Design, synthesis, and biological evaluation of hydroquinone derivatives as novel inhibitors of the sarco/endoplasmic reticulum calcium ATPase

Abstract

Analogues of the compound 2,5-di-tert-butylhydroquinone (BHQ) are capable of inhibiting the enzyme sarco/endoplasmic reticulum ATPase (SERCA) in the low micromolar and submicromolar concentration ranges. Not only are SERCA inhibitors valuable research tools, but they also have potential medicinal value as agents against prostate cancer. This study describes the synthesis of 13 compounds representing several classes of BHQ analogues, such as hydroquinones with a single aromatic substituent, symmetrically and unsymmetrically disubstituted hydroquinones, and hydroquinones with omega-amino acid tethers attached to their hydroxyl groups. Structure-activity relationships were established by measuring the inhibitory potencies of all synthesized compounds in bioassays. The assays were complemented by computational ligand docking for an analysis of the relevant ligand/receptor interactions.

Figure 1

Representative SERCA inhibition assays. Relative enzyme activity as a function of inhibitor concentration (●: 5a; ○: 6; ▼: 2d).

Figure 2

SERCA/inhibitor interactions analyzed by computational docking. Panels A-C: Binding profiles of the representative inhibitors 5a (A), 2c (B), and 9 (C). Diagrams were created with LIGPLOT . Panel D: Docking-predicted binding poses of 5a (yellow), 2c (orange), and 9 (red).

Scheme 1

Synthesis of monosubstituted and unsymmetrically disubstituted hydroquinones.

Scheme 2

Synthesis of symmetrically di-alkylated hydroquinones.

Scheme 3

Synthesis of di-allylhydroquinone.

Scheme 4

Synthesis of BHQ analogues with linkers.