Biomaterial Database

Synthesis and biological evaluation of basic side chain derivatives of Analog II as pure antiestrogens and antitumor agents. 1995

R A Magarian, and K S Avor, and L B Overacre, and J Kunchandy, and T R Paxton

Medicinal Chemistry/Pharmacodynamics Department, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City 73190, USA.

In an effort to prepare effective non-steroidal antiestrogens without intrinsic estrogenicity and with greater antagonism than those of the triarylethylenes (tamoxifen; TAM) four N-substituted (Z)-1,1-dichloro-2-[4-(2-aminoethoxy)phenyl]-3-phenylcyclopropa ne derivatives of the antiestrogen, Analog II, in which the basic side chains contain cyclic (piperidino and piperazino) and non-cyclic (dimethyl amino and diethyl amino) moieties, were synthesized. These compounds were prepared from an intermediate methanesulfonyloxyethoxy side chain ester of 1,1-dichloro-2,3-cis-diphenylcyclopropane using their respective side chain bases in triethylamine and acetonitrile. The gem-dichloro-cis-diarylcyclopropane derivatives were tested for their ability to inhibit the growth-stimulating effect of estradiol on immature mouse uteri and the growth of estrogen receptor (ER)-positive MCF-7E3, ER-negative MDA-MB-231 and the ER-positive MCF-7LY2 antiestrogen-resistant breast cancer cells in culture. The introduction of the various aminoethoxy side chains into Analog II did not improve its ER-binding affinity. Like Analog II, the derivatives did not exhibit any intrinsic estrogenicity, and compounds 9 and 10 antagonized estradiol action more completely than the parent compound. None of the compounds potentiated the uterine weight gain from the stimulating dose of estradiol (0.03 micrograms). Derivatives 9 (150 micrograms), 10 (150 micrograms) and 11 (150 micrograms) had uterine mean weights significantly below the estradiol-treated group, and were better antagonists than Analog II and MER25 at the same concentrations. All compounds exhibited a statistically significant (P < 0.01) reduction in control growth (antitumor activity) from 0.01 to 10 nM concentration in the MCF-7E3 cells. At 10 nM concentration, 8 (66%) and 9 (64%) had the greater antitumor activity over 10 (58%) and 11 (58%). No activity in this cell line was observed for Analog II, TAM and ICI 182,780. Antitumor action was also demonstrated in the MDA-MB-231 cells for all derivatives at 1.0 microM dose, with 9 having the greatest (27%) inhibition of control growth, followed by 8 (20%), 10 (18%) and 11 (12%). Analog II and ICI 182,780 had no antitumor activity in this cell line, while TAM exhibited only 8% inhibition. In the MCF-7E3 cell line at 1.0 microM, 9 exhibited 86% inhibition of the estradiol-stimulated growth (antiestrogenic activity), followed by 8 (64%), 10 (52%) and 11 (21%).(ABSTRACT TRUNCATED AT 400 WORDS)

UI	MeSH Term	Description	Entries
D011955	Receptors, Drug	Proteins that bind specific drugs with high affinity and trigger intracellular changes influencing the behavior of cells. Drug receptors are generally thought to be receptors for some endogenous substance not otherwise specified.	Drug Receptors,Drug Receptor,Receptor, Drug
D001943	Breast Neoplasms	Tumors or cancer of the human BREAST.	Breast Cancer,Breast Tumors,Cancer of Breast,Breast Carcinoma,Cancer of the Breast,Human Mammary Carcinoma,Malignant Neoplasm of Breast,Malignant Tumor of Breast,Mammary Cancer,Mammary Carcinoma, Human,Mammary Neoplasm, Human,Mammary Neoplasms, Human,Neoplasms, Breast,Tumors, Breast,Breast Carcinomas,Breast Malignant Neoplasm,Breast Malignant Neoplasms,Breast Malignant Tumor,Breast Malignant Tumors,Breast Neoplasm,Breast Tumor,Cancer, Breast,Cancer, Mammary,Cancers, Mammary,Carcinoma, Breast,Carcinoma, Human Mammary,Carcinomas, Breast,Carcinomas, Human Mammary,Human Mammary Carcinomas,Human Mammary Neoplasm,Human Mammary Neoplasms,Mammary Cancers,Mammary Carcinomas, Human,Neoplasm, Breast,Neoplasm, Human Mammary,Neoplasms, Human Mammary,Tumor, Breast
D004354	Drug Screening Assays, Antitumor	Methods of investigating the effectiveness of anticancer cytotoxic drugs and biologic inhibitors. These include in vitro cell-kill models and cytostatic dye exclusion tests as well as in vivo measurement of tumor growth parameters in laboratory animals.	Anticancer Drug Sensitivity Tests,Antitumor Drug Screens,Cancer Drug Tests,Drug Screening Tests, Tumor-Specific,Dye Exclusion Assays, Antitumor,Anti-Cancer Drug Screens,Antitumor Drug Screening Assays,Tumor-Specific Drug Screening Tests,Anti Cancer Drug Screens,Anti-Cancer Drug Screen,Antitumor Drug Screen,Cancer Drug Test,Drug Screen, Anti-Cancer,Drug Screen, Antitumor,Drug Screening Tests, Tumor Specific,Drug Screens, Anti-Cancer,Drug Screens, Antitumor,Drug Test, Cancer,Drug Tests, Cancer,Screen, Anti-Cancer Drug,Screen, Antitumor Drug,Screens, Anti-Cancer Drug,Screens, Antitumor Drug,Test, Cancer Drug,Tests, Cancer Drug,Tumor Specific Drug Screening Tests
D004958	Estradiol	The 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids.	17 beta-Estradiol,Estradiol-17 beta,Oestradiol,17 beta-Oestradiol,Aerodiol,Delestrogen,Estrace,Estraderm TTS,Estradiol Anhydrous,Estradiol Hemihydrate,Estradiol Hemihydrate, (17 alpha)-Isomer,Estradiol Monohydrate,Estradiol Valerate,Estradiol Valeriante,Estradiol, (+-)-Isomer,Estradiol, (-)-Isomer,Estradiol, (16 alpha,17 alpha)-Isomer,Estradiol, (16 alpha,17 beta)-Isomer,Estradiol, (17-alpha)-Isomer,Estradiol, (8 alpha,17 beta)-(+-)-Isomer,Estradiol, (8 alpha,17 beta)-Isomer,Estradiol, (9 beta,17 alpha)-Isomer,Estradiol, (9 beta,17 beta)-Isomer,Estradiol, Monosodium Salt,Estradiol, Sodium Salt,Estradiol-17 alpha,Estradiol-17beta,Ovocyclin,Progynon-Depot,Progynova,Vivelle,17 beta Estradiol,17 beta Oestradiol,Estradiol 17 alpha,Estradiol 17 beta,Estradiol 17beta,Progynon Depot
D005260	Female		Females
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D001667	Binding, Competitive	The interaction of two or more substrates or ligands with the same binding site. The displacement of one by the other is used in quantitative and selective affinity measurements.	Competitive Binding
D013047	Specific Pathogen-Free Organisms	Animals or humans raised in the absence of a particular disease-causing virus or other microorganism. Less frequently plants are cultivated pathogen-free.	Pathogen-Free Organisms,Specific Pathogen Free,Organism, Pathogen-Free,Organism, Specific Pathogen-Free,Organisms, Pathogen-Free,Organisms, Specific Pathogen-Free,Pathogen Free Organisms,Pathogen Free, Specific,Pathogen Frees, Specific,Pathogen-Free Organism,Pathogen-Free Organism, Specific,Pathogen-Free Organisms, Specific,Specific Pathogen Free Organisms,Specific Pathogen-Free Organism
D013329	Structure-Activity Relationship	The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.	Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships