Design and Synthesis of Novel Breast Cancer Therapeutic Drug Candidates Based upon the Hydrophobic Feedback Approach of Antiestrogens

Based upon hydrophobic feedback approaches, we designed and synthesized novel sulfur-containing ER&#945; modulators (<b>4</b> and <b>5</b>) as breast cancer therapeutic drug candidates. The tetrahydrothiepine derivative <b>5a</b> showed the highest binding affinity toward ER&#945; because of its high hydrophobicity, and it acted as an agonist toward MCF-7 cell proliferation. The corresponding alkylamino derivative <b>5d</b> maintained high binding affinity to ER&#945; and potently inhibited MCF-7 cell proliferation (IC₅₀: 0.09 &#956;M). Docking simulation studies of compound <b>5d</b> with the ER&#945; BD revealed that the large hydrophobic moiety of compound <b>5d</b> fit well into the hydrophobic pocket of the ER&#945; LBD and that the sulfur atom of compound <b>5d</b> formed a sulfur&#8722;&#960; interaction with the amino acid residue His524 of the ER&#945; LBD. These interactions play important roles for the binding affinity of compound <b>5d</b> to the ER&#945; LBD.

Abstract licence: CC BY

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