{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T16:52:35Z","timestamp":1774630355761,"version":"3.50.1"},"reference-count":42,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,1,9]],"date-time":"2020-01-09T00:00:00Z","timestamp":1578528000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Science Technology and Development Fund","award":["5386"],"award-info":[{"award-number":["5386"]}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Tamoxifen (TAM) is currently the endocrine treatment of choice for all stages of breast cancer; it has proven success in ER positive and ER negative patients. TAM is activated by endogenous CYP450 enzymes to the more biologically active metabolites 4\u2010hydroxytamoxifen and endoxifen mainly via CYP2D6 and CYP3A4\/5. CYP2D6 has been investigated for polymorphism; there is a large interindividual variation in the enzyme activity, this drastically effects clinical outcomes of tamoxifen treatment. Here in we report the design and synthesis of 10 novel compounds bearing a modified tamoxifen skeleton, ring <jats:bold>C<\/jats:bold> is substituted with different ester groups to bypass the CYP2D6 enzyme metabolism and employ esterase enzymes for activation. All compounds endorse flexibility on ring <jats:bold>A<\/jats:bold>. Compounds (<jats:bold>II\u2013X<\/jats:bold>) showed MCF\u20107% growth inhibition &gt;50% at a screening dose of 10\u2009\u03bcM. These results were validated by yeast estrogen screen (YES) and E\u2010Screen assay combined with XTT assay. Compound <jats:bold>II<\/jats:bold> (<jats:italic>E\/Z<\/jats:italic> 4\u2010[1\u20134\u2010(3\u2010Dimethylamino\u2010propoxy)\u2010phenyl)\u20103\u2010(4\u2010methoxy\u2010phenyl)\u20102\u2010methyl\u2010propenyl]\u2010phenol) showed nanomolar antiestrogenic activity (IC<jats:sub>50<\/jats:sub> =\u2009510\u2009nM in YES assay) and was five times more potent in inhibiting the growth of MCF\u20107 BUS (IC<jats:sub>50<\/jats:sub> =\u200996\u2009nM) compared to TAM (IC<jats:sub>50<\/jats:sub> =\u2009503\u2009nM). Esterified analogues <jats:bold>VI<\/jats:bold>, <jats:bold>VII<\/jats:bold> were three times more active than TAM on MCF\u20107 BUS (IC<jats:sub>50<\/jats:sub> =\u2009167\u2009nM). Novel analogues are prodrugs that can ensure equal clinical outcomes to all breast cancer patients.<\/jats:p>","DOI":"10.1002\/ddr.21637","type":"journal-article","created":{"date-parts":[[2020,1,9]],"date-time":"2020-01-09T07:01:59Z","timestamp":1578553319000},"page":"444-455","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Synthesis of novel flexible tamoxifen analogues to overcome CYP2D6 polymorphism and their biological evaluation on MCF\u20107 cell line"],"prefix":"10.1002","volume":"81","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8869-3387","authenticated-orcid":false,"given":"Nermin S.","family":"Ahmed","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology German University in Cairo  Cairo Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jannette","family":"Wober","sequence":"additional","affiliation":[{"name":"Institute of Zoology, Faculty of Biology Technische Universit\u00e4t Dresden  Dresden Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,1,9]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867003375056"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2016.02.026"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00543-16"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b00813"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdu007"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.4081\/oncol.2012.e15"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.44.6625"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.4062\/biomolther.2012.20.3.256"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.97105734"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.30.8.869"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminoncol.2011.01.002"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.65.8.3470-3472.1999"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.3109\/00498259209046639"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.4155\/fmc.15.181"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo952279l"},{"issue":"6","key":"e_1_2_8_17_1","first-page":"622","article-title":"The National Cancer Institute: Cancer drug discovery and development program","volume":"19","author":"Grever M. R.","year":"1992","journal-title":"Seminars in Oncology"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep32213"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1023827017224"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2004-0050"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1031"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-4731(87)91040-5"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-016-2932-6"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1042\/CBI20100763"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.114546"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-004-0926-7"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm400364h"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2015.08.032"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm500569h"},{"issue":"2","key":"e_1_2_8_30_1","first-page":"147","article-title":"Antiestrogenically active 2\u2010benzyl\u20101,1\u2010diarylbut\u20102\u2010enes: Synthesis, structure\u2010 activity relationships and molecular modeling study for flexible estrogen receptor antagonists","volume":"2","author":"Meegan M.","year":"2006","journal-title":"MycoKeys"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm001119l"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612023393404"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/83.11.757"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-009-0328-y"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(91)90114-U"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/etc.5620150303"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2010.05.015"},{"issue":"17","key":"e_1_2_8_38_1","first-page":"4827","article-title":"Evaluation of a soluble tetrazolium\/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines","volume":"48","author":"Scudiero D. A.","year":"1988","journal-title":"Cancer Research"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81717-1"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002800050021"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.95103s7113"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/0277-5379(90)90241-K"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.95103844"}],"container-title":["Drug Development Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fddr.21637","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ddr.21637","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ddr.21637","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ddr.21637","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T23:29:49Z","timestamp":1760398189000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/ddr.21637"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,9]]},"references-count":42,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2020,6]]}},"alternative-id":["10.1002\/ddr.21637"],"URL":"https:\/\/doi.org\/10.1002\/ddr.21637","archive":["Portico"],"relation":{},"ISSN":["0272-4391","1098-2299"],"issn-type":[{"value":"0272-4391","type":"print"},{"value":"1098-2299","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,9]]},"assertion":[{"value":"2019-10-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-12-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-01-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}