Design and synthesis of novel flexible ester-containing analogs of tamoxifen and their evaluation as anticancer agents.

Background: Tamoxifen (TAM) is metabolized to the more active 4-hydroxytamoxifen by CYP2D6 enzyme. Due to the genetic polymorphisms in CYP2D6, clinical outcomes of TAM treatment vary. Novel flexible TAM analogs with altered activation pathway were synthesized and were tested for their antiproliferative action on MCF-7 cell lines and their binding affinity for ERα and ERβ.

Results: All compounds showed better antiproliferative activity than TAM. Compound 3 showed 80-times more ERα binding than TAM, 900-times more selectivity toward ERα. Compound 3 was tested on the entire National Cancer Institute cancerous cell lines; results indicated a broad spectrum anticancer activity.

Conclusion: The novel analogs were more potent than TAM with higher selectivity toward ERα and with potential metabolic stability toward CYP2D6.