N-Alkoxypyrazoles as biomimetics for the alkoxyphenyl group in tamoxifen
The preparation of a series of novel analogues of the selective antiestrogen tamoxifen is reported. 1 Z-alkoxyphenyl group in tamoxifen has been replaced by a N-alkoxypyrazole, while functionalised phenyl groups or heteroaromatics were introduced at the 2 Z-position using sequential Suzuki cross cou...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2003-04, Vol.11 (8), p.1883-1899 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Wenckens, Martin Jakobsen, Palle Vedsø, Per Huusfeldt, Per Olaf Gissel, Birgitte Barfoed, Marianne Lundin Brockdorff, Bettina Lykkesfeldt, Anne E Begtrup, Mikael |
| description | The preparation of a series of novel analogues of the selective antiestrogen tamoxifen is reported. 1
Z-alkoxyphenyl group in tamoxifen has been replaced by a
N-alkoxypyrazole, while functionalised phenyl groups or heteroaromatics were introduced at the 2
Z-position using sequential Suzuki cross coupling of 1,2-(bis)borylpinacol 1-phenylbutene with 4- or 5-iodo-1-
N,
N-dimethylaminoethyl or propyl-pyrazoles. Approximately 50 tamoxifen analogues were obtained and tested in an estrogen receptor (ERα) affinity assay. Several compounds exhibited binding affinities 2–5-fold lower than tamoxifen. Dose–response experiments with six selected compounds were carried out using two different human breast cancer cell lines, MCF-7 and the tamoxifen resistant cell line MCF-/TAM
R-1. Both cell lines exhibited growth inhibition upon treatment with the tamoxifen analogues. Co-treatment of the cells, with estradiol and the individual compounds, were also performed. The results indicated that the observed growth inhibitory effect was mediated by the ERα. Analogues of the potent antiestrogen 4-hydroxytamoxifen (4-OHT) were synthesised where the 1
E-4-hydroxyphenyl was replaced by a 1-hydroxypyrazol-4-yl group. However, modest growth inhibition of MCF-7 cells was observed upon treatment with these analogues. In contrast, 1
Z-, 2
Z-ringclosed tamoxifen analogue (
59) was shown to possess antiproliferative effects on MCF-7 and MCF-/TAM
R-1 cells in lower doses than tamoxifen.
Graphic |
| doi_str_mv | 10.1016/S0968-0896(02)00566-7 |
| format | Article |
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Z-alkoxyphenyl group in tamoxifen has been replaced by a
N-alkoxypyrazole, while functionalised phenyl groups or heteroaromatics were introduced at the 2
Z-position using sequential Suzuki cross coupling of 1,2-(bis)borylpinacol 1-phenylbutene with 4- or 5-iodo-1-
N,
N-dimethylaminoethyl or propyl-pyrazoles. Approximately 50 tamoxifen analogues were obtained and tested in an estrogen receptor (ERα) affinity assay. Several compounds exhibited binding affinities 2–5-fold lower than tamoxifen. Dose–response experiments with six selected compounds were carried out using two different human breast cancer cell lines, MCF-7 and the tamoxifen resistant cell line MCF-/TAM
R-1. Both cell lines exhibited growth inhibition upon treatment with the tamoxifen analogues. Co-treatment of the cells, with estradiol and the individual compounds, were also performed. The results indicated that the observed growth inhibitory effect was mediated by the ERα. Analogues of the potent antiestrogen 4-hydroxytamoxifen (4-OHT) were synthesised where the 1
E-4-hydroxyphenyl was replaced by a 1-hydroxypyrazol-4-yl group. However, modest growth inhibition of MCF-7 cells was observed upon treatment with these analogues. In contrast, 1
Z-, 2
Z-ringclosed tamoxifen analogue (
59) was shown to possess antiproliferative effects on MCF-7 and MCF-/TAM
R-1 cells in lower doses than tamoxifen.
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Z-alkoxyphenyl group in tamoxifen has been replaced by a
N-alkoxypyrazole, while functionalised phenyl groups or heteroaromatics were introduced at the 2
Z-position using sequential Suzuki cross coupling of 1,2-(bis)borylpinacol 1-phenylbutene with 4- or 5-iodo-1-
N,
N-dimethylaminoethyl or propyl-pyrazoles. Approximately 50 tamoxifen analogues were obtained and tested in an estrogen receptor (ERα) affinity assay. Several compounds exhibited binding affinities 2–5-fold lower than tamoxifen. Dose–response experiments with six selected compounds were carried out using two different human breast cancer cell lines, MCF-7 and the tamoxifen resistant cell line MCF-/TAM
R-1. Both cell lines exhibited growth inhibition upon treatment with the tamoxifen analogues. Co-treatment of the cells, with estradiol and the individual compounds, were also performed. The results indicated that the observed growth inhibitory effect was mediated by the ERα. Analogues of the potent antiestrogen 4-hydroxytamoxifen (4-OHT) were synthesised where the 1
E-4-hydroxyphenyl was replaced by a 1-hydroxypyrazol-4-yl group. However, modest growth inhibition of MCF-7 cells was observed upon treatment with these analogues. In contrast, 1
Z-, 2
Z-ringclosed tamoxifen analogue (
59) was shown to possess antiproliferative effects on MCF-7 and MCF-/TAM
R-1 cells in lower doses than tamoxifen.
Graphic</description><subject>Antineoplastic agents</subject><subject>Benzene Derivatives - chemistry</subject><subject>Benzene Derivatives - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Biomimetic Materials - chemistry</subject><subject>Biomimetic Materials - pharmacology</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - metabolism</subject><subject>Cell Division - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Resistance, Neoplasm</subject><subject>Estradiol - pharmacology</subject><subject>Estrogen Receptor alpha</subject><subject>Female</subject><subject>General aspects</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrazoles - chemistry</subject><subject>Pyrazoles - pharmacology</subject><subject>Receptors, Estrogen - drug effects</subject><subject>Receptors, Estrogen - metabolism</subject><subject>Tamoxifen - analogs & derivatives</subject><subject>Tamoxifen - pharmacology</subject><subject>Tumor Cells, Cultured</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0E1P3DAQgGELtYJl6U8A5dKKHtL6cxKfKoRoqYTaQ-nZ8scEDEm82FnE9tc3sKty7MmXZ2asl5BjRj8xyuDzL6qhrWmr4ZTyj5QqgLrZIwsmQdZCaPaGLP6RA3JYyh2llEvN9skB46B006gFufxRn_X36Wmz2mT7J_VYKlsqF9MQB5yiL1WXcjXdYmW37BbHTV_d5LReVXGsJjukp9jheETedrYv-G73LsnvrxfX55f11c9v38_PrmovGjnVbXAOnNBaK8otB-ABdOgcdK5xgQYtVHCSa6WCaARYTm0LUvrWagQGnViSD9u9q5we1lgmM8Tise_tiGldTCOYVAzEDNUW-pxKydiZVY6DzRvDqHlOaF4Smuc-hnLzknAeX5KT3YG1GzC8Tu2azeD9Dtjibd9lO_pYXp0EMa-Ss_uydTjneIyYTfERR48hZvSTCSn-5yt_ATMBjf0</recordid><startdate>20030417</startdate><enddate>20030417</enddate><creator>Wenckens, Martin</creator><creator>Jakobsen, Palle</creator><creator>Vedsø, Per</creator><creator>Huusfeldt, Per Olaf</creator><creator>Gissel, Birgitte</creator><creator>Barfoed, Marianne</creator><creator>Lundin Brockdorff, Bettina</creator><creator>Lykkesfeldt, Anne E</creator><creator>Begtrup, Mikael</creator><general>Elsevier Ltd</general><general>Elsevier Science</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20030417</creationdate><title>N-Alkoxypyrazoles as biomimetics for the alkoxyphenyl group in tamoxifen</title><author>Wenckens, Martin ; Jakobsen, Palle ; Vedsø, Per ; Huusfeldt, Per Olaf ; Gissel, Birgitte ; Barfoed, Marianne ; Lundin Brockdorff, Bettina ; Lykkesfeldt, Anne E ; Begtrup, Mikael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c374t-8dbb6b3999502a2662d69dfb6fb7bd0d935db42955d3736a20a8644c8a9e616f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Antineoplastic agents</topic><topic>Benzene Derivatives - chemistry</topic><topic>Benzene Derivatives - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Biomimetic Materials - chemistry</topic><topic>Biomimetic Materials - pharmacology</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - metabolism</topic><topic>Cell Division - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Resistance, Neoplasm</topic><topic>Estradiol - pharmacology</topic><topic>Estrogen Receptor alpha</topic><topic>Female</topic><topic>General aspects</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyrazoles - chemistry</topic><topic>Pyrazoles - pharmacology</topic><topic>Receptors, Estrogen - drug effects</topic><topic>Receptors, Estrogen - metabolism</topic><topic>Tamoxifen - analogs & derivatives</topic><topic>Tamoxifen - pharmacology</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wenckens, Martin</creatorcontrib><creatorcontrib>Jakobsen, Palle</creatorcontrib><creatorcontrib>Vedsø, Per</creatorcontrib><creatorcontrib>Huusfeldt, Per Olaf</creatorcontrib><creatorcontrib>Gissel, Birgitte</creatorcontrib><creatorcontrib>Barfoed, Marianne</creatorcontrib><creatorcontrib>Lundin Brockdorff, Bettina</creatorcontrib><creatorcontrib>Lykkesfeldt, Anne E</creatorcontrib><creatorcontrib>Begtrup, Mikael</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wenckens, Martin</au><au>Jakobsen, Palle</au><au>Vedsø, Per</au><au>Huusfeldt, Per Olaf</au><au>Gissel, Birgitte</au><au>Barfoed, Marianne</au><au>Lundin Brockdorff, Bettina</au><au>Lykkesfeldt, Anne E</au><au>Begtrup, Mikael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>N-Alkoxypyrazoles as biomimetics for the alkoxyphenyl group in tamoxifen</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2003-04-17</date><risdate>2003</risdate><volume>11</volume><issue>8</issue><spage>1883</spage><epage>1899</epage><pages>1883-1899</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>The preparation of a series of novel analogues of the selective antiestrogen tamoxifen is reported. 1
Z-alkoxyphenyl group in tamoxifen has been replaced by a
N-alkoxypyrazole, while functionalised phenyl groups or heteroaromatics were introduced at the 2
Z-position using sequential Suzuki cross coupling of 1,2-(bis)borylpinacol 1-phenylbutene with 4- or 5-iodo-1-
N,
N-dimethylaminoethyl or propyl-pyrazoles. Approximately 50 tamoxifen analogues were obtained and tested in an estrogen receptor (ERα) affinity assay. Several compounds exhibited binding affinities 2–5-fold lower than tamoxifen. Dose–response experiments with six selected compounds were carried out using two different human breast cancer cell lines, MCF-7 and the tamoxifen resistant cell line MCF-/TAM
R-1. Both cell lines exhibited growth inhibition upon treatment with the tamoxifen analogues. Co-treatment of the cells, with estradiol and the individual compounds, were also performed. The results indicated that the observed growth inhibitory effect was mediated by the ERα. Analogues of the potent antiestrogen 4-hydroxytamoxifen (4-OHT) were synthesised where the 1
E-4-hydroxyphenyl was replaced by a 1-hydroxypyrazol-4-yl group. However, modest growth inhibition of MCF-7 cells was observed upon treatment with these analogues. In contrast, 1
Z-, 2
Z-ringclosed tamoxifen analogue (
59) was shown to possess antiproliferative effects on MCF-7 and MCF-/TAM
R-1 cells in lower doses than tamoxifen.
Graphic</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>12659775</pmid><doi>10.1016/S0968-0896(02)00566-7</doi><tpages>17</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry, 2003-04, Vol.11 (8), p.1883-1899 |
| issn | 0968-0896 1464-3391 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Antineoplastic agents Benzene Derivatives - chemistry Benzene Derivatives - pharmacology Biological and medical sciences Biomimetic Materials - chemistry Biomimetic Materials - pharmacology Breast Neoplasms - drug therapy Breast Neoplasms - metabolism Cell Division - drug effects Dose-Response Relationship, Drug Drug Resistance, Neoplasm Estradiol - pharmacology Estrogen Receptor alpha Female General aspects Humans Medical sciences Pharmacology. Drug treatments Pyrazoles - chemistry Pyrazoles - pharmacology Receptors, Estrogen - drug effects Receptors, Estrogen - metabolism Tamoxifen - analogs & derivatives Tamoxifen - pharmacology Tumor Cells, Cultured |
| title | N-Alkoxypyrazoles as biomimetics for the alkoxyphenyl group in tamoxifen |
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