Starting from the natural monomeric limonoids 1 and 1′, we designed and synthesized eight new limonoid dimers of four skeletons (two symmetric and two non-symmetric), containing a rotationally hindered C15C15′ central axis (2, 2′), an embedded C15-spiro-fused 2H-pyran motif (3, 3′), and an axially chiral C15–C15′ central bond (4, 4′, and 5a, 5b), respectively, by oxidative carbon–carbon radical coupling. The dimeric architectures of these compounds, particularly absolute configurations of C15C15′ and C15–C15′ central axes, were unequivocally determined by extensive NMR investigations, single-crystal X-ray diffraction analyses, and electronic circular dichroism spectral comparison. The C₂-symmetric dimer 5b with a (M)-configured C15–C15′ central axis exhibited selective and potent cytotoxicities against human triple-negative breast cancer (TNBC) MD-MBA-231 and MD-MBA-453 cells with IC₅₀ values of 5.57 ± 1.48 and 3.93 ± 0.75 μM, respectively. This induces cell-cycle arrest in the G2/M phase and apoptosis, and enhances the accumulation of reactive oxygen species (ROS) in cells. Importantly, 5b suppressed the growth of MDA-MB-453 tumor xenografts with no significant side effects in Balb/c nude mice. After intravenous injection with 5b at a dose of 30 mg kg⁻¹ every two days for four weeks, the inhibitory rate for TNBC MDA-MB-453 tumor xenografts was 63.83%. It was concluded that not only the presence of 6R-OH/6′R-OH groups, but also the stable (M)-configuration of the C15–C15′ central axis is pivotal for the in vivo anti-TNBC activity of 5b. This is the first report on an axially chiral limonoid dimer with in vivo anticancer activity.

中文翻译：

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柠檬苦素二聚体的支架多样性导向合成：发现一种具有体内抗乳腺癌活性的轴向手性药物†

从天然单体柠檬苦素开始1和1'中，我们设计并合成了八个新柠檬苦素类二聚体四个骨架（两个对称和两个非对称的），其包含可旋转受阻C15 C15'中心轴（2，2' ），嵌入式C15-螺稠合的2 ħ吡喃基序（3，3' ）和一个轴向手性C15-C15'中心键（4，4' ，和图5a，图5b），分别由氧化的碳-碳自由基偶合。这些化合物的二聚体结构，尤其是C15的绝对构型通过广泛的NMR研究，单晶X射线衍射分析和电子圆二色性光谱比较，明确确定了C15'和C15–C15'的中心轴。具有M构型的C15–C15'中心轴的C ₂对称二聚体5b对具有IC _50的人三阴性乳腺癌（TNBC）MD-MBA-231和MD-MBA-453细胞表现出选择性和强力的细胞毒性值分别为5.57±1.48和3.93±0.75μM。这诱导了细胞周期在G2 / M期的停滞和凋亡，并增强了细胞中活性氧（ROS）的积累。重要的是5b抑制了Balb / c裸鼠中MDA-MB-453肿瘤异种移植物的生长，而没有明显的副作用。每两天以30 mg kg ^-1的剂量静脉注射5b，持续4周后，TNBC MDA-MB-453肿瘤异种移植的抑制率为63.83％。得出的结论是，不仅6的存在ř -OH / 6' - [R -OH基团，也有稳定（中号的C15-C15的） -构型“中心轴线枢转是在体内的抗TNBC活性5B。这是关于具有体内抗癌活性的轴向手性柠檬苦素二聚体的首次报道。