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Structure-based design of eugenol analogs as potential estrogen receptor antagonists.

ABSTRACT: Eugenol is an essential oil mainly found in the buds and leaves of clove (Syzygium aromaticum (L.) Merrill and Perry), which has been reported to have activity on inhibition of cell proliferation and apoptosis induction in human MCF-7 breast cancer cells. This biological activity is correlated to its activity as an estrogen receptor antagonist. In this article, we present the construction and validation of structure-based virtual screening (SBVS) protocols to identify the potent estrogen receptor ? (ER) antagonists. The selected protocol, which gave acceptable enrichment factors as a virtual screening protocol, subsequently used to virtually screen eugenol, its analogs and their dimers. Based on the virtual screening results, dimer eugenol of 4-[4-hydroxy-3-(prop-2-en-1- yl)phenyl]-2-(prop-2-en-1-yl)phenol is recommended to be developed further in order to discover novel and potent ER antagonists.

SUBMITTER: Anita Y

PROVIDER: S-EPMC3488830 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Structure-based design of eugenol analogs as potential estrogen receptor antagonists.

Anita Yulia Y Radifar Muhammad M Kardono Leonardus Bs LB Hanafi Muhammad M Istyastono Enade P EP

Bioinformation 20121001 19

Eugenol is an essential oil mainly found in the buds and leaves of clove (Syzygium aromaticum (L.) Merrill and Perry), which has been reported to have activity on inhibition of cell proliferation and apoptosis induction in human MCF-7 breast cancer cells. This biological activity is correlated to its activity as an estrogen receptor antagonist. In this article, we present the construction and validation of structure-based virtual screening (SBVS) protocols to identify the potent estrogen recepto ...[more]

PMID: 23144548

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Project description:As part of our program to develop estrogen receptor (ER) targeted imaging and therapeutic agents we chose to evaluate 11?-substituted estradiol analogs as a representative scaffold. Previous synthetic studies provided an entry into this class of compounds and other work indicated that 11?-(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 11?-aryl estradiol analogs or their potential as scaffolds for drug conjugation.We prepared and characterized a series of 11?-(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 ER?-LBD. Functional assays used the induction of alkaline phosphatase in Ishikawa cells to determine potency of the compounds as ER agonists or antagonists.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 ER?-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 11?-substituent than upon the nature of the terminal groupWe have developed a synthetic strategy that provides facile access to potent 11?-(4-substituted phenyl) estradiol analogs. The resultant compounds retain high affinity for the ER?-LBD and, more importantly, demonstrate potent antagonist activity in cells. Large functionalities distal to the 11?-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 11?-aryl estradiol analogs as potential drug delivery systems and imaging agents.

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Structure-based design of eugenol analogs as potential estrogen receptor antagonists.

Publications

Structure-based design of eugenol analogs as potential estrogen receptor antagonists.

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