CN101239980B - 免疫受体调节剂偶联体前体和偶联体及其应用 - Google Patents
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Abstract
本发明涉及一种免疫受体调节剂偶联体前体和偶联体，及其制备方法，和在免疫调节中的应用。其化学结构通式为[I]：
本发明的有益效果为：通过免疫受体调节剂偶联体前体及其偶联体，使其用于抗病毒，抗流感和禽流感以及各种急慢性病毒性疾病和其它疾病如抗微生物和抗肿瘤等的免疫调节，具有较好的效果。
Description
技术领域
本发明涉及一种免疫受体调节剂偶联体前体和偶联体，及其制备方法，和在免疫调节中的应用。
背景技术
免疫激动剂和免疫抗原(如疫苗，免疫多肽，免疫蛋白，免疫多糖，免疫多聚核苷及酸，灭活的细胞和灭活的微生物等)的联合应用或者偶联，往往产生提高的免疫效应(World Chin J Digestol 2005 September 15；13(17)：2078-2081 & Vaccine，Volume 23，Issue45，1 November 2005，Pages 5263-5270).本发明合成了一系列免疫受体调节剂偶联体前体，以及它们和免疫抗原的偶联体。
发明内容
本发明的目的在于提供一系列免疫受体调节剂偶联体前体和偶联体，以提高它们的免疫效应。
本发明的另一目的在于提供上述免疫受体调节剂偶联体前体和偶联体在药物上的应用。
本发明是有关一系列免疫受体调节剂偶联体前体及其偶联体，其化学结构通式为[I]：
通式[I]中：
X1代表O，S，Se或NRR
R代表氢，各种直链的或支链的烷基，卤代烷基，烷氧基烷基.环烷基，杂环烷基，酰氧基烷基，芳基或杂芳基.
R1代表氢，各种直链的或支链的，取代的和未取代的烷基，烷氧基烷基，各种取代的羰基(包括醛基，酯基，酰胺基等)，硝基，腈基，卤素；
当R2代表各种生物配体(包括疫苗，免疫多肽，免疫蛋白，免疫多糖，免疫多聚核苷及酸，灭活的细胞和灭活的微生物等)的情况下，
X2代表如下所示的化学基团：
当R2代表H原子时，X2代表如下所示的化学基团：
以OVA为例的蛋白的偶联体25，26，27，28的结构式代表如下：
在通式[I]中，当X2代表单键时，R2代表氢原子.或者当X2代表次甲基(-CH2-)时，R2代表如下化学基团：
其中n＝0----10；R3代表卤素或者磺酰氧基和各种酰氧基；代表性化合物19，20，21，23的结构式如下所示：
以偶联前体化合物5，8，11为例的合成路线(Scheme 1)如下所示：
以偶联前体化合物13和17为例的合成路线(Scheme 2)如下所示：
以化合19，20，21，23，24为例的合成路线(Scheme 3)如下所示：
本发明的有益效果为：通过免疫受体调节剂偶联体前体及其偶联体，使其用于抗病毒，抗流感和禽流感以及各种急慢性病毒性疾病和其它疾病如抗微生物和抗肿瘤等的免疫调节，具有较好的效果。
本发明的制备方法，具有工艺简单，成品收率高的优点。
附图说明：
图1偶联物25和非偶联物6的的IFN-γ诱导对比
图2偶联物25和非偶联物6的IL-12诱导对比
具体实施方式：
化合物3的合成：
将化合物1(403mg，1mmol)和300mL TEA的10mL DMF溶液中，加入110mg的氯甲酸乙酯.混合物搅拌反应3小时，真空蒸馏除去DMF，残余物中加入100mL乙酸乙酯，用水洗一次，盐水洗一次.有机层分离出，无水硫酸钠干燥.减压蒸馏除去乙酸乙酯，得化合物2，可直接用于化合物3的合成.将得到的化合物2溶于100mL的无水乙醇，加入1毫升的活性镍(R-Ni)，通入氢气至40psi(约2.8大气压)，密封氢化12小时.过滤除去催化剂，滤液减压浓缩，硅胶柱层析分离纯化(洗脱液：二氯甲烷-甲醇10∶1)，得化合物3(311mg，65％).ESIMS：m/z 480.3(MH+).
化合物5的合成：
将化合物3(100mg，0.21mmol)和TEA100μL溶解于10mL的DMF中，加入化合物4(59mg，0.22mmol).室温搅拌12小时.真空蒸馏除去DMF，残余物中加入100mL乙酸乙酯，用水洗一次，盐水洗一次.有机层分离出，无水硫酸钠干燥.减压蒸馏除去乙酸乙酯，残余物硅胶柱层析分离纯化(洗脱液：二氯甲烷-甲醇20∶1)，得化合物5(101mg，76％).ESIMS：m/z 631.5(MH+).
化合物8的合成：
将化合物6(100mg，0.24mmol)溶解于10mL的DMF中，加入丁二酸酐(25mg，0.24mmol)，于室温搅拌3小时.再加入N-羟基丁二酰亚胺(28mg，0.24mmol).另将DCC(54mg，0.25mmol)溶解于2mL的无水四氢呋喃中，于0℃滴加到上述DMF溶液中.混合物搅拌过夜，过滤，滤液减压蒸馏除去溶剂，残余和20毫升乙酸乙酯混合搅拌1小时，再过滤，滤液浓缩至较小体积，用硅胶柱层析分离纯化(洗脱液：二氯甲烷)，得化合物8(96mg，65％).ESIMS：m/z 614.4(MH+).
化合物11的合成：
将化合物9(120mg，0.25mmol)和化合物10(56mg.0.25mmo1)混合于20mL的乙二醇二甲醚中，加入0.2mL的冰醋酸，混合物室温反应24小时.析出固体，过滤，干燥得产物11(146mg，85％).ESIMS：m/z 686.6(MH+).
化合物13的合成：
将化合物9(120mg，0.25mmol)和化合物12(101mg.0.25mmol)混合于20mL的无水乙二醇二甲醚中，减压蒸馏至干(小于60℃)得固体，用乙酸乙酯重结晶得化合物13(98.8mg，48％).ESIMS：m/z 824.6(MH+).
化合物15的合成：
将化合物3(100mg，0.21mmol)和14(23mg，0.11mmol)混合溶解于20毫升的干燥DMF中，于0℃下慢慢加入DCC(45.5mg，0.22mmol)的1mL THF溶液，加完后，于室温反应24小时，减压蒸干溶剂，残余溶于50毫升乙酸乙酯并搅拌2小时，过滤，滤液浓缩，残余物用硅胶柱层析分离纯化(洗脱液：二氯甲烷∶甲醇＝20∶1)，得化合物15(84mg，67％).ESIMS：m/z 1134.2(MH+).
化合物16的合成：
将化合物15(113.3mg，0.1mmol)溶解于无水乙醇20mL中，加入NaBH4(23mg，0.6mmol)，混合物室温搅拌12小时，减压下于小于30℃浓缩至较小体积，混合物于0℃下加入50mL的1N HCl溶液中，用乙酸乙酯提取(2×50mL)，水洗，盐水洗，无水硫酸钠干燥，减压蒸馏干，残余用硅胶柱层析分离纯化(洗脱液：二氯甲烷∶甲醇＝10∶1)，得化合物16(92mg，81％).ESIMS：m/z 568.5(MH+).
化合物17的合成：
将化合物16(113.5mg，0.2mmol)溶解于10mL的二氯甲烷中，另将2，2′-二吡啶过硫化物(176.2mg，0.8mmol)溶解于15mL的二氯甲烷溶液缓慢滴加到16的二氯甲烷溶液中，混合物于室温搅拌18小时，减压浓缩，残余物用硅胶柱层析分离纯化(洗脱液：二氯甲烷∶甲醇＝10∶1)，得化合物17(88mg，65％).ESIMS：m/z 677.6(MH+).
化合物23的合成：
将化合物6(100mg，0.24mmol)溶解于10毫升的无水吡啶中，再加入DMAP(30mg，0，24mmol)，冷却到0℃，慢慢滴加化合物22(63mg，0.24mmol)的无水四氢呋喃溶液.加完后继续于10℃搅拌2小时.将反应混合物倾倒于50毫升冰水中，用二氯甲烷提取(3×50mL)，合并提取液，盐水洗涤一次，无水硫酸钠干燥.过滤，滤液减压浓缩，残余物用硅胶柱层析分离纯化(洗脱液：二氯甲烷)，得化合物23(126mg，82％).ESIMS：m/z 641.5(MH+).
用合成化合物23的同样方法得19，20，21.
化合物24的合成：
将化合物23与浓盐酸混合，与室温搅拌12小时，减压(小于40℃)浓缩至干，得化合物24(100％).ESIMS：m/z 568.5(MH+)
化合物8和OVA protein的偶联物25合成：
将100mg的OVA(ovalbumin，鸡卵白蛋白，平均分子量45000)溶解于2mL的蒸馏水，与50mg化合物8的20mL的DMSO溶液混合.于室温搅拌过夜.混合物液中加入碳酸氢钠饱和溶液2毫升，均匀搅拌30分钟，用PD-10脱盐柱分离(Amershamdisposable PD-1 desalting column)，将含产品OVA结合物的流出液(用280nM吸收波检测)合并，冷冻干燥.用质谱确定平均分子量为47492.确定产品25包含了5个化合物8的对应单体.用同样的方法合成了26，27，28.
生物活性测试方法：
方法：ELISA
试剂和条件：
人体外周血单核细胞用重力沉降法离心分离得到。离心机为Ficoll-Hypaque.将分离出的细胞悬浮在RPMI1640媒介中，添加10％的FBS，L-谷氨酸，青霉素/链霉素(RP1O，Invitrogen)，植于96井的试板。用本发明中的化合物25---28，在浓度0.1--10μM激发细胞，于37℃，5％的CO2环境下，培养24小时。用Luminex仪(Austin，TX)测量α-干扰素和白介素的水平。图1和图2中的所示的结果为平均值。
图1和图2为偶联物25和非偶联物6的免疫激动效应对比：图1化合物25和6的IFN-γ诱导对比；图2化合物25和6的IL-12诱导对比。由图中可以看出，偶联物的免疫效果有较大的提高。
Claims (4)
1.一种免疫受体调节剂偶联体前体和偶联体，其化学结构通式为[I]：
X1代表0、S、Se；
R代表烷基、卤代烷基、烷氧基烷基；
R1代表氢；
(1)当R2代表生物配体的情况下，所述的生物配体为免疫多肽、免疫蛋白、灭活的细胞或灭活的微生物，X2代表如下所示的化学基团的任一种：
(2)当R2代表H原子时，X2代表如下所示的化学基团的任一种：
(3)当X2代表亚甲基(-CH2-)时，R2代表如下化学基团的任一种：
其中n＝0--10；R3代表卤素、磺酰氧基。
2.根据权利要求1所述的免疫受体调节剂偶联体前体及其偶联体，为如下结构式的任一种：
3.免疫受体调节剂偶联体前体或其偶联体，具有如下结构：
4.一种权利要求1所述的免疫受体调节剂偶联体前体及其偶联体在制备抗病毒的免疫调节药物上的应用。
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| EP2132209B8 (en) | 2007-03-19 | 2014-04-16 | AstraZeneca AB | 9-substituted-8-oxo-adenine compounds as toll-like receptor (tlr7 ) modulators |
| JPWO2008114819A1 (ja) | 2007-03-20 | 2010-07-08 | 大日本住友製薬株式会社 | 新規アデニン化合物 |
| CA2686163A1 (en) | 2007-05-08 | 2008-11-13 | Astrazenca Ab | Imidazoquinolines with immuno-modulating properties |
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| WO2010088924A1 (en) | 2009-02-06 | 2010-08-12 | Telormedix Sa | Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration |
| US9050319B2 (en) | 2010-04-30 | 2015-06-09 | Telormedix, Sa | Phospholipid drug analogs |
| CN103221067B (zh) | 2010-04-30 | 2016-01-06 | 泰勒麦迪克斯公司 | 磷脂药物类似物 |
| JP5978225B2 (ja) | 2010-12-16 | 2016-08-24 | 大日本住友製薬株式会社 | 治療に有用なイミダゾ［４，５−ｃ］キノリン−１−イル誘導体 |
| EP2651943B1 (en) | 2010-12-17 | 2017-03-22 | Sumitomo Dainippon Pharma Co., Ltd. | Purine derivatives |
| CN103254304A (zh) * | 2012-05-30 | 2013-08-21 | 深圳大学 | 免疫激动剂偶联体、其制备方法及免疫激动剂偶联体在抗肿瘤中的应用 |
| CN102993265B (zh) * | 2012-10-10 | 2015-05-13 | 深圳大学 | 免疫受体调节剂偶联体及其制备方法和应用、制备其的偶联前体以及合成偶联前体的化合物 |
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| CN115192726A (zh) * | 2018-04-03 | 2022-10-18 | 深圳大学 | 免疫激动剂靶向化合物的合成及其应用 |
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