Design, Synthesis, And Evaluation Of Rhein Derivatives As Anti-tumor Agents

Cancer is one of the critical diseases, that do harm to the health and has been the second largest killer because of its high incidence and mortality all over the world. Due to the complexity of cancer etiology, the serious side effects of clinically used anticancer drugs and multidrug resistance of cancer, and the compounds from natural products not only have unique structures and various mechanisms, but also present the better security, searching for novel anticancer drugs from natural products is urgently needed.Rhein(4,5-dihydroxyanthraquinone-2-carboxylic acid) is the primary anthraquinone in the roots of rhubarb. It has anti-inflammation, antitumor, anti-Alzheimer’s disease, antibacterial, antiviral, antioxidant. A recent study showed that rhein can inhibit tumor cell proliferation and induce apoptosis of human tumor cells, including in A549 cells, HL-60 cells, NPC cells, SCC-4 cells, MCF-7 cells, SGC-7901 cells, Hep G2 cells and Bel-7402 cells. Moreover, the study also showed that rhein could prevent tumor growth through a variety of antitumor mechanism, including down-regulation of matrix metalloproteinases-9 and vascular endothelial growth factor, increase the level of Bax and decrease the level of Bcl-2, mitochondrial permeability transition. Although these results suggest that rhein may be a potent antitumor drug, the clinical application of rhein has been hampered by its poor bioavailability, low aqueous solubility and leading to gastrointestinal disorder. Therefore, the design and development of more potent and water soluble derivatives of rhein is urgent for the application of rhein-based antitumor agents in the clinic.Previous studies of the modification of Gambogic acid and gambogenic acid have revealed that introduction of amino moiety to a molecule usually improves its water solubility, accelerates the interaction of both H-bond donor and acceptor with the intended biological targets. In order to get target compounds with better water solubility, anticancer and high bioavailability activity, a lot of rhein derivatives were designed and synthesized.Accordingly, twenty-four target compounds were designed and synthesized by coupling various hydrophilic alkanolamines to the 2-carboxyl of rhein, and their structures were established by IR, HRMS, 1H-NMR spectra. Solubility test showed that all compounds were 10.04 to 15.08 mg/m L in water, which was 220 to 330-fold better than that of rhein(0.0456 mg/m L). All of rhein derivatives displayed more potent anti-tumor activity than rhein, and most of them were even stronger than 5-FU, particularly, 4s, 4t, and 4v displayed more potent antiproliferative activities(IC50: 3.01-5.28 μM on A549 cells, 5.92-7.63 μM on Mcf-7, 0.33-0.85 μM on Hep G2 cells, 0.31-0.83 μM on HCT116, 2.36-6.49 μM on Bel-7402 and 4.48-7.31μM on Bel-7402/5-FU cells). Compound 4v was further found to induce HCT116 cell apoptosis. Moreover, compound 4v induce cell cycle G2/M-phase arrest via downregulation of CDK1 and cyclin B in HCT116 cells.