The synthesis of two isomeric testosterone dimers and an androstenedione dimer is reported. The design takes advantage of an efficient transformation of testosterone leading to the synthesis of the key diene, 7α-(buta-1,3-dienyl)-4-androsten-17β-ol-3-one, through an elimination reaction. It was found that in some instances the same reaction led to partial epimerization of the 17β-hydroxyl group into the 17α-hydroxyl group. The specific orientation of the hydroxyl function was confirmed by NMR spectroscopy. Capitalizing on this unforeseen side reaction, several dimers were assembled using an olefin metathesis reaction with Hoveyda-Grubbs catalyst. This led to the formation of two isomeric testosterone dimers with 17α-OH or 17β-OH (14α and 14β) as well as an androstenedione dimer (14). The new dimers and their respective precursors were tested on androgen-dependent (LNCaP) and androgen independent (PC3 and DU145) prostate cancer cells. It was discovered that the most active dimer was made of the natural hormone testosterone (14β) with an average IC₅₀ of 13.3 μM. In LNCaP cells, 14β was ∼5 times more active than the antiandrogen drug cyproterone acetate (IC₅₀ of 12.0 μM vs. 59.6 μM, respectively). At low concentrations (0.25–0.5 μM), 14α and 14β were able to completely inhibit LNCaP cell growth induced by testosterone or dihydrotestosterone. Furthermore, cross-reactivity of androgen-based dimers with sterol-metabolizing cytochrome P450 3A4 was explored and the results are disclosed herein.

报告了两种异构睾酮二聚体和雄烯二酮二聚体的合成。该设计利用睾酮的有效转化，通过消除反应合成关键二烯 7α-(buta-1,3-dienyl)-4-androsten-17β-ol-3-one。发现在某些情况下，相同的反应导致 17β-羟基部分差向异构化为 17α-羟基。羟基官能团的特定取向由核磁共振光谱证实。利用这种不可预见的副反应，使用 Hoveyda-Grubbs 催化剂的烯烃复分解反应组装了几个二聚体。这导致形成两种异构睾酮二聚体，分别为 17α-OH 或 17β-OH（14α和14β）以及雄烯二酮二聚体（14 )。新的二聚体及其各自的前体在雄激素依赖性（LNCaP）和雄激素非依赖性（PC3 和 DU145）前列腺癌细胞上进行了测试。发现最活跃的二聚体由天然激素睾酮 ( 14β ) 制成，平均 IC ₅₀为 13.3 μM。在 LNCaP 细胞中，14β的活性是抗雄激素药物醋酸环丙孕酮的约 5 倍（IC ₅₀分别为 12.0 μM 和 59.6 μM）。在低浓度 (0.25–0.5 μM)、14α和14β能够完全抑制由睾酮或二氢睾酮诱导的LNCaP细胞生长。此外，探索了基于雄激素的二聚体与甾醇代谢细胞色素 P450 3A4 的交叉反应性，结果在本文中公开。