第六亞型組蛋白去乙醯酶抑制劑作為潛能抗多形性膠質母細胞瘤之設計與合成

Design and Synthesis of HDAC6 Selective Inhibitors as Potential Agent Against Glioblastoma

王光瑞(Kuang-Jui Wang)

指導教授 ： 陳基旺

國立臺灣大學/醫學院/藥學研究所/碩士(2016年)

https://doi.org/10.6342/NTU201602295

摘要

本論文主旨為發展第六亞型組蛋白去乙醯酶抑制劑作為治療惡性腦癌―多形性膠質母細胞瘤可行性之研究。
三環結構的萘二甲醯亞胺(naphthalimide)是常見的螢光發光基團。本論文以此作為核心基團，以對甲基苯連結異羥肟酸(hydroxamate)，在對位及間位做取代基修飾，共合成出七個目標化合物，探討結構活性關係。其中化合物13d (HDAC6 IC50 = 0.1 nM, HDAC1 IC50 = 108 nM)的HDAC6抑制活性低於nM，且對HDAC1選擇性達到1080倍，而腦癌細胞U87MG的細胞毒性達0.92 μM。在構效關係上，對位氧取代或氮取代基團可以增加活性;而間位的取代則會失去活性。
另一部分，由於褪黑激素(melatonin)具有進入血腦障壁及低毒性的特色，因此以褪黑激素為主結構設計成HDAC6 抑制劑，並合成出兩個化合物作模式設計的可能性。其中化合物16a的HDAC6 IC50 5.5 nM 且U87MG的細胞毒性也達到0.97 μM。藥動研究發現16a和16b會快速吸收代謝。在褪黑激素的2號位做三氟甲基取代會使口服吸收率降低。化合物16a的腦血濃度比會隨著時間而增加，在1.5小時達到3.77倍。
總結本論文提供兩類化合物，作為潛力抗多形性膠質母細胞瘤藥物研究的可行性，其藥動學仍有待改善。

關鍵字

第六亞型組蛋白去乙醯?抑制劑 ； 多形性膠質母細胞瘤 ； ?二甲醯亞胺 ； 褪黑激素

並列摘要

The aim of this thesis is to develop histone deacetylase 6 (HDAC6) selective inhibitors for the potential glioblastoma multiforme treatment.
The tricyclic naphthalimide is a well-known pro-fluorophore. To design and synthesize HDAC6 inhibitors, we employed naphthalimide as the core structure and connected with hydroxamate group through p-toyl linker, and seven target compounds were synthesized for SAR study. Compound 13d (HDAC6 IC50 = 0.1 nM, HDAC1 IC50 = 108 nM) showed sub-nM inhibition against HDAC6 and 1080 times of selectivity against HDAC6 over HDAC1, and U87MG IC50 0.92 μM. From SAR studies, O-substitution or N-substitution at para position provided better activities. However, substitutions at meta position lost inhibition against HDAC and cancer cell lines.
Second part, melatonin was also selected as a core structure for HDAC6 inhibitor design, due to its blood-brain barrier penetrating and non-toxic properties, and two derivatives were synthesized. Compound 16a demonstrated IC50 0.97 μM against glioblastoma cell line with HDAC6 IC50 5.5 nM. Both 16a and 16b has a rapid absorption and metabolic properties. Trifluoromethyl at melatonin C2 position will lead to poor bioavailability. In vivo Kp of 16a increases with time, and Kp at 1.5 hr is 3.77.
To sum up, two scaffolds of HDAC6 inhibitors were developed for the potential therapeutic agents against glioblastoma in this study. Further studies on the improvement of pharmacokinetic properties are needed.

並列關鍵字

histone deacetylase 6 ； HDAC6 ； glioblastoma multiforme ； GBM ； naphthalimide ； melatonin

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