Synthesis of Cytotoxic Antiestrogens and Control Compounds (Nafoxidine)

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2014

Author dc:creator

• Simpson, David Michael

• Chemistry, Organic
• Chemistry, Pharmaceutical

Identifier

(UMI)AAI8711878

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/70364