Tamoxifen (TAM) is used in treatment of hormonal dependent breast cancer, both in premenopausal and postmenopausal women. TAM is intrinsically metabolized by CYP450 enzymes to more active metabolites. Recent reports identified CYP2D6, an enzyme involved in the conversion of TAM to the more potent 4-OH-TAM, is encoded by the CYP2D6 gene, which is highly polymorphic. Women with inactive alleles are poor metabolizers; in many cases they suffer acquired TAM resistance. Herein we report synthesis and biological evaluation of novel TAM analogues with flexible triaryl skeleton, the para hydroxylation site of ring C is blocked by a carbamate group. The novel analogues can thus elude CYP2D6 metabolism. Hydrolysis of the carbamate moiety is mediated via carboxylesterases. Compound 3d [E/Z Benzyl-carbamic acid4-{2-benzyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-but-1-enyl}-phenyl ester] showed GI50 = 0.09 µM on MCF-7 nearly 18 times more potent than TAM and GI50 = 1.84 µM on MDA-MB231 nearly 3.5 times more potent than TAM. To further validate our hypothesis, metabolites of selected novel analogues were determined in vitro under different incubation conditions. The hydoxylated analogues were obtained under non CYP2D6 dependent conditions. Compound 8d, a benzyl carbamate derivative, was the least-stable analog and showed the highest rate of metabolism among all tested analogues. Our in-silico model showed the novel flexible analogues can still adopt an antiestrogenic binding profile occupying the same pocket as 4-OH-TAM. These novel prodrugs encourage further search for flexible TAM analogues that can circumvent the CYP2D6 allelic variation and additionally display improved pharmacokinetic properties.

Design, synthesis, and metabolite identification of tamoxifen esterase-activatable prodrugs

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