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 ER alpha and ER beta. Results: All compounds showed better antiproliferative activity than TAM. Compound 3 showed 80-times more ER alpha binding than TAM, 900-times more selectivity toward ER alpha. 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 ER alpha and with potential metabolic stability toward CYP2D6.