Design and Synthesis of Amido-, Amino-, and Ureido-anthraquinones as Potential Antitumor Agent

• Main Authors: Hung-Wei Chen, 陳虹瑋
• Other Authors: 忻凌偉
• Format: Others
• Language: zh-TW
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/47996848522561445657

碩士 === 國立臺灣大學 === 藥學研究所 === 93 === The anthracenedione is the nucleus of several important antitumor agents such as mitoxantrone. Mitoxantrone is a synthetic aminoanthraquinone used in clinic for the treatment of leukemia etc. The possible mechanisms of mitoxantrone include intercalation into DNA base pairs, inhibition of topoisomerase II, and production of free radicals. Our aim is to synthesize novel anthraquinones which could show higher activity and lower toxicity than mitoxantrone. In our strategy, we keep the planar tricyclic system and the –[(aminoethyl)amino] side chains of mitoxantrone. The side chains could be the linkers upon which the amino acids could be introduced. The presence of amino acids might prove very useful in terms of drug specificity. We have synthesized a series of amidoanthraquinones in which the anthracenedione structure are linked to amino acids via amide linkages. However, the amide backbone is not stable to proteolytic hydrolysis. Recently an increasing amount of attention has been focused on the application of the urea moiety as a replacement for the amide bond in peptidomimetics. Due to the difference in backbone structure, oligoureas may differ from peptides in hydrogen-bonding properties, lipophilicity, stability, and conformational flexibility. Moreover, oligoureas are resistant to proteolytic hydrolysis. These characteristics of oligoureas may be useful in improving pharmacokinetic properties relative to peptides. In order to synthesize the ureidoanthraquinines, we developed a convenient general method with microwave-assisted for the synthesis of urea monomers. Besides, we are trying to develop the aminoanthraquinones as mitoxantrone derivatives. Several novel anthraquinones showed significant cytotoxicity against different human cancer cell lines. Further pharmacological evaluation of these promising compounds is recently in progress.