本文選題：HIV-1 + CCR5拮抗劑　； 參考：《浙江大學(xué)》2014年碩士論文

【摘要】：AIDS是由感染人類免疫缺陷病毒(HIV)所引起的免疫缺陷綜合癥,是威脅人類健康的致命疾病之一。目前臨床上廣泛采用的治療方式是高活性抗逆轉(zhuǎn)錄病毒療法(HAART),雖然HAART可以降低HW-1°病毒感染后的發(fā)病率和致死率,但是長期使用這種治療方案會(huì)產(chǎn)生治療毒性和病毒耐藥性,因此開發(fā)新的HIV的治療方法仍然是當(dāng)前研究的熱點(diǎn)。病毒進(jìn)入抑制劑可以有效地預(yù)防HIV感染,研究者發(fā)現(xiàn)趨化因子受體5(CCR5)是病毒與宿主細(xì)胞結(jié)合的主要位點(diǎn)之一。這一發(fā)現(xiàn)促使許多研究人員開發(fā)CCR5拮抗劑,同時(shí)也避免了HAART的缺陷。 本論文中,我們以TAK-220為先導(dǎo)化合物,設(shè)計(jì)了哌啶-4-甲酰胺衍生物及1-環(huán)己基哌啶衍生物兩大系列共44個(gè)全新結(jié)構(gòu)的化合物。對(duì)所合成的所有化合物進(jìn)行了基于基于鈣流模型的CCR5拮抗活性的測(cè)試,發(fā)現(xiàn)化合物2-89、2-96、2-97及2-98具有很強(qiáng)的CCR5拮抗活性(IC50分別為4.78,5.67,2.04及1.35nM),比陽性藥naraviroc(IC50=11.38rnM)更優(yōu)。另外,對(duì)6個(gè)哌啶-4-甲酰胺衍生物進(jìn)行了體外抗HIV-1病毒測(cè)試,部分化合物顯示出一定的抗HIV-1病毒活性。上述研究,為進(jìn)一步設(shè)計(jì)新型的CCR5拮抗劑提供了實(shí)驗(yàn)依據(jù)。
[Abstract]:AIDS is a kind of immunodeficiency syndrome caused by human immunodeficiency virus (HIV) infection, and it is one of the fatal diseases threatening human health. At present, highly active antiretroviral therapy is widely used in clinic. Although HAART can reduce the morbidity and mortality of HW-1 擄virus infection, long-term use of this treatment can produce therapeutic toxicity and virus resistance. Therefore, the development of a new treatment for HIV is still the focus of current research. Virus entry inhibitors can effectively prevent HIV infection, and the chemokine receptor 5 CCR5 is one of the major sites for virus binding to host cells. The discovery prompted many researchers to develop CCR5 antagonists while avoiding the HAART flaw. In this thesis, we designed four novel compounds of piperidine-4-formamide derivative and 1-cyclohexyl-piperidine derivative with TAK-220 as the leading compound. All the synthesized compounds were tested for CCR5 antagonistic activity based on calcium current model. It was found that the IC50 of compounds 2-89O2-96O2-97 and 2-98 with strong CCR5 antagonistic activity were 4.785.6c2.04 and 1.35nMN, respectively, which were superior to the positive drug Naraviroca IC5011.38rnM. In addition, six piperidine-4-formamide derivatives were tested for anti-HIV-1 virus in vitro. Some of the compounds showed certain anti-HIV-1 activity. These studies provide experimental basis for the further design of new CCR5 antagonists.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914.5;R96
，

本文編號(hào)：1817380