設計與合成氟化半胱氨酸蒽醌類化合物作為有潛力的正子斷層掃描腫瘤造影劑

Abstract

本研究的目的是以mitoxantrone (MX) 為基本模板，來設計與合成一系列新穎的氟化半胱氨酸蒽醌類抗腫瘤化合物，作為具潛力用於測量腫瘤細胞增生的正子斷層掃描造影劑。所以為模擬氟十八造影劑的合成，本研究以四丁基氟化銨為氟化試劑，並優化其氟化反應的反應條件，以便大量製備單一氟化的反應中間體，並且期望將來能應用在正子斷層掃描上。 利用將含氟官能基導入MX 骨架而設計的一系列氟化半胱氨酸蒽醌類抗腫瘤化合物2-4 和26 已經成功地被合成出來，並且進行人類前列腺癌細胞株的抑制活性試驗，由結果可以得知，化合物4 為抑制活性最強的化合物(IC50 = 0.43 M)，甚至還比臨床常用的MX活性好。此外，也可以發現本系列化合物的活性強度依硫原子與氟原子間的碳鏈長度增加而增強，但其活性強弱間相差並不大，並未因為碳鏈增長而使活性有明顯的上昇。另外，也利用測定DNA 的熔化溫度來加以探討這些蒽醌類化合物的抗癌機轉，及其和DNA 雙股螺旋的作用關係，以作為未來藥理活性篩選的初步評估。

The aim of this study is to utilize mitoxantrone (MX) as templates to synthesize potential S-fluoroalkylcysteine-anthraquinone antitumor imaging agents that are potential to be employed to measure tissue and tumor proliferation with positron emission tomography (PET). Therefore, in order to simulate the synthesis of 18F imaging agents, the fluorination method with tetrabutyl- ammonium fluoride (TBAF) was chosen, and the reaction condition of this mono-fluorination was optimized to large scale. Fluoroaminoanthraquinone derivatives 2-4 and 26 with fluorine attached to MX backbone have been designed and synthesized. The antitumor activity of these compound was also evaluated with prostate cancer cell line (PC-3). According to the result, compound 4 has the best antitumor activity (IC50 = 0.43 M) and is even better than MX. Otherwise, we can find that the antitumoractivity is more and more potent from short to long carbon chain between sulfur and fluorine atom. It can be the basis of further drug design. Moreover, we utilized the DNA melting temperature measurement technique to provide information about the antitumor mechanism and the interaction of synthetic anthraquinones and DNA double helix. These information can be the initial pharmacological evaluation for our compounds in the future.