title: Influence of the length and positioning of the antiestrogenic side chain of endoxifen and 4-hydroxytamoxifen on gene activation and growth of estrogen receptor positive cancer cells.
abstract: Tamoxifen has biologically active metabolites: 4-hydroxytamoxifen (4OHT) and endoxifen. The E-isomers are not stable in solution as Z-isomerization occurs. We have synthesized fixed ring (FR) analogues of 4OHT and endoxifen as well as FR E and Z isomers with methoxy and ethoxy side chains. Pharmacologic properties were documented in the MCF-7 cell line, and prolactin synthesis was assessed in GH3 rat pituitary tumor cells. The FR Z-isomers of 4OHT and endoxifen were equivalent to 4OHT and endoxifen. Other test compounds used possessed partial estrogenic activity. The E-isomers of FR 4OHT and endoxifen had no estrogenic activity at therapeutic serum concentrations. None of the newly synthesized compounds were able to down-regulate ER levels. Molecular modeling demonstrated that some compounds would each create a best fit with a novel agonist conformation of the ER. The results demonstrate modulation by the ER complex of cell replication or gene transcription in cancer.
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University , 3970 Reservoir Road NW, Research Building, Suite E501, Washington, D.C. 20057, United States.
authors.forename: Philipp Y
authors.initials: PY
authors.lastname: Maximov
authors.forename: Daphne J
authors.initials: DJ
authors.lastname: Fernandes
authors.forename: Russell E
authors.initials: RE
authors.lastname: McDaniel
authors.forename: Cynthia B
authors.initials: CB
authors.lastname: Myers
authors.forename: Ramona F
authors.initials: RF
authors.lastname: Curpan
authors.forename: V Craig
authors.initials: VC
authors.lastname: Jordan
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003508:Cycloheptanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D003508:Cycloheptanes; D020847:Estrogen Receptor Modulators; D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene; C055492:4-hydroxy-N-desmethyltamoxifen