Synthesis of novel flexible tamoxifen analogues to overcome CYP2D6 polymorphism and their biological evaluation on MCF-7 cell line.
Drug Dev Res
; 81(4): 444-455, 2020 06.
Article
em En
| MEDLINE
| ID: mdl-31916635
ABSTRACT
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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tamoxifeno
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Neoplasias da Mama
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Antineoplásicos Hormonais
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Citocromo P-450 CYP2D6
Limite:
Female
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article