第一部分 設計與嘗試合成吖啶酮衍生物作為潛在ABC轉運蛋白抑制劑,第二部分 設計與合成吡唑雜環衍生物作為system xc-蛋白抑制劑

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Title:	第一部分設計與嘗試合成吖啶酮衍生物作為潛在ABC轉運蛋白抑制劑,第二部分設計與合成吡唑雜環衍生物作為system xc-蛋白抑制劑
Other Titles:	Part 1: Design and Attempted Synthesis of Acridone Derivatives as Potential ABC Transporters Inhibitors,Part 2: Design and Synthesis of Pyrazole Derivatives as System xc- Inhibitors
Authors:	張家瑋 JHANG,JIA-WEI
Contributors:	吳雨珊 WU,YU-SHAN 化學系
Keywords:	胱氨酸/谷氨酸反轉運蛋白 system Xc-
Date:	2018
Issue Date:	2018-11-07T04:34:51Z (UTC)
Abstract:	第一部分ABC轉運蛋白(ATP-binding cassette transporters)是一種轉運蛋白，在生物體內負責將細胞內的代謝物以及毒性物質排出細胞外，以達到保護細胞的目的。當抗癌藥物不斷的刺激癌細胞時，癌細胞會過度表達ABC轉運蛋白，將抗癌藥物排出細胞外，以導致化療藥物無法有效毒殺癌細胞，使癌細胞產生多重抗藥性(multidrug resistance，MDR)。因此，多重抗藥性的發生是癌s症病患化療成功的主要障礙。Acridones為黃酮類化合物是天然的生物鹼，其衍生物elacridar具有抑制ABCB1以及ABCG2的能力。我們以acridones作為主體架構，並進行官能基修飾設計與合成acridones的衍生物。以amine化合物與4-acridinecarboxylic acid進行偶合反應形成acridones的衍生物，但在偶合時4-acridinecarboxylic acid只有被醯氯化試劑或是偶合試劑所活化，卻無法與amine化合物偶合。推測可能因為4-acridinecarboxylic acid的acridones結構與amine化合物上的苯環之間立體阻礙過大，才導致無法順利偶合而無法合成出最終產物。第二部分在中樞神經系統中system xc-主要負責細胞膜上將細胞外L-Cys2以及細胞外的L-Glu以1:1的方式進行交換。交換後的L-Cys2至細胞內後迅速的降解成L-CysH，在藉由細胞內的酵素促進合成Glutathione(GSH)以達到氧化保護細胞或腫瘤的目的。當大量排出L-Glu會導致原本應為興奮性傳遞物質轉變成興奮性毒性影響。由於腦中的神經細胞因興奮性中毒甚至死亡所騰出的空間恰巧提供了神經膠質瘤細胞生長所需的空間。本研究參考Patel研究團隊所設計出isoxazoles類型抑制劑的藥效基團模型，設計出一系列以pyrazole為中心雜環為主體的16個衍生物。2、3號位取代衍生物透過witting反應將hydrazine與dialkyl ethylenedicarboxylates進行合成。1、3號位取代衍生物透過銅催化反應將hydrazones與dialkyl ethylenedicarboxylates進行合成。在藥物濃度為50 μM 的MTT、L-Glu外排測試以及14C-cysteine吸收測試中，間位雙苯環取代前端區域為pyridazinedione的BBXc23具有最好的抑制效果，可有效抑制具有system xc-過度表達的膠質瘤母細胞(glioblastomas, GBM)，阻止L-Glu與L-Cys2的交換並且具有較低的細胞毒性。 Part 1:ABC(ATP-binding cassette) transporter proteins are responsible for the cellular efflux of metabolites or toxic substances to protect cells. Overexpression of ABC transporter protein occur when tumor cells are stimulated continuously by chemotherapeutic drugs,that to causing lack of drug accumulation drugs which lead to development of multidrug resistance (MDR). The development of MDR is a major obstacle to successful chemotherapeutic treatment of cancer patients.Acridones are naturally occurring alkaloids and one of its derivatives, Elacridar was shown to inhibit both ABC transporter proteins ABCB1 and ABCG2. In this study,acridone was used as lead compound to design and synthesize acridone derivatives. These derivatives were planned to be synthesized by coupling 4-acridinecarboxylic acid with respective amines. We have,however,only managed to prepare the acid chlorides and the activated acids. Nucleophilic attack by amine did not occur presumably due to the steric hindrance between the phenyl ring on the amine and acridone moiety.Part 2:System xc- mediates the exchange of extracellular L-cystine and intracellular L-glutamate across the cellular plasma membrane in a 1:1 manner. After the exchange, the intracellular L-cystine is rapidly reduced to L-CysH which is enzymatically incorporated into Glutathione(GSH) that can protect cell or tumors. when the efflux of L-Glu through system xc- becomes excessive, its function within the CNS turns from an excitatory transmitter to excitotoxin. Excitoxine caurse are cell poisoning/death which also vacating room for tumor expansion.In this study,we take pharmacophore model of isoxazole analogues by Patel et al as reference to design and synthesize sixteen pyrazole derivatives as system xc- inhibitors. 2,3-disubstituted derivatives were synthesized by witting reaction of hydrazine and dialkyl ethylenedicarboxylates. 1,3-disubstituted derivatives were synthesized by copper-catalyzed reaction of hydrazones and dialkyl ethylenedicarboxy-lates. At drug concentration of 50 μM,BBXc23 showed low cytotoxicity for glioblastoma cell,and BBXc23 also exhibited good inhibition for both L-glu efflux and cysteine uptake, which indicated that this compound may be a good system xc- inhibition.
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