Synthesis of α-methylstilbenes using an aqueous Wittig methodology and application toward the development of potent human aromatase inhibitors
| Autor: | Alison C. Holloway, Sergio Raez-Villanueva, Denis J. Crankshaw, Alexander J. Nielsen, James McNulty |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Clinical Biochemistry
Pharmaceutical Science 010402 general chemistry 01 natural sciences Biochemistry chemistry.chemical_compound Structure-Activity Relationship Aromatase Drug Development Drug Discovery Stilbenes Humans Phosphonium Molecular Biology Aqueous solution biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Aromatase Inhibitors Aryl Organic Chemistry Hydrogen bromide Regioselectivity Water Combinatorial chemistry 0104 chemical sciences chemistry Wittig reaction biology.protein Molecular Medicine Bioisostere |
| Zdroj: | Bioorganicmedicinal chemistry letters. 29(11) |
| ISSN: | 1464-3405 |
| Popis: | The development of aqueous Wittig methodology for the synthesis of α-methylstilbenes using tripropylphosphine-derived phosphonium salts is described. The Wittig olefination reaction was high yielding and allowed isolation of stilbenes by simple filtration and washing with water. The novel phosphonium salts employed were accessed via a highly efficient, regioselective addition of hydrogen bromide to styrenes. Application of the α-methylstilbenes toward the synthesis of a collection of stilbenoid-triazoles is reported and their inhibition of CYP450 19A1 (aromatase) investigated. The overall structure-activity profile provided additional evidence on the aryl halide-ketone bioisostere hypothesis and identified 6c as a potent inhibitor of aromatase in vitro (Ki = 8 nM). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect