ABSTRACT
Based upon hydrophobic feedback approaches, we designed and synthesized novel sulfur-containing ERα modulators (4 and 5) as breast cancer therapeutic drug candidates. The tetrahydrothiepine derivative 5a showed the highest binding affinity toward ERα because of its high hydrophobicity, and it acted as an agonist toward MCF-7 cell proliferation. The corresponding alkylamino derivative 5d maintained high binding affinity to ERα and potently inhibited MCF-7 cell proliferation (IC50: 0.09 µM). Docking simulation studies of compound 5d with the ERα BD revealed that the large hydrophobic moiety of compound 5d fit well into the hydrophobic pocket of the ERα LBD and that the sulfur atom of compound 5d formed a sulfur-π interaction with the amino acid residue His524 of the ERα LBD. These interactions play important roles for the binding affinity of compound 5d to the ERα LBD.
Subject(s)
Breast Neoplasms/drug therapy , Estrogen Antagonists/pharmacology , Estrogen Receptor Modulators/pharmacology , Estrogen Receptor alpha/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Estrogen Antagonists/chemical synthesis , Estrogen Receptor Modulators/chemical synthesis , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/metabolism , Female , Humans , Hydrophobic and Hydrophilic Interactions/drug effects , MCF-7 Cells , Structure-Activity Relationship , Sulfur/chemistryABSTRACT
We designed and synthesized 4,4'-(piperidin-4-ylidenemethylene)bisphenol derivatives as novel tunable estrogen receptor (ER) modulators. The introduction of hydrophobic substituents on the nitrogen atom of the piperidine ring enhanced ERα binding affinity. In addition, the introduction of four methyl groups adjacent to the piperidine ring nitrogen atom remarkably enhanced ERα binding affinity. N-Acetyl-2,2,6,6-tetramethylpiperidine derivative 3b showed high ERα binding affinity, high MCF-7 cell proliferation inducing activity, and high metabolic stability in rat liver S9 fractions.