Flexible etherified and esterified triphenylethylene derivatives and their evaluation on ER positive and triple negative breast cancer cell lines

Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM). It is currently the endocrine treatment of choice for all stages of breast cancer and a prophylactic for women with high risk of breast cancer. TAM is majorly metabolized to more potent 4-hydroxytamoxifen and endoxifen via CYP2D6 and CYP3A 4/5. CYP2D6 is polymorphic enzyme and has around 63 alleles; this remarkably affects the clinical outcome of tamoxifen treatment. Herein we report novel TAM analogues that are hydrolyzed via esterases to avoid the genetic polymorphism of the CYP2D6. The novel compounds bear an element of flexibility, via insertion of a methylene group between ring A and the ethylene backbone. Ring A bears a para methoxy substituent whereas ring B bears different alkoxyamino side chains. In series 1, ring C bears either a propionate or a decanoate ester. In series 2, Ring B and C bear homo dialkoxyamino groups. Compound VII bearing an OH group on ring C showed highest relative anti-estrogenic activity = 0.18 in presence of 1 nM E2. Compound VI bearing an OH group on ring C showed highest growth inhibitory activity on MCF-7 (GI₅₀ =0.15 µM), which is ten- fold more potent than TAM (GI₅₀ =1.58 µM) whereas it showed growth inhibitory activity on MDA-MB-231 (GI₅₀ =1.71 µM), which is five fold more potent than TAM (GI₅₀ =6.31 µM). Compound XIII was the most potent among homo dialkoxyamino derivatives (GI₅₀ =0.44) on both MCF-7 and MDA-MB-231 respectively. It showed no ERα anti-estrogenic activity.