Suberoylanilide Hydroxamic Acid (SAHA)類似物作為潛能抗癌藥物之設計與合成

本論文主旨為設計與合成suberoylanilide hydroxamic acid (SAHA)類似物作為潛能histone deacetylase (HDAC)抑制劑與抗癌劑。主要內容為將SAHA結構中與HDAC的金屬有結合作用的hydroxamic acid官能基固定住而設計出目標化合物，這些hydroxamic acid衍生物可分成兩類，一種是hydroxamic acid相連結於苯環上(1及2a,b)，另一種則是建構於喹唑啉酮環中(3及4)。在化合物1的合成中，中間物5是從aniline經由六個反應步驟製備而成，其中包含Friedel-Crafts acylation(與succinic anhydride作用)產生linker接於苯環上，將羧酸化合物5進行酯化之後再與hydroxylamine作用可得到hydroxamic acid產物1。為合成化合物2a,b，含碘苯甲酸化合物25a,b經由Heck reaction與vinyl acetic acid反應之後，接著醯胺生成反應與水解反應可得到苯甲酸衍生物30a,b，之後再與methyl chloroformate反應，緊接著與O-benzylhydroxylamine作用，最後藉由氫化反應可得到hydroxmic acid 2a,b。含碘的喹唑啉酮化合物40及41是利用anthranilic acid經由三個反應步驟合成而得，接著進行Heck reaction與醯胺生成反應可分別產生44及45，而目前正準備將化合物44和45進行氫化反應以生成化合物3與4。目標化合物1、2a,b以及3的前驅化合物44藉由MTT分析方法對A549、AGS、HepG2、HT-29與PC-3五種人類癌細胞株進行體外細胞毒性測試。化合物2b顯示對A549、AGS、HepG2以及HT-29癌細胞株具有生長抑制活性，GI50在4.29-7.36 μM之間；化合物44也能抑制A549、AGS、HT-29 (最有效，GI50為1.54 μM)和PC-3癌細胞株活性。在酵素活性抑制分析方面，化合物2b被發現為一HDAC抑制劑(IC50=11.5 μM)。此外，化合物3與4的最後階段的合成工作未來可望能進行。

關鍵字

抗癌藥物； HDAC ；抑制劑

並列摘要

The aim of this thesis is to design and synthesize homologues of suberoylanilide hydroxamic acid (SAHA) as potential histone deacetylase (HDAC) inhibitors and anticancer agents. Based on SAHA, the target compounds were designed by conformational restriction of the hydroxamic acid group involved in the metal binding interactions with HDAC. The designed hydroxamic acid derivatives are divided into two classes: with the hydroxamic acid group attached to a phenyl ring (1 and 2a,b) and built into a quinazolinone ring (3 and 4). In the synthesis of compound 1, the required intermediate 5 was prepared from aniline via six reaction steps, including a Friedel-Crafts acylation with succinic anhydride to attach the linker to the benzene ring. Esterification of acid 5 followed by treatment of hydroxylamine gave the hydroxamic acid product 1. To synthesize compounds 2a,b the benzoic acid derivatives 30a,b were prepared from iodo-substituted benzoates 25a,b via Heck reaction with vinylacetic acid and then amide formation and hydrolysis reactions. Treatment of acids 30a,b with methyl chloroformate followed by reaction with O-benzylhydroxylamine and hydrogenation led to hydroxamic acids 2a,b. The iodo-substituted quinazolinones 40 and 41, prepared from anthranilic acid via three reaction steps, were subjected to Heck reaction and then amide formation reaction to give 44 and 45, respectively. The hydrogenation reaction of compounds 44 and 45 will be carried out to produce the desired products 3 and 4, respectively. Target compounds 1 and 2a,b and the precursor compound 44 (for 3) were evaluated for the in vitro cytotoxic activity against five human cancer cell lines (A549, AGS, HepG2, HT-29, and PC-3) by MTT assay. Compound 2b showed significant growth inhibition against A549, AGS, HepG2, and HT-29 cancer cell lines with GI50 values in the range of 4.29-7.36 μM. Compound 44 was also found to be cytotoxic toward A549, AGS, HT-29 (most sensitive, GI50 = 1.54 μM), and PC-3 cancer cell lines. In the enzyme inhibition assay, compound 2b proved to be active as an HDAC inhibitor with an IC50 value of 11.5 μM. In addition, studies on compound 3 and 4 are still underway.

並列關鍵字

SAHA ； HDAC ； anticancer

參考文獻

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Suberoylanilide Hydroxamic Acid (SAHA)類似物作為潛能抗癌藥物之設計與合成

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