設計與合成具抗癌潛力之醯胺基、胺基及脲基蒽醌類化合物

Abstract

蒽二酮為許多重要抗癌藥物的核心骨架，如 mitoxantrone 等。Mitoxantrone 為經由合成得到的胺基蒽醌類化合物，臨床上用來治療白血病等。Mitoxantrone 的可能抗癌機轉包括有嵌入去氧核醣核酸鹼基對中，抑制 topoisomerase II 和產生自由基。本研究的目的在於設計並合成具有比 mitoxantrone 較高抗癌活性和較低毒性的一系列新穎蒽醌類化合物，在本實驗室的合成策略中，我們保留了 mitoxantrone 的平面三環結構及雙-[(2-胺乙基)胺基]支鏈，這支鏈可作為和胺基酸的連接部分，而接上胺基酸已證實對於增加藥物的專一性是非常有用的。本實驗室中已成功合成出一系列的醯胺基蒽醌類化合物，此種化合物中蒽二酮結構經由醯胺鍵連結胺基酸。然而，醯胺鍵易受蛋白質酶水解影響，因而已有大量的注意力集中在將醯胺鍵部份置換成尿素骨架。由於骨架結構上的差異，尿素架構聚仿胜肽在形成氫鍵的性質、脂溶性、穩定性和構形的彈性皆異於醯胺骨架之聚仿胜肽。此外，尿素架構聚仿胜肽不易受蛋白質水解影響。而為了合成新一系列具有尿素骨架的脲基蒽醌類化合物，本實驗室利用微波加熱器來協助開發更有效率的尿素單體合成方法。此外，我們亦試著開發和 mitoxantrone 同類的胺基蒽醌類化合物。本論文中開發的數個蒽醌類化合物，在不同的人類癌細胞株中表現有意義的細胞毒殺作用，而更進一步的藥理評估正在進行中。

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.