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Breast cancer has become the number one killer of women. In our previous study, an active compound, ION-31a, with potential anti-metastasis activity against breast cancer was identified through the synthesis of ionone alkaloid derivatives. In the present study, we aimed to identify the therapeutic target of ION-31a. We used a fluorescence tag labeled probe, molecular docking simulation, and surface plasmon resonance (SPR) analysis to identify the target of ION-31a. The main target of ION-31a was identified as heat shock protein 90 (HSP90). Thus, ION-31a is a novel HSP90 inhibiter that could suppress the metastasis of breast cancer and angiogenesis significantly in vitro and in vivo. ION-31a acts via inhibiting the HSP90/hypoxia inducible factor 1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) pathway and downregulating downstream signal pathways, including protein kinase B (AKT)/mammalian target of rapamycin (mTOR), AKT2/protein kinase C epsilon (PKCζ), extracellular regulated kinase 1/2 (ERK1/2), focal adhesion kinase (FAK), and mitogen-activated protein kinase 14 (p38MAPK) pathways. ION-31a affects multiple effectors implicated in tumor metastasis and has the potential to be developed as an anti-metastatic agent to treat patients with breast cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

β-ionone, a cyclic terpenoid compound present in many fruits, has been showed a broad spectrum of biological activities. In this paper, we synthesized a panel of β-ionone derivatives and tested their anti-proliferation activity on cancer cell by the MTT assay. The results showed that most of the β-ionone derivatives were more active than β-ionone and curcumin. Particularly, the β-ionone derivatives (1a, 1d and 1g) with ortho-substituents on the aromatic ring exhibited much stronger cytotoxicity than their corresponding meta- and para-substituted compounds. Importantly, the cytotoxicity of the β-ionone derivatives (1a, 1d and 1g) were relationship with their reactive oxygen species (ROS)-generation abilities, which could lead to the redox imbalance, lipid peroxidation, the loss of mitochondrial membrane potential (MMP), the activation of Bax and Caspase 3, followed by cell apoptosis. This work suggest that the "ortho effect", the ROS-generation ability and drawing fluorine atom into drugs may play a potent role in enhancing the anticancer activity of β-ionone derivatives., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Ionone alkaloid 9-(N,N-dimethyl)-4,7-megastigmedien-3-one (compound 1) is a new anti-metastatic natural product. However, it was previously reported as optical isomers mixture. Herein, the optical isomers (6a-6d) of compound 1 were synthesized. The absolute configurations of 6a-6d were determined by ECD experiments and calculated spectra with time-dependent density functional theory (TDDFT). The anti-metastatic effects of the optical isomers were examined by transwell assay. These results revealed that compound 6a had potential anti-metastatic activity with an IC 50 value of 0.512 ± 0.093 μM., (Copyright © 2018 Elsevier B.V. All rights reserved.)