【作者】 李雪梅；

【导师】 闫红； 曾程初；

【作者基本信息】 北京工业大学 ， 生物医学工程， 2006， 硕士

【摘要】 芳基β-二酮酸衍生物是迄今为止所报道的唯一具有细胞内抗病毒活性的HIV-1整合酶抑制剂。它能够选择性地抑制HIV-1整合酶两个催化功能中的链转移过程。本论文在分析了芳基β-二酮酸类HIV-1整合酶抑制剂研究现状的基础上,提出将磺酰胺芳基β-二酮酸和喹噁啉酮衍生物的合成作为研究目标。研究了含有磺酰胺结构的芳基β-二酮酸和喹噁啉酮衍生物的合成。设计合成了10个含有不同取代基如-Cl, -CH₃, -OCH₃, -NO₂的磺酰胺芳基β-二酮酸衍生物50a-e和51a-e。考虑到羧基的存在使得以上磺酰胺芳基β-二酮酸化合物在化学和生物学上不稳定、生物利用度不高的缺点,根据生物等排原理,进一步设计合成了10个喹噁啉酮衍生物52a-e和53a-e。以上所合成的芳基β-二酮酸和喹噁啉酮衍生物的结构均得到核磁共振谱、红外光谱及质谱的验证。分析了喹噁啉酮衍生物52a、53b、53c、53d的晶体结构。结果表明分子内的氢键作用以及喹噁啉酮环上两个氮原子的sp2杂化使得喹噁啉酮衍生物的支链与其中心芳基共平面,这与二酮酸母体结构一致,从而进一步证实了当初的设计。采用紫外-可见光谱的手段,研究喹噁啉酮衍生物在有机溶剂中与金属离子的选择性和亲和力的大小。实验结果表明它们能选择性识别Cu²⁺,并且磺酰胺单元处于芳基的间位时,其配位常数Ks值比其处于对位时大100倍左右。更多还原

【Abstract】 β-diketo acid derivatives are the only HIV-1 integrase with anti-viral activity in cell until now. It can selectively inhibit strand transfer reaction of HIV-1 IN catalytic domain. The inhibitory molecular basis of diketoacid derivatives is to interact with catalytic domain of IN selectively. In the paper, the synthesis of sulfonamide arylβ-diketo acids and quinoxalinone derivatives is the aim of our research based on the analysis priminary fact of arylβ-diketo acids HIV-1 integrase inhibitors.We have investigated the detailed synthesis of sulfonamide-containing arylβ-diketo acid derivatives and quinoxalinone derivatives. We design and synthesize ten different sulfonamide-containing arylβ-diketo acid derivatives 50a-e and 51a-e with the substitute of -H, -Cl, -CH3, -OCH3, -NO2 respectively. The existence of carboxyl make the diketo acid derivatives instability in chemistry and biology and also have the disadvantage of low utilization in the body, so we design quinoxalinone derivatives as its bioisostere and synthesize ten quinoxalinone derivatives from 52a to 53e. The above compounds were confirmed by the methods of NMR, IR and MS.The X-ray crystal structure of 52a, 53b, 53c and 53d were further analysed. Because of the existence of intramolecular hydrogen bond and the sp2 hybrid configuration of two N atoms, there was a similar arrangement between the chain of quinoxalinone derivatives and diketo acid derivatives, which further confirmed our above design.We investigated the recognition and affinity of target compounds covalent with metal ion by UV-Vis spectro in organic solvent. The experiment results demonstrated that the quinoxalone derivatives could selectively recognize Cu²⁺, and the Ks of the sulfonamide unit in the meta position of phenyl ring is 100 times than that in the para position.更多还原