Synthesis and anticancer properties of a hybrid molecule with the testosterone and estradiol head-groups.

[Display omitted] • The first hybrid molecule made of testosterone and estradiol is reported. • It exhibits IC 50 of 4.9 μM on ER + breast cancer cells (MCF7). • It had lower inhibitory potency on LNCaP (AR +) prostate cancer cells (IC 50 > 5 μM). • Active against colon (IC 50 of 3.5 μM) and melanoma cancer cells (IC 50 of 2.3 μM). • Cross-reactivity of the new hybrid molecule with CYP3A4 was also examined. This is the first report on a unique hybrid molecule made of estradiol and testosterone (TS). This distinctive hybrid molecule (1) was designed to interact with both the estrogen receptor (ER) and the androgen receptor (AR) found in hormone-dependent female and male cancer cells, and was synthesized using ethynylestradiol (17EE) as the estrogenic component and 7α-(4-azido-but-2-enyl)-4-androsten-17β-ol-3-one as the androgenic counterpart in a seven-step reaction with ∼ 26 % overall yield. We reasoned that the dual receptor binding ability could allow 1 to act as an antihormone. This was tested on hormone-dependent and hormone-independent breast cancer (BCa) and prostate cancer (PCa) cells. The antiproliferative activity was also assessed on colon and skin cancer cells. We found that 1 was active against MCF7 (ER +) BCa cells (IC 50 of 4.9 μM), had lower inhibitory potency on LNCaP (AR +) PCa cells (IC 50 > 5 μM) and no effect on PC3 and DU145 (AR-) PCa cells. This suggests that the estrogenic component of 1 can interact with the ER on MCF7 cells more effectively than the androgenic component with the AR on LNCaP PCa cells, possibly due to a suboptimal spacer or linkage site(s). Nonetheless, the hybrid 1 was active against colon (HT-29) and melanoma (M21) cancer cells (IC 50 of 3.5 μM and 2.3 μM, respectively), and had low cross-reactivity with the drug- and androgen-metabolizing cytochrome P450 3A4 (CYP3A4, IC 50 ≫ 5 µM). These findings demonstrate the anticancer potential of 1 and warrant further explorations on this new type of hybrids. [ABSTRACT FROM AUTHOR]

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