| Malignant which is also called cancer is a serious threat to human life and health, according to IARC report, there has been 14.1 million people suffered from cancer worldwide, of which 8.2 million people died of cancer. 40 years later, global new cases of cancer and related deaths will reach 27 million and 17.3 million, which is an important problem for human to solve. In recent years, that a large number of active natural ingredients derived from plants and animals become an important way to find innovatative anti-tumor drugs. Finding a new structure, a novel mechanism of the active ingredient of efficient, low toxicity as a lead compound from the natural plant and animal species, and modifying or altering its structure, is an important direction for the development of anticancer drugs.Rhein which belongs to hydroxyl anthraquinone derivatives is an active and iconic ingredient of traditional Chinese medicine(rhubarb, knotweed, polygonum, etc.). It is structurally similar to tetracycline which makes it have a wide range of pharmacological activity such as anti-ulcer, anti-inflammatory, hypoglycemic lipid-lowering etc. Meanwhile, rhein also have some anti-tumor activity and exhibited outstanding efficacy in synergistic anti-tutor. However, the rigid structure of rhein leads to its poor solubility, resulting in decreased bioavailability which makes it an urgent requirement to modify its structure to improve its solubility.Amino acid is the most important physiologically active substance in life activities, and it is involved in many biochemical processes in vivo activity. Tumor is the proliferation strong tissue, and its demand for amino acid is much larger than normal tissue. For this reason, the amino acid fragment was introduced into rhein structure in order to increase its selectivity for the identification of tumor cells, enhance drug solubility, ease cytotoxic of drugs and improve its bioavailability, etc.Currently,the study about rhein mainly focuse on its pharmacological activity and structure of the 3rd digit derivatization, derivatization on its 1,8-bit and 3-position at the same time is rare. Introducing amino acids into its 3rd digit while its 1,8-bit was derivatized has not been reported.In this dissertation, a series of rhein-amino acid derivatives(32 derivatives in total) were designed and synthesized to test their cytotoxicity for cervical cancer cells(Hela), human hepatoma cells(Hep G-2), human breast cancer cells(MCF-7), human oral epidermoid carcinoma(KB) cells and human embryonic kidney(HEK-293T) in vitro. The results revealed that the compound 7l4 displayed the antitumor activities with IC50 of 9.39 mM, 4.49 mM, 3.61 mM, 4.92 mM and 1.63 mM against Hela, MCF-7, Hep G-2, KB and HEK-293 T, respectively, which make inhibitory activity increase 10-90 fold compared to the lead compound rhein. And its solubility was also greatly improved. Preliminary structure-activity relationships indicated that introducing alkyl benzene in 1,8-position and valine in 3-position can effectively enhance the inhibitory activity. And seven derivatives were selected to test their ability to interact with DNA, we found that all these conpounds could strongly bind to DNA. In order to synthesize this class of rhein derivatives in a more efficient way, one new method for amide bond formation has been developed in this dissertation. Concerning amide bond susceptible to hydrolysis, we established for the first time 2-pyrrole-carbaldiminato-Cu(II) complexes as novel and high efficient catalyst for one-pot three-component 1,3-dipolar cycloaddition for 1,4-disubstituted 1,2,3-triazoles synthesis in water at room temperature in order to replace amide bond for trizoles. In addition, the low catalyst loading(1 mol%), ambient reaction conditions, high regioselectivity presented herein, are the salient features of this protocol, which made the operation much more practical. However, it may due to low activitity of substrates that this method failed to apply into the synthesis of rhein-amino acids derivatives. |
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