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Janjic, Jelena M. (2005) DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW AGENTS TARGETING ESTROGEN RECEPTOR-ALPHA AND -BETA. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The two known estrogen receptors, ERa and ERb, are the products of different genes on separate chromosomes. Of these, ERa has been the most extensively studied, and its expression in breast cancer determines the ER+ phenotype. ERb, on the other hand, was discovered only recently and its role in breast cancer pathology remains unclear. ERb inhibits E2-induced proliferation of T47D breast cancer cells in addition to decreasing the expression of cell cycle related genes. Clinical studies have shown a positive correlation between ERâ expression with disease-free survival and overall survival in breast cancer patients. ERb activation with a selective ERb agonist could antagonize the stimulating activity of the ERa in breast cancer cells, and such an ERb agonist could help overcome acquired resistance. Therefore, this work began a search for such agents. A one-pot hydrozirconation-transmetallation-aldimine addition sequence that leads to allylic amides, homoallylic amides and C-cyclopropylalkylamides was significantly accelerated by microwave technology and used for library preparation. The conventional methodology provided a first generation discovery library. A potentially antiestrogenic compound was identified in a transcriptional screening assay from this library, C-cyclopropylalkylamide 26a (O-ethyl-N-{2-[(1S*,2R*)-2-{(R*)[(diphenylphosphinoyl)amino](phenyl)methyl}cyclopropyl]-ethyl}-N-[(4-methylphenyl)sulfonyl]carbamate; a.k.a. CK1-183).Following up on these findings and with the goal to expand the scope of the synthesis methodology, a second generation library of allylic amides and C-cyclopropylalkylamides was prepared. The new library was screened in a fluorescence polarization based homogenous in vitro assay at ERa, and hits were further evaluated in cell-based assays. Three new C-cyclopropylalkylamides, 37c, 37a and 39c, were identified with improved potency over the lead agent 26a against 17b-estradiol (E2) stimulated MCF-7 cells. This second generation library was screened against both ERs. The screening results served to build an SAR model of allylic amides and C-cyclopropylalkylamides at ERa and ERb. A hit from the ERa screen, C-cyclopropylalkylamide 37d (N-(R*)-(((1R*,2R*)-2-butylcyclopropyl)-(4-(phenyl)phenyl)methyl)benzamide), contained a biphenyl core and served as a starting point for the design and synthesis of a third generation of C-cyclopropylalkylamide ER targeting agents. Biphenyl C-cyclopropylalkylamides represent novel structural scaffolds for design and synthesis of ERa and ERb targeting agents and a novel avenue for selective estrogen receptor modulator (SERM) development.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Janjic, Jelena
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDay, Billy Wbday@pitt.eduBDAY
Committee CoChairWipf, Peterpwipf@pitt.eduPWIPF
Committee MemberNichols, Marknichols@pitt.eduNICHOLS
Committee MemberMokotoff, Michaelmoagie@pitt.eduMOAGIE
Committee MemberXie, Wenwex6@pitt.eduWEX6
Date: 20 December 2005
Date Type: Completion
Defense Date: 8 December 2005
Approval Date: 20 December 2005
Submission Date: 14 December 2005
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: allylic amides; ER-beta selective; homoallylic amides; hydrozirconation; SERM; Tamoxifen resistance; C-cyclopropylalkylamide; estrogen receptor
Other ID:, etd-12142005-095556
Date Deposited: 10 Nov 2011 20:10
Last Modified: 15 Nov 2016 13:54


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