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, 20 (8), 2603-13

Development of a New Class of Aromatase Inhibitors: Design, Synthesis and Inhibitory Activity of 3-phenylchroman-4-one (Isoflavanone) Derivatives

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Development of a New Class of Aromatase Inhibitors: Design, Synthesis and Inhibitory Activity of 3-phenylchroman-4-one (Isoflavanone) Derivatives

Kevin Bonfield et al. Bioorg Med Chem.

Abstract

Aromatase (CYP19) catalyzes the aromatization reaction of androgen substrates to estrogens, the last and rate-limiting step in estrogen biosynthesis. Inhibition of aromatase is a new and promising approach to treat hormone-dependent breast cancer. We present here the design and development of isoflavanone derivatives as potential aromatase inhibitors. Structural modifications were performed on the A and B rings of isoflavanones via microwave-assisted, gold-catalyzed annulation reactions of hydroxyaldehydes and alkynes. The in vitro aromatase inhibition of these compounds was determined by fluorescence-based assays utilizing recombinant human aromatase (baculovirus/insect cell-expressed). The compounds 3-(4-phenoxyphenyl)chroman-4-one (1h), 6-methoxy-3-phenylchroman-4-one (2a) and 3-(pyridin-3-yl)chroman-4-one (3b) exhibited potent inhibitory effects against aromatase with IC(50) values of 2.4 μM, 0.26 μM and 5.8 μM, respectively. Docking simulations were employed to investigate crucial enzyme/inhibitor interactions such as hydrophobic interactions, hydrogen bonding and heme iron coordination. This report provides useful information on aromatase inhibition and serves as a starting point for the development of new flavonoid aromatase inhibitors.

Figures

Figure 1
Figure 1
Molecular structures of the aromatase natural substrate and selected inhibitors. (a) Androstenedione, the natural substrate; (b) anastrozole (Arimidex®), a representative example of third-generation aromatase inhibitors in clinical use; (c), chrysin (from blue passion flower), a representative example of a naturally occurring flavone aromatase inhibitor; (d), biochanin A (from red clover), the most potent naturally occurring isoflavone aromatase inhibitor.
Figure 2
Figure 2
Aromatase inhibition by selected isoflavanone compounds and ketoconazole. Relative fluorescence is proportional to enzyme activity. Logistic fit reveals the IC50, a measure of potency (inhibitor concentration required to inhibit half of the enzyme’s activity).
Figure 3
Figure 3
Representations of molecular docking performed in this study. The inhibitor is depicted as green sticks. The heme group is shown in orange. Selected relevant amino acid residues in aromatase are shown as sticks (white, H; black, C; blue, N; red, O). Lines are drawn between the atoms likely involved in hydrogen bonding or heme coordination. (a) 5,6-Benzoisoflavanone 1g; (b) 4′-phenoxyisoflavanone 1h; (c) 6-methoxyisoflavanone 2a; (d) 3′,5′-dimethoxyisoflavanone 2g; and (e) inhibitor 3-(pyridin-3-yl)chroman-4-one 3b.
Figure 4
Figure 4
(a) Structural features of isoflavanones required for effective inhibition of aromatase; (b) structural similarity between isoflavanone scaffold and aromatase natural substrate—androstenedione.
Scheme 1
Scheme 1
Structure and design strategy of isoflavanone aromatase inhibitors.
Scheme 2
Scheme 2
Microwave-assisted annulation reactions of hydroxyaldehydes and alkynes.

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