{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/70364"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/70364","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Synthesis of Cytotoxic Antiestrogens and Control Compounds (Nafoxidine)","abstract":"With the hope of achieving selective receptor-mediated toxicity limited to estrogen receptor-containing cells of breast cancer, potentially cytotoxic conjugates of an antiestrogen, desmethylnafoxidine, were prepared. Two short and efficient routes for the synthesis of a nafoxidine precursor were developed, one featuring the alpha-phenylation of a ketone and one the nickel-catalyzed cross-coupling of a Grignard reagent with a vinyl bromide. These routes lead to the same intermediate, which possesses distinctively protected aromatic and aliphatic hydroxyl groups. Methods for the selective deprotection of these groups, reprotection by groups with different reactivity patterns, if required, and the functionalization of the aliphatic hydroxyl group with the cytotoxic alkylating and acylating moieties, were developed. The binding affinity of these derivatives indicates that nonaromatic, hydrogen-bond accepting groups on the side chain are well tolerated by the estrogen receptor during binding of the ligand. The aziridine derivative of desmethylnafoxidine formed a covalent attachment in the estrogen binding site with 80% of the estrogen receptor within 1 hour when it was present in a 10-fold excess.","abstract_html":"With the hope of achieving selective receptor-mediated toxicity limited to estrogen receptor-containing cells of breast cancer, potentially cytotoxic conjugates of an antiestrogen, desmethylnafoxidine, were prepared. Two short and efficient routes for the synthesis of a nafoxidine precursor were developed, one featuring the alpha-phenylation of a ketone and one the nickel-catalyzed cross-coupling of a Grignard reagent with a vinyl bromide. These routes lead to the same intermediate, which possesses distinctively protected aromatic and aliphatic hydroxyl groups. Methods for the selective deprotection of these groups, reprotection by groups with different reactivity patterns, if required, and the functionalization of the aliphatic hydroxyl group with the cytotoxic alkylating and acylating moieties, were developed. The binding affinity of these derivatives indicates that nonaromatic, hydrogen-bond accepting groups on the side chain are well tolerated by the estrogen receptor during binding of the ligand. The aziridine derivative of desmethylnafoxidine formed a covalent attachment in the estrogen binding site with 80% of the estrogen receptor within 1 hour when it was present in a 10-fold excess.","abstract_has_math":false,"creators":["Simpson, David Michael"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-12-15T23:18:57Z","date_published":"2014-12-15T23:18:57Z","updated_at":"2026-07-22T22:26:02Z","subjects":["Chemistry, Organic","Chemistry, Pharmaceutical"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["(UMI)AAI8711878"],"render_values":[{"text":"(UMI)AAI8711878","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/2142/70364","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Simpson, David Michael"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2014-12-15T23:18:57Z","10000-01-01","1987"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Chemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Chemistry, Organic","Chemistry, Pharmaceutical"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/70364","(UMI)AAI8711878"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["With the hope of achieving selective receptor-mediated toxicity limited to estrogen receptor-containing cells of breast cancer, potentially cytotoxic conjugates of an antiestrogen, desmethylnafoxidine, were prepared. Two short and efficient routes for the synthesis of a nafoxidine precursor were developed, one featuring the alpha-phenylation of a ketone and one the nickel-catalyzed cross-coupling of a Grignard reagent with a vinyl bromide. These routes lead to the same intermediate, which possesses distinctively protected aromatic and aliphatic hydroxyl groups. Methods for the selective deprotection of these groups, reprotection by groups with different reactivity patterns, if required, and the functionalization of the aliphatic hydroxyl group with the cytotoxic alkylating and acylating moieties, were developed. The binding affinity of these derivatives indicates that nonaromatic, hydrogen-bond accepting groups on the side chain are well tolerated by the estrogen receptor during binding of the ligand. The aziridine derivative of desmethylnafoxidine formed a covalent attachment in the estrogen binding site with 80% of the estrogen receptor within 1 hour when it was present in a 10-fold excess.","A series of lipophilic, aromatic control compounds for the cytotoxic antiestrogens were also prepared. These compounds have no detectable affinity for the estrogen receptor, and thus are suitable control compounds for examining whether the cytotoxic effects of the conjugates of antiestrogens are receptor-mediated. A non-reactive control compound for the antiestrogens was also prepared, and was used to study the role of antiestrogen binding sites in the action of antiestrogens in receptor-containing cells.","The aziridine derivative of desmethylnafoxidine was prepared in a tritiated form with high radiochemical purity and specific activity. This derivative, when present in a 3.8-fold excess over the receptor concentration, covalently labeled 97% of the receptor from lamb uterus within 1 hour.","Made available in DSpace on 2014-12-15T23:18:57Z (GMT). No. of bitstreams: 1 8711878.pdf: 4078543 bytes, checksum: be5c29688994ab87e5e3f507784f60ed (MD5) Previous issue date: 1987","Embargo set by: Seth Robbins for item 70530 Lift date: Forever Reason: Restricted to the U of I community idenfinitely during batch ingest of legacy ETDs","Restricted to the U of I community idenfinitely during batch ingest of legacy ETDs","U of I Only","143 p.","Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1987."]},{"key":"dc:title","label":"Title","values":["Synthesis of Cytotoxic Antiestrogens and Control Compounds (Nafoxidine)"]}]}],"canonical_facts":{"dc:creator":["Simpson, David Michael"],"dc:date":["2014-12-15T23:18:57Z","10000-01-01","1987"],"dc:description":["With the hope of achieving selective receptor-mediated toxicity limited to estrogen receptor-containing cells of breast cancer, potentially cytotoxic conjugates of an antiestrogen, desmethylnafoxidine, were prepared. Two short and efficient routes for the synthesis of a nafoxidine precursor were developed, one featuring the alpha-phenylation of a ketone and one the nickel-catalyzed cross-coupling of a Grignard reagent with a vinyl bromide. These routes lead to the same intermediate, which possesses distinctively protected aromatic and aliphatic hydroxyl groups. Methods for the selective deprotection of these groups, reprotection by groups with different reactivity patterns, if required, and the functionalization of the aliphatic hydroxyl group with the cytotoxic alkylating and acylating moieties, were developed. The binding affinity of these derivatives indicates that nonaromatic, hydrogen-bond accepting groups on the side chain are well tolerated by the estrogen receptor during binding of the ligand. The aziridine derivative of desmethylnafoxidine formed a covalent attachment in the estrogen binding site with 80% of the estrogen receptor within 1 hour when it was present in a 10-fold excess.","A series of lipophilic, aromatic control compounds for the cytotoxic antiestrogens were also prepared. These compounds have no detectable affinity for the estrogen receptor, and thus are suitable control compounds for examining whether the cytotoxic effects of the conjugates of antiestrogens are receptor-mediated. A non-reactive control compound for the antiestrogens was also prepared, and was used to study the role of antiestrogen binding sites in the action of antiestrogens in receptor-containing cells.","The aziridine derivative of desmethylnafoxidine was prepared in a tritiated form with high radiochemical purity and specific activity. This derivative, when present in a 3.8-fold excess over the receptor concentration, covalently labeled 97% of the receptor from lamb uterus within 1 hour.","Made available in DSpace on 2014-12-15T23:18:57Z (GMT). No. of bitstreams: 1 8711878.pdf: 4078543 bytes, checksum: be5c29688994ab87e5e3f507784f60ed (MD5) Previous issue date: 1987","Embargo set by: Seth Robbins for item 70530 Lift date: Forever Reason: Restricted to the U of I community idenfinitely during batch ingest of legacy ETDs","Restricted to the U of I community idenfinitely during batch ingest of legacy ETDs","U of I Only","143 p.","Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1987."],"dc:identifier":["http://hdl.handle.net/2142/70364","(UMI)AAI8711878"],"dc:subject":["Chemistry, Organic","Chemistry, Pharmaceutical"],"dc:title":["Synthesis of Cytotoxic Antiestrogens and Control Compounds (Nafoxidine)"],"dc:type":["text"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:26:02Z"}