl) estradiol analogs: Transition from estrogen receptor agonists to antagonists
Hanson, Robert N.,Hua, Edward,Adam Hendricks,Labaree, David,Hochberg, Richard B.
experimental part, p. 3768 - 3780 (2012/08/28)
Introduction: As part of our program to develop estrogen receptor (ER) targeted imaging and therapeutic agents we chose to evaluate 11β-substituted estradiol analogs as a representative scaffold. Previous synthetic studies provided an entry into this class of compounds and other work indicated that 11β-(substituted aryl) estradiol analogs were potent antagonists of the ER. Little information existed about the specific structural features involved in the transition from agonism to antagonism for the 11β-aryl estradiol analogs or their potential as scaffolds for drug conjugation. Methods: We prepared and characterized a series of 11β-(4-Substituted phenyl) estradiol analogs using modifications of existing synthetic methods. The new compounds, as well as standard steroidal agonists and antagonists, were evaluated as competitive ligands for the ERβ-LBD. Functional assays used the induction of alkaline phosphatase in Ishikawa cells to determine potency of the compounds as ER agonists or antagonists. Results: The synthetic strategy successfully generated a series of compounds in which the 4-substituent was sequentially modified from hydroxyl to methoxy to azidoethoxy/N,N-dimethylaminoethoxy and eventually to a prototypical 1,4-naphthoquinone-containing moiety. The new compounds all retained high relative binding affinity (RBA) for the ERα-LBD, ranging from 13-83% that of estradiol. No subtype selectivity was observed. More importantly, the transition from agonist to antagonist activity occurs at the 4-methoxy stage where the compound is a mixed antagonist. More notably, antagonism appeared to be more dependent upon the size of the 11β-substituent than upon the nature of the terminal group Conclusions: We have developed a synthetic strategy that provides facile access to potent 11β-(4-substituted phenyl) estradiol analogs. The resultant compounds retain high affinity for the ERα-LBD and, more importantly, demonstrate potent antagonist activity in cells. Large functionalities distal to the 11β-phenyl ring had little additional effect on either affinity or efficacy, suggesting the incorporation of diverse imaging or biologically active groups can be attached without significantly compromising the ER-binding capacity. Future studies are in progress to exploit the 11β-aryl estradiol analogs as potential drug delivery systems and imaging agents.
STEROIDAL ANTI-HORMONE HYBRIDS
-
Page/Page column 46-47, (2010/08/08)
Disclosed are novel compounds and compositions for inhibition of androgen and estrogen receptor signaling, methods for inhibiting androgen signaling, methods for inhibiting estrogen signaling, methods for inhibiting the interaction between a co-regulatory protein and an androgen or estrogen receptor, and methods for treating cancer.
EPOXIDATION OF ESTRA-5(10),9(11)-DIENE DERIVATIVES; A CONVENIENT SYNTHESIS OF 11Β-VINYLESTRONE ACETATE
Napolitano, Elio,Fiaschi, Rita,Hanson, Robert N.
, p. 323 - 326 (2007/10/02)
The title compound has been prepared from 17β-hydroxyestra-4,9(10)-dien-3-one, 1, in a sixstep synthesis requiring only one purification and providing a 58percent overall yield.The key steps of the synthesis are the regio- and stereo-selective epoxidation of 3,3:17,17-bis(ethylenedioxy)-estra-5(10),9(11)-diene, 2e, to yield the corresponding 5α,10α-epoxide derivative using hydrogen peroxide and hexafluoroacetone, followed by the copper(I)-catalyzed conjugate opening of the vinyl epoxide by vinylmagnesium bromide.A variety of extra-5(10),9(11)-diene derivatives differing for substitution at C-17 were also regio- and stereo-selectively epoxidized.
