黄酮类Vif-A3G拮抗剂的设计与合成
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摘要
黄酮类化合物是一类存在于自然界,具有2-苯基色原酮结构的化合物,具有广泛的药理活性,其中对HIV-1病毒的抑制作用引起人们的广泛关注。课题组前期研究发现槲皮素衍生物6-21具有抑制HIV-1 Vif-A3G相互作用的活性,其中8位磺酸基是明显增强化合物该活性的基团,归纳文献可知,磺酰胺是作用于该靶点的重要基团,因此,拟开展一系列黄酮类衍生物与HIV-1 Vif相互作用的研究工作。
首先利用计算机辅助药物设计的方法,基于文献报道的小分子抑制剂建立药效团模型,发现6-21与其有较好的匹配结果,于是在该模型基础上设计了目标分子——8位取代的黄酮类磺酰胺衍生物；以A3G模型为受体的分子对接工作中,发现该系列的衍生物可通过氢键、π-σ等方式很好的作用于A3G与Vif结合的重要部位,预测该系列衍生物对A3G也有一定的结合亲和力。
其次在化学合成部分,为获得结构改造所需原料,进行了黄酮糖苷类物质的水解反应,应用强阳离子交换树脂CT-450作为催化剂,以水为溶剂,条件温和,是一种操作简便、原料转化率高、催化剂可循环套用的绿色水解方法,且循环套用对收率无影响,其中芦丁的水解反应最高收率可达98.6%,经HPLC检测其纯度最高可达98%。以8位取代的槲皮素磺酰胺衍生物为目标分别设计两条路线：第一条路线的磺化反应中,通过控制温度分别得到了相应的一磺化和二磺化产物以及其异构体,解析了化合物6的晶体结构,该路线以乙酰基为羟基保护基,未成功得到目标物；第二条路线以甲基为保护基,以氯磺酸为磺酰化试剂,成功分离得到3个磺酰胺衍生物。本文中所得到的所有化合物结构通过核磁、质谱等手段得到表征。
Flavonoids (2-phenyl chromone) exist in nature with extensive activities especially for HIV-1. It has already been found that 6-21 which is a derivative of quercetin could inhibit HIV-1 Vif-A3G effectively.8-sulfonic group of 6-21 could enhance the activity. Therefore, a series of flavonoid derivatives may be developed to disrupt the interaction with Vif-A3G.
Firstly, Computer Aided Drug Design was used to establish a pharmacophore model and dock.6-21 could match the pharmacophore very well. In addition, the sulfamine is a vital group. Therefore, a series of flavonoid-8-sulfamine derivatives were designed. Moreover, by LigandFit of Discovery Studio, the prominent activity of the compounds has been predicted in the key sites of A3G-Vif in manner of hydrogen bond andπ-σinteraction.
Secondly, the hydrolysis reactions of flavonoid glycosides were performed to form raw materials of the target compounds. CT-450 was used as a catalyst instead of the traditional proton acid. Meanwhile, water acts as the solvent which provids a mild condition. A convenient, high-convertible, and recyclic method was found. In addition, the recycle had few effect on the yield. Two routes were carried out to modify the flavonoids. In route 1, the mono-sulfonated sodium and di-sulfonated sodium of flavonoids were obtained through adjusting the reaction temperature. Moreover, the crystal structure of 6 was determined by X-ray diffraction. However, the target compounds were not generated with acetyl protective group. In route 2, acetyl group was insteaded by methyl group. Chlorosulfonic acid was used to be sulfonylation agent. Three sulfamide derivatives of quercetin were synthetized and their structures were confirmed by 1HNMR,13CNMR, MS, et al.
首先利用计算机辅助药物设计的方法,基于文献报道的小分子抑制剂建立药效团模型,发现6-21与其有较好的匹配结果,于是在该模型基础上设计了目标分子——8位取代的黄酮类磺酰胺衍生物；以A3G模型为受体的分子对接工作中,发现该系列的衍生物可通过氢键、π-σ等方式很好的作用于A3G与Vif结合的重要部位,预测该系列衍生物对A3G也有一定的结合亲和力。
其次在化学合成部分,为获得结构改造所需原料,进行了黄酮糖苷类物质的水解反应,应用强阳离子交换树脂CT-450作为催化剂,以水为溶剂,条件温和,是一种操作简便、原料转化率高、催化剂可循环套用的绿色水解方法,且循环套用对收率无影响,其中芦丁的水解反应最高收率可达98.6%,经HPLC检测其纯度最高可达98%。以8位取代的槲皮素磺酰胺衍生物为目标分别设计两条路线：第一条路线的磺化反应中,通过控制温度分别得到了相应的一磺化和二磺化产物以及其异构体,解析了化合物6的晶体结构,该路线以乙酰基为羟基保护基,未成功得到目标物；第二条路线以甲基为保护基,以氯磺酸为磺酰化试剂,成功分离得到3个磺酰胺衍生物。本文中所得到的所有化合物结构通过核磁、质谱等手段得到表征。
Flavonoids (2-phenyl chromone) exist in nature with extensive activities especially for HIV-1. It has already been found that 6-21 which is a derivative of quercetin could inhibit HIV-1 Vif-A3G effectively.8-sulfonic group of 6-21 could enhance the activity. Therefore, a series of flavonoid derivatives may be developed to disrupt the interaction with Vif-A3G.
Firstly, Computer Aided Drug Design was used to establish a pharmacophore model and dock.6-21 could match the pharmacophore very well. In addition, the sulfamine is a vital group. Therefore, a series of flavonoid-8-sulfamine derivatives were designed. Moreover, by LigandFit of Discovery Studio, the prominent activity of the compounds has been predicted in the key sites of A3G-Vif in manner of hydrogen bond andπ-σinteraction.
Secondly, the hydrolysis reactions of flavonoid glycosides were performed to form raw materials of the target compounds. CT-450 was used as a catalyst instead of the traditional proton acid. Meanwhile, water acts as the solvent which provids a mild condition. A convenient, high-convertible, and recyclic method was found. In addition, the recycle had few effect on the yield. Two routes were carried out to modify the flavonoids. In route 1, the mono-sulfonated sodium and di-sulfonated sodium of flavonoids were obtained through adjusting the reaction temperature. Moreover, the crystal structure of 6 was determined by X-ray diffraction. However, the target compounds were not generated with acetyl protective group. In route 2, acetyl group was insteaded by methyl group. Chlorosulfonic acid was used to be sulfonylation agent. Three sulfamide derivatives of quercetin were synthetized and their structures were confirmed by 1HNMR,13CNMR, MS, et al.
引文
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