Scaffold diversity-oriented synthesis of limonoid dimers: discovery of an axially chiral agent with in vivo anti-breast cancer activity

Abstract

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.