| Cancer has been a common and frequently-occurring disease which threats to human health. Conventional cancer therapy has many disadvantages, such as poor selectivity, large side effects and drug resistance. Ligand-drug delivery system is developed by linking drug with ligand, targeting the specific receptors overexpessed on the surface of tumor cells. The drug can be delivered targeting to tumor cells or tissue with directing by ligand. Therefore, the drug is actively released to the target and drug selectivity and action are increased. In recent years, ligand-drug delivery system has become an effective way for anti-cancer therapy. Because small molecule compounds have the relatively low molecular weight, can rapidly spread out of the blood vessel, and rapidly penetrate into the depths of the tissue, small molecule-drug conjugates have attracted more attention from pharmaceutical researchers. Podophyllotoxin (PPT), a natural compound extracted from the podophyllum plants, is known to have important anti-viral and antineoplastic properties. In recent years, many works have shown that the podophyllotoxin is a very important anti-cancer drug precursor. And more attention has been paid to the anti-cancer activities of its derivatives.In this paper, we reviewed a series of ligand-drug delivery system in the trials and literatures, talked about the anti-tumor mechanism and structure-activity relationship of podophyllotoxin, and described the principles in the design of small molecule-drug conjugates. On this basis, we designed and synthesized two small molecule-drug conjugates using biotin as the ligand,-S-S- as the linker, and 4'-demethylepipodophyllotoxin as the active drug. All the preparation procedures for these two compounds were described and all of them were characterized by 1H NMR, 13C NMR, HPLC-HRMS and melt point.The antiproliferative activities of our compounds were evaluated by MTT method against the selected tumor cell lines, including the human acute promyelocytic leukemia cell HL-60 (biotin receptor overexpression), and human cervical carcinoma cell Hela (biotin receptor overexpression). Our compounds displayed potent in vitro antiproliferative activity, which was weaker than that of etoposide. Further intensively biological evaluation and mechanism research of compounds are undergoing.The construction of huge compound libraries plays a key role in the development of new drugs. Nitrogen-heterocycle compounds occupy a large proportion in marketed drugs, so it is important to construct a huge amount of nitrogen-heterocyclic libraries for the discovery of lead compounds. Three libraries with 50 compounds were developed via novel methodologies. Firstly, we have developed a novel, convenient and economical strategy to prepare functionalized benzo[f]indole-4,9-dione derivatives from vinyl azides and 2-hydroxynaphthalene-1,4-dione in the presence of Mn(II) acetate with good to excellent yields. Secondly, we have developed an efficient approach for the construction of spirofuranone-lactams from readily available vinyl azides and 4-hydroxycoumarin via thermal decomposition of vinyl azides to 2H-azirines, followed by an intramolecular nucleophilic attack and 4-exo-trig cyclization. Lastly, substituted 2-aminothiazoles have been synthesized from ?-nitro-epoxides, cyanamide and sodium sulfide via a facile, three-component, and eco-friendly protocol with good to excellent yields. All of these 50 compounds were identified by 1H NMR,13C NMR, HPLC-HRMS and melt point, and their further biological evaluation is also undergoing. |
PDF Full Text Request