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

• Main Authors: JHANG,JIA-WEI, 張家瑋
• Other Authors: WU,YU-SHAN
• Format: Others
• Language: zh-TW
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/qg9258

碩士 === 東海大學 === 化學系 === 105 === 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.