CN100491389C - 唾液酸结合性免疫球蛋白样凝集素抑制剂 - Google Patents
唾液酸结合性免疫球蛋白样凝集素抑制剂 Download PDFInfo
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Abstract
本发明涉及对受体分子具有高亲合力的唾液酸结合性免疫球蛋白样凝集素(SIGLEC)抑制剂。本发明提供的SIGLEC抑制剂能特别对某一已知的SIGLEC分子具有选择性。本发明还提供了制备这些SIGLEC抑制剂的方法,以及增加对某一特定SIGLEC分子选择性的方法。本发明还提供了含有该抑制剂的药物组合物以及这些抑制剂在医学上的应用。
Description
技术领域
这项发明是关于唾液酸结合性免疫球蛋白样凝集素(Siglec)抑制剂以及含有此种抑制剂的药品组分。此外,此发明还提供了提高该抑制剂结合选择性的方法,并详述了此抑制剂的医学适应症。
技术背景
Siglecs(能与唾液酸结合的免疫球蛋白样凝集素)是类Ig型凝集素,其结构特征是具有一个能介导唾液酸结合的N端V组区段,其Ig区中C2组Ig区数目不同。凝集素家族最初是在单独研究唾液酸黏附素(Siglec-1CD169)和CD22(Siglec-2)时发现的。唾液酸黏附素(Siglec-1 CD169)是一类巨噬细胞凝集素类黏附分子。CD22是一个Ig超家族的B细胞特异性表面抗原(IgSF),在激活B细胞过程中发挥重要作用。在体外测定唾液酸复合糖时发现这两种分子都能介导细胞之间的相互作用。克隆唾液酸黏附素表明其结构序列高度类似于CD22分子,因此认为,另外两个IgSF蛋白:髓磷脂相关性球蛋白(MAG/Siglec-4)和CD33(Siglec-3,以前并不知道该分子结合到唾液酸),因具有此种结构关系也都归属于Siglec家族。人类其它6个Siglec分子(Siglec5—10)也已经被鉴定出来,其特征也被描述。这些以前不为人知的分子显示出其细胞内外序列均高度类似于CD33,因此它们总的被称为“CD33相关SIGLECS”(文献1综述)。文献7描述了来源于人树突状细胞的Siglec-11的克隆及特点。
表1概述了上面所提到的Siglec的发现及潜在功能。
表1 Siglec的发现及潜在功能
名称 | 发现 | 功能 |
唾液酸粘附素(Sn,Siglec-1) | 巨噬细胞亚群 | 巨噬细胞间的相互作用 |
CD22(Siglec-2) | B淋巴细胞 | 调节B细胞介导的免疫反应;骨髓归巢 |
CD33(Siglec-4) | 髓系前体细胞 | 不明 |
髓磷脂相关球蛋白(MAGSiglec-4a):雪旺氏细胞髓磷脂蛋白(SMP,Siglec-4b) | 中枢和外周神经系统的有髓细胞(少树突细胞和雪旺氏细胞) | 接受髓磷脂的结构和功能;调节轴突生长 |
OB-BP2(Siglec-5) | 中性粒细胞;单核细胞 | 不明,可能参与信号转导 |
OB-BP1(Siglec-6) | 胎盘(合体滋养层细胞);B淋巴细胞 | 不依赖于SIA的高亲合力LEPTIN结合;Sia键的功能不明 |
p75/AIRM1(Siglec-7) | NK细胞 | NK细胞的抑制性受体 |
Siglec-8 | 嗜酸性粒细胞 | 不明,可能参与信号转导 |
Siglec-9 | 单核细胞,中性粒细胞;CD16<sup>+</sup>CD56<sup>-</sup>细胞 | 不明,可能参与信号转导 |
Siglec-10 | B细胞,单核细胞及其它白细胞 | 不明,可能参与信号转导 |
Siglec-11 | 树突状细胞,单核细胞及其它白细胞 | 细胞识别,信号转导 |
从上面表格可以看出Siglec还参与减轻免疫反应,维持组织髓磷脂在中枢神经系统及血细胞生成。
由Siglec介导的作用有两种类型:一是通过结合Siglec分子,引起表达相应Siglec的细胞产生信号(如抑制B细胞介导的免疫反应;通过磷酸化ITIM来抑制NK细胞的细胞毒性);二是与Siglec相结合的细胞产生信号(如MAG/Siglec-4)调节神经元轴突的生长(1、2))
Siglecs与其不同的配体结合时可引起两种效应(3):第一,单价物质可减少Siglec分子之间以及与其它分子间生物学上的交联,这可减弱信号;第二,多价物质则能增强触发信号。因此,选用一些合适的特异性物质对这些过程进行双向调节是可能的。
唾液酸是九碳糖大家族的俗称,包括了所有神经氨酸或KDN的衍生物。一般来说,它们通常存在于与大量的蛋白质或脂质相连的低聚糖链的暴露的非还原端上。
SIGLEC上唾液酸结合位点存在于N末端区域,此区是一V组区,并有特征性的Siglec的结构。此结合位点的位置及参与结合的氨基酸是通过X线对Siglec-1(唾液酸黏附素)和2,3-唾液酸乳糖形成的结晶进行结构分析发现的。用合成的唾液酸的衍生物(5,6)进行半抗原抑制试验可确定唾液酸的结合部位的作用。简而言之,研究表明,在其它方面,唾液酸的C-9位羟基在H键结合时提供一个H供体,起实质性作用。此羟基可被一个氨基取代(5)。
SIGLEC必须有与结合位点亲合力很高的配体才能对生物功能进行调节。
因此,本发明的目的是提供具有高亲合力的SIGLEC抑制剂。特别是提供能够尽可能特异性地结合到单一SIGLEC受体上的高亲合力的SIGLEC抑制剂。
发明内容
下面是可实现本发明的目的SIGLEC抑制剂的通式:
X代表负电荷基团,选自羧基、磷酸根、硫酸根以及它们的衍生物;
Y代表H原子、烃基或芳基、羟基、聚糖、多聚体载体分子或它们的衍生物;
Z选自O,N,C和S原子;
R1代表H原子、羟基,或它们的衍生物;
R2代表羟基或氨基,或是它们的衍生物;
R3代表羟基或是其衍生物;
R4代表羟基或是其衍生物;
R5代表一个取代或未被取代的氨基,取代物选自于取代或未被取代的甲酰、烷酰基、环烷酰基、芳香酰基、杂芳香酰基、烃基、芳基、环炔或杂芳基,这些残基都包含一个或多个未饱和键;其中R4作为H原子受体;
R5作为H原子供体;
R6代表H原子或烃基、离子基团或它们的衍生物;
R6’代表H原子或烃基、离子基团或它们的衍生物;至少一个选自R6和R6’的取代物是一疏水基团,最好是H原子或甲基;
R7代表H原子或是其它基团,最好是一个能提高Siglec抑制剂药理特性的基团。
下面说明了一些本说明书中使用的专业术语。
“Siglec”包括所有的Siglec分子,参考文献8中可获得关于Siglec分子的详细定义。例如,Siglec分子中Siglec-1到Siglec-10的氨基酸序列可参考文献1(表1)。有关Siglec-11的序列可参考文献7,此外,也可从公用数据库(Entraez)中获得有关Siglec分子的氨基酸序列(网址:www.ncbi.nlm.nih.gov./entrez)。从这方面看,Siglec-1分子可存在于自然界的自然发生的细胞或人工模拟环境中。
“Siglec抑制剂”通常是表示具有抑制唾液酸分子(尤其是其天然配体)结合到Siglec蛋白的化合物。本发明中,Siglec抑制剂是激活还是灭活一个特定的Siglec蛋白,取决于该抑制剂本身的结构。可参考的唾液酸化合物是甲基-α-5’-N-乙酰神经氨酸。这种抑制剂最好是通过半抗原抑制试验确定。半抗原抑制试验是用一个兔源性Fc嵌合体(此嵌合体由Siglec的N端和人IgG的Fc段构成)与放射标记的抗Fc抗体混合后,再与各种浓度的待测抑制剂一起孵育,然后加入合适的靶细胞(首选人红细胞)。经过4℃孵育过夜后,通过洗涤清除未结合的化合物,结合部分的放射性就可以被确定。用这种方法获得的资料可确定引起50%的结合位点抑制时所需的抑制剂浓度(IC50值)(5,6)。此试验中最好的操作方法是:用10μl具有103Bq125I与相同体积、三倍浓度的待测物质进行混合,4℃孵育一小时,随后加入10μl靶细胞悬液(最好是0.25—0.5%的人红细胞),4℃孵育过夜。未结合的放射活性物质用200μl清洗缓冲液(最好是含有0.1%(w/v)牛血清白蛋白的磷酸根缓冲液生理盐水)清洗5次将其去除。Y计数器可确定细胞结合活性。作为控制,通常将不含待测物质的经过及未经唾液酸酶处理的细胞的结合力作为对照。将无抑制剂处理的获得抑制数值定为0,唾液酸酶处理的细胞所活动的数值定为100%。
“衍生物”总的来说与残基X,Y,R1—R4有关,神经氨酸中此类基团被生物等效(BIOISOSTERIC)基团所取代,后者表现出同样的生物学活性。本领域技术人员已熟知“生物等效(BIOISOSTERIC)”概念。
“取代的甲酰、烷酰基、芳香酰基、杂芳酰基、烃基、芳基、环炔或异芳基”,是指这些相关的基团上有取代,但并不改变其生物学特性。其中包括低碳烃基取代物,如甲基、乙基、丙基、丁基。
本发明中X代表一个负电荷基团,推测它可能与Siglec受体的精氨酸残基形成一个盐桥。其天然发生的取代物是一个羧基。适宜的衍生物包括如磷酸根或硫酸根,此外,膦酸根或磺酸根也可作为其衍生物,其他的衍生物还有亚甲基羧基或乙烯羧基。
本发明中Y代表H原子、烃基或芳基、羟基、聚糖、多聚体载体分子或它们的衍生物。天然发生取代物是一个羟基。这个羟基适宜的衍生物是一个氨基或一个硫代基。适宜的聚糖是己糖、氨基己糖和/或戊糖或它们的衍生物,最好是葡萄糖或半乳糖或是它们的衍生物。此外,聚糖可以是寡聚糖和多糖。寡聚糖和多糖可来源于一个或多个单体(混合糖)。本发明中要求的多聚体载体分子是具有提高药理作用的分子,如延长滞留时间。结合许多Siglec抑制剂配体的多聚体载体分子可促进交联,并随后引起Siglec受体分子的激活。因此,可通过应用这种多聚体载体分子进行很好的调节。
本发明要求的载体分子包含有一个核心,而数量不等的本发明提供的抑制剂通过合适的衬底固定到载体中。通过对含有核心和本发明提供的抑制剂的多聚体可控制其预期的药理学效应。多聚体(核心)是树状聚合大分子(dendrimers)、聚丙烯酰胺或聚丙交酯(polylacde)。本发明提供的抑制剂可以是通过化学或酶学的方法结合到多聚体上。
本发明中Z选自O,N,C或S原子。
本发明中R1代表H原子,羟基或他们的衍生物。适合的羟基的衍生物是在应用中可被取代的氨基或硫代基。
本发明中R2代表羟基或氨基,或是它们的衍生物,天然发生的替代物是一个乙酰氨基。合适的衍生物是如那些氨基被乙酰基、丙酰基、丁基、戊基取代的物质。烷酰基可被一个或更多的卤素原子所取代。从文献5中化合物4至12还可找到更多衍生物。对R2位进行修饰可提高针对特定Siglec分子的Siglec抑制剂的特异性。
本发明中R3代表羟基或是其衍生物。就此方面,其合适的衍生物,如可在实际应用中被取代氨基或硫代基。
本发明中R4代表羟基或是其衍生物。就此方面,其合适的衍生物是那些可作为H离子受体的基团。如:其衍生物中可以是氨基或硫代基,其可在实际应用中被取代,作为H受体的性质则被保留。
本发明中R6和R6’相互独立地代表H原子或羟基,或带电基团或者他们的衍生物,至少一个选自R6和R6’的取代物是一疏水基团,最好是H原子或甲基。合适的衍生物是一些低碳烃基取代物如甲基、乙基、丙基、丁基。合适的阴离子基团如:羧基、磷酸根、硫酸根。
本发明中R7代表一个H原子或其它基团,这些基团最好能提高Siglec抑制剂的药理学特性。具有提高Siglec抑制剂的药理学特性的基团可以是多聚体载体分子。完整的Siglec抑制剂最好应该具有恰当的亲水性,使得该抑制剂在亲水相和疏水相中具有相同分散性。
此外,本发明中还考虑到Siglec抑制剂共价或非共价结合天然复合糖或糖蛋白的作用。
令人惊奇的是,将疏水性取代物引入到9-氨基-9-脱氧-唾液酸(尤其是神经氨酸)的氨基上,就可获得5’-乙酰神经氨酸相关的更高亲合力的Siglec抑制剂。根据优选的实施例,能获得特异性结合某些Siglec蛋白并能抑制它们的Siglec抑制剂。
根据优选的实施例,烷酰基选自乙酰基,丙酰基,丁酰基,戊酰基,己酰基,庚酰基,辛酰基,壬酰基和癸酰基,优选己酰基.本发明中带支链的烷酰基也可以考虑。
进一步,优选的实施例中,环烷酰基选自C3-C6环烷酰基,优选环己烷酰基。
优选的实施例中芳酰基选自C4-C15芳酰基,优选苯甲酰基、萘甲酰基或蒽甲酰基,由此这些残基主要影响抑制剂的选择性。通过适当的选择能够以此调整抑制剂的选择性。
另一优选的实施例中,杂芳碳酰基选自吡啶碳酰基,喹那定酰基及苯硫代酰基。
另一实施例中烃基选自C1-C20的烃基,最好是选自甲基、乙基、丙基、丁基、戊基、己基。
本发明中具有支链的烃基也可考虑
另一实施例中环烃基选自C3-C6环烃基。
另一实施例中芳基选自苯基,萘基,二苯基及蒽基。本发明中芳基也可选自缩合及未缩合的芳基。
杂芳基选自吡啶基,喹那定基及苯硫基。
根据本发明,杂芳基还包括本领域技术人员已知缩合杂芳环和非缩合杂芳环。
一个首选的化合物是甲基-α-9-N-(萘基-2-羰基)-氨基-9-脱氧—Neu-5AC。此唾液酸衍生物结合到Siglec-1的能力比对照化合物(2-α-甲基-5-N-乙酰-神经氨酸)约强12倍,结合到Siglec-4a的能力更强(比对照化合物约强236倍)。
甲基-α-9-N-(联苯-4-羰基)-氨基9-脱氧-Neu5Ac也要作为优选。此化合物结合Siglec-2的能力比对照化合物2-a-甲基-5-N-乙酰基-9-神经氨酸约强150倍。
另外,甲基-α-9-N-苯氨基-9-脱氧-Neu-5AC也作为优选。此化合物结合Siglec-4a(MAG)的能力比对照化合物2-α-甲基-5-N-乙酰基-神经氨酸约强704倍。
根据本发明的优选实施例,本发明提供的SIGLEC抑制剂中:
X代表位于轴向位置的羧基;
Y代表氢原子,甲氧基、苄氧基或一个羟基的衍生物;
Z代表个O原子;
R1代表羟基;
R2代表氨基乙酰基;
R3代表羟基;
R4代表羟基;
R6代表H原子;
R6’代表H原子;
R7代表H原子。
除了Y以外,这里所引用的取代物与唾液酸中天然发生的取代物相匹配。
本发明还提供了具有Siglec高亲合力的Siglec抑制剂的的制造方法,其包括如下步骤:
A、在神经氨酸或其衍生物的R5位置引入选自本发明提供残基的取代物;
B、测定上述取代物产物与某一Siglec分子亲合力;
C、选择出具有高亲合力的产物;
D、根据实际需要,可对C步产物,在除R5位外的其他位置进行取代,优选R2位置。
本发明发现,将一个疏水性取代物引入神经氨酸或其衍生物的R5位,可获得具有针对Siglec分子的较高亲合力的Siglec抑制剂。可通过结合试验或半抗原抑制试验,可对针对某一特定Siglec分子测定产物的亲合力。半抗原抑制试验所需的实验条件,前已述及,优选文献5,6所述。通过进一步在R5位之外引入,最好是R2位,取代物,可增强针对某一特定Siglec分子所选出的产物的亲合力。适合的R5位的取代物也是适合于R2位的取代物。
本研究还提供了提高Siglec抑制剂结合选择性的方法,包括在神经氨酸或其衍生物的R5位上引入权利要求1—10之一中所述的选自R5残基的取代物。
对本领域技术人员来说,根据他们的专业知识,按照本项发明来合成这个化合物原则上是可能的。首选的合成原料是5-N-乙酰基神经氨酸。可通过一系列反应生成烃基、芳基、烃基-α-O-或α-S-糖苷。
下一步是用一个氨基取代5-N-乙酰基神经氨酸中O或S-糖苷C9位(本发明中的R5)的羟基。这种转换可通过合适化合物9-O-甲苯磺酰(9-O-tosyl)完成。此反应最好使用改良的反应完成。因此,该方法获得9-氨基-9-脱氧-5-N-乙酰-神经氨酸的烃基、芳基、烃基-α-O或α-S-糖苷可提供合成5-N-乙酰-9-(联苯-4-羰基)-氨基-9-脱氧-神经氨酸或其类似物(此类似物C-9(本发明中的R5)位稳定的氨基上有一个可变的芳基)所需的烃基、芳基、烃基-α-O或α-S-糖苷。多种方法可使氨基获得酸性功能,如用盐酸或酸酐,或借助碳化二亚胺,或通过硝基苯酚、五氟酚等来激活其酸性功能
本项发明还提供了药物组合物,它包括至少一种本发明提供Siglec抑制剂及一种药学上可用的载体。根据优选的实施例,用于治疗的Siglec抑制剂对于Siglec分子应尽可能具有选择性。药学上可用的载体对本领域技术人员来说是早已熟知的。此外还要有合适的稀释剂。一般来说,任何一种给药方法都是可行的,即可通过静脉、腹腔内、皮下、皮内注射及口服给药,但首选的是口服给药。
医生可按常规决定给药剂量。
另外,本发明中Siglec抑制剂还可用于治疗由Siglec介导的疾病,尤其是免疫系统疾病。Siglec-2参与B细胞介导的免疫反应,因此,本发明中的Siglec抑制剂可用于调节B细胞介导的免疫反应。基于以上观点,过敏反应、自身免疫性疾病、慢性炎症都可用Siglec抑制剂进行治疗。
Siglec-4a具有轴突生长抑制效应,本发明中的Siglec抑制剂可用来对抗Siglec-4的轴突生长抑制作用,因此具有促进损伤的神经的再生能力,如可用于治疗截瘫。再如,Siglec-7参与调控自然杀伤细胞(NK细胞)的细胞毒性作用,因此根据本发明的唾液酸衍生物可用来调节这些细胞的细胞毒性。如可用于治疗肿瘤、病毒感染尤其是AIDS。
有研究提示,其它的Siglecs参与调控免疫系统,参考表1。因此本发明提供Siglec抑制剂也用来调控免疫系统。
本发明提供的Siglec抑制剂可增强B细胞介导的免疫反应,这点可通过Ca2+分泌增多得到证实。采用本发明的Siglec抑制剂可引起Ca2+分泌增多,已经在鼠Daudi细胞或B细胞试验中得到验证。此发明中,运用Siglec抑制剂可增强B细胞介导的免疫反应。这一事实为免疫缺陷病治疗药物的研制开辟了新的前景。与此相关的首选化合物是甲基-α-9-N-(联二苯基-4-羰基)-氨基-9-脱氧-Neu5AC(举例子中已提到)。此种化合物还表现出对人CD22高度选择性亲合力,这些抑制剂可能的医学适应症是那些B细胞激活失调引起的免疫性疾病,如临床上常见的各种免疫缺陷病(CVID)和IgA缺陷症。CVID病人B细胞不能启动有效的免疫反应,并表现出低丙种球蛋白血症,他们易于发生严重感染。目前治疗仅靠免疫球蛋白,但后者因具有很强的风险性、较窄的适应范围而被认为是一个有争议的疗法。IgA缺陷症的病人也可用免疫球蛋白治疗,但基于上述原因以及该类病人通常症状轻微,其应用并不广泛。
下面用例子对该发明进行了说明,但本发明的范围不应局限于此。在利用本发明时,本领域技术人员能够根据本发明实施其他应用。
具体实施方式
材料和方法
Siglec抑制剂的合成
将上面提到的一种物质:甲基-α-5-N-乙酰基-9--氨基-9-脱氧-神经氨酸上的氨基酰化作为例子。这里描述了合成甲基-α-5-N-乙酰基-9-N-(联苯-4-羰基)-氨基-9-脱氧-神经氨酸的方法。
甲基-α-5-N-乙酰基-9--叠氮基-9-脱氧-神经氨酸(1)
1、根据文献提供的方法,经过对酯基适当的9-叠氮化和皂化作用,从甲基-α-5-N-乙酰基-9-O-甲苯磺酰基-神经氨酸甲酯中合成。
2.采用Mitsunobu反应体系,通过化学反应,直接从已知的甲基-α-N-乙酰基-神经氨酸合成。
将0.1g甲基-α-5-N-乙酰基-神经氨酸的三乙氨盐溶于0.4ml干吡啶和1ml N,N-二甲基-甲酰氨中(DMF),得到的溶液在真空中浓缩,再用干燥的DMF熏1—2次(A)。0.19g的四甲基胍溶于0.25ml干吡啶和1ml DMF所形成的混合液中,得到的溶液在真空中浓集,再用干燥DMF熏1—2次(B)。将A溶液溶于0.8ml DMF中,并加入B溶液和0.13ml98—100%甲酸形成的混合液,将A+B溶液加入到含有0.17g三苯膦和0.125ml偶氮二碳酸二异丙酯(diisopropylazodicarboxylate)的干燥1.2ml四氢呋喃混合液中,使用前需先在0℃孵育15分钟。反应温度控制在0℃—20℃,大约24小时后终止反应,并加入0.5ml甲醇。得到的溶液在真空中浓缩,用乙酸乙酯/H2O或亚甲氯/H2O震荡摇出,并用硅胶色谱仪测定(闪烁法)。
洗脱物:首先甲醇/乙酸乙酯/乙酸(20%)1/6/1,后为1/4/1。
产率:理论上为70—80%
甲基-a-5-N-乙酰基-9-氨基-9-脱氧-神经氨酸(2)
在常压下用氧化钯在水中对9-叠氮化合物(1)进行氢化。
产率:95%
甲基-α-5-N-乙酰基-9-N-(联苯-4-羰基)-氨基-9-脱氧-神经氨酸(3)
在含有N,N’二环己基碳二酰亚胺的乙酸乙酯中,0.4g联苯-4-羧酸与0.28g硝基苯酚,室温下发生化学反应,生成联苯(4)-羧酸4-硝基苯酯,后者在乙酸乙酯/二乙酯/己烷中结晶析出。
甲基-α-5-N-乙酰基-9-脱氧-神经氨酸(2)30mg溶于0.6ml干燥DMF中,在室温下,在12.9ml三乙胺存在的前提下,与39mg上述硝苯基酯反应完全。通过硅胶色谱仪进行纯化分析(闪烁法)。
洗脱物:首先甲醇/乙酸乙酯/乙酸(20%)1/6/1,后用1/5/1,最后1/4/1。化合物(3)的产率:93%
高分辨NMR分光镜检查及FAB-MS可显示合成产物的结构。
半抗原抑制试验
半抗原抑制试验在参考文献(5,6)提供的实验条件下进行。
结果
表2
结构 | Siglec-4a(MAG) | Siglec-1(唾液酸黏附素) | Siglec-2(人CD22) | Siglec-2(鼠CD22) | ||||
IC50 | rIP | IC50 | rIP | IC50 | rIP | IC50 | rIP | |
甲基-α-Neu5Ac | 4716 | 1.0 | 884 | 1.0 | 1388 | 1.0 | 4689 | 1.0 |
硫代甲基-α-Neu5Ac | 2775 | 1.3 | 600 | 0.8 | 1367 | 1.6 | 4250 | 1.1 |
硫代苄基-α-Neu5Ac | 2000 | 3.0 | 280 | 4.1 | n.d. | n.d. | n.d. | n.d. |
2,3-唾液酰基乳糖 | 1600 | 7.3 | 385 | 2.4 | n.d. | n.d. | n.d. | n.d. |
甲基-α-5-N-乙醇酰基-神经氨酸 | n.d | n.d. | n.d. | n.d. | 1013 | 1.0 | 703 | 8.3 |
甲基-α-甲基-α-5-N-氯乙酰基-神经氨酸 | 280 | 17.1 | 625 | 1.9 | n.d. | n.d. | n.d. | n.d. |
甲基-α-甲基-α-5-N-氯乙酰氨基乙酰-神经氨酸 | >>10mM(90%) | n.a. | 2500 | 0.4 | n.d. | n.d. | n.d. | n.d. |
苄基-α-5-N-丙酮-神经氨酸 | 2500 | 4.8 | 215 | 3.4 | n.d. | n.d. | n.d. | n.d. |
苄基-α-5-N-丁酮-神经氨酸 | 5300 | 1.5 | 250 | 2.7 | n.d. | n.d. | n.d. | n.d. |
苄基-α-5-N-苯甲酰-神经氨酸 | <10mM(27%) | >0.27 | >10mM(63%) | <0.05 | n.d. | n.d. | n.d. | n.d. |
甲基-<u>α-酮基脱氧-壬酸(KDN)</u> | >>10mM(225%) | <<0.5 | >1mM(74%) | <0.8 | >>1mM(117%) | <<2 | >2mM(74%) | <1.5 |
甲基-α-5-N-(乙氧基环丁二酮)-神经氨酸 | 4300 | 0.5 | >>5mM | <<0.15 | 940 | 2.3 | 3367 | 1.5 |
(92%) | ||||||||
甲基-α-9-二甲亚砜-9-脱氧-Neu5Ac | 697 | 8.5 | 2000 | <0.05 | n.d. | n.d. | n.d. | n.d. |
甲基-α-9-硫代甲基-9-脱氧-Neu5Ac | >10mM(116%) | <<0.27 | 5000 | <<0.05 | n.d. | n.d. | n.d. | n.d. |
甲基α-9-甲磺酰-9-脱氧-Neu5Ac | 3400 | 0.1 | 2000 | <<0.05 | n.d. | n.d. | n.d. | n.d. |
甲基-α-9-N-氨基乙酰-9-脱氧-Neu5Ac | 3400 | 3.3 | 7480 | 0.3 | n.d. | n.d. | n.d. | n.d. |
甲基I-α-9-N-<u>草酰二胺</u>-氨基-9-脱氧-Neu5Ac | n.d. | n.d. | >4000(57%) | <0.2 | n.d. | n.d. | n.d. | n.d. |
甲基-α-9-羧基-Neu5Ac | >>1000(87%) | <<2.4 | >4000(c3%) | <0.2 | n.d. | n.d. | n.d. | n.d. |
甲基-α-9-N-乙酰-氨基-9-脱氧-Neu5Ac | 2150 | 3.7 | 3817 | 0.2 | 1800 | 0.6 | 1.750 | 2.7 |
结构 | Siglec-4a(MAG) | Siglec-1(唾液酸黏附素) | Siglec-2(人CD22) | Siglec-2(鼠CD22) | ||||
IC50 | rIP | IC50 | rIP | IC50 | rIP | IC50 | rIP | |
甲基-α-9-N-三氯乙酰基-氨基-9-脱氧-Neu5Ac | 550 | 10 | 4000 | 0.5 | n.d. | n.d. | n.d. | n.d. |
甲基-α-9-N-硫代乙酰-氨基-9-脱氧-Neu5Ac | 733 | 6.5 | 6000 | 0.3 | n.d. | n.d. | n.d. | n.d. |
甲基-α-9-N-乙酰乙酰基-氨基-9-脱氧-Neu5Ac | 1007 | 6.2 | >10mM(62%) | <0.05 | n.d. | n.d. | n.d. | n.d. |
甲基-α-9-N-己酰基-氨基-9-脱氧-Neu5Ac | 198 | 54 | 1458 | 07 | n.d. | n.d. | n.d. | n.d. |
甲基-α-9-N-环己酰基-氨基-9-脱氧-Neu5Ac | 110 | 50 | >>1mM(93%) | 0.2 | 383 | 4.1 | 760 | 6.9 |
甲基-α-9-N-(2,3-二乙酰基氨基丙酰基)-氨基-9-脱氧-Neu5Ac | 2500 | 2.3 | >>10mM(80%) | <<0.1 | n.d. | n.d. | n.d. | n.d. |
甲基-α-9-N-(氨基乙酸)<sub>2</sub>-氨基-9-脱氧-Neu5Ac | 5000 | 0.9 | >>10mM(100%) | <<0.1 | n.d. | n.d. | n.d. | n.d. |
甲基-α-9-N-(氨基乙酸)<sub>3</sub>-氨基-9-脱氧-Neu5Ac | >10mM(88%) | <<0.27 | <<10mM(11%) | >>0.05 | n.d. | n.d. | n.d. | n.d. |
甲基-α-9-N-(乙氧基环丁二酮)-氨基-9-脱氧-Neu5Ac | 240 | 32 | 1333 | 0.2 | n.d. | n.d. | n.d. | n.d. |
甲基-α-9-N-(吡啶-3-酰基)-氨基-9-脱氧-Neu5Ac | 25 | 170 | 4000 | 0.5 | 445 | 2.3 | 335 | 14 |
甲基I-α-9-N-苯甲酰-氨基-9-脱氧-Neu5Ac | 7 | 704 | 539 | 1.8 | 290 | 5.7 | 1094 | 3.7 |
甲基-α-9-N-(3,5-二羟基苯甲酰基)-氨基-9-脱氧-Neu5Ac | 28 | 166 | 525 | 1.7 | 73 | 19 | 1467 | n.d. |
甲基-α-9-N-(乙酰氨基苯甲酰基)-氨基-9-脱氧-Neu5Ac | 62 | 77 | 295 | 3.0 | 580 | 2.4 | 1033 | n.d. |
甲基-α-9-N-(苯乙酰)-氨基-9-脱氧-Neu5Ac | 367 | 7 | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. |
甲基-α-9-N-(2,4-硝基苯甲酰)-氨基-9-脱氧-Neu5Ac | 205 | 18 | 733 | 0.3 | 287 | 7.7 | 593 | 7.9 |
甲基-α-9-N-(4-茴香酰)-氨基-9-脱氧-Neu5Ac | 12 | 393 | 42 | 8.4 | 120 | 19 | 667 | 7.4 |
甲基I-α-9-N-(五氟化苯甲酰基)-氨基-9-脱氧-Neu5Ac | 107 | 42 | 7000 | 0.3 | 360 | 3.3 | 2500 | 2.0 |
结构 | Siglec-4a(MAG) | Siglec-1(唾液酸黏附素) | Siglec-2(人CD22) | Siglec-2(鼠CD22) | ||||
IC50 | rIP | IC50 | rIP | IC50 | rIP | IC50 | rIP | |
甲基-a-9-N-(联苯-4-羰基)-氨基-9-脱氧-Neu5AC | 22 | 218 | 52 | 13 | 4 | 150 | 1220 | 5.0 |
甲基-a-9-N-(联苯-4-乙酰基)-氨基-9-脱氧-Neu5AC | n.d. | n.d. | 3000 | 0.3 | 35 | 29 | 123 | 48 |
甲基-a-9-N-(联苯-2-乙酰-氨基-9-脱氧-Neu5AC | n.d. | n.d. | 2600 | 0.3 | 97 | 10 | 647 | 9.5 |
甲基-a-9-N-(苯氧基-3-苯甲酰)-氨基-9-脱氧-Neu5AC | n.d. | n.d. | 540 | 1.5 | 10 | 111 | 887 | 6.7 |
甲基-a-9-N-(联苯-乙酰)-氨基-9-脱氧-Neu5AC | 150 | 31 | 4400 | 0.2 | 35 | n.d. | 103 | n.d. |
甲基-a9-N-(萘基-2-酰基)-氨基-9-脱氧-Neu5AC | 20 | 236 | 78 | 12 | 6 | 167 | 270 | 18 |
甲基-a-9-N-(萘基-1-酰基)-氨基-9-脱氧-Neu5AC | 56 | 84 | 3000 | 0.3 | 37 | 27 | 92 | 64 |
甲基-a-9-N-(萘基-2-乙酰)-氨基-9-脱氧-Neu5AC | 367 | 13 | 1750 | 0.5 | 8 | 131 | 71 | 83 |
甲基-a-9-N-(蒽-5-酰基)-氨基-9-脱氧-Neu5AC | 162 | 28 | 750 | 0.5 | 338 | 4.9 | 647 | 7.4 |
甲基-a-9-N-(环丁二酮)-氨基-9-脱氧-Neu5AC | n.d. | n.d. | n.d. | n.d. | 180 | 5.7 | 620 | 7.4 |
甲基-a-9-N-(喹那啶羰基2-酰基)-氨基-9-脱氧-Neu5AC | 87 | 54 | >>2.5mM(100%) | <<0.2 | 41 | n.d | >>10mM(100%) | n.d. |
甲基-a-9-N-丹磺酰基-氨基-9-脱氧-Neu5AC | 317 | 19 | 260 | 2.6 | n.d. | n.d. | n.d. | n.d. |
甲基-a-9-N-荧光黄酰基-氨基-9-脱氧-Neu5AC | 106 | 41 | >>1.5mM(121%) | <<0.5 | 77 | 28 | 100 | 48 |
IC50值是指在半抗原抑制试验中,Siglec抑制剂引起50%结合位点抑制时,该抑制剂的浓度。每种唾液酸衍生物的rIP值是通过对照化合物5-N-乙酰神经氨酸的IC50值与待测化合物的IC50值的比值来确定的。riP值>1.0的唾液酸衍生物比参考的化合物具有更好的结合力,而riP值<1.0的唾液酸衍生物比参考的化合物结合力差。n.d.表示没有测定。
化合物BPC--Neu5AC被用来按已知的方法评价选择性和活性,在BPC-Neu5AC存在的情况下,用抗IgM抗体刺激Daudi细胞可引起Ca2+浓度增高。这种化合物也可明显提高经抗IgM刺激的人血B淋巴细胞内Ca2+浓度。这些资料提示,经过处理的细胞内Ca2+信号增强是由于选择性抑制CD22的配体结合区域引起的。配体结合的减弱引起CD22胞内段抑制剂区的部分激活。
(甲基-α-9-N-(联苯-4-羰基)-氨基-9-脱氧-Neu5Ac)(BPC-Neu5Ac)
参考文献
1.Crocker et al,Immunology 102(2001),1-14.
2.Crocker et al,(2000)The Siglec family of 1-type lectins in Carbohydrates in Chemistryand Biology,Vol.4,B.Ernst et al,publisher,Wiley-VCH,pp.579-595.
3.Kelm,S.(2001),Ugands for Siglecs.in.Mammalian Carbohydrate RecognitionSystems,P.R.Crocker,publisher(Berdin,Springer),pp.153-176.
4.May et al.Mol.Cell 1(1998),719-728.
5.Kelm et al,Eur,J.Biochem,255(1998),663-672.
6.Strange et al,Eur,J.Biochem,258(1998),677-685.
7.U.N et al,Cloning and Characterization of Siglec-11,a novel sialic acid binding memberof the Ig Superfamily from human dendritic cells,J.Biol.Chemistry 2001(in printing).
8 Crocker et al,Glycobiology 8(1996),V.
Claims (21)
1、具有如下结构的唾液酸结合性免疫球蛋白样凝集素抑制剂:
X 代表负电荷基团,选自羧基、磷酸根、硫酸根、膦酸根、磺酸根、亚甲基羧基或乙烯羧基;
Y 代表H原子、烃基、芳基、羟基或其衍生物、聚糖或多聚体载体分子,所述羟基衍生物为氨基、巯基、甲氧基或苄氧基,所述聚糖选自己糖、氨基己糖和/或戊糖、葡萄糖或半乳糖、寡聚糖或多糖;
Z 为O原子;
R1 代表H原子或羟基或其衍生物,所述羟基衍生物为氨基或巯基;
R2 代表羟基、氨基或被乙酰基、丙酰基、丁基或戊基取代的氨基,其中,烷酰基可被一个或多个卤素原子取代;
R3 代表羟基或其衍生物,所述羟基衍生物为氨基或巯基;
R4 代表羟基或其衍生物,所述羟基衍生物为氨基或巯基;
R5 代表一个取代的氨基,取代物选自于取代或未被取代的芳香酰基、杂芳香酰基、芳基、或杂芳基,这些残基都包含一个或多个未饱和键;其中芳香酰基选自除苯甲酰基外的C4-C15芳香酰基;其中R4 作为H原子受体,R5作为H原子供体;
R6 代表H原子、烃基或离子基团,所述烃基选自甲基、乙基、丙基或丁基,所述离子集团选自羧基、磷酸根或硫酸根;
R6’ 代表H原子、烃基或离子基团,所述烃基选自甲基、乙基、丙基或丁基,所述离子集团选自羧基、磷酸根或硫酸根;至少一个选自R6和R6’的取代物是一疏水基团,选自H原子或甲基;
R7 代表H原子。
2.根据权利要求1所述的Siglec抑制剂,其特征在于芳香酰基选自萘甲酰基或蒽甲酰基。
3.根据权利要求1所述的Siglec抑制剂,其特征在于杂芳香酰基选自吡啶酰基,喹那定羰基和苯硫酰基.
4.根据权利要求1所述的Siglec抑制剂,其特征在于芳基选自苯基,萘基及蒽基。
5.根据权利要求1所述的Siglec抑制剂,其特征在于杂芳基选自于吡啶基和苯硫基。
6.根据权利要求1所述的Siglec抑制剂,其特征在于
X 代表位于轴向位置的羧基;
Y 代表氢原子、甲氧基、苄氧基、氨基或巯基;
Z 代表个O原子;
R1 代表羟基;
R2 代表氨基乙酰基;
R3 代表羟基;
R4 代表羟基;
R6 代表H原子;
R6’ 代表H原子;
R7 代表H原子。
7.提高抑制剂亲和选择性的方法,包括在神经氨酸或其衍生物的R5位上引入权利要求1—6之一中所述的R5残基取代物。
8.合成具有对SIGLEC分子高亲合力Siglec抑制剂的方法,包括:
A.在神经氨酸或其衍生物的R5位上引入权利要求1—6之一中所述的R5残基取代物;
B.测定上一步产物对某一SIGLEC分子的亲合力;
C.选择具有高亲合力的产物。
9.根据权利要求8所述的合成具有对SIGLEC分子高亲合力Siglec抑制剂的方法,其特征在于对上述C步产物的在除R5位外的其他位置进行取代。
10.根据权利要求9所述的合成具有对SIGLEC分子高亲合力Siglec抑制剂的方法,其特征在于所述除R5位外的其他位置为R2.
11.药物组合物,含有权利要求1—6之一所述的Siglec抑制剂和药学上适合的载体。
12.权利要求1—6之一所述的Siglec抑制剂在制备治疗Siglec介导的疾病的药物中的应用。
13.权利要求1—6之一所述的Siglec抑制剂在制备用于调节B细胞介导的的免疫反应药物中的应用。
14.根据权利要求13所述的Siglec抑制剂在制备治疗过敏反应,自身免疫性疾病和慢性炎症药物中的应用。
15.权利要求1—6之一所述的Siglec抑制剂在制备改善损伤神经的再生能力的药物中的应用。
16.根据权利要求15所述的Siglec抑制剂在制备治疗截瘫和多发性硬化药物中的应用。
17.权利要求1—6之一所述的Siglec抑制剂在制备调节NK细胞的细胞毒性药物中的应用。
18.根据权利要求17所述的Siglec抑制剂在制备治疗肿瘤性疾病药物中的应用。
19.根据权利要求17所述的Siglec抑制剂在制备治疗病毒感染药物中的应用。
20.根据权利要求13所述的Siglec抑制剂在制备增强B细胞免疫反应药物中的应用。
21.根据权利要求20所述的应用,适用于免疫缺陷病人。
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DE2001129332 DE10129332A1 (de) | 2001-06-19 | 2001-06-19 | Sialinsäure-Derivate als Siglec-Inhibitoren |
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WO2007105094A1 (en) * | 2006-03-14 | 2007-09-20 | Universität Basel | Method for the identification of new leads for drug candidates |
WO2007120815A2 (en) * | 2006-04-12 | 2007-10-25 | The Regents Of The University Of California | Methods for treating lymphocyte-associated disorders by modulation of siglec activity |
US9018245B2 (en) | 2006-12-26 | 2015-04-28 | Japan Science And Technology | Method for promoting immune response comprising inhibiting CD22 function in B cells |
DE102007046388A1 (de) * | 2007-09-21 | 2009-09-10 | Universität Hamburg | Entwicklung eines Bindungsassays und Darstellung neuartiger Inhibitoren des Myelin Assoziierten Glycoproteins |
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EP2610263A1 (de) | 2011-12-30 | 2013-07-03 | Brossmer, Reinhard | Sialinsäure-Dimere |
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