Synthesis of novel flexible tamoxifen analogues to overcome CYP2D6 polymorphism and their biological evaluation on MCF-7 cell line

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Tamoxifen (TAM) is currently the endocrine treatment of choice for all stages of breast cancer; it has proven success in ER positive and ER negative patients. TAM is activated by endogenous CYP450 enzymes to the more biologically active metabolites 4-hydroxytamoxifen and endoxifen mainly via CYP2D6 and CYP3A4/5. CYP2D6 has been investigated for polymorphism; there is a large interindividual variation in the enzyme activity, this drastically effects clinical outcomes of tamoxifen treatment. Here in we report the design and synthesis of 10 novel compounds bearing a modified tamoxifen skeleton, ring C is substituted with different ester groups to bypass the CYP2D6 enzyme metabolism and employ esterase enzymes for activation. All compounds endorse flexibility on ring A. Compounds (II–X) showed MCF-7% growth inhibition >50% at a screening dose of 10 μM. These results were validated by yeast estrogen screen (YES) and E-Screen assay combined with XTT assay. Compound II (E/Z 4-[1–4-(3-Dimethylamino-propoxy)-phenyl)-3-(4-methoxy-phenyl)-2-methyl-propenyl]-phenol) showed nanomolar antiestrogenic activity (IC50 = 510 nM in YES assay) and was five times more potent in inhibiting the growth of MCF-7 BUS (IC50 = 96 nM) compared to TAM (IC50 = 503 nM). Esterified analogues VI, VII were three times more active than TAM on MCF-7 BUS (IC50 = 167 nM). Novel analogues are prodrugs that can ensure equal clinical outcomes to all breast cancer patients.


Original languageEnglish
Pages (from-to)444-455
Number of pages12
JournalDrug Development Research
Issue number4
Publication statusPublished - 1 Jun 2020

External IDs

PubMed 31916635
ORCID /0000-0001-5397-7972/work/142245274


Sustainable Development Goals

ASJC Scopus subject areas


  • Carboxylesterases, CYP2D6, E-Screen, Hydroxy-Tamoxifen, MCF-7, polymorphism, tamoxifen, triphenylethylene, XTT assay, YES assay