Synthesis and antiprogestational properties of novel 17-fluorinated steroids

Klaus Nickisch; Hareesh B. Nair; Narkunan Kesavaram; Baishakhi Das; Robert Garfield; Shao Qing Shi; Shylesh S. Bhaskaran; Sandra L. Grimm; Dean P. Edwards

doi:10.1016/j.steroids.2013.04.003

Synthesis and antiprogestational properties of novel 17-fluorinated steroids

Klaus Nickisch, Hareesh B. Nair, Narkunan Kesavaram, Baishakhi Das, Robert Garfield, Shao Qing Shi, Shylesh S. Bhaskaran, Sandra L. Grimm, Dean P. Edwards

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

Progesterone receptor (PR) plays a key role in reproductive functions, and compounds that inhibit progesterone action (antiprogestins) have potential use in the treatment of estrogen- and progesterone-dependent diseases, including uterine leiomyomas and breast cancer. In the present study, we chemically synthesized novel 17-fluorinated steroids and evaluated the cytotoxicity profiles of these compounds in T47D breast cancer cells compared to the activity of known antiprogestins, including ZK230 211, RU-486, CDB2914, CDB4124 and ORG33628. We analyzed in vitro receptor-binding assays and PR-transactivation assays to establish the antiprogestational activity of these molecules. The representative antiprogestin EC304 was found to inhibit in vitro tumorigenicity in a dose-dependent fashion in T47D cells by a colony formation assay at 1 and 10 nM concentrations. The potent in vivo antiprogestational activity of EC304 was also demonstrated in an antinidation assay for the interruption of early pregnancy in rats. The strong antiprogestational activity and absence of antiglucocorticoid activity in EC compounds may demonstrate their utility in the treatment of leiomyoma, endometriosis and breast cancer.

Original language	English (US)
Pages (from-to)	909-919
Number of pages	11
Journal	Steroids
Volume	78
Issue number	9
DOIs	https://doi.org/10.1016/j.steroids.2013.04.003
State	Published - 2013
Externally published	Yes

Keywords

Antiprogestin
Breast cancer
Fluorine

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Endocrinology
Pharmacology
Clinical Biochemistry
Organic Chemistry

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10.1016/j.steroids.2013.04.003

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title = "Synthesis and antiprogestational properties of novel 17-fluorinated steroids",

abstract = "Progesterone receptor (PR) plays a key role in reproductive functions, and compounds that inhibit progesterone action (antiprogestins) have potential use in the treatment of estrogen- and progesterone-dependent diseases, including uterine leiomyomas and breast cancer. In the present study, we chemically synthesized novel 17-fluorinated steroids and evaluated the cytotoxicity profiles of these compounds in T47D breast cancer cells compared to the activity of known antiprogestins, including ZK230 211, RU-486, CDB2914, CDB4124 and ORG33628. We analyzed in vitro receptor-binding assays and PR-transactivation assays to establish the antiprogestational activity of these molecules. The representative antiprogestin EC304 was found to inhibit in vitro tumorigenicity in a dose-dependent fashion in T47D cells by a colony formation assay at 1 and 10 nM concentrations. The potent in vivo antiprogestational activity of EC304 was also demonstrated in an antinidation assay for the interruption of early pregnancy in rats. The strong antiprogestational activity and absence of antiglucocorticoid activity in EC compounds may demonstrate their utility in the treatment of leiomyoma, endometriosis and breast cancer.",

keywords = "Antiprogestin, Breast cancer, Fluorine",

author = "Klaus Nickisch and Nair, {Hareesh B.} and Narkunan Kesavaram and Baishakhi Das and Robert Garfield and Shi, {Shao Qing} and Bhaskaran, {Shylesh S.} and Grimm, {Sandra L.} and Edwards, {Dean P.}",

note = "Funding Information: This work was supported in part by NIH Grant ROI DK40903 ( DPE ).",

year = "2013",

doi = "10.1016/j.steroids.2013.04.003",

language = "English (US)",

volume = "78",

pages = "909--919",

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T1 - Synthesis and antiprogestational properties of novel 17-fluorinated steroids

AU - Nickisch, Klaus

AU - Nair, Hareesh B.

AU - Kesavaram, Narkunan

AU - Das, Baishakhi

AU - Garfield, Robert

AU - Shi, Shao Qing

AU - Bhaskaran, Shylesh S.

AU - Grimm, Sandra L.

AU - Edwards, Dean P.

N1 - Funding Information: This work was supported in part by NIH Grant ROI DK40903 ( DPE ).

PY - 2013

Y1 - 2013

N2 - Progesterone receptor (PR) plays a key role in reproductive functions, and compounds that inhibit progesterone action (antiprogestins) have potential use in the treatment of estrogen- and progesterone-dependent diseases, including uterine leiomyomas and breast cancer. In the present study, we chemically synthesized novel 17-fluorinated steroids and evaluated the cytotoxicity profiles of these compounds in T47D breast cancer cells compared to the activity of known antiprogestins, including ZK230 211, RU-486, CDB2914, CDB4124 and ORG33628. We analyzed in vitro receptor-binding assays and PR-transactivation assays to establish the antiprogestational activity of these molecules. The representative antiprogestin EC304 was found to inhibit in vitro tumorigenicity in a dose-dependent fashion in T47D cells by a colony formation assay at 1 and 10 nM concentrations. The potent in vivo antiprogestational activity of EC304 was also demonstrated in an antinidation assay for the interruption of early pregnancy in rats. The strong antiprogestational activity and absence of antiglucocorticoid activity in EC compounds may demonstrate their utility in the treatment of leiomyoma, endometriosis and breast cancer.

AB - Progesterone receptor (PR) plays a key role in reproductive functions, and compounds that inhibit progesterone action (antiprogestins) have potential use in the treatment of estrogen- and progesterone-dependent diseases, including uterine leiomyomas and breast cancer. In the present study, we chemically synthesized novel 17-fluorinated steroids and evaluated the cytotoxicity profiles of these compounds in T47D breast cancer cells compared to the activity of known antiprogestins, including ZK230 211, RU-486, CDB2914, CDB4124 and ORG33628. We analyzed in vitro receptor-binding assays and PR-transactivation assays to establish the antiprogestational activity of these molecules. The representative antiprogestin EC304 was found to inhibit in vitro tumorigenicity in a dose-dependent fashion in T47D cells by a colony formation assay at 1 and 10 nM concentrations. The potent in vivo antiprogestational activity of EC304 was also demonstrated in an antinidation assay for the interruption of early pregnancy in rats. The strong antiprogestational activity and absence of antiglucocorticoid activity in EC compounds may demonstrate their utility in the treatment of leiomyoma, endometriosis and breast cancer.

KW - Antiprogestin

KW - Breast cancer

KW - Fluorine

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Synthesis and antiprogestational properties of novel 17-fluorinated steroids

Abstract

Keywords

ASJC Scopus subject areas

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