1. Synthesis of α-methylstilbenes using an aqueous Wittig methodology and application toward the development of potent human aromatase inhibitors.
- Author
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Nielsen AJ, Raez-Villanueva S, Crankshaw DJ, Holloway AC, and McNulty J
- Subjects
- Aromatase Inhibitors chemical synthesis, Aromatase Inhibitors chemistry, Dose-Response Relationship, Drug, Humans, Molecular Structure, Stilbenes chemical synthesis, Stilbenes chemistry, Structure-Activity Relationship, Water chemistry, Aromatase metabolism, Aromatase Inhibitors pharmacology, Drug Development, Stilbenes pharmacology
- Abstract
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 (K
i = 8 nM)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2019
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