CN106573962B - 新颖的聚糖共轭物及其用途 - Google Patents
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- CN106573962B CN106573962B CN201580045205.4A CN201580045205A CN106573962B CN 106573962 B CN106573962 B CN 106573962B CN 201580045205 A CN201580045205 A CN 201580045205A CN 106573962 B CN106573962 B CN 106573962B
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Abstract
本揭示内容包含一种免疫组合物,其是包含(a)一包含载体及一或多聚糖的聚糖共轭物,其中一或多聚糖中的每一个聚糖皆是经由连结子与载体形成共轭,以及非必要性的(b)一佐剂。该一或多聚糖是一Globo H衍生物。
Description
背景技术
肿瘤相关糖类抗原(Tumor associated carbohydrate antigen,TACA)会过量表现于癌细胞表面,且与肿瘤细胞的附着及转移相关。1因此,许多癌症疫苗即是针对TACA进行设计研发。2基于多数TACA并无法有效诱发免疫反应,目前已发展出数种方法来增加糖类疫苗的免疫性,包含与载体蛋白结合3、与免疫佐剂一同施用4、使用非天然的糖苷键(glycosidic linkage)5、聚集抗原6、单分子多价疫苗7及异-聚糖多价疫苗8。利用该多个方法已设计出几种对标的聚糖结构能产生显著免疫反应的糖类疫苗,用以治疗癌症并进入人体临床测试。3,9在该多个糖类疫苗中,Theratope及GMK加上佐剂QS-21的临床试验已证实其对时间-疾病(time-to-disease)与整体存活率之间没有显著差异。推测原因可能是由于该多个疫苗无法引发病患产生大量与T细胞相关的免疫反应。10具体来说,Theratope及GMK虽可引发病患产生高量的IgM,却无法使其产生强烈的免疫IgG反应;无法有效提升IgG免疫反应乃是研发糖类疫苗亟需克服的难题之一。11
Globo H(GH;Fucα1→2Galβ1→3GalNacβ1→3Galα1→4Galβ1→4Glc)是Globo是列鞘糖脂(glycosphingolipid)的成员之一。1983年首次发现会过量表现于人类畸胎瘤细胞及乳癌MCF-7细胞12;之后亦陆续被证实会于乳癌、前列腺癌、卵巢癌、胰脏癌、脑癌、子宫内膜癌、胃癌、大肠直肠癌及肺癌等癌细胞上过量表现。13利用KLH作为载体,并以QS-21作为佐剂而由Livingston及Danishefsky两人制成的Globo H疫苗,在临床试验第I期已证实可治疗转移性乳癌病患。14经改善其合成方式后15,目前该疫苗已在台湾进行晚期乳癌病患的第III期临床试验,并于美国、韩国、香港及印度进行晚期乳癌病患的第II期临床试验;以及在台湾进行卵巢癌病患的第II期临床试验。然而,早期的临床试验结果指出,疫苗诱发出IgM抗体的含量仍会高于IgG抗体的含量。14,16近期,发明人利用白喉类毒素交互反应物质197(diphtheria toxoid cross-reactive material(CRM)197(DT))作为载体,并以糖脂C34作为佐剂,研发出一较佳的疫苗,该疫苗可诱发抗体类型转换(class switch)以产生大量可对抗GH、GH的片段Gb5及SSEA4的IgG抗体,上述GH、GH的片段Gb5及SSEA4均会表现于乳癌细胞及癌症干细胞上。13b
相关研究已证实修饰糖类抗原结构(modification of carbohydrate antigenstructure,MCAS)可有效提升免疫反应。17举例来说,在改造B型脑膜炎球菌的荚膜多糖时,将α-(2,8)-连接的聚唾液酸(α-(2,8)-linked polysialic acid,PSA)的N-乙酰基置换为N-丙酰基可诱发高量抗体反应,以辨识N-丙酰基PSA,以及天然的N-乙酰基PSA。18相似的修饰方法亦可应用于STn19及GM320抗体,据以产生可同时辨识修饰及天然形式的抗原的高效价抗体。该多个结果指出,修饰聚糖抗原的N-苯乙酰基、N3、N-氟乙酰基或N-双氟乙酰基可改善其免疫诱发能力。19a,c此外,Schultz等人则指出,将对硝基苯基丙胺酸(p-nitrophenylalanine)嵌入肿瘤坏死因子(tumor necrosis factor-α,TNF-α)可破坏免疫耐受性,并引发对TNF-α的抗体反应。21目前虽已有多项研发是利用聚糖作为抗原,然主要仍是以修饰N端双糖(STn)、三糖(GM3)及聚唾液酸(PSA)方式为主,其余则是利用氟化MUC1糖肽抗原来进行制备。18a,19a,d,20,22相关领域缺乏一整体策略来制备糖类疫苗,据以引发长效型IgG反应。
发明内容
本发明是关于利用本揭示内容所述的特定化学基团来修饰Globo H的还原端葡萄糖或是非还原端海藻糖(fucose),可引发可专一辨识Globo H(GH)、Gb5及SSEA4的大量的IgG抗体反应。由包含此非天然聚糖结构的免疫组合物所引发的抗体可辨识会表现GH的肿瘤细胞(MCF-7),并产生与补体相关的细胞毒杀反应来对抗肿瘤细胞。
据此,本发明是关于合成型聚糖共轭物、包含该合成型聚糖共轭物的免疫组合物及疫苗。本发明亦是关于利用合成型聚糖共轭物及其免疫组合物来治疗癌症或降低个体罹患癌症的风险的方法。
在一方式中,本发明是关于式(I)的化合物,
或其盐类,
其中,
X1是-OR或-SR,其中R是氢、或是氧或硫的保护基、可任选取代的C1-10烷基、可任选取代的芳香基、可任选取代的酰基或可任选取代的亚胺基(imidoyl);
R1及R2是分别选自由氢、卤素、可任选取代的烷基、可任选取代的烯基、可任选取代的炔基、可任选取代的杂环基、可任选取代的芳香基、-N3、-NO2、-N(RB)2、-N(RA)C(O)RA、-ORA、-OC(O)RA、-SRA、-C(O)N(RB)2、-CN、-C(O)RA、-C(O)ORA、-S(O)RA、-SO2RA、-SO2N(RB)2及-NHSO2RB所组成群组;
RA是选自由氢、可任选取代的烷基、可任选取代的烯基、可任选取代的炔基、可任选取代的杂环基、可任选取代的芳香基所组成的群组;
RB是选自由氢、可任选取代的烷基、可任选取代的烯基、可任选取代的炔基、可任选取代的杂环基、可任选取代的芳香基所组成的群组;以及
若R1是-OH,则R2不是-CH3;若R2是-CH3,则R1不是-OH。
在另一方式中,本发明是关于一种免疫组合物,包含(a)一聚糖共轭物,其是包含至少一种与连结子(linker)结合的聚糖及载体(carrier),其中该至少一种聚糖是借由该连结子而与该载体形成共轭;以及(b)一非必要性的佐剂,其中该至少一种与连结子结合的聚糖具有式(II)的化学结构:
其中,
R1及R2是分别选自由氢、卤素、可任选取代的烷基、可任选取代的烯基、可任选取代的炔基、可任选取代的杂环基、可任选取代的芳香基、-N3、-NO2、-N(RB)2、-N(RA)C(O)RA、-ORA、-OC(O)RA、-SRA、-C(O)N(RB)2、-CN、-C(O)RA、-C(O)ORA、-S(O)RA、-SO2RA、-SO2N(RB)2及-NHSO2RB所组成的群组;
RA是选自由氢、可任选取代的烷基、可任选取代的烯基、可任选取代的炔基、可任选取代的杂环基、可任选取代的芳香基所组成的群组;
RB是选自由氢、可任选取代的烷基、可任选取代的烯基、可任选取代的炔基、可任选取代的杂环基、可任选取代的芳香基所组成的群组;以及
若R1是-OH,则R2不是-CH3;若R2是-CH3,则R1不是-OH。
或者是,该至少一种与连结子结合的聚糖具有式(IV)的化学结构:
式(IV)
其中,R1、R2、RA及RB分别如式(II)的定义;若R1是-OH,则R2不是-CH3;若R2是-CH3,则R1不是-OH。
在本发明一实施方式中,R1是-OH、-F、-N3、-NO2或芳氧基。
在另一实施方式中,R2是-CH3、-CH2F、-CH2N3、-CH2NO2、-CH2OH或炔基。
在另一实施方式中,R1是-OH,且R2是-CH2F、-CH2N3、-CH2NO2、-CH2OH或-C≡CH。
“n”一词在本说明书是指介于1到10的正整数。因此,n可以是1、2、3、4、5、6、7、8、9或10。
在另一实施方式中,连结子是一是异-(hetero-)或同-(homo-)双功能链接子(bifunctional linker)。
在另一实施方式中,连结子是-L1L2-,其中L1是一键结、-O-、-S-、-NRL1a-、-C(=O)-、-NRL1aC(=O)-、-NRL1aC(=O)O-、-C(=O)NRL1a-、-OC(=O)NRL1a-、-SC(=O)-、-C(=O)S-、-OC(=O)-、-C(=O)O-、-NRL1aC(=S)-、-C(=S)NRL1a-、反式-CRL1b=CRL1b-、顺式-CRL1b=CRL1b-、-C≡C-、-OC(RL1b)2-、-C(RL1b)2O-、-NRL1aC(RL1b)2-、-C(RL1b)2NRL1a-、-SC(RL1b)2-、-C(RL1b)2S-、-S(=O)2O-、-OS(=O)2-、-S(=O)2NRL1a-、-NRL1aS(=O)2-或可任选取代的C1-20烃链,其中该烃链中一或多个碳原子可任选地由-O-、-S-、-NRL1a-、-C(=O)-、NRL1aC(=O)-、-NRL1aC(=O)O-、-C(=O)NRL1a-、-OC(=O)NRL1a-、-SC(=O)-、-C(=O)S-、-OC(=O)-、-C(=O)O-、-NRL1aC(=S)-、-C(=S)NRL1a-、反式-CRL1b=CRL1b-、顺式-CRL1b=CRL1b-、-C≡C-、-S(=O)2O-、-OS(=O)2-、-S(=O)2NRL1a-或-NRL1aS(=O)2-取代,其中RL1a是氢、可任选取代的C1-6烷基,或一氮保护基,或是RL1a亦可与邻近的碳原子连结以形成一可任选取代的杂环;且其中各RL1b是独立选自于由氢、卤素、可任选取代的C1-10烷基、可任选取代的烯基、可任选取代的炔基、可任选取代的碳环(carbocyclyl)、可任选取代的杂环基、可任选取代的芳香基、可任选取代的杂芳基所组成的群组;或是RL1b可与邻近的碳、氮或氧原子连结以形成一可任选取代的碳环或杂环;或是二RL1b化学基团可链接以形成一可任选取代的碳环或可任选取代的杂环;且L2是一源自于能与载体及L1交互反应的交联剂(crosslinking reagent)的官能团。
在另一实施方式中,连结子包含至少一硫原子、羧酸酯基(carboxylate group)、酰胺基(amide group)、氨基甲酸酯基(carbamate group)、碳酸基(carbonate group)、硫代氨基甲酸酯基(thiocarbamate group)、硫碳酸类(thiocarbonate group)、硫醚基(thioether group)、丁二酰胺基(succinamide group)、正-羟基丁二酰胺基(n-hydroxysuccinamide group)或其组合物。
在另一实施方式中,载体可以是蛋白、脂质、脂质化蛋白、病毒、多肽或糖肽的树枝状聚合物(dendrimer)。在某些实施例中,载体是一包含T细胞抗原决定位置(epitope)的多肽。
载体可以是一蛋白,选自由破伤风类毒素(tetanus toxoid,TT)、白喉类毒素(diphtheria toxoid,DT)、白喉类毒素交互反应物质197(diphtheria toxin cross-reacting material 197,CRM197)、破伤风类毒素的片段C(fragment C of TT)、键孔血蓝蛋白(Keyhole limpet hemocyanin,KLH)、胎牛血清白蛋白(bovine serum albumin,BSA)、蛋白D(protein D)、外膜蛋白(outer-membrane protein,OMP)及肺炎球菌溶血素(pneumolysin)所组成的群组。
在另一实施方式中,载体蛋白是选自由TT、DT及CRM197所组成的群组。在另一实施方式中,载体蛋白是CRM197,且聚糖共轭物具有式(III)的化学结构:
其中,
m是一介于1到38的正整数;且
若R1是-OH,则R2不是-CH3;若R2是-CH3,则R1不是-OH。
“m”一词在本说明书中是一介于1至38的正整数。在本发明一实施方式中,m是一介于1至30的正整数,或一介于1至20的正整数。举例来说,m可以是1、2、3、4、6、8、10、15、20、30或38。
本发明的另一方式是关于一聚糖共轭物的混合物,其是包含至少二种上述的聚糖共轭物。在某些实施方式中,聚糖混合物的w的平均值约由1.0到38.0,或约由1.0到10.0,或约为5.7、4.9、2.9、2.8或3.1。
免疫组合物可非必要性地包含一佐剂。佐剂可以是一能与树突细胞的CD1d分子结合的糖脂。在某些实施方式中,佐剂可以是C34、Gluco-C34、7DW8-5、C17、C23、C30、α-神经酰胺半乳糖(α-galactoceramide)、铝盐、鲨烯(Squalene)、MF59或QS-21。
免疫组合物包含一免疫或药学有效量的上述聚糖共轭物。
在另一方式中,本发明是关于一种用以使个体产生对抗癌症的免疫反应的免疫组合物。癌症可以选自由脑癌、肺癌、乳癌、口腔癌、食道癌、胃癌、肝癌、胆管癌、胰脏癌、大肠直肠癌、肾脏癌、骨癌、皮肤癌、子宫颈癌、卵巢癌及前列腺癌所组成的群组。或者是,本发明是关于上述免疫组合物的用途,其是可用以制备一药物以治疗癌症病患,其中该免疫组合物可诱发癌细胞产生细胞毒杀反应、引发对抗癌症的免疫反应、产生可专一结合及/或中和一或多种癌细胞表面抗原的抗体,其中该一或多种癌细胞表面抗原是选自由Globo H、SSEA-3及SSEA-4所组成的群组。
在本发明一实施方式中,所述抗体主要是IgG抗体。免疫组合物主要可用以引发IgG1、IgG2b、IgG2c及IgG3的表现。
在再一方式中,本发明是关于一种可对抗上述免疫组合物的单克隆抗体。
在另一方式中,本发明是关于一种包含上述免疫组合物及一药学上可接受的赋形剂的癌症疫苗。癌症疫苗可以包含单一剂量或多剂量的本发明聚糖共轭物、该聚糖共轭物的混合物或其免疫组合物。癌症疫苗可用以治疗或降低个体罹患癌症的风险。癌症疫苗可包含用以阐述使用方法及告知个体或医疗人员处方讯息的相关信息。该多个信息可由美国食品药物管理局(U.S.Food and Drug Administration,FDA)等监管机构取得。癌症疫苗亦可具选择性地包含用以投予化合物或组合物的器材,举例来说,用以非口服投予的注射器。
在另一方式中,本发明是关于用以治疗及/或减少个体罹患癌症风险的方法,该方法包含对有需要的个体投予一治疗有效量的上述免疫组合物或癌症疫苗。
该治疗可减少肿瘤体积大小、消除恶性细胞、抑制转移、防止癌症复发、减少或杀死转移性癌症、延长存活时间及/或延长进展成肿瘤的时间。
该治疗更可包含在投予上述免疫组合物或癌症疫苗之前、期间或之后对该个体投予额外的治疗。额外的治疗可以是一化疗药剂或一放射线治疗。
在另一实施方式中,本发明是关于一种对一哺乳动物(例如人类病患)进行免疫接种使其能对抗癌症的方法,该方法包含对该哺乳动物投予一药学有效量的上述免疫组合物或癌症疫苗。可利用皮下注射方式对该哺乳动物投予该免疫组合物或癌症疫苗。
所述癌症包含,但不限于,脑癌、肺癌、乳癌、口腔癌、食道癌、胃癌、肝癌、胆管癌、胰脏癌、大肠直肠癌、肾脏癌、骨癌、皮肤癌、子宫颈癌、卵巢癌及前列腺癌。
在另一方式中,本发明是关于用以合成上述聚糖的方法。
在另一方式中,本发明是关于用以制备上述免疫组合物或癌症疫苗的方法。在本发明一实施方式中,用以制备上述免疫组合物的方法包含下列步骤:
(i)提供式(X)的化合物:
其中R1、R2、RA及RB分别如式(II)的定义;若R1是-OH,则R2不是-CH3;若R2是-CH3,则R1不是-OH;
(ii)令式(X)的化合物与一胺基活化的(amino-active)双功能链接子反应,以制备一第一反应产物;以及
(iii)令该第一反应产物与一载体蛋白反应,以制备一聚糖共轭物;以及
(iv)非必要性地混合一佐剂以制备本发明组合物。
在本发明一实施方式中,该胺基活化的双功能链接子是一具有4到6个碳原子的二羧酸(dicarboxylic acid)。
上述发明内容仅用以阐述本发明某些实施方式。本发明其余技术特征及实施方式可进一步参阅本揭示内容、图式、实施例及申请专利范围。
附图说明
图1A-C是关于IgG抗体的图式,该多个IgG抗体是由GH衍生物-DT共轭物所制备,且可分别用以对抗GH、Gb5及SSEA4。
图2是关于由GH衍生物-DT共轭物所制备的可辨识GH表现肿瘤细胞(MCF-7)的小鼠抗体。
图3是关于由GH衍生物所产生的抗体,其是可引发与补体相关的细胞毒杀(complement-dependent cytotoxicity,CDC)以消除GH表现肿瘤细胞。
具体实施方式
化学物定义
本揭示内容的化学元素及特定的官能团皆是依照第75版的Handbook ofChemistry and Physics,CAS版本的化学元素周期表所定义。此外,有机化学、特定官能团及相关化学反应可参见Thomas Sorrell,Organic Chemistry,University ScienceBooks,Sausalito,1999;Smith and March,March’s Advanced Organic Chemistry,第5版本,John Wiley&Sons,Inc.,New York,2001;Larock,Comprehensive OrganicTransformations,VCH Publishers,Inc.,New York,1989;及Carruthers,Some ModernMethods of Organic Synthesis,第3版本,Cambridge University Press,Cambridge,1987。
本说明书所述的化合物可包含一或多非对称中心,且可以不同异构物形式(例如,镜像异构物及/或非镜像异构物)存在。举例来说,本揭示内容所述的化合物可以是单独存在的镜像异构物、非镜像异构物或几何异构物,亦可以是立体异构物的混合物(包含外消旋混合物及包含一或多种立体异构物的混合物)。可利用本领域技术人员所熟知的方法由混合物中分离各异构物,包含掌性高压液相层析法(high pressure liquidchromatography,HPLC)及掌性盐类的形成及结晶;或是利用非对称合成法来制备异构物。举例来说,相关信息可参见Jacques et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981);Wilen et al.,Tetrahedron 33:2725(1977);Eliel,Stereochemistry of Carbon Compounds(McGraw–Hill,NY,1962);及Wilen,Tablesof Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of NotreDame Press,Notre Dame,IN 1972)。本发明亦包含上述化合物,其可以单一形式存在或是由不同异构物所组成的组合物形式存在。
当列举一数值范围时,该数值范围包含所述范围内的各数值及次范围。举例来说,“C1-6”包含C1、C2、C3、C4、C5、C6、C1-6、C1-5、C1-4、C1-3、C1-2、C2-6、C2-5、C2-4、C2-3、C3-6、C3-5、C3-4、C4-6、C4-5及C5-6。
在本说明书中,“烷基”(Alkyl)是指一具有1到20个碳原子的直链型或支链型饱和烃基的自由基(C1-20烷基)。在某些实施方式中,烷基具有1到10个碳原子(C1-10烷基)、1到9个碳原子(C1-9烷基)、1到8个碳原子(C1-8烷基)、1到7个碳原子(C1-7烷基)、1到6个碳原子(C1-6烷基)、1到5个碳原子(C1-5烷基)、1到4个碳原子(C1-4烷基)、1到3个碳原子(C1-3烷基)或1到2个碳原子(C1-2烷基)。烷基亦可指1个碳原子(C1烷基)。
在某些实施方式中,烷基具有2到6个碳原子(C2-6烷基)。例示性的C1-6烷基包含,但不限于,甲基(methyl,C1)、乙基(ethyl,C2)、正丙基(n-propyl,C3)、异丙基(iso-propyl,C3)、正丁基(n-butyl,C4)、三级丁基(tert-butyl,C4)、二级丁基(sec-butyl,C4)、异丁基(iso-butyl,C4)、正戊基(n-pentyl,C5)、3-戊基(3-pentanyl,C5)、3-甲基-1-丁基(amyl,C5)、新戊基(neopentyl,C5)、3-甲基-2-丁基(3-methyl-2-butanyl,C5)、叔戊基(tertiaryamyl,C5)、正己基(n-hexyl,C6)、正庚基(n-heptyl,C7)及正辛基(n-octyl,C8)等。除非另有定义,否则各烷基皆可独立以任选取代基取代,即烷基可为无取代基的烷基(一“无取代烷基”)或以一或多取代基取代的烷基(一“有取代烷基”)。在某些实施方式中,烷基是无取代基的C1-10烷基(例如-CH3)。在某些实施方式中,烷基是具有取代基的C1-10烷基。
在本说明书中,“烯基”(Alkenyl)是指具有2到20个碳原子、一或多碳-碳双键且无三键的直链型或支链型烃基的自由基(C2-20烯基)。烯基可以具有2到10个碳原子(C2-10烯基)、2到9个碳原子(C2-9烯基)、2到8个碳原子(C2-8烯基)、2到7个碳原子(C2-7烯基)、2到6个碳原子(C2-6烯基)、2到5个碳原子(C2-5烯基)、2到4个碳原子(C2-4烯基)、2到3个碳原子(C2-3烯基)或2个碳原子(C2烯基)。该一或多个碳-碳双键可以位于中间(例如2-丁烯基,2-butenyl)或末端(例如1-丁烯基,1-butenyl)。例示性的C2-4烯基包含,但不限于,乙烯基(ethenyl,C2)、1-丙烯基(1-propenyl,C3)、2-丙烯基(2-propenyl,C3)、1-丁烯基(1-butenyl,C4)、2-丁烯基(2-butenyl,C4)及丁二烯基(butadienyl,C4)等。例示性的C2-6烯基包含,但不限于,C2-4烯基、戊烯基(pentenyl,C5)、戊二烯基(pentadienyl,C5)、己烯基(hexenyl,C6)、庚烯基(heptenyl,C7)、辛烯基(octenyl,C8)及辛二烯基(octatrienyl,C8)等。除非另有定义,否则各烯基皆可分别以任选取代基取代,即烯基可为无取代基的烯基(一“无取代烯基”)或以一或多取代基取代的烯基(一“有取代烯基”)。举例来说,烯基可以是无取代基的C2-10烯基,或是具有取代基的C2-10烯基。
在本说明书中,“炔基”(Alkynyl)是指具有2到20个碳原子、一或多碳-碳三键及非必要性的一或多双键的直链型或支链型烃基的自由基(C2-20炔基)。在某些实施方式中,炔基可以具有2到10个碳原子(C2-10炔基)、2到9个碳原子(C2-9炔基)、2到8个碳原子(C2-8炔基)、2到7个碳原子(C2-7炔基)、2到6个碳原子(C2-6炔基)、2到5个碳原子(C2-5炔基)、2到4个碳原子(C2-4炔基)、2到3个碳原子(C2-3炔基)或2个碳原子(C2炔基)。该一或多个碳-碳三键可以位于中间(例如2-丁炔基,2-butynyl)或末端(例如1-丁炔基,1-butynyl)。例示性的C2-4炔基包含,但不限于,乙炔基(ethynyl,C2)、1-丙炔基(1-propynyl,C3)、2-丙炔基(2-propynyl,C3)、1-丁炔基(1-butynyl,C4)及2-丁炔基(2-butynyl,C4)等。例示式的C2-6炔基包含,但不限于,上述C2-4炔基、戊炔基(pentynyl,C5)、己炔基(hexynyl,C6)、庚炔基(heptynyl,C7)及辛炔基(octynyl,C8)等。除非另有定义,否则各炔基皆可独立以任选取代基取代,即炔基可为无取代基的炔基(一“无取代炔基”)或以一或多取代基取代的炔基(一“有取代炔基”)。举例来说,炔基可以是无取代基的C2-10烯基,或是具有取代基的C2-10炔基。
在本说明书中,“杂环基”(Heterocyclyl)或“杂环”(heterocyclic)是指具有环碳原子(ring carbon atom)及1到4个环杂原子(ring heteroatom)的3到10员非芳香族环状系统的自由基,其中各杂原子可以分别选自由氮、氧、硫、硼、磷及硅所组成的群组(3-10员杂环基)。在某些实施方式中,杂原子是分别选自由氮、硫及氧所组成的群组。在包含一或多氮原子的杂环基中,可利用碳或氮原子来进行连接。杂环基可以是一单环(单环杂环基,monocyclic heterocyclyl)或一融合、键结或螺旋环状系统,例如双环系统(双环杂环基),且可以是饱和型或不饱和型。杂环双环系统可在一或双环中包含一或多杂原子。“杂环基”(Heterocyclyl)亦可包含环状系统,其中杂环可利用碳环或杂环上的自由基或键结与一或多碳环融合,或利用杂环上的自由基或键结与一或多芳香基或杂芳香基融合,其中该连接点是位于杂环上;在此情况下,环中成员的数量即为该杂环系统中该环中成员的数量。除非另有定义,否则各杂环基皆可分别以任选取代基取代,即杂环基可为无取代基的杂环基(一“无取代杂环基”)或以一或多取代基取代的杂环基(一“有取代杂环基”)。举例来说,杂环基可以是无取代基的3-10员的杂环基,亦可以是具有取代基的3-10员的杂环基。
在本说明书中,“芳香基”(Aryl)是指具有单环或多环(例如双环或三环)的4n+2芳环系统(例如共享6、10或14π电子的环状数组)的自由基,其中该芳环系统具有6-14个环碳原子及0个杂原子(C6-14芳香基)。在某些实施方式中,芳香基可以具有6个环碳原子(C6芳香基,例如苯基)、10个环碳原子(C10芳香基,例如1-萘基(1-naphthyl)及2-萘基等萘基)或14个环碳原子(C14芳香基,例如蒽基(anthracyl))。“芳香基”(Aryl)亦包含环状系统,其中芳环可透过芳环上的自由基或键结与一或多碳环或杂环融合;在该多个情况下,碳原子的数量即为芳环系统中碳原子的数量。除非另有定义,否则各芳香基皆可分别以任选取代基取代,即芳香基可为无取代基的芳香基(一“无取代芳香基”)或以一或多取代基取代的芳香基(一“有取代芳香基”)。举例来说,杂环基可以是无取代基的C6-14芳香基,亦可以具是有取代基的C6-14芳香基。
在本说明书中,烷基、烯基、炔基、碳环、杂环基、芳香基及杂芳香基等二价桥接基(divalent bridging group)更可指以-ene结尾的官能团团,例如亚烷基(alkylene)、伸烯基(alkenylene)、亚炔基(alkynylene)、亚碳环(carbocyclylene)、亚杂环(heterocyclylene)、亚芳基(arylene)及亚杂芳基(heteroarylene)。
在本说明书中,“烷氧基”(alkoxy或alkyloxy)是指一-O-烷基自由基,其中该烷基为可任选取代的烷基。例示性的烷氧基包含,但不限于,甲氧基(methoxy)、乙氧基(ethoxy)、
正丙氧基(n-propoxy)、异丙氧基(isopropoxy)、正丁氧基(n-butoxy)、异丁氧基(iso-butoxy)、二级丁氧基(sec-butoxy)及三级丁氧基(tert-butoxy)。
“芳氧基”(aryloxy)在本说明书是指一-O-芳香基,其中该芳香基为可任选取代的芳香基。
在本说明书中,“可任选取代的”(optionally substituted)一词是指一有取代的或无取代的官能团。
烷基、烯基、炔基、碳环、杂环、芳香基及杂芳香基在本说明书中,可为任选取代的(例如有取代的或无取代的烷基、有取代的或无取代的烯基、有取代的或无取代的炔基、有取代的或无取代的碳环、有取代的或无取代的杂环、有取代的或无取代的芳香基,或是有取代的或无取代的杂芳香基)。一般来说,“有取代的”(substituted)一词不论是否以“可任选的”(optionally)一词加以修饰,皆是指化学基团(例如碳或氮原子)中以可允许的取代基置换至少一个氢原子,例如取代后会产生稳定的化合物(例如不会自动进行重组、环化、去除等反应的化合物)的取代。除非另有定义,否则一“有取代的”(substituted)基团于一或多个可取代位置具有一个取代基,且当多于一个位置被取代时,各位置的取代基可以是相同或不同的。“有取代的”(substituted)一词亦包含以有机化合物中所有可允许的取代基所置换的取代,该多个取代基皆会产生稳定的化合物。本发明可利用单一或所有组合取代以产生稳定的化合物。为此,氮原子等杂原子可具有氢取代基及/或任何上述的适合的取代基,借以稳定杂原子的价数并产生稳定的官能团。
“卤”(Halo)或“卤素”(halogen)是指氟(fluorine,fluoro,-F)、氯(chlorine,chloro,-Cl)、溴(bromine,bromo,-Br)或碘(iodine,iodo,-I)。
“酰基”(Acyl)是指一选自由-C(=O)Raa,-CHO、-CO2Raa、-C(=O)N(Rbb)2、-C(=NRbb)Raa、-C(=NRbb)ORaa、-C(=NRbb)N(Rbb)2、-C(=O)NRbbSO2Raa、-C(=S)N(Rbb)2、-C(=O)SRaa及-C(=S)SRaa所组成的群组的官能团,其中Raa及Rbb分别如上述定义。
在价数允许的情况下,氮原子可以是取代的或无取代的,且包含一级、二级、三级及四级氮原子。例示性的氮原子取代基包含,但不限于,氢、-OH、-ORaa、-N(Rcc)2、-CN、-C(=O)Raa、-C(=O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(=NRbb)Raa、-C(=NRcc)ORaa、-C(=NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(=S)N(Rcc)2、-C(=O)SRcc、-C(=S)SRcc、-P(=O)2Raa、-P(=O)(Raa)2、-P(=O)2N(Rcc)2、-P(=O)(NRcc)2、C1-10烷基、C1-10全卤烷基(perhaloalkyl)、C2-10烯基、C2-10炔基、C3-10碳环、3-14员的杂环基、C6-14芳香基及5-14员的杂芳香基,或是加入二个固定于氮原子的Rcc基团以形成一3-14员的杂环或5-14员的异芳环,其中各烷基、烯基、炔基、碳环、杂环、芳香基及杂芳香基可分别以0、1、2、3、4或5Rdd基团取代,且其中Raa、Rbb、Rcc及Rdd分别如上述的定义。
在某些实施方式中,氧原子上的取代基可以是氧保护基(亦指一羟基保护基)。氧保护基包含,但不限于,-Raa、-N(Rbb)2、-C(=O)SRaa、-C(=O)Raa、-CO2Raa、-C(=O)N(Rbb)2、-C(=NRbb)Raa、-C(=NRbb)ORaa、-C(=NRbb)N(Rbb)2、-S(=O)Raa、-SO2Raa、-Si(Raa)3、-P(Rcc)2、-P(Rcc)3、-P(=O)2Raa、-P(=O)(Raa)2、-P(=O)(ORcc)2、-P(=O)2N(Rbb)2及-P(=O)(NRbb)2,其中Raa、Rbb及Rcc分别如上述定义。氧保护基为本领域技术人员所熟知的化学保护基团,且包含该多个阐述于Protecting Groups in Organic Synthesis,T.W.Greene andP.G.M.Wuts,第3版,John Wiley&Sons,1999的保护基团,该文献在此一并纳入以供参照。
例示性的氧保护基包含,但不限于,甲基、甲氧甲基(methoxylmethyl,MOM)、甲硫甲基(methylthiomethyl,MTM)、叔丁硫甲基(t-butylthiomethyl)、(苯二甲硅烷基)甲氧甲基((phenyldimethylsilyl)methoxymethyl,SMOM)、苄氧甲基(benzyloxymethyl,BOM)、对甲氧基苄氧甲基(p-methoxybenzyloxymethyl,PMBM)、(4-甲氧基苯氧基)甲基((4-methoxyphenoxy)methyl,p-AOM)、愈创木酚甲基(guaiacolmethyl,GUM)、叔丁氧甲基(t-butoxymethyl)、4-戊烯基氧甲基(4-pentenyloxymethyl,POM)、硅烷氧甲基(siloxymethyl)、2-甲氧基乙氧基甲基(2-methoxyethoxymethyl,MEM),、2,2,2-三氯乙氧基甲基(2,2,2-trichloroethoxymethyl)、双(2-氯乙氧基)甲基(bis(2-chloroethoxy)methyl)、2-(三甲基硅烷基)乙氧甲基(2-(trimethylsilyl)ethoxymethyl,SEMOR)、四氢哌喃基(tetrahydropyranyl,THP)、3-溴四氢哌喃基(3-bromotetrahydropyranyl)、四氢噻喃基(tetrahydrothiopyranyl)、1-甲氧基环己基(1-methoxycyclohexyl)、4-甲氧基四氢哌喃基(4-methoxytetrahydropyranyl,MTHP)、4-甲氧基四氢噻喃基(4-methoxytetrahydrothiopyranyl)、S,S-二氧-4-甲氧基四氢噻喃基(4-methoxytetrahydrothiopyranyl S,S-dioxide)、1-[(2-氯-4-甲基)苯基]-4-甲氧基哌啶-4-基(1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,CTMP)、1,4-二恶烷-2-基(1,4-dioxan-2-yl)、四氢喃基(tetrahydrofuranyl)、四氢噻吩基(tetrahydrothiofuranyl)、2,3,3a,4,5,6,7,7a-八氢-7,8,8-三甲基-4,7-亚甲基苯呋喃-2-基(2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)、1-乙氧乙基(1-ethoxyethyl)、1-(2-氯乙氧基)乙基(1-(2-chloroethoxy)ethyl)、1-甲基-1-甲氧乙基(1-methyl-1-methoxyethyl)、1-甲基-1-苄氧乙基(1-methyl-1-benzyloxyethyl)、1-甲基-1-苄氧基-2-氟乙基(1-methyl-1-benzyloxy-2-fluoroethyl)、2,2,2,-三氯乙基(2,2,2-trichloroethyl)、2-三甲基硅烷乙基(2-trimethylsilylethyl)、2-(苯氢硒基)乙基(2-(phenylselenyl)ethyl)、叔丁基(t-butyl)、烯丙基(allyl)、对氯苯基(p-chlorophenyl)、对甲氧苯基(p-methoxyphenyl)、2,4-二硝基苯基(2,4-dinitrophenyl)、苄基(benzyl(Bn))、对甲氧苄基(p-methoxybenzyl)、3,4-二甲氧苄基(3,4-dimethoxybenzyl)、邻硝基苄基(o-nitrobenzyl)、对硝基苄基(p-nitrobenzyl)、对卤代苄基(p-halobenzyl)、2,6-二氯苄基(2,6-dichlorobenzyl)、对氰基苄基(p-cyanobenzyl)、对苯基苄基(p-phenylbenzyl)、2-皮考基(2-picolyl)、4-皮考基(4-picolyl)、3-甲基-2-皮考基N-环氧基(3-methyl-2-picolyl N-oxido)、二苯甲基(diphenylmethyl)、p,p’-二硝基二苯甲基(p,p’-dinitrobenzhydryl)、5-二苯环庚基(5-dibenzosuberyl)、三苯甲基(triphenylmethyl)、α-萘基二苯甲基(α-naphthyldiphenylmethyl)、对甲氧苯基二苯甲基(p-methoxyphenyldiphenylmethyl)、二(对甲氧苯基)苯基甲基(di(p-methoxyphenyl)phenylmethyl)、三(对甲氧苯基)甲基(tri(p-methoxyphenyl)methyl)、4-(4’-溴苯甲酰甲基氧基苯基)二苯基甲基(4-(4’-bromophenacyloxyphenyl)diphenylmethyl)、4,4′,4″-三(4,5-二氯邻苯二甲酰亚氨基苯基)甲基(4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl)、4,4′,4″-三(乙酰丙酰基氧基苯基)甲基(4,4′,4″-tris(levulinoyloxyphenyl)methyl)、4,4′,4″-三(苯甲酰基氧基苯基)甲基(4,4′,4″-tris(benzoyloxyphenyl)methyl)、3-(咪唑-1-基)双(4′,4″-二甲氧苯基)甲基(3-(imidazole-1-yl)bis(4′,4″-dimethoxyphenyl)methyl)、1,1-双(4-甲氧基苯基)-1′-芘基甲基(1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl)、9-蒽基(9-anthryl)、9-(9-苯基)占吨基(9-(9-phenyl)xanthenyl)、9-(9-苯基-10-氧代)蒽基(9-(9-phenyl-10-oxo)anthryl)、1,3-苯并二硫杂环戊-2-基、(1,3-benzodithiolan-2-yl)、苯并异噻唑基S,S-二环氧基(benzisothiazolyl S,S-dioxide)、三甲基硅烷基(trimethylsilyl,TMS)、三乙硅烷基(triethylsilyl,TES)、三异丙硅烷基(triisopropylsilyl,TIPS)、二甲异丙硅烷基(dimethylisopropylsilyl,IPDMS)、二乙异丙硅烷基(diethylisopropylsilyl,DEIPS)、二甲己硅烷基(dimethylthexylsilyl)、叔丁基二甲硅烷基(t-butyldimethylsilyl,TBDMS)、叔丁基二苯硅烷基(t-butyldiphenylsilyl,TBDPS)、三苄基硅烷基(tribenzylsilyl)、三对二甲苯硅烷基(tri-p-xylylsilyl)、三苯硅烷基(triphenylsilyl)、二苯甲硅烷基(diphenylmethylsilyl,DPMS)、叔丁基甲氧苯硅烷基(t-butylmethoxyphenylsilyl,TBMPS)、甲酸酯(formate)、苯甲酰甲酸酯(benzoylformate)、乙酸酯(acetate)、氯乙酸酯(chloroacetate)、二氯乙酸酯(dichloroacetate)、三氯乙酸酯(trichloroacetate)、三氟乙酸酯(trifluoroacetate)、甲氧乙酸酯(methoxyacetate)、三苯甲氧乙酸酯(triphenylmethoxyacetate)、苯氧乙酸酯(phenoxyacetate)、对氯苯氧乙酸酯(p-chlorophenoxyacetate)、3-苯丙酸酯(3-phenylpropionate)、4-氧代戊酸酯(乙酰丙酸酯,4-oxopentanoate,levulinate),4,4-(亚乙基二硫代)戊酸酯(4,4-(ethylenedithio)pentanoate)、乙酰丙酰基二硫缩醛(levulinoyldithioacetal)、新戊酸酯(pivaloate)、金刚烷二甲酸酯(adamantoate)、巴豆酸酯(crotonate)、4-甲氧基巴豆酸酯(4-methoxycrotonate)、苯甲酸酯(benzoate)、对苯基苯甲酸酯(p-phenylbenzoate)、2,4,6-三甲基苯甲基酯(2,4,6-trimethylbenzoate,mesitoate)、碳酸甲酯(methyl carbonate)、碳酸9-茀基甲酯(9-fluorenylmethylcarbonate,Fmoc)、碳酸乙酯(ethyl carbonate)、碳酸2,2,2-三氯乙酯(2,2,2-trichloroethyl carbonate,Troc)、碳酸2-(三甲基硅烷基)乙酯(2-(trimethylsilyl)ethyl carbonate,TMSEC)、碳酸2-(苯基磺酰基)乙酯(2-(phenylsulfonyl)ethylcarbonate,Psec)、碳酸2-(三苯基磷鎓基)乙酯(2-(triphenylphosphonio)ethylcarbonate,Peoc)、碳酸异丁酯(isobutyl carbonate)、碳酸乙烯酯(vinyl carbonate)、碳酸烯丙酯(allyl carbonate)、碳酸叔丁酯(t-butyl carbonate,BOC)、碳酸对硝基苯酯(p-nitrophenyl carbonate)、碳酸苄酯(benzyl carbonate)、碳酸对甲氧基苄酯(p-methoxybenzyl carbonate)、碳酸3,4-二甲氧基苄酯(3,4-dimethoxybenzyl carbonate)、碳酸邻硝基苄酯(o-nitrobenzyl carbonate)、碳酸对硝基苄酯(p-nitrobenzylcarbonate)、硫代碳酸S-苄酯(S-benzyl thiocarbonate)、碳酸4-乙氧基-1-萘酯(4-ethoxy-1-napththyl carbonate)、二硫代碳酸甲酯(methyl dithiocarbonate)、2-碘代苯甲酸酯(2-iodobenzoate)、4-叠氮丁酸酯(4-azidobutyrate)、4-硝基-4-甲基戊酸酯(4-nitro-4-methylpentanoate)、邻(二溴甲基)苯甲酸酯(o-(dibromomethyl)benzoate)、2-甲酰基苯磺酸酯(2-formylbenzenesulfonate)、2-(甲硫基甲氧基)乙基碳酸酯(2-(methylthiomethoxy)ethyl)、4-(甲硫基甲氧基)丁酸酯(4-(methylthiomethoxy)butyrate)、2-(甲硫基甲氧基甲基)苯甲酸酯(2-(methylthiomethoxymethyl)benzoate)、2,6-二氯-4-甲基苯氧基乙酸酯(2,6-dichloro-4-methylphenoxyacetate)、2,6-二氯-4-(1,1,3,3-四甲基丁基)苯氧基乙酸酯(2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate)、2,4-双(1,1-二甲基丙基)苯氧基乙酸酯(2,4-bis(1,1-dimethylpropyl)phenoxyacetate)、氯二苯基乙酸酯(chlorodiphenylacetate)、异丁酸酯(isobutyrate)、单琥珀酸酯(monosuccinoate)、(E)-2-甲基-2-丁烯酸酯((E)-2-methyl-2-butenoate)、邻(甲氧基羰基)苯甲酸酯(o-(methoxyacyl)benzoate)、α-萘甲酸酯(α-naphthoate)、硝酸酯(nitrate)、N,N,N’,N’-四甲基二氨基磷酸烷基酯(alkyl N,N,N’,N’-tetramethylphosphorodiamidate)、N-苯基氨基甲酸酯(alkyl N-phenylcarbamate)、硼酸酯(borate)、次磺酸二甲基瞵酯(dimethylphosphinothioyl)、次磺酸2,4二硝基苯酯(alkyl 2,4-dinitrophenylsulfenate)、硫酸酯(sulfate)、甲磺酸酯(methanesulfonate,mesylate)、苄磺酸酯(benzylsulfonate)及甲苯磺酸酯(tosylate,Ts)。
其他定义
除非本说明书另有定义,否则此处所用的科学与技术词汇的含义与本发明所属技术领域中具有通常知识者所理解与惯用的意义相同。此外,在不和上下文冲突的情形下,本说明书所用的单数名词“一”(a或an)及“该”(the)均涵盖该名词的复数型;而所用的复数名词时亦涵盖该名词的单数型。同时,在此处“一”(a或an)、“至少一”(at least one)及“一或多”(one or more)为可互换的词汇。“包含”(comprising或including)及“具有”(having)亦为可互换的词汇。
除非本说明书另有定义,否则本发明是利用本领域技术人员所熟知的分子生物学、微生物学、重组DNA及免疫学等传统生物技术来进行相关实验。该多个技术可参见于先前文献。举例来说,Molecular Cloning A Laboratory Manual,第2版by Sambrook,Fritsch and Maniatis(Cold Spring Harbor Laboratory Press,1989);DNA Cloning,Volumes I and II(D.N.Glover ed.,1985);Culture Of Animal Cells(R.I.Freshney,Alan R.Liss,Inc.,1987);Immobilized Cells And Enzymes(IRL Press,1986);B.Perbal,A Practical Guide To Molecular Cloning(1984);the treatise,Methods InEnzymology(Academic Press,Inc.,N.Y.);Gene Transfer Vectors For MammalianCells(J.H.Miller and M.P.Calos eds.,1987,Cold Spring Harbor Laboratory);Methods In Enzymology,Vols.154and 155(Wu et al.eds.),Immunochemical MethodsIn Cell And Molecular Biology(Mayer and Walker,eds.,Academic Press,London,1987);Antibodies:A Laboratory Manual,by Harlow and Lane s(Cold Spring HarborLaboratory Press,1988);及Handbook Of Experimental Immunology,Volumes I-IV(D.M.Weir and C.C.Blackwell,eds.,1986)。
在本说明书中,“聚糖”(glycan)一词是指一种多糖(polysaccharide)或寡糖(oligosaccharide)。聚糖在本说明书中是指诸如糖蛋白(glycoprotein)、糖脂(glycolipid)、糖肽(glycopeptide)、糖蛋白质体(glycoproteome)、肽聚糖(peptidoglycan)、脂多糖(lipopolysaccharide)及蛋白糖(proteoglycan)等复合糖体(glycoconjugate)的糖部分。聚糖通常仅包含单糖间的O-糖苷键(O-glycosidiclinkage)。举例来说,纤维素是一种由β-1,4-连结的D-葡萄糖所组成的聚糖(或更具体来说,葡聚糖),而几丁质则是一种由β-1,4-连结的N-乙酰基-D-葡萄糖胺所组成的聚糖。聚糖可以是由单糖残基组合而成的同或异聚合物,且可以直链或支链形式存在。聚糖可与蛋白质连结,形成糖蛋白或蛋白糖。聚糖多表现于细胞的外表面。O-及N-连结的聚糖主要表现于真核生物中,原核生物则较少。在序列段(sequon)中,N-连结的聚糖会与天门冬胺酸(asparagine)的R-基团氮(N)连结。该序列段是一Asn-X-Ser或Asn-X-Thr序列,其中X可以是坚果糖(praline)以外的任何氨基酸。
“抗原”(antigen)一词在本说明书中是指任何可引发免疫反应的物质。
“免疫性”(immunogenicity)一词在本说明书中是指一免疫原、抗原或疫苗刺激产生免疫反应的能力。
“CD1d”一词在本说明书中是指一糖蛋白的CD1(分化群1,cluster ofdifferentiation 1)家族的一员,其中该糖蛋白会表现于不同人类抗原呈现细胞(antigen-presenting cell)的表面。呈现脂质的CD1d会活化自然杀手T细胞(naturalkiller T cell)。CD1d具有一深层的抗原结合沟槽,据以和糖脂抗原结合。表现于树突细胞(dendritic cell)的CD1d分子可结合并呈现糖脂神经酰胺(Galactosylceramide,GalCer)相似物,例如C34。
“抗原决定位置”(epitope)一词在本说明书是指一抗原分子的部分,可与抗体或T细胞受器的抗原结合位置接触。
“疫苗”(vaccine)一词在本说明书是指一包含抗原的制剂,该抗原包含致病微生物(死毒或减毒)或其部分成分,例如蛋白、多肽或多糖;该制剂可用以引发免疫反应以对抗由该微生物所造成的疾病。疫苗制剂可以是天然的、合成的或由重组DNA技术而得。
“抗原专一性”(antigen specific)一词在本说明书是指一细胞族群的特性,当投予特定的抗原或抗原片段时,可造成特定细胞增生。
在本说明书中,“专一结合”(specifically binding)一词是指结合对(bindingpairs)(例如抗体及抗原)之间的交互作用。在不同情况下,可利用亲合常数(affinityconstant)来表示专一结合的程度,其中该亲合常数约为每公升10-6摩尔、每公升10-7摩尔或每公升10-8摩尔。
“流式细胞仪”(flow cytometry或FACS)一词是指一种可用以检验悬浮于液体水柱的颗粒或细胞的物理及化学特性的技术,该技术主要是透过光学及电子检测设备来进行分析。
除非本说明书另有定义,否则此处所用的科学与技术词汇的含义与本发明所属技术领域中具有通常知识者惯用者相同。此处选用及描述多种实施方式与实施例来解释本发明的原理及应用性,借使本技术领域中熟习此技艺者可据以实现本发明,并基于所欲的特定用途来利用本发明的各种实施方式与各种适当的变形。为阐述及揭示特定化学材料、细胞株、载体、动物、仪器设备、统计分析及方法,在此将本揭示内容所引用的公开文献及专利纳入作为参照。引用且/或讨论该多个文献的目的仅在阐明本发明的实施方式,而非承认该文献为此处所述的本发明的现有技术。
本发明实施方式
本发明是关于意外发现以经修饰的Globo H衍生物抗原与载体蛋白-白喉类毒素交互反应物质(diphtheria toxoid cross-reactive material,CRM197)连结后,与作为佐剂的糖脂C34合并使用,可引发强烈的IgG免疫反应,因而可专一性地辨识Globo H(GH)、Gb5及SSEA4。在某些实施方式中,修饰Globo H是指在Globo H还原端葡萄糖的C-6位置包含有一氟、一叠氮基(azido)或一邻苯基(O-phenyl)。在某些实施方式中,修饰Globo H是指在其非还原端海藻糖的C-6位置包含有一叠氮基。由该多个疫苗所产生的抗体可辨识GH表现肿瘤细胞(MCF-7),并引发与补体相关的细胞毒杀反应来对抗肿瘤细胞。本发明提供癌症疫苗研发领域一种新颖的策略方法。
本揭示内容是关于Globo H衍生物,其中各衍生物的还原及/或非还原端皆经过修饰处理。相较于天然的Globo H,该多个Globo H衍生物可引发强烈的免疫反应(例如,引发对抗Globo H、Gb5及SSEA4的IgG抗体)。
化合物
本发明提供了数种具有经修饰的糖类抗原(Globo H)的新颖化合物、包含该多个新颖化合物的聚糖共轭物、免疫组合物及疫苗。
在一方式中,本发明是关于式(I)的化合物:
或其盐类,
其中,
X1是-OR或-SR,其中R是氢、或是氧或硫的保护基、可任选取代的C1-10烷基、可任选取代的芳香基、可任选取代的酰基或可任选取代的亚胺基;
R1及R2是分别选自由氢、卤素、可任选取代的烷基、可任选取代的烯基、可任选取代的炔基、可任选取代的杂环基、可任选取代的芳香基、-N3、-NO2、-N(RB)2、-N(RA)C(O)RA、-ORA、-OC(O)RA、-SRA、-C(O)N(RB)2、-CN、-C(O)RA、-C(O)ORA、-S(O)RA、-SO2RA、-SO2N(RB)2及-NHSO2RB所组成群组;
RA是选自由氢、可任选取代的烷基、可任选取代的烯基、可任选取代的炔基、可任选取代的杂环基、可任选取代的芳香基所组成的群组;
RB是选自由氢、可任选取代的烷基、可任选取代的烯基、可任选取代的炔基、可任选取代的杂环基、可任选取代的芳香基所组成的群组;以及
若R1是-OH,则R2不是-CH3;若R2是-CH3,则R1不是-OH。
在本发明一实施方式中,X1具有α构型。在本发明另一实施方式中,X1具有β构型。
在本发明另一实施方式中,X1是选自由-ORA、-OH及-O(保护基团)所组成的群组。在本发明另一实施方式中,X1是-ORA,其中RA可以是无取代的C1-10烷基、无取代的芳香基、无取代的酰基或无取代的亚胺基,或是其中RA可以是有取代的C1-10烷基、有取代的芳香基、有取代的酰基或有取代的亚胺基。
在本发明另一实施方式中,X1是-SRA。在本发明另一实施方式中,X1是选自由-SH及-S(保护基团),以及-SCH3所组成的群组。在本发明另一实施方式中,X1是-SRA,其中RA可以是无取代的C1-10烷基、无取代的芳香基、无取代的酰基或无取代的亚胺基,或是其中RA可以是有取代的C1-10烷基、有取代的芳香基、有取代的酰基或有取代的亚胺基。
在本发明另一实施方式中,X1是C1-10烷氧基、C1-3烷氧基或甲氧基。在本发明另一实施方式中,X1是α-甲氧基。
在本发明另一实施方式中,X1是选自由α-甲硫基(alpha-thiomethyl)、β-甲硫基(beta-thiomethyl)、α-硫代甲苯基(alpha-thiocresyl)、β-硫代甲苯基(beta-thiocresyl)、α-叔-丁二苯硅氧基(alpha-t-butyldiphenylsilyloxy)、β-叔-丁二苯硅氧基(beta-t-butyldiphenylsilyloxy)及α-甲氧基(alpha-methoxy)所组成的群组。
在本发明另一实施方式中,R1是-N3或-N(RW)2,其中各RW分别为氢或氮保护基。举例来说,R1可以是-NH2。
在本发明另一实施方式中,R1是-NHRW或-N(RW)2,其中RW是氮保护基。在某些实施方式中,R1是选自由-N3、-NH(Cbz)、-NH(Boc)、-NH(Fmoc)、-NHC(O)CCl3、-NHC(O)CH3及-N(C(O)CH3)2所组成的群组。
在本发明另一实施方式中,R2是-N3或-N(RW)2,其中各RW分别为氢或氮保护基。在本发明另一实施方式中,R2是-NH2、-NHRW或-N(RW)2,其中RW是氮保护基。在本发明另一实施方式中,R2是选自由-N3、-NH(Cbz)、-NH(Boc)、-NH(Fmoc)、-NHC(O)CCl3、-NHC(O)CH3及-N(C(O)CH3)2所组成的群组。
在本发明另一实施方式中,R1及R2是相同的化学基团。
在本发明另一实施方式中,R1是-OH。在本发明另一实施方式中,R1是-OH且R2是-CH2F、-CH2N3、CH2NO2、-CH2OH或-C≡CH。
在本发明另一实施方式中,R1是-F且R2是-CH3,或是R1是-N3且R2是-CH3,或是R1是-NO2且R2是-CH3。
例示性的式(I)化合物包含,但不限于,
可利用本领域技术人员所熟知的方法或本揭示内容所述方法来合成Globo H衍生物。或参酌美国专利US20140051127所述方法。
免疫组合物
在另一方式中,本发明是关于一种免疫组合物,其是包含(a)一聚糖共轭物,包含至少一种与连结子结合的聚糖以及一载体,其中该至少一种聚糖是借由连结子与载体形成共轭;以及(b)一非必要性的佐剂,其中该至少一种与连结子结合的聚糖具有式(II)的化学结构:
其中R1及R2的定义分别如上所述。
在本发明一实施方式中,连结子是一异-或同-双功能链接子。
在本发明另一实施方式中,连结子包含至少一硫原子、羧酸酯基、酰胺基、氨基甲酸酯基、碳酸基、硫代氨基甲酸酯基、硫碳酸基、硫醚、丁二酰胺、正-羟基丁二酰胺或其的任何组合。
在本发明另一实施方式中,连结子是-L1-L2-,其中L1是一键结、-O-、-S-、-NRL1a-、-C(=O)-、-NRL1aC(=O)-、-NRL1aC(=O)O-、-C(=O)NRL1a-、-OC(=O)NRL1a-、-SC(=O)-、-C(=O)S-、-OC(=O)-、-C(=O)O-、-NRL1aC(=S)-、-C(=S)NRL1a-、反式-CRL1b=CRL1b-、顺式-CRL1b=CRL1b-、-C≡C-、-OC(RL1b)2-、-C(RL1b)2O-、-NRL1aC(RL1b)2-、-C(RL1b)2NRL1a-、-SC(RL1b)2-、-C(RL1b)2S-、-S(=O)2O-、-OS(=O)2-、-S(=O)2NRL1a-、-NRL1aS(=O)2-或可任选取代的C1-20烃链;可任选地,该烃链中一或多个碳原子可由–O–、–S–、–NRL1a-、–C(=O)–、NRL1aC(=O)–、–NRL1aC(=O)O–、–C(=O)NRL1a-、–OC(=O)NRL1a-、–SC(=O)–、–C(=O)S–、–OC(=O)–、–C(=O)O–、–NRL1aC(=S)–、–C(=S)NRL1a-、反式–CRL1b=CRL1b–、顺式–CRL1b=CRL1b–、–C≡C–、–S(=O)2O–、–OS(=O)2–、–S(=O)2NRL1a-或–NRL1aS(=O)2–取代,其中RL1a是氢、可任选取代的C1-6烷基或一氮保护基,或是RL1a亦可与邻近的碳原子连结以形成一可任选取代的杂环;且其中各RL1b是分别选自于由氢、卤素、可任选取代的C1-10烷基、可任选取代的烯基、可任选取代的炔基、可任选取代的碳环、可任选取代的杂环基、可任选取代的芳香基、可任选取代的杂芳基所组成的群组;或是RL1b可与邻近的碳、氮或氧原子连结以形成一可任选取代的碳环或杂环;或是二RL1b化学基团可链接以形成一可任选取代的碳环或可任选取代的杂环;且L2是源自于能与载体及L1交联的交联剂的官能团。
载体可以是蛋白、脂质、脂质化蛋白、病毒、多肽或糖肽的树枝状聚合物。在某些实施例中,载体是一包含T细胞抗原决定位置的多肽。例示性的载体蛋白包含,但不限于,破伤风类毒素(tetanus toxoid,TT)、白喉类毒素(diphtheria toxoid,DT)、白喉类毒素交互反应物质197(CRM197)、破伤风类毒素的片段C(fragment C of TT)、键孔血蓝蛋白(Keyholelimpet hemocyanin,KLH)、胎牛血清白蛋白(bovine serum albumin,BSA)、蛋白D(proteinD)、外膜蛋白(outer-membrane protein,OMP)、肺炎球菌溶血素(pneumolysin)及其余白喉类毒素交互反应物质或白喉类毒素的突变蛋白,例如CRM176、CRM228、CRM 45(Uchida etal J.Biol.Chem.218;3838-3844,1973)、CRM 9、CRM 45、CRM102、CRM 103及CRM107等本领域技术人员所熟知的突变形式。
在本发明另一实施方式中,聚糖共轭物具有式(IV-a)或(IV-b)的化学结构:
其中m是一介于1到40的正整数。
在本发明另一实施方式中,m是一介于1到38的正整数,或一介于1到20的正整数。在本发明另一实施方式中,m是1、2、4、6、8、10、15、20、30或38。
在另一方式中,本发明是关于一种聚糖共轭物的混合物,其是包含至少二种上述的聚糖共轭物。
在本发明另一实施方式中,Globo H衍生物可以借由连结子与载体形成共轭,据以产生一聚糖共轭物。各共轭物可以包含相同或不同的Globo H衍生物的一或多个分子(例如1-40、1-20、1-25、1-30、5-20、5-25、5-30或5-35)。可利用本揭示内容所述方法或本领域技术人员所熟知的方法来制备聚糖共轭物。或可参见美国专利编号8,268,969所述方法。
本揭示内容的免疫组合物可包含一免疫有效量的本发明聚糖共轭物。
可利用本揭示内容所述方法或本领域技术人员所熟知的方法来合成本发明化合物。或可参见美国专利US20140051127。
本发明免疫组合物可包含一或多种佐剂。适用的佐剂乃为本领域技术人员所熟知(例如C34、7DW8-5、C17、C23、铝盐、鲨烯、MF59或QS-21)。
在本说明书中,“铝佐剂”(alum adjuvant)一词是指具有免疫佐剂活性的铝盐。该试剂在溶液中可吸附并沉淀蛋白抗原;所产生的沉淀物能减缓疫苗中抗原的释放速度,进而改善疫苗的免疫性。
在本说明书中,“免疫佐剂”(immunologic adjuvant)一词是指一种与免疫原连结的物质,可增加或修饰免疫原所产生的免疫反应。本揭示内容的α-糖脂神经酰胺相似物即是作为一种免疫佐剂,将疫苗投予至病患体内后,可刺激病患的免疫系统产生相关免疫反应,据以修饰或增加疫苗的效用。在一例示性的实施方式中,相似物C34是作为佐剂。C34及其余α-糖脂神经酰胺相似物的结构及其应用可参见美国专利编号7,928,077。
“糖脂”(glycolipid)一词在本说明书是指一种与糖接合的脂质,可作为细胞辨识的标记。
糖脂C34、C23及7DW8-5具有下列化学结构:
免疫组合物更可包含一药学上可接受的赋形剂。上述免疫组合物可包含一药学有效量的本发明聚糖共轭物。
在另一方式中,本发明是关于一癌症疫苗,其是包含一上述的免疫组合物及一药学上可接受的赋形剂。
本发明癌症疫苗可包含单一剂量或多剂量的本发明聚糖共轭物、该聚糖共轭物的混合物或其免疫组合物。癌症疫苗可用以治疗或降低个体罹患癌症的风险。癌症疫苗可包含用以阐述使用方法及告知个体或医疗人员处方讯息的相关信息。该多个信息可由美国食品药物管理局(U.S.Food and Drug Administration,FDA)等监管机构取得。癌症疫苗亦可具选择性地包含用以投予化合物或组合物的器材,举例来说,用以非口服投予的注射器。
药学配方
本发明免疫组合物可以与剂型兼容且能产生治疗、保护及免疫功效的剂量投予至个体。投予量将取决于欲进行治疗的个体,包含,举例来说,个体免疫系统合成抗体的能力,以及在特定情况下,产生细胞相关免疫反应(cell-mediated immune response)的能力。实际的活性成分投予量将取决于医疗人员的判断。然而,本领域技术人员亦可决定适当的剂量范围。投予剂量及方法会随着实际情况不同而有所不同,然可包含一初次投予及后续的投予。疫苗的剂量亦会随着投予路径及宿主体积大小而改变
本发明免疫组合物亦可投予至动物体内,使其产生抗体,并利用该抗体来治疗及诊断肿瘤。于动物(例如小鼠、兔子、山羊、绵羊或马)体内制备单株及双株抗体及其片段的方法乃为本领域技术人员所熟知的技术。举例来说,可参见Harlow and Lane,(1988)Antibodies:A Laboratory Manual,Cold Spring Harbor Laboratory,New York。“抗体”(antibody)一词包含完整的免疫球分子(immunoglobulin)及其片段,例如Fab、F(ab')2、Fv、scFv(单链抗体,single chain antibody)及dAb(域抗体,domain antibody;Ward,et.al.(1989)Nature,341,544)。
本揭示内容的组合物可包含于一药学组合物中,其中该药学组合物更可包含本领域技术人员在阅读本揭示内容后可推得的其他活性成份、载体、赋形剂或辅助药剂。
药学组合物可较佳地包含至少一种药学上可接受的载体。在该种药学组合物中,本揭示内容的组合物将形成“活性化合物”(active compound),或作为“活性试剂”(activeagent)。一药学上可接受的载体包含与投予药物相容的溶剂、分散介质、涂膜、抗菌及抗真菌试剂、等渗及吸收延迟剂等。补充型活性化合物亦可包含于组合物中。一药学组合物可依其投予路径而配制为不同剂型。例示性的投予路径包含非口服投予(例如静脉注射、真皮注射、皮下注射)、口服投予(例如吸入)、穿皮投予(局部)、经粘膜投予及直肠投予。用以非口服、真皮或皮下投予的溶液或悬浮液可包含下列成份:一无菌的稀释液(例如注射用水、磷酸盐缓冲液、定性油、聚乙二醇、甘油、丙二醇或其他合成溶剂)、抗菌试剂(例如苯甲醇或亚硫酸氢钠)、抗氧化剂(例如抗坏血酸或亚硫酸氢钠)、螯合剂(例如乙二胺四乙酸,ethylenediaminetetraacetic acid)、缓冲液(例如乙酸盐、柠檬酸盐或磷酸盐)及用以调整张力的试剂(例如氯化钠或葡萄糖)。可利用酸或碱(例如盐酸或氢氧化钠)来调整pH值。非口服剂型可配制于安瓶、抛弃式注射器或玻璃或塑料制成的多剂量瓶。
临床应用
本发明是关于聚糖共轭物、免疫组合物或可用以治疗一个体的癌症(例如肺癌、大肠癌、胰脏癌、胆道癌或子宫内膜癌)、良性瘤或血管新生等增生性疾病的疫苗。
亦可将本发明免疫组合物或疫苗投予至人类或动物体内以制备抗体,据以治疗及诊断癌症。或是利用本发明免疫组合物或疫苗来制备可结合至Gloo H、SSEA-3及/或SSEA-4的抗体。于动物(例如小鼠、兔子、山羊、绵羊或马)体内制备单株及双株抗体及其片段的方法乃为本领域技术人员所熟知的技术。举例来说,可参见Harlow and Lane,(1988)Antibodies:A Laboratory Manual,Cold Spring Harbor Laboratory,New York。“抗体”(antibody)一词包含完整的免疫球分子(immunoglobulin)及其片段,例如Fab、F(ab')2、Fv、scFv(单链抗体,single chain antibody)及dAb(域抗体,domain antibody;Ward,et.al.(1989)Nature,341,544)。
本发明聚糖共轭物、免疫组合物或疫苗可用以治疗或诊断癌症,该多个癌症包含,但不限于听神经瘤(acoustic neuroma)、腺癌(adenocarcinoma)、肾上腺癌(adrenalgland cancer)、肛门癌(anal cancer)、淋巴管内瘤(lymphangiosarcoma)、淋巴管内皮肉瘤(lymphangioendotheliosarcoma)、血管肉瘤(angiosarcoma或hemangiosarcoma)、阑尾癌(appendix cancer)、良性单株球蛋白症(benign monoclonal gammopathy)、胆道癌(biliary cancer)、胆管癌(cholangiocarcinoma)、膀胱癌(bladder cancer)、乳癌(breast cancer或mammary cancer)、乳腺癌(adenocarcinoma of the breast)、乳突癌(papillary carcinoma of the breast)、乳髓质癌(medullary carcinoma of thebreast)、脑癌(brain cancer)、脑膜瘤(meningioma)、神经胶质瘤(glioma)、星状细胞瘤(astrocytoma)、寡树突神经胶细胞瘤(oligodendroglioma)、神经管胚细胞瘤(medulloblastoma)、支气管癌(bronchus cancer)、类癌瘤(carcinoid tumor)、子宫颈癌(cervical cancer)、子宫颈腺癌(cervical adenocarcinoma)、绒毛膜癌(choriocarcinoma)、脊索瘤(chordoma)、颅咽管瘤(craniopharyngioma)、大肠直肠癌(colorectal cancer)、大肠癌(colon cancer)、直肠癌(rectal cancer)、大肠直肠腺癌(colorectal adenocarcinoma)、上皮细胞癌(epithelial carcinoma)、室管膜瘤(ependymoma)、内皮肉瘤(endotheliosarcoma)、卡波西氏肉瘤(Kaposi's sarcoma)、多特发性出血性肉瘤(multiple idiopathic hemorrhagic sarcoma)、子宫内膜癌(endometrial cancer)、子宫癌(uterine cancer)、子宫肉瘤(uterine sarcoma)、食道癌(esophageal cancer)、食道腺癌(adenocarcinoma of the esophagus)、巴雷特腺癌(Barrett’s adenocarinoma)、尤恩氏肉瘤(Ewing sarcoma)、眼癌(eye cancer)、眼内黑色素瘤(intraocular melanoma)、视网膜母细胞瘤(retinoblastoma)、熟悉嗜伊红性白血球增高(familiar hypereosinophilia)、胆囊癌(gall bladder cancer)、胃癌(gastriccancer)、胃腺癌(stomach adenocarcinoma)、胃肠道间质瘤(gastrointestinal stromaltumor,GIST)、头颈部癌(head and neck cancer)、头颈部鳞状细胞癌(head and necksquamous cell carcinoma)、口腔癌(oral cancer)、口腔鳞状细胞癌(oral squamouscell carcinoma,OSCC)、咽喉癌(throat cancer)、喉癌(laryngeal cancer)、咽癌(pharyngeal cancer)、鼻咽癌(nasopharyngeal cancer)、口咽癌(oropharyngealcancer)、血癌(hematopoietic cancer)、白血病(leukemia)、急性淋巴性白血病(acutelymphocytic leukemia,ALL)、急性骨髓性白血病(acute myelocytic leukemia,AML)、慢性骨髓性白血病(chronic myelocyticleukemia,CML)、慢性淋巴性白血病(chroniclymphocytic leukemia,CLL)、淋巴瘤(lymphoma)、霍奇金淋巴瘤(Hodgkin lymphoma,HL)、非霍奇金淋巴瘤(non-Hodgkin lymphoma,NHL)、滤泡性淋巴瘤(follicular lymphoma)、慢性淋巴性白血病/小淋巴性淋巴瘤(chronic lymphocytic leukemia/small lymphocyticlymphoma,CLL/SLL)、套细胞淋巴瘤(mantle cell lymphoma,MCL)、边缘区B细胞淋巴瘤(marginal zone B-cell lymphoma)、粘膜相关淋巴组织淋巴瘤(mucosa-associatedlymphoid tissue(MALT)lymphoma)、结边缘区B细胞淋巴瘤(nodal marginal zone B-celllymphoma)、脾边缘区B细胞淋巴瘤(splenic marginal zone B-cell lymphoma)、原发性纵隔B细胞淋巴瘤(primary mediastinal B-cell lymphoma)、柏基特淋巴瘤(Burkittlymphoma)、淋巴浆细胞淋巴瘤(lymphoplasmacytic lymphoma)、华氏巨球蛋白血症(macroglobulinemia)、毛细胞白血病(hairy cell leukemia,HCL)、免疫母细胞性大细胞淋巴瘤(immunoblastic large cell lymphoma)、前趋B淋巴母细胞淋巴瘤及原发性中枢神经系统淋巴瘤(precursor B-lymphoblastic lymphoma and primarycentral nervous system(CNS)lymphoma)、T细胞NHL(T-cell NHL)、前趋T淋巴母细胞淋巴瘤/白血病(precursor T-lymphoblastic lymphoma/leukemia)、周边T细胞淋巴瘤(peripheral T-cell lymphoma,PTCL)、皮肤T细胞淋巴瘤(cutaneous T-cell lymphoma,CTCL)、蕈样肉芽肿(mycosis fungiodes)、塞扎里综合征(Sezary syndrome)、血管免疫母细胞T细胞淋巴瘤(angioimmunoblastic T-cell lymphoma)、结外天然杀手T细胞淋巴瘤(extranodal natural killer T-cell lymphoma)、肠病型T细胞淋巴瘤(enteropathytype T-cell lymphoma)、皮下脂膜炎样T细胞淋巴瘤(subcutaneous panniculitis-likeT-cell lymphoma)、间变性大细胞淋巴瘤(anaplastic large cell lymphoma)、上述白血病/淋巴瘤的混合性肿瘤、多发性骨髓瘤(multiple myeloma,MM)、重链病(heavy chaindisease)、α-链病(alpha chain disease)、γ-链病(gamma chain disease)、μ-链病(muchain disease)、血管母细胞瘤(hemangioblastoma)、炎性肌纤维母肿瘤(inflammatorymyofibroblastic tumors)、免疫细胞性淀粉样变性(immunocytic amyloidosis)、肾脏癌(kidney cancer)、肾母细胞瘤(nephroblastoma)、肾细胞癌(renal cell carcinoma)、肝癌(liver cancer或hepatocellular cancer)、恶性肝癌(malignant hepatoma)、肺癌(lung cancer)、支气管肺癌(bronchogenic carcinoma)、小细胞肺癌(small cell lungcancer,SCLC)、非小细胞肺癌(non-small cell lung cancer,NSCLC)、肺腺癌(adenocarcinoma of the lung)、平滑肌肉瘤(leiomyosarcoma,LMS)、肥大细胞增多症(mastocytosis)、系统性肥大细胞增多症(systemic mastocytosis)、骨髓增生异常综合症(myelodysplastic syndrome,MDS)、间皮瘤(mesothelioma)、骨髓增殖性疾病(myeloproliferative disorder,MPD)、真性红细胞增多症(polycythemia Vera,PV)、原发性血小板增多症(essential thrombocytosis,ET)、特发性骨髓性增生(agnogenicmyeloid metaplasia,AMM)、骨髓纤维化(myelofibrosis,MF)、慢性特发性骨髓纤维化(chronic idiopathic myelofibrosis)、慢性粒细胞白血病(chronic myelocyticleukemia,CML)、慢性中性粒细胞白血病(chronic neutrophilic leukemia,CNL)、增多综合症(hypereosinophilic syndrome,HES)、神经母细胞瘤(neuroblastoma)、神经纤维瘤(neurofibroma)、第1型或第2型神经纤维瘤病(neurofibromatosis(NF)type 1or type2)、许旺细胞瘤(schwannomatosis)、神经内分泌癌(neuroendocrine cancer)、胃肠胰神经内分泌肿瘤(gastroenteropancreatic neuroendoctrine tumor,GEP-NET)、类癌瘤(carcinoid tumor)、骨肉瘤(osteosarcoma)、卵巢癌(ovarian cancer)、囊腺癌(cystadenocarcinoma)、卵巢胚胎癌(ovarian embryonal carcinoma)、卵巢腺癌(ovarianadenocarcinoma)、乳突状腺癌(papillary adenocarcinoma)、胰脏癌(pancreaticcancer)、胰脏腺癌(pancreatic andenocarcinoma)、导管内乳头状粘液瘤(intraductalpapillary mucinous neoplasm,IPMN)、胰岛细胞瘤(islet cell tumor)、阴茎癌(penilecancer)、阴茎和阴囊的佩吉特氏病(Paget’s disease of the penis and scrotum)、松果体瘤(pinealoma)、原始神经外胚层肿瘤(primitive neuroectodermal tumor,PNT)、前列腺癌(prostate cancer或prostate adenocarcinoma)、直肠癌(rectal cancer)、横纹肌肉瘤(rhabdomyosarcoma)、唾液腺癌(salivary gland cancer)、皮肤癌(skin cancer)、鳞状细胞癌(squamous cell carcinoma,SCC)、角化棘皮瘤(keratoacanthoma,KA)、黑色素瘤(melanoma)、基底细胞癌(basal cell carcinoma,BCC)、小肠癌(small bowel cancer)、阑尾癌(appendix cancer)、软组织肉瘤(soft tissue sarcoma)、恶性纤维组织细胞瘤(malignant fibrous histiocytoma,MFH)、脂肪肉瘤(liposarcoma)、恶性神经鞘瘤(malignant peripheral nerve sheath tumor,MPNST)、软骨肉瘤(chondrosarcoma)、纤维肉瘤(fibrosarcoma)、粘液肉瘤(myxosarcoma)、皮脂腺癌(sebaceous gland carcinoma)、汗腺癌(sweat gland carcinoma)、滑液膜瘤(synovioma)、睾丸癌(testicular cancer)、精原细胞瘤(seminoma)、睾丸胚胎癌(testicular embryonal carcinoma)、甲状腺癌(thyroid cancer)、甲状腺乳突状癌(papillary carcinoma of the thyroid或papillarythyroid carcinoma,PTC)、甲状腺髓样癌(medullary thyroid cancer)、尿道癌(urethralcancer)、阴道癌和外阴癌(vaginal cancer and vulvar cancer)、外阴的佩吉特氏病(Paget’s disease of the vulva)。在某些实施方式中,本发明的聚糖共轭物、免疫组合物及疫苗可用以治疗脑癌、肺癌、乳癌、口腔癌、食道癌、胃癌、肝癌、胆管癌、胰腺癌、直肠癌、肾脏癌、骨癌、皮肤癌、子宫颈癌、卵巢癌及前列腺癌。
如同上述,一有效量的本发明聚糖共轭物、免疫组合物或疫苗可经由适当的路径投予至有治疗需要的个体体内。该个体(例如人类)可以是一罹患癌症、疑似罹患癌症或易于罹患癌症的个体。该有效量可有效引发对共轭物或组合物中聚糖结构具有专一性的免疫反应,或足以产生可抑制肿瘤生长及/或减少肿瘤大小的免疫反应,或有效延缓标的癌症发病或减少癌症发展风险。确切的投予剂量将依个体不同而有所差异,举例来说,个体的种族、年龄及生理状况、副作用或疾病的严重程度、特定的化合物种类及投药方式等。特定剂量可一天投予3次、一天投予2次、一天投予1次、隔天投予、每三天投予1次、每周投予1次、每二周投予1次、每三周投予1次或每四周投予1次。可多次投予本发明聚糖共轭物、免疫组合物或疫苗(例如2次、3次、4次、5次、6次、7次、8次、9次、10次、11次、12次、13次、14次或更多次)。
对一体重为70公斤的成人而言,一有效量的本发明聚糖共轭物、免疫组合物或疫苗可包含每单位剂型的约0.0001毫克至约3000毫克、约0.0001毫克至约2000毫克、约0.0001毫克至约1000毫克、约0.001毫克至约1000毫克、约0.01毫克至约1000毫克、约0.1毫克至约1000毫克、约1毫克至约1000毫克、约1毫克至约100毫克、约10毫克至约1000毫克,或约100毫克至约1000毫克的组合物。
为产生特定的治疗功效,可以口服或非口服方法投予本发明聚糖共轭物、免疫组合物或疫苗,可每天投予或一天投予一或多次的约每公斤个体体重0.001到100毫克、约每公斤个体体重0.01到50毫克;较佳是约每公斤个体体重0.1到40毫克;较佳是约每公斤个体体重0.5到30毫克,约每公斤个体体重0.01到10毫克,约每公斤个体体重0.1到10毫克;更佳是约每公斤个体体重1到25毫克的剂量。
当可想见,本揭示内容是以成人为例,用以例示性地阐述投予本发明聚糖共轭物、免疫组合物或疫苗的剂量范围。医疗人员或本领域技术人员可自行换算投予至孩童或青少年的剂量范围,该剂量范围可以少于或等于投予至成人的剂量范围。
本发明的聚糖共轭物、免疫组合物或疫苗可与一或多种其他的治疗活性剂合并投予至个体体内。借由合并投予来改善本发明聚糖共轭物、免疫组合物或疫苗的生物可用率(bioavailability)、减少及/或改变其生理代谢、抑制其排出及/或改变其于个体体内的分布。当可想见,该种治疗可对相同疾病产生特定的治疗功效,及/或产生不同的治疗功效。
可在投予本发明聚糖共轭物、免疫组合物或疫苗之前或之后投予一或多种其他的治疗活性剂。一般来说,各试剂可以单剂投予及/或依照试剂的特性于特定时间点投予。合并治疗中其他的治疗活性剂可配制为单一组合物以同时投予,或是配制为不同组合物分次投予。合并治疗时需考虑本发明化合物与其他治疗活性剂的兼容性及/或能否产生特定的治疗功效。可预期地,合并治疗中其他治疗活性剂的利用性不会超过其个别使用时的利用性。在某些情况下,其利用性会低于其个别使用时的利用性。
本发明聚糖共轭物、免疫组合物或疫苗可与一或多种其他药剂合并使用;举例来说,该多个药剂可以是抗癌药剂,其是包含生物治疗抗癌药剂及化学治疗药剂。
生物治疗抗癌药剂包含,但不限于,干扰素(interferon,例如干扰素-α、干扰素-γ)、细胞素(cytokine,例如肿瘤坏死因子(tumor necrosis factor))、疫苗、造血生长激素(hematopoietic growth factor)、单株血清治疗(monoclonal serotherapy)、免疫刺激(immunostimulant)及或免疫调节剂(immunodulatory agent,例如IL-1、2、4、6或12)、免疫细胞生长激素(immune cell growth factor,例如GM-CSF)及抗体(例如贺癌平(Herceptin,trastuzumab)、T-DM1、癌思停(AVASTIN,bevacizumab)、爱必妥(ERBITUX,cetuximab)、维克替比(Vectibix,panitumumab)、利妥昔(Rituxan,rituximab)、百克沙(Bexxar,tositumomab))。
化学治疗药剂包含,但不限于,抗雌性素(anti-estrogen,例如他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)及甲地孕酮(megestrol))、黄体释素促效剂(LHRHagonist,例如戈舍瑞林(goscrclin)及醋酸亮丙瑞林(leuprolide))、抗雄性素(anti-androgen,例如氟他胺(flutamide)及比卡鲁胺(bicalutamide))、光动力治疗(photodynamic therapies,例如维替泊芬(vertoporfin,BPD-MA)、酞菁(phthalocyanine)、光敏剂Pc4(photosensitizer Pc4)及去甲氧基竹红菌素(demethoxy-hypocrellin A,2BA-2-DMHA))、氮芥(nitrogen mustard,例如环磷酰胺(cyclophosphamide)、异环磷酰胺(ifosfamide)、氯乙环磷酰胺(trofosfamide)、苯丁酸氮芥(chlorambucil)、雌莫司汀(estramustine)及美法仑(melphalan))、亚硝基尿素(nitrosoureas,例如卡莫司汀(carmustine,BCNU)及洛莫司汀(lomustine,CCNU))、烷基磺酸(alkylsulphonate,例如白消安(busulfan)及苏消安(treosulfan))、三氮烯(triazene,例如达卡巴嗪(dacarbazine)及替莫唑胺(temozolomide))、含铂化合物(platinumcontaining compound,例如顺铂(cisplatin)、卡铂(carboplatin)及奥沙利铂(oxaliplatin))、长春花生物碱(vinca alkaloid,例如长春新碱(vincristine)、长春花碱(vinblastine)、长春地辛(vindesine)及长春瑞滨(vinorelbine))、类紫杉醇(taxoid,例如紫杉醇(paclitaxel)或与纳米粒子白蛋白结合的紫杉醇(Abraxane)、与十二碳六烯酸结合的紫杉醇(DHA-paclitaxel,Taxoprexin)、与聚谷氨酸结合的紫杉醇(PG-paclitaxel,paclitaxel poliglumex,CT-2103,XYOTAX)、肿瘤活化前趋药物ANG1005(Angiopep-2boundto three molecules of paclitaxel)、紫杉醇-EC-1(paclitaxel bound to the erbB2-recognizing peptide EC-1)及与葡萄糖结合的紫杉醇(例如依托泊苷(etoposide)、磷酸依托泊苷(etoposide phosphate)、替尼泊苷(teniposide)、托泊替康(topotecan)、9-氨基喜树咸(9-aminocamptothecin)、康托替康(camptoirinotecan)、伊立替康(irinotecan)、甲磺酸(crisnatol)及丝裂霉素C(mytomycin C))等紫杉醇等效物)、抗代谢药物(anti-metabolite)、二氢叶酸还原酶抑制剂(DHFR inhibitor,例如氨甲喋呤(methotrexate)、二氯甲氨蝶呤(dichloromethotrexate)、三甲蝶呤(trimetrexate)及依达曲沙(edatrexate))、肌苷-5'-单磷酸去氢酶抑制剂(IMP dehydrogenase inhibitor,例如霉酚酸(mycophenolic acid)、噻唑呋林(tiazofurin)、利巴韦林(ribavirin)及EICAR))、核糖核苷酸还原酶抑制剂(ribonuclotide reductase inhibitor,例如羟基尿素(hydroxyurea)及去铁胺(deferoxamine))、尿嘧啶相似物(uracil analog,例如5-氟尿嘧啶(5-fluorouracil,5-FU)、氟尿苷(floxuridine)、脱氧氟尿苷(doxifluridine)、雷替曲塞(ratitrexed)、替加氟尿嘧啶(tegafur-uracil)及卡培他滨(capecitabine))、胞嘧啶相似物(cytosine analog,例如阿糖胞苷(cytarabine,ara C或cytosine arabinoside)及氟达拉滨(fludarabine))、嘌呤相似物(purine analog,例如巯基嘌呤(mercaptopurine)及硫鸟嘌呤(Thioguanine))、维生素D3相似物(Vitamin D3analog,例如EB 1089、CB 1093及KH 1060)、异戊二烯抑制剂(isoprenylation inhibitor,例如洛伐他汀(lovastatin))、多巴胺能神经毒素(dopaminergic neurotoxin,例如1-甲基-4-苯基吡啶离子(1-methyl-4-phenylpyridinium ion))、细胞周期抑制剂(例如星形孢菌素(staurosporine))、放线菌素(actinomycin,例如放线菌素D)、博莱霉素(bleomycin,例如博莱霉素A2、博莱霉素B2及培洛霉素(peplomycin))、蒽环类药物(anthracycline,例如柔红霉素(daunorubicin)、多柔比星(doxorubicin)、聚乙二醇化脂质体多柔比星(pegylated liposomal doxorubicin)、伊达比星(idarubicin)、表柔比星(epirubicin)、吡柔比星(pirarubicin)、佐柔比星(zorubicin)及米托蒽醌(mitoxantrone))、多重抗药性抑制剂(MDR inhibitor,例如维拉帕米(verapamil))、钙离子三磷酸腺苷酶抑制剂(Ca2+ATPase inhibitor,例如毒胡萝卜素(thapsigargin))、伊马替尼(imatinib)、沙利度胺(thalidomide)、来那度胺(lenalidomide)、酪胺酸激酶抑制剂(tyrosine kinase inhibitor,例如阿西替尼(axitinib,AG013736)、波舒(bosutinib,SKI-606)、尼布(cediranib,RECENTINTM,AZD2171)、达沙替尼(dasatinib,BMS-354825)、厄洛替尼(erlotinib,)、吉非替尼(gefitinib,)、伊马替尼(imatinib,CGP57148B,STI-571)、拉帕替尼(lapatinib, )、来他替尼(lestaurtinib,CEP-701)、那替尼(neratinib,HKI-272)、尼洛(nilotinib,)、马沙尼(semaxanib,semaxinib,SU5416)、舒尼替尼(sunitinib,SU11248)、托西尼布(toceranib,)、凡德他尼(vandetanib,ZD6474)、瓦他拉尼(vatalanib,PTK787,PTK/ZK)、曲妥珠单抗(trastuzumab,)、贝伐单抗(bevacizumab,)、利妥昔单抗(rituximab,)、西妥昔单抗(cetuximab,)、帕尼单抗(panitumumab,)、兰尼单抗(ranibizumab,)、尼洛(nilotinib,)、索拉非尼(sorafenib,)、依维莫司(everolimus,)、阿仑单抗(alemtuzumab,)、吉妥单抗(gemtuzumab ozogamicin,)、西罗莫司(temsirolimus,)、ENMD-2076、PCI-32765、AC220、多韦替尼乳酸盐(dovitinib lactate,TKI258,CHIR-258)、BIBW 2992(TOVOKTM)、SGX523、PF-04217903、PF-02341066、PF-299804、BMS-777607、ABT-869、MP470、BIBF1120AP24534、JNJ-26483327、MGCD265、DCC-2036、BMS-690154、CEP-11981、替洛尼(tivozanib,AV-951)、OSI-930、MM-121、XL-184、XL-647、及/或XL228)、蛋白酶抑制剂(proteasome inhibitor,例如硼替佐米(bortezomib,Velcade))、哺乳类斥消灵标的蛋白抑制剂(mTOR inhibitor,例如雷帕霉素(rapamycin)、西罗莫司(temsirolimus,CCI-779)、依维莫司(everolimus,RAD-001)、雷帕霉素衍生物(ridaforolimus,AP23573,Ariad)、AZD8055(AstraZeneca)、BEZ235(Novartis)、BGT226(Norvartis)、XL765(Sanofi Aventis)、PF-4691502(Pfizer)、GDC0980(Genetech)、SF1126(Semafoe)及OSI-027(OSI))、奥利默森(oblimersen)、吉西他滨(gemcitabine)、洋红霉素(carminomycin)、亚叶酸钙(leucovorin)、培美曲塞(pemetrexed)、环磷酰胺(cyclophosphamide)、达卡巴嗪(dacarbazine)、甲基芐肼(procarbizine或procarbazine)、泼尼松龙(prednisolone)、地塞米松(dexamethasone)、喜树碱(campathecin)、普卡霉素(plicamycin)、天门冬酰胺酶(asparaginase)、氨基蝶呤(aminopterin)、甲氨蝶呤(methopterin)、紫菜霉素(porfiromycin)、美法仑(melphalan)、异长春碱(leurosidine)、环氧长春碱(leurosine)、苯丁酸氮芥(chlorambucil)、曲贝替定(trabectedin)、海绵内酯(discodermolide)、洋红霉素(carminomycin)及六甲基三聚氰胺(hexamethylmelamine)。
以本发明聚糖共轭物、免疫组合物或疫苗治疗的个体是一哺乳动物,例如人类或牲畜(例如狗、猫、牛、猪、马、绵羊或山羊)。该个体亦可是一非人类的基因转殖动物,例如基因转殖小鼠或基因转殖猪。
实施例
下文提出多个实验例来说明本发明的某些方式,以利本发明所属技术领域中具有通常知识者实作本发明,且不应将该多个实验例视为对本发明范围的限制。据信本领域技术人员在阅读了此处提出的说明后,可在不需过度解读的情形下,完整利用并实践本发明。此处所引用的所有公开文献,其全文皆视为本说明书的一部分。
实施例1:合成GH-乳糖(GH-Lac)衍生物
流程图1阐述了合成GH-乳糖衍生物2-6的方法。酶:GalK:半乳糖激酶(galactokinase)、AtUSP:UDP-糖焦磷酸化酶(UDP-sugar pyrophosphorylase)、LgtC:α1,4-半乳糖苷基-转移酶(α1,4-galactosyl-transferase)、PK:丙酮酸激酶(pyruvatekinase)、PPA:无机焦磷酸酶(inorganic pyrophosphatase)、GlmU:N-乙酰葡萄糖胺-1-磷酸尿苷酰转移酶(N-acetyl glucosamine-1-phosphate uridyltransferase)、NahK:N-乙酰己糖胺酶(N-acetylhexosamine kinase)、LgtD:β1,3-N-乙酰半乳糖胺转移酶(β1,3-N-acetylgalactosaminyltransferase)、FKP:双功能的海藻糖酶/GDP-L-海藻糖焦磷酸化酶(bifunctional fucokinase/GDP-L-fucose pyrophosphorylase)、FutC:α-1,2-海藻糖转移酶(α-1,2-fucosyltransferase)。
依据已知方法由乳糖衍生物11-15合成GH-乳糖衍生物2-6(还原端衍生物)(流程图1)。15a以半乳糖、α1,4-半乳糖苷基-转移酶(LgtC)及UDP-Gal再生系统来合成Gb3-乳糖衍生物16-20,其中该UDP-Gal再生系统包含UDP-糖焦磷酸化酶(AtUSP)、半乳糖激酶(GalK)、丙酮酸激酶(PK)及无机焦磷酸酶(PPA)。已知LgtC可用以合成α-(1→4)-半乳糖化衍生物。31在本实验中,LgtC亦具有良好活性以制备乳糖衍生物(11-15)。Gb3-F 16、Gb3-苯基NO2 19及Gb3-NO2 20的产率分别为92、81及95%,而Gb3-N3 17及Gb3-苯基18的产率则分别为67及69%。
利用Gb3-乳糖衍生物16-20作为受子(acceptor),利用半乳糖胺、β1,3-N-乙酰半乳糖胺转移酶(LgtD)及UDP-GalNac再生系统来合成Gb4衍生物21-25,其中该UDP-GalNac再生系统包含N-乙酰己糖胺酶(NahK)、N-乙酰葡萄糖胺-1-磷酸尿苷酰转移酶(GlmU)、丙酮酸激酶(PK)及无机焦磷酸酶(PPA)。15a经过量表现并分析确认后,32利用LgtD来糖基化受子Gb3-F16、Gb3-N3 17及Gb3-苯基18,以得到产率分别为90、87及89%的Gb4-F 21、Gb4-N3 22及Gb4-苯基23。由Gb3-苯基NO2 19及Gb3-NO2 20得到产率分别为72及61%的Gb4-苯基NO224及Gb4-NO2 25。
以β1,3-N-乙酰半乳糖胺转移酶(LgtD)及UDP-gal再生系统由Gb4衍生物21-25及半乳糖得到Gb5-乳糖衍生物26-30。15aGb5-F 26、GB5-N3 27、Gb5-苯基28、Gb5-苯基NO2 29及Gb5NO2 30的产率约为55%到79%。
以α-1,2-海藻糖转移酶(FutC)、双功能的海藻糖酶/GDP-L-海藻糖焦磷酸化酶(FKP)、无机焦磷酸酶(PPA)、丙酮酸激酶(PK)及海藻糖由Gb5-乳糖衍生物26-30来合成GH-乳糖衍生物2-6。15a以受子Gb5-F 26及Gb5-苯基28来得到产率分别为75及93%的GH-F 2及GH-苯基4。利用受子Gb5-N3 27、Gb5-苯基NO2 29及Gb5-NO2 30来得到产率分别为49、65及66%的GH-N3 3、GH-苯基NO2 5及GH-NO2 6。
实施例2:合成GH-海藻糖(GH-Fuc)衍生物
流程图2阐述以化学酶合成GH-海藻糖衍生物的方法。反应条件:FKP、Fut C、PPA、PK、Mg2+、ATP、GTP。
如现有技术所述,结合海藻糖衍生物及受子Gb5寡糖,并以重组FKP、α-1,2-海藻糖转移酶(FutC)、PPA及PK来合成GH-海藻糖衍生物7-10(非还原端衍生物)(流程图2)。15a先以现有技术所述的化学方法合成起始材料-具有戊胺31的Gb5寡糖。29再以化学酶方法得到产率约为43%到83%的GH-海藻糖衍生物7-10。即使化合物36会与FKP进行反应以产生GDP-36,其仍旧非为一适当的FutC供体(donor),且仅能产生极微量的产物。此外,化合物37非为FKP的受体,且不会产生GDP-37中间产物。
利用核磁共振光谱(nuclear magnetic resonance(NMR)spectroscopy)及高解析质谱(high-resolution mass spectrometry,HRMS)来分析各经纯化的GH衍生物及其截断形式的化学结构。
实施例3:合成GH衍生物-DT共轭物
流程图3阐述合成以GH-乳糖及GH-海藻糖修饰的疫苗的方法。
为合成GH-乳糖及GH-海藻糖的DT-共轭物(1-DT至10-DT),将胺端的GH-乳糖衍生物2-6或GH-海藻糖衍生物7-10与同双功能的对硝基苯基(p-nitrophenyl)连结子反应,以高产率地提供相对应的半酯。以反相层析法纯化后,于磷酸盐缓冲液(pH 7.8)中结合半酯及DT,反应至隔日(流程图3)。以基质辅助雷射脱附游离飞行时间质谱法(MALDI-TOF MS)来分析结合至DT的GH衍生物的数量。表1阐述了MALDI-TOF分析平均糖结合的结果。a波峰m/z。
表1
实施例4:合成GH-乳糖及GH-海藻糖衍生物的前趋物
依据与有效糖核苷酸再生结合的酶方法,30,15a以糖甘转移酶(LgtC,LgtD,Futc)及辅因子再生系统(UDP-Gal,UDP-GalNAc,GDP-Fuc)来制备GH-乳糖及GH-海藻糖衍生物。以化学方法合成起始乳糖衍生物11-15及海藻糖衍生物32-37(流程图4-8)。
流程图4:合成乳糖结构单元(11)
以已知方法合成化合物S1。1于0℃的环境中,将咪唑(imidazole,208毫克,3.07mmol)加入包含S1(630毫克,1.02mmol)的DMF(30mL)溶液中,并加入291微升(1.13mmol)的叔丁基(氯)二苯基硅烷(tert-Butyl(chloro)diphenylsilane)。将反应混合物缓慢加热至室温。连续搅拌13个小时以浓缩反应溶液。将残基溶于0℃的砒啶(pyridine,20毫升),并加入乙酐(acetic anhydride,401微升,3.93mmol)。将反应混合物缓慢加热至室温。连续搅拌10小时后,于0℃缓慢加入甲醇(1毫升)以中止反应,于减压环境中移除挥发性物质。利用乙酸乙酯(80毫升)萃取残基,以饱和的NaHCO3溶液洗涤,再以Na2SO4干燥后,过滤并浓缩产物。以快速硅胶层析(flsash silica get chromatography,溶于己烷的0-40%EtOAc)进行纯化,以制得S2(667毫克,64%)。1H NMR(600MHz,CDCl3)δ7.78-7.71(m,4H)、7.46-7.25(m,11H)、5.43(s,1H)、5.23-5.15(m,2H)、4.95(m,1H)、4.87-4.81(m,2H)、4.42(d,J=8.0Hz,1H)、4.32-4.30(dd,J=1.4,12.5Hz,1H)、4.25(d,J=3.6Hz,1H)、4.14(t,J=9.6Hz,1H)、4.07(d,J=1.5,12.5Hz,1H)、3.96-3.90(m,2H)、3.85-3.81(m,1H)、3.44-3.40(m,1H)、3.31-3.30(m,2H)、3.08(m,2H)、2.08-2.00(m,9H)、1.77(s,3H)、1.60-1.58(m,2H)、1.48-1.45(m,2H)、1.41(s,9H)、1.35-1.33(m,2H)、1.05(s,9H)。13C NMR(150MHz,CDCl3)δ170.69、170.66、169.83、168.64、155.99、137.55、136.02、135.43、133.50、132.20、129.95、129.92、129.20、128.26、127.93、127.67、126.54、101.40、100.60、100.26、75.23、74.26、73.36、72.36、72.21、71.68、69.22、68.99、68.62、66.27、61.12、29.77、29.08、28.44、26.84、23.30、20.90、20.82、20.80、20.59、19.45。以HRMS(ESI-TOF,MNa+)计算得C53H71NO17SiNa+1044.4383,可得1044.4404。
于0℃的环境中,将AcOH(246微升,4.10mmol)加入包含S2(425毫克,0.41mmol)的THF溶液中。加入4.1毫升(4.10mmol)的溶于THF且浓度为1.0M的四丁基氟化铵(tetrabutylammonium fluoride)溶液。将反应混合物缓慢加热至室温。连续搅拌7小时后,于减压环境下浓缩反应溶液。利用乙酸乙酯(70毫升)萃取残基,以饱和的NaHCO3溶液洗涤,再以Na2SO4干燥后,过滤并浓缩产物。以快速管柱层析(column chromatography,溶于己烷的50-80%EtOAc)进行纯化,以制得S3(279毫升,87%)。1H NMR(600MHz,CDCl3)δ7.47-7.42(m,2H)、7.40-7.32(m,3H)、5.44(s,1H)、5.26-5.15(m,2H)、4.92-4.83(m,2H)、4.57(m,2H)、4.45(d,J=8.0Hz,1H)、4.31-4.23(m,2H)、4.01(dd,J=12.4,1.5Hz,1H)、3.90(m,2H)、3.83-3.74(m,2H)、3.48-3.44(m,2H)、3.37(d,J=9.7Hz,1H)、3.06(m,2H)、2.01(dd,J=6.4,2.8Hz,12H)、1.56-1.54(m,2H),1.48-1.30(m,13H)。13C NMR(150MHz、CDCl3)δ170.94、170.60、169.88、169.05、156.21、137.74、129.37、128.44、126.72、101.54、101.14、100.86、79.35、75.30、74.68、73.49、72.64、72.31、71.84、70.11、69.40、68.78、66.47、60.46、40.63、29.78、29.20、28.63、23.21、21.06、20.95。以HRMS(ESI-TOF,MNa+)计算得C37H53NO17Na+806.3206,可得806.3212。
于0℃的环境中,将130微升(1.2mmol)的2,6-二甲基吡啶(2,6-lutidine)加入包含S3(221毫克,0.28mmol)的干DCM(10毫升)溶液中。加入150微升(1.2mmol)的二乙胺基三氟化硫(Diethylaminosulfur trifluoride)。以超音波振荡8小时,再真空浓度产物。以快速硅胶管柱层析(溶于己烷的10-50%EtOAc)进行纯化,以得到S4(129毫克,59%)。1H NMR(600MHz,CDCl3)δ7.47-7.39(m,2H)、7.39-7.32(m,3H)、5.45(s,1H)、5.28-5.18(m,2H)、4.92-4.85(m,2H)、4.72-4.55(m,2H)、4.55-4.41(m,2H)、4.32-4.24(m,2H)、4.02(dd,J=12.4,1.4Hz,1H)、3.90-3.80(m,2H)、3.51-3.41(m,3H)、3.07(dd,J=12.9,6.4Hz,2H)、2.01(dd,J=5.9,4.3Hz,12H)、1.58-1.51(m,2H)、1.51-1.38(m,11H)、1.38-1.26(m,2H)。19F NMR(470MHz,CDCl3)δ-234.24(td,J=47.2,29.6Hz)。13C NMR(150MHz、CDCl3)δ170.97、170.43、169.85、169.06、156.16、137.62、129.41、128.45、126.68、101.49、100.99、100.92、81.51、80.36、79.28、74.67、74.64、74.03、73.90、73.39、72.72、72.21、71.71、69.99、69.32、68.68、66.59、40.63、29.86、29.18、28.62、23.32、21.08、20.94。以HRMS(ESI-TOF,MNa+)计算得C37H52FNO16Na+808.3162,可得808.3185。
将NaOMe(5毫克)加入包含S4(105毫克,0.13mmol)的甲醇(10毫升)溶液中。加入Amberlite IR-120中和反应溶液后,过滤并浓缩产物。以5毫升的溶于水的90%TFA处理残基。连续搅拌2小时后,以反相管柱层析法(RP-18)浓缩并纯化反应溶液,据此制得乳糖衍生物11(49毫克,89%)。
5-胺戊基β-D-吡喃半乳糖-(1→4)-6-脱氧-6-氟-β-D-葡萄糖呱喃糖苷(化合物11)
(5-aminopentylβ-D-galactopyranosyl-(1→4)-6-deoxy-6-fluoro-β-D-glucopyranoside(Compound 11))
1H NMR(600MHz,D2O)δ4.88-4.71(m,1H)、4.54(d,J=8.0Hz,1H)、4.46(d,J=7.8Hz,1H)、3.93-3.90(m,2H)、3.84-3.65(m,8H)、3.56(dd,J=10.0,7.8Hz,1H)、3.34(dd,J=9.3,8.1Hz,1H)、3.02(t,J=7.5Hz,2H)、1.75-1.65(m,4H)、1.51-1.43(m,2H).19F NMR(471MHz,D2O)δ-234.79(td,J=47.8,31.6Hz)。13C NMR(150MHz、D2O)δ105.60、104.84、84.54、83.43、79.71、79.67、78.00、76.88、75.96、75.84、75.42、75.14、73.56、72.90、71.19、63.71、41.98、30.82、29.05、24.73。以HRMS(ESI-TOF,MH+)计算得C17H32FNO10H+430.2083,可得430.2092。
流程图5:合成乳糖结构单元(12)
于0℃的环境中,将4-甲苯磺酰氯(4-toluenesulfonyl chloride,0.8克,4.23mmol)加入包含S1(1.9克,3.51mmol)的砒啶溶液(30毫升)中。将反应混合物缓慢加热至室温。连续搅拌8小时后,以快速管柱层析浓缩并纯化反应溶液(溶于DCM的2-8%甲醇),以制得S5(1.2克,45%);1H NMR(600MHz,CDCl3)δ7.78-7.76(d,J=8.0Hz,2H)、7.44-7.42(m,2H)、7.34(m,3H)、7.24-7.23(d,J=8.0Hz,2H)、5.49(s,1H)、4.61(m,1H)、4.52(d,J=10.3Hz,1H)、4.38(d,J=7.9Hz,1H)、4.28-4.17(m,2H)、4.15(d,J=3.5Hz,1H)、4.02-4.00(m,1H)、3.77-3.72(m,2H)、3.61-3.55(m,4H)、3.49-3.41(m,3H)、3.32(m,1H)、2.38(s,3H)、1.58-1.55(m,2H)、1.47-1.44(m,2H)、1.40(s,9H)、1.36-1.33(m,2H)。13C NMR(150MHz、CDCl3)δ156.26、137.72、132.87、130.03、129.45、128.52、128.24、126.63、102.79、102.46、101.49、79.29、77.76、75.35、74.77、73.44、72.77、72.61、70.33、70.11、69.47、69.05、67.14、40.61、29.85、29.25、28.64、23.38、21.82。利用HRMS(ESI-TOF,MNa+)计算得C36H51NO15SNa+792.2872,可得792.2798。
于110℃的环境中,将叠氮化钠(sodium azide,169毫克,2.60mmol)加入包含S5(204毫克,0.26mmol)的DMF溶液(5毫升)中。连续搅拌14小时后,以快速管柱层析浓缩并纯化反应溶液(溶于DCM的2-8%甲醇),以制得S6(148毫克,89%)。1H NMR(600MHz,CDCl3)δ7.44(m,2H)、7.33-7.31(m,3H)、5.46(s,1H)、4.29-4.24(m,2H)、4.20(d,J=12.5Hz,1H)、4.04(m Hz,1H)、3.97(d,J=12.2Hz,1H)、3.84(m,1H)、3.72-3.63(m,1H)、3.60-3.33(m,10H)、3.26(s,1H)、3.04(m,2H)、1.59-1.57(m,2H)、1.45-1.19(m,13H)。13C NMR(150MHz、CDCl3)δ137.57、129.45、128.47、126.48、103.37、102.58、101.42、79.91、79.34、75.46、74.62、74.53、73.47、72.58、70.47、69.96、69.12、67.05、51.17、40.43、29.73、29.24、28.56、23.33。以HRMS(ESI-TOF,MNa+)计算得C29H44N4O12Na+663.2848,可得663.2859。
以5毫升的溶于水的90%TFA处理S6(122毫克),并搅拌2小时,以反相管柱层析(RP-18)浓缩及纯化产物,以制得乳糖衍生物12(80毫克,93%)。
5-胺戊基β-D-吡喃半乳糖-(1→4)-6-叠氮基-6-脱氧-β-D-葡萄糖呱喃糖苷(化合物12)
(5-aminopentylβ-D-galactopyranosyl-(1→4)-6-azido-6-deoxy-β-D-glucopyranoside(Compound 12))
1H NMR(600MHz,D2O)δ4.54(d,J=8.1Hz,1H)、4.44(d,J=7.8Hz,1H)、3.98-3.91(m,2H)、3.85-3.60(m,10H)、3.55(dd,J=9.9,7.8Hz,1H)、3.38-3.32(m,1H)、3.06-2.99(m,2H)、1.76-1.65(m,4H)、1.52-1.43(m,2H)。13C NMR(150MHz、D2O)δ105.84、104.76、82.08、78.14、76.98、76.40、75.54、75.25、73.64、72.93、71.26、63.76、53.14、42.09、30.92、29.13、24.83。以HRMS(ESI-TOF,MH+)计算得C17H32N4O10H+453.2191,可得453.2201。
流程图6:合成乳糖结构单元(13)
于0℃的环境中,将25微升(0.27mmol)的酚及70毫克(0.27mmol)的三苯基磷(triphenylphosphine)加入包含S3(190毫克,0.24mmol)的干DCM溶液(10毫升)中。加入38微升(0.27mmol)的偶氮二甲酸二乙酯(Diethyl azodicarboxylate)。以超音波振荡4小时,再真空浓缩产物。以快速硅胶管柱层析(溶于己烷的10-50%)纯化残基,以制得S7(138毫克,67%)。1H NMR(600MHz,CDCl3)δ7.43-7.42(dd,J=7.7,1.7Hz,2H)、7.36-7.31(m,3H)、7.31-7.26(m,2H)、6.98-6.90(m,3H)、5.42(s,1H)、5.26-5.17(m,2H)、4.94(dd,J=9.7,8.0Hz,1H)、4.67(dd,J=10.3,3.7Hz,1H)、4.49-4.44(m,3H)、4.26-4.23(m,3H)、4.17(m,1H)、4.06-3.96(m,2H)、3.80(dt,J=9.7,6.3Hz,1H)、3.66(m,1H)、3.43(dt,J=9.6,6.6Hz,1H)、3.34(s,1H)、3.05(d,J=6.2Hz,2H)、2.01(s,3H)、2.00(s,3H)、1.97(s,3H)、1.88(s,3H)、1.59-1.48(m,2H)、1.48-1.38(m,11H)、1.36-1.19(m,2H)。13C NMR(150MHz、CDCl3)δ170.89、170.56、169.88、168.91、158.56、156.15、137.67、129.82、129.37、128.42、126.67、121.71、115.00、101.49、101.01、100.79、79.23、75.35、74.07、73.28、72.80、72.36、71.83、69.83、69.26、68.68、66.51、65.92、40.63、29.81、29.17、28.62、23.28、21.02、20.94、20.93、20.84。以HRMS(ESI-TOF,MNa+)计算得C43H57NO17Na+882.3519,可得882.3542。
将NaOMe(3毫克)加入包含S7(110毫克,0.12mmol)的甲醇溶液(5毫升)中,再搅拌6小时。以Amberlite IR-120中和反应溶液后,进行过滤及浓缩。以5毫升的溶于水的90%TFA处理残基。搅拌2小时后,以反相管柱层析(RP-18)浓缩及纯化反应溶液,以制得乳糖衍生物13(45毫克,78%)。
5-胺戊基β-D-吡喃半乳糖-(1→4)-6-O-苯基-β-D-葡萄糖呱喃糖苷(化合物13)
(5-aminopentylβ-D-galactopyranosyl-(1→4)-6-O-phenyl-β-D-glucopyranoside(Compound 13))
1H NMR(600MHz,D2O)δ7.42(dd,J=8.7,7.4Hz,2H)、7.12-7.07(m,3H)、4.55(d,J=8.0Hz,1H)、4.46(dd,J=11.1,1.6Hz,1H)、4.37(dd,J=11.1,4.0Hz,1H)、4.30(d,J=7.8Hz,1H)、3.96-3.87(m,3H)、3.84(d,J=3.4Hz,1H)、3.79-3.67(m,4H)、3.56(dd,J=4.0,8.3Hz,1H)、3.52(m,1H)、3.45-3.35(m,2H)、3.02(t,J=7.5Hz,2H)、1.73-1.63(m,4H)、1.50-1.41(m,2H)。13C NMR(150MHz、CDCl3)δ163.11、135.23、135.21、127.09、120.35、108.11、107.54、82.71、80.68、79.65、78.32、78.17、77.73、76.06、75.44、73.81、71.22、66.35、44.62、33.46、31.66、27.34。利用HRMS(ESI-TOF,MH+)计算得C23H37NO11H+504.2439,可得504.2450。
流程图7:合成乳糖结构单元(14)
于室温中,将42毫克(0.30mmol)的4-硝基苯酚(4-nitrophenol)及81毫克(0.30mmol)的三苯基磷加入包含S3(220毫克,0.28mmol)的干DCM溶液(10毫升)中。加入43微升(0.30mmol)的偶氮二甲酸二乙酯。以超音波振荡5小时,再真空浓缩产物。以快速硅胶管柱层析(溶于己烷的20-60%EtOAc)纯化残基,以制得S8(235毫克,92%)。1H NMR(600MHz,CDCl3)δ8.19(d,J=8.9Hz,2H)、7.41(d,J=6.2Hz,2H)、7.33(m,3H)、7.00(d,J=8.9Hz,2H)、5.43(s,1H)、5.23-5.19(m,2H)、4.90(t,J=8.8Hz,1H)、4.76(dd,J=10.3,2.7Hz,1H)、4.52(s,1H)、4.47(d,J=7.7Hz,2H)、4.36(d,J=10.4Hz,1H)、4.26-4.24(m,3H)、4.04-3.93(m,2H)、3.78-3.73(m,2H)、3.41(m,2H)、3.03(d,J=5.5Hz,2H)、2.05-1.94(m,9H)、1.87(s,3H)、1.56-1.35(m,13H)、1.29-1.91(m,2H)。13C NMR(150MHz、CDCl3)δ170.72、170.26、169.73、168.72、163.43、156.06、142.12、137.53、129.30、128.33、126.53、126.13、114.89、101.33、100.93、100.61、79.13、77.43、75.31、73.60、73.18、72.54、72.00、71.72、69.99、69.34、68.53、66.71、66.56、40.50、29.75、29.06、28.52、23.16、20.89、20.82、20.81、20.80。利用HRMS(ESI-TOF,MNa+)计算得C43H56N2O19Na+927.3369,可得927.3377。
将NaOMe(3毫克)加入包含S8(155毫克,0.17mmol)的甲醇溶液(5毫升)中,再搅拌6小时。以Amberlite IR-120中和反应溶液后,进行过滤及浓缩。以5毫升的溶于水的90%TFA处理残基。搅拌2小时后,以反相管柱层析(RP-18)浓缩及纯化反应溶液,以制得乳糖衍生物14(78毫克,83%)。
5-胺戊基β-D-吡喃半乳糖-(1→4)-6-O-对硝基苯基-β-D-葡萄糖呱喃糖苷(化合物14)
(5-aminopentylβ-D-galactopyranosyl-(1→4)-6-O-p-nitrophenyl-β-D-glucopyranoside(Compound 14))
1H NMR(600MHz,D2O)δ8.29(d,J=9.3Hz,2H)、7.20(d,J=9.3Hz,2H)、4.57-4.53(m,3H)、4.32(d,J=7.7Hz,1H)、3.97-3.84(m,4H)、3.84-3.66(m,4H)、3.60(dt,J=11.7,5.8Hz,1H)、3.53(dd,J=9.9,7.7Hz,1H)、3.47(dd,J=9.9,3.4Hz,1H)、3.41-3.35(m,1H)、2.97(t,J=7.5Hz,2H)、1.69-1.63(m,4H)、1.45-1.41(m,2H)。13C NMR(150MHz、D2O)δ163.56、141.49、126.22、115.08、103.07、102.25、77.72、75.43、74.34、72.85、72.78、72.45、70.74、70.16、68.47、66.40、61.03、39.34、28.17、26.48、22.07。以HRMS(ESI-TOF,MH+)计算得C23H36N2O13H+549.2290,可得549.2294。
流程图8:合成乳糖结构单元(15)
于110℃的环境中,将碘化钠(363毫克,2.40mmol)加入包含S3(188毫克,0.24mmol)的DMF溶液(5毫升)中。搅拌14小时后,以快速管柱层析浓缩并纯化反应溶液(溶于DCM的2-8%甲醇),以制得S9(146毫克,84%)。1H NMR(600MHz,MeOD)δ7.52-7.46(m,2H)、7.30-7.28(m,3H)、5.58(s,1H)、4.48-4.43(m,1H)、4.27(dd,J=7.8,4.0Hz,1H)、4.20-4.09(m,3H)、3.89-3.78(m,2H)、3.66-3.49(m,5H)、3.42-3.13(m,4H)、3.00(t,J=7.0Hz,2H)、1.69-1.55(m,2H)、1.49-1.28(m,13H)。13C NMR(150MHz、MeOD)δ157.17、138.13、128.51、127.64、126.08、103.78、102.62、100.81、83.24、78.43、75.91、74.32、73.84、73.45、72.09、70.48、69.57、68.78、66.92、46.63、39.93、29.27、29.05、27.44、22.94。以HRMS(ESI-TOF,MNa+)计算得C29H44INO12Na+748.1800,可得748.1758。
将亚硝酸钠(124毫克,1.80mmol)加入包含S9(133毫克,0.18mmol)的DMF溶液(5毫升)中,于室温反应2天。以快速管柱层析浓缩并纯化反应溶液(溶于DCM的2-8%甲醇),以制得S10(40毫克,35%)。1H NMR(600MHz,MeOD)δ7.45(dt,J=4.3,2.3Hz,2H)、7.27-7.25(m,3H)、5.55(s,1H)、5.12(dd,J=13.6,2.5Hz,1H)、4.59-4.44(m,6H)、4.36(d,J=7.5Hz,1H)、4.23(d,J=7.8Hz,1H)、4.14-4.07(m,4H)、3.67-3.49(m,5H)、3.48-3.39(m,2H)、3.18-3.14(m,1H)、2.93(t,J=7.0Hz,2H)、1.56-1.45(m,2H)、1.39-1.32(m,11H)、1.32-1.24(m,2H)。13C NMR(150MHz、MeOD)δ157.20、138.17、128.56、127.69、126.10、103.60、102.87、100.86、79.81、78.45、75.91、75.74、74.62、73.23、72.10、71.38、70.17、69.68、68.78、67.01、39.91、29.25、29.02、27.44、22.90。以HRMS(ESI-TOF,MNa+)计算得C29H44N2O14Na+667.2685,可得667.2726。
以5毫升的溶于水的90%TFA处理S10(40毫克,0.06mmol),并搅拌2小时,以反相管柱层析(RP-18)浓缩及纯化产物,以制得乳糖衍生物15(22毫克,78%)
5-胺戊基β-D-吡喃半乳糖-(1→4)-6-脱氧-6-硝基-β-D-葡萄糖呱喃糖苷(化合物15)
(5-aminopentylβ-D-galactopyranosyl-(1→4)-6-deoxy-6-nitro-β-D-glucopyranoside(Compound 15))
1H NMR(600MHz,D2O)δ4.56(d,J=8.1Hz,1H)、4.47(d,J=7.8Hz,1H)、4.34(d,J=9.5Hz,1H)、3.95(d,J=3.3Hz,1H)、3.86-3.65(m,8H)、3.57(dd,J=9.9,7.9Hz,1H)、3.35(t,J=8.6Hz,1H)、3.04-2.97(m,2H)、1.66(m,4H)、1.47-1.38(m,2H)。13C NMR(150MHz、D2O)δ105.84、104.88、82.22、78.46、78.25、76.89、75.36、75.24、73.91、73.53、73.37、71.21、63.71、42.06、30.93、29.09、24.76。以HRMS(ESI-TOF,MH+)计算得C17H32N2O12H+457.2028,可得457.2036。
利用已知方法合成化合物33、34、35、36及37。
合成Gb3-乳糖衍生物
在15毫升离心管中加入5.0毫升的包含乳糖衍生物(10-15毫克)、半乳糖(1.0等量)、PEP(4.4等量)、ATP二纳盐(0.1等量)、UTP二纳盐(0.1等量)、MgCl2(10mM)、α1,4-半乳糖苷基-转移酶(LgtC,3.0单位)、半乳糖激酶(GalK,2.0单位)、UDP-糖焦磷酸化酶(AtUSP,2.8单位)、丙酮酸激酶(PK,2.5单位)及无机焦磷酸酶(PPA,2.5单位)的Tris-HCl缓冲液(100mM,pH 7.0)以进行反应。将反应混合物置于室温,并以300rmp的转速作用至隔日。以5:3:2正丁醇/乙酸/水作为显影溶剂,并将培养盘以溶于乙醇的大茴香醛(anisaldehyde)进行染色,以TLC分析观测结果。将离心管置于热水浴槽(80℃)作用10分钟,离心(10000rpm,15分钟)后真空浓缩其上清液。以C-18胶层析纯化液态残基,再以浓度梯度冲提液(由100%水到溶于水的80%甲醇)来进行冲提。仅收集包含产物的分液,冷冻干燥后,以NMR光谱仪及HRMS来分析所得产物。
合成Gb4-乳糖衍生物
在15毫升离心管中加入3.0毫升的包含Gb3衍生物(8-12毫克)、N-乙酰半乳糖胺(N-acetylgalactosamine,GAlNAc,1.1等量)、PEP(4.4等量)、ATP二纳盐(0.1等量)、UTP二纳盐(0.1等量)、MgCl2(10mM)、β1,3-N-乙酰半乳糖胺转移酶(β1,3GalNAcT,LgtD,3.5单位)、N-乙酰己糖胺酶(NahK,5.0单位)、N-乙酰葡萄糖胺-1-磷酸尿苷酰转移酶(GlmU,3.0单位)、PK(2.5单位)及PPA(2.5单位)的Tris-HCl缓冲液(100mM,pH 7.0)以进行反应。将反应混合物置于室温,并以300rmp的转速作用至隔日。以5:3:2正丁醇/乙酸/水作为显影溶剂,并将培养盘以溶于乙醇的大茴香醛进行染色,以TLC分析观测结果。将离心管置于热水浴槽(80℃)作用10分钟,离心(10000rpm,15分钟)后真空浓缩其上清液。以C-18胶层析纯化液态残基,再以浓度梯度冲提液(由100%水到溶于水的80%甲醇)来进行冲提。仅收集包含产物的分液,冷冻干燥后,以NMR光谱仪及HRMS来分析所得产物。
合成Gb5-乳糖衍生物
在15毫升离心管中加入3.0毫升的包含Gb4衍生物(5-8毫克)、半乳糖(1.1等量)、PEP(4.4等量)、ATP二纳盐(0.1等量)、UTP二纳盐(0.1等量)、MgCl2(10mM)、β-1,3-N-乙酰半乳糖胺转移酶(β1,3GalT,LgtD,5.0单位)、GalK(2.5单位)、AtUSP(4.0单位)、PK(2.5单位)及PPA(2.5单位)的Tris-HCl缓冲液(100mM,pH 7.0)以进行反应。将反应混合物置于室温,并以300rmp的转速作用至隔日。以3:2:2正丁醇/乙酸/水作为显影溶剂,并将培养盘以溶于乙醇的大茴香醛进行染色,以TLC分析观测结果。将离心管置于热水浴槽(80℃)作用10分钟,离心(10000rpm,15分钟)后真空浓缩其上清液。以C-18胶层析纯化液态残基,再以浓度梯度冲提液(由100%水到溶于水的70%甲醇)来进行冲提。仅收集包含产物的分液,冷冻干燥后,以NMR光谱仪及HRMS来分析所得产物。
合成Globo H-乳糖衍生物或Globo H-海藻糖衍生物
在15毫升离心管中加入3.0毫升的包含Gb5衍生物(4-6毫克)、L-海藻糖或其衍生物(1.2等量)、PEP(4.4等量)、ATP二纳盐(0.1等量)、GTP二纳盐(0.1等量)、MgCl2(10mM)、α-1,2-海藻糖转移酶(FutC,3.0单位)、双功能的海藻糖酶/GDP-L-海藻糖焦磷酸化酶(FKP)、PK(2.5单位)及PPA(2.5单位)的Tris-HCl缓冲液(100mM,pH 7.0)以进行反应。将反应混合物置于室温,并以300rmp的转速作用至隔日。以3:2:2正丁醇/乙酸/水作为显影溶剂,并将培养盘以溶于乙醇的大茴香醛进行染色,以TLC分析观测结果。将离心管置于热水浴槽(80℃)作用10分钟,离心(10000rpm,15分钟)后真空浓缩其上清液。以C-18胶层析纯化液态残基,再以浓度梯度冲提液(由100%水到溶于水的80%甲醇)来进行冲提。仅收集包含产物的分液,冷冻干燥后,以NMR光谱仪及HRMS来分析所得产物。
5-胺戊基α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-脱氧-6-氟-β-D-葡萄糖呱喃糖苷(化合物16)
(5-aminopentylα-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-deoxy-6-fluoro-β-D-glucopyranoside(Compound 16))
1H NMR(600MHz,D2O)δ4.97(d,J=3.9Hz,1H)、4.94-4.70(m,1H)、4.53(d,J=8.0Hz,1H)、4.53(d,J=7.7Hz,1H)、4.37(t,J=6.5Hz,1H)、4.05(dd,J=7.9,3.2Hz,2H)、3.98-3.64(m,14H)、3.60(dd,J=10.3,7.8Hz,1H)、3.33(dd,J=9.3,8.1Hz,1H)、2.92(m,2H)、1.76-1.64(m,4H)、1.52-1.42(m,2H)。19F NMR(470MHz、CDCl3)δ-234.92(td、J=47.0、32.9Hz)。13C NMR(150MHz、D2O)δ103.29、102.15、100.31、81.94、80.82、77.40、77.36、75.40、74.29、73.35、73.23、72.87、72.15、70.87、70.81、70.25、69.13、68.92、68.53、60.49、60.38、39.37、28.17、26.55、22.07。以HRMS(ESI-TOF,MH+)计算得C23H42FNO15H+592.2611,可得592.2620。
5-胺戊基α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-叠氮基-6-脱氧-β-D-葡萄糖呱喃糖苷(化合物17)
(5-aminopentylα-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-azido-6-deoxy-β-D-glucopyranoside(Compound 17))
1H NMR(600MHz,D2O)δ4.97(d,J=3.9Hz,1H)、4.55(d,J=8.0Hz,1H)、4.49(d,J=7.8Hz,1H)、4.37(t,J=6.6Hz,1H)、4.06(dd,J=7.6,3.0Hz,2H)、4.00-3.56(m,16H)、3.34(t,J=8.6Hz,1H)、3.01-2.94(t,J=7.2Hz,2H)、1.72-1.66(m,4H)、1.49-1.43(m,2H)。13CNMR(150MHz、D2O)δ106.16、104.71、103.03、82.33、80.03、78.20、77.04、76.44、75.62、74.89、73.61、73.55、72.99、71.87、71.66、71.28、63.23、63.10、53.12、42.21、30.97、29.78、24.88。以HRMS(ESI-TOF,MH+)计算得C23H42N4O15H+615.2719,可得615.2734。
5-胺戊基α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-O-苯基-β-D-葡萄糖呱喃糖苷(化合物18)
(5-aminopentylα-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-O-phenyl-β-D-glucopyranoside(Compound 18))
1H NMR(600MHz,D2O)δ7.43(t,J=8.0Hz,2H)、7.11(m,3H)、4.94(d,J=3.9Hz,1H)、4.56(d,J=8.0Hz,1H)、4.48(d,J=10.3Hz,1H)、4.42(dd,J=10.9,3.5Hz,1H)、4.35(m,2H)、4.04(d,J=3.0Hz,1H)、3.97-3.81(m,8H)、3.79-3.65(m,4H)、3.65-3.48(m,3H)、3.37(t,J=8.3Hz,1H)、2.98(t,J=6.7Hz,2H)、1.68(s,4H)、1.47(dd,J=14.6,7.4Hz,2H)。13CNMR(150MHz、D2O)δ160.54、132.68、124.56、117.82、105.93、104.97、103.00、80.47、80.05、78.23、77.13、75.83、75.73、74.84、73.54、73.43、72.92、71.85、71.65、71.26、68.62、63.23、63.15、42.12、30.93、29.34、24.81。以HRMS(ESI-TOF,MH+)计算得C29H47NO16H+666.2968,可得666.2979。
5-胺戊基α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-O-对硝基苯基-β-D-葡萄糖呱喃糖苷(化合物19)
(5-aminopentylα-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-O-p-nitrophenyl-β-D-glucopyranoside(Compound 19))
1H NMR(600MHz,D2O)δ8.29(d,J=9.3Hz,2H)、7.20(d,J=9.3Hz,2H)、4.94(d,J=4.0Hz,1H)、4.59-4.50(m,3H)、4.37(d,J=7.7Hz,1H)、4.34(t,J=5.7Hz,1H)、4.04(d,J=2.8Hz,1H)、3.99(d,J=2.7Hz,1H)、3.97-3.84(m,4H)、3.84-3.66(m,4H)、3.73-3.66(m,5H)、3.60-3.53(m,2H)、3.39-3.36(m,1H)、,2.97(t,J=7.5Hz,2H)、1.68-1.63(m,4H)、1.46-1.41(m,2H)。13C NMR(150MHz、D2O)δ166.28、144.25、128.97、117.83、106.20、104.97、102.99、80.82、79.96、78.25、77.13、75.68、75.56、74.86、73.54、73.43、72.93、71.85、71.65、71.25、69.09、63.22、63.12、42.15、30.94、29.56、24.84。以HRMS(ESI-TOF,MH+)计算得C29H46N2O18H+711.2818,可得711.2800。
5-胺戊基α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-脱氧-6-硝基-β-D-葡萄糖呱喃糖苷(化合物20)
(5-aminopentylα-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-deoxy-6-nitro-β-D-glucopyranoside(Compound 20))
1H NMR(600MHz,D2O)δ4.96(d,J=3.9Hz,1H)、4.54(m,2H)、4.36(t,J=6.2Hz,1H)、4.31(d,J=9.2Hz,1H)、4.05-4.03(m,2H)、3.99-3.51(m,15H)、3.32(m,1H)、3.00(m,2H)、1.68-1.60(m,4H)、1.46-1.40(m,2H)。13C NMR(150MHz、D2O)δ102.70、101.73、100.04、79.37、76.98、75.20、73.91、72.59、71.80、70.45、70.40、70.34、69.95、68.86、68.61、68.32、65.87、60.19、60.13、52.12、39.71、29.10、28.16、22.00。利用HRMS(ESI-TOF,MH+)计算得C23H42N2O17H+619.2556,可得619.2559。
5-胺戊基2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-脱氧-6-氟-β-D-葡萄糖呱喃糖苷(化合物21)
(5-aminopentyl 2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-deoxy-6-fluoro-β-D-glucopyranoside(Compound 21))
1H NMR(600MHz,D2O)δ4.93(d,J=3.9Hz,1H)、4.92-4.74(m,2H)、4.75(d,J=10.5Hz,1H)、4.66(d,J=8.3Hz,1H)、4.55(d,J=8.0Hz,1H)、4.53(d,J=7.8Hz,1H)、4.41(t,J=6.5Hz,1H)、4.28(d,J=2.5Hz,1H)、4.07(d,J=3.1Hz,1H)、4.02-3.64(m,18H)、3.62(dd,J=10.2,7.8Hz,1H)、3.34(m,1H)、2.99(t,J=7.5Hz,2H)、2.07(s,3H)、1.75-1.64(m,4H)、1.55-1.43(m,2H)。19F NMR(471MHz、D2O)δ-234.84(td、J=47.0、32.9Hz).13C NMR(150MHz、D2O)δ177.91、106.06、105.95、104.89、103.15、84.69、83.57、81.42、80.22、80.18、79.97、78.16、77.68、77.05、76.10、75.98、75.65、74.85、73.59、73.52、73.03、71.67、70.50、70.35、63.74、63.11、63.07、55.35、42.19、30.95、29.68、24.99、24.85。以HRMS(ESI-TOF,MH+)计算得C31H55FN2O20H+795.3405,可得795.3429。
5-胺戊基2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-叠氮基-6-脱氧-β-D-葡萄糖呱喃糖苷(化合物22)
(5-aminopentyl 2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-azido-6-deoxy-β-D-glucopyranoside(Compound 22))
1H NMR(600MHz,D2O)δ4.94(d,J=3.9Hz,1H)、4.66(d,J=8.4Hz,1H)、4.56(d,J=8.0Hz,1H)、4.51(d,J=7.8Hz,1H)、4.40(t,J=6.6Hz,1H)、4.28(d,J=2.6Hz,1H)、4.07(d,J=3.1Hz,1H)、4.02-3.57(m,22H)、3.35(t,J=8.5Hz,1H)、2.99(t,J=7.5Hz,2H)、2.07(s,3H)、1.76-1.63(m,4H)、1.48(dt,J=15.5,7.7Hz,2H)。13C NMR(150MHz、D2O)δ177.91、106.19、105.95、104.72、103.13、82.41、81.43、79.90、78.23、77.68、77.07、76.44、75.66、74.85、73.59、73.53、73.00、72.99、71.67、70.50、70.34、63.74、63.11、63.05、55.36、53.13、42.17、30.97、29.57、24.99、24.88。以HRMS(ESI-TOF,MH+)计算得C31H55N5O20H+818.3513,可得818.3543。
5-胺戊基2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-O-苯基-β-D-葡萄糖呱喃糖苷(化合物23)
(5-aminopentyl 2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-O-phenyl-β-D-glucopyranoside(Compound 23))
1H NMR(600MHz,D2O)δ7.40(t,J=7.8Hz,2H)、7.08(m,3H)、4.89(d,J=3.8Hz,1H)、4.64(d,J=8.4Hz,1H)、4.54(d,J=7.9Hz,1H)、4.47-4.31(m,4H)、4.25(d,J=2.3Hz,1H)、4.00-3.84(m,9H)、3.84-3.67(m,9H)、3.67-3.45(m,3H)、3.43-3.34(m,1H)、2.98(m,2H)、2.05(s,3H)、1.66(m,4H)、1.44(m,2H)。13C NMR(150MHz、D2O)δ177.92、160.53、132.66、124.54、117.79、105.96、105.95、104.96、103.10、81.41、80.58、79.91、78.24、77.67、77.15、75.83、75.77、75.58、74.80、73.52、73.40、72.99、72.90、71.67、70.50、70.33、68.64、63.74、63.10、55.34、42.06、30.92、29.13、25.00、24.80。利用HRMS(ESI-TOF,MH+)计算得C37H60N2O21H+869.3761,可得869.3795。
5-胺戊基2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-O-对硝基苯基-β-D-葡萄糖呱喃糖苷(化合物24)
(5-aminopentyl 2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-O-p-nitrophenyl-β-D-glucopyranoside(Compound 24))
1H NMR(600MHz,D2O)δ8.29(d,J=9.1Hz,2H)、7.20(d,J=9.2Hz,2H)、4.90(d,J=3.8Hz,1H)、4.65(d,J=8.4Hz,1H)、4.56(m,3H)、4.41-4.33(m,2H)、4.25(d,J=2.6Hz,1H)、4.02-3.74(m,13H)、3.73-3.63(m,7H)、3.61-3.52(m,2H)、3.38(t,J=8.7Hz,1H)、2.87(t,J=7.3Hz,2H)、2.06(s,3H)、1.66-1.59(m,4H)、1.44-1.40(m,2H)。13C NMR(150MHz、D2O)δ177.90、166.28、144.25、128.97、117.83、106.20、105.93、104.97、103.10、81.39、80.92、79.85、78.27、77.68、77.16、75.72、75.57、74.83、73.52、73.42、73.00、72.89、71.66、70.50、70.32、69.11、63.74、63.10、55.36、42.08、30.94、29.20、24.99、24.82。利用HRMS(ESI-TOF,MH+)计算得C37H59N3O23H+914.3612,可得914.3609。
5-胺戊基2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-脱氧-6-硝基-β-D-葡萄糖呱喃糖苷(化合物25)
(5-aminopentyl 2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-deoxy-6-nitro-β-D-glucopyranoside(Compound 25))
1H NMR(600MHz,D2O)δ4.96-4.90(m,1H)、4.68-4.50(m,4H)、4.39(t,J=6.1Hz,1H)、4.32(d,J=9.4Hz,1H)、4.27(d,J=2.0Hz,1H)、4.05(dd,J=9.6,2.9Hz,1H)、4.01-3.64(m,19H)、3.64-3.53(m,1H)、3.38-3.29(m,1H)、3.07-2.91(m,2H)、2.05(s,3H)、1.70-1.60(m,4H)、1.47-1.40(m,2H)。13C NMR(150Hz、D2O)δ175.16、103.45、103.22、102.10、100.37、79.82、78.70、77.08、75.53、74.92、74.24、72.71、72.08、71.09、70.77、70.75、70.60、70.25、68.91、67.74、67.58、60.98、60.35、60.24、52.59、39.31、39.29、28.18、26.37、22.23、22.01。以HRMS(ESI-TOF,MH+)计算得C31H55N3O22H+822.3350,可得822.3357。
5-胺戊基β-D-吡喃半乳糖-(1→3)-2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-脱氧-6-氟-β-D-葡萄糖呱喃糖苷(化合物26)
(5-aminopentylβ-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-deoxy-6-fluoro-β-D-glucopyranoside(Compound 26))
1H NMR(600MHz,D2O)δ4.97-4.84(m,2H)、4.71(d,J=8.5Hz,1H)、4.54(d,J=8.0Hz,1H)、4.51(d,J=7.8Hz,1H)、4.46(d,J=7.8Hz,1H)、4.40(t,J=6.4Hz,1H)、4.26(d,J=2.7Hz,1H)、4.19(d,J=3.0Hz,1H)、4.11-4.03(m,2H)、3.95(m,6H)、3.91-3.50(m,18H)、3.33(t,J=8.7Hz,1H)、2.98(m,2H)、2.04(s,3H)、1.70-1.67(m,4H)、1.54-1.33(m,2H)。19FNMR(471MHz、D2O)δ-234.85(td、J=47.0、28.2Hz)。13C NMR(150MHz、D2O)δ175.11、104.79、103.31、102.89、102.13、100.38、81.92、80.80、79.55、78.63、77.45、77.41、77.19、75.40、74.98、74.59、74.29、73.34、73.22、72.89、72.43、72.08、72.03、70.82、70.57、70.28、70.25、68.90、68.55、67.97、67.58、62.45、60.98、60.94、60.34、60.31、51.48、39.43、28.19、26.91、22.25、22.09。HRMS(ESI-TOF,MH+)计算得C37H65FN2O25H+957.3933,可得957.3969。
5-胺戊基β-D-吡喃半乳糖-(1→3)-2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-叠氮基-6-脱氧-β-D-葡萄糖呱喃糖苷(化合物27)
5-aminopentyl(β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-azido-6-deoxy-β-D-glucopyranoside(Compound 27))
1H NMR(600MHz,D2O)δ4.94(d,J=3.7Hz,1H)、4.72(d,J=8.6Hz,1H)、4.56(d,J=8.0Hz,1H)、4.52(d,J=7.8Hz,1H)、4.48(d,J=7.8Hz,1H)、4.40(t,J=6.4Hz,1H)、4.28(d,J=2.0Hz,1H)、4.21(d,J=2.8Hz,1H)、4.16-4.04(m,2H)、4.04-3.89(m,7H)、3.89-3.51(m,19H)、3.35(t,J=8.5Hz,1H)、3.02(t,J=7.6Hz,2H)、2.05(s,3H)、1.79-1.68(m,4H)、1.49-1.47(m,2H)。13C NMR(150MHz、CDCl3)δ180.40、110.09、108.73、108.18、107.26、105.66、84.95、84.85、83.94、82.43、80.76、80.27、79.89、79.61、78.98、78.20、77.73、77.38、76.13、75.87、75.55、75.50、74.20、73.85、73.26、72.87、66.28、66.23、65.64、65.59、56.78、55.67、44.64、33.48、31.75、27.55、27.39。利用HRMS(ESI-TOF,MH+)计算得C37H65N5O25H+980.4041,可得980.4080。
5-胺戊基β-D-吡喃半乳糖-(1→3)-2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-O-苯基-β-D-葡萄糖呱喃糖苷(化合物28)
(5-aminopentylβ-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-O-phenyl-β-D-glucopyranoside(Compound 28))
1H NMR(600MHz,D2O)δ7.43(t,J=7.2Hz,2H)、7.11(d,J=8.2Hz,3H)、4.91(d,J=3.5Hz,1H)、4.71(t,J=8.3Hz,1H)、4.56(t,J=7.6Hz,1H)、4.48-4.36(m,5H)、4.26(s,1H)、4.20(a,1H)、4.09(t,J=10.1Hz,1H)、3.98-3.63(m,22H)、3.59-3.51(m,3H)、3.39(t,J=8.3Hz,1H)、2.91(m,2H)、2.05(s,3H)、1.67(m,4H)、1.45(m,2H)。13C NMR(150MHz、D2O)δ177.87、160.55、132.68、124.57、117.82、107.55、105.96、105.64、104.97、103.10、82.31、81.37、80.57、79.91、78.24、77.74、77.34、77.15、75.83、75.77、75.20、74.79、73.40、73.33、73.00、71.66、71.31、70.72、70.32、68.65、65.21、63.74、63.69、63.10、54.23、42.28、31.01、30.15、25.01、24.87。以HRMS(ESI-TOF,MH+)计算得C43H70N2O26+H:1031.4290,可得1031.4300。
5-胺戊基β-D-吡喃半乳糖-(1→3)-2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-O-对硝基苯基-β-D-葡萄糖呱喃糖苷(化合物29)
(5-aminopentylβ-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-O-p-nitrophenyl-β-D-glucopyranoside(Compound 29))
1H NMR(600MHz,D2O)δ8.30(d,J=9.3Hz,2H)、7.20(d,J=9.3Hz,2H)、4.91(d,J=3.6Hz,1H)、4.71(d,J=8.5Hz,1H)、4.57(d,J=5.8Hz,3H)、4.47(d,J=7.7Hz,1H)、4.41-4.33(m,2H)、4.26(s,1H)、4.20(d,J=2.6Hz,1H)、4.00(m,1H)、3.93-3.62(m,21H)、3.59-3.53(m,3H)、3.38(t,J=8.8Hz,2H)、2.88(t,J=7.3Hz,2H)、2.04(s,3H)、1.58(m,4H)、1.42-1.25(m,2H)。13C NMR(150MHz、D2O)δ175.10、163.52、141.49、126.21、115.07、104.80、103.47、102.87、102.22、100.34、79.55、78.60、78.15、77.07、75.52、74.98、74.59、74.39、72.97、72.81、72.44、72.06、70.65、70.57、70.24、70.20、68.90、68.55、67.97、67.56、66.35、60.98、60.94、60.33、51.49、39.41、28.21、26.92、22.26、22.10。利用HRMS(ESI-TOF,MH+)计算得C43H69N3O28H+1076.4140,可得1076.4135。
5-胺戊基β-D-吡喃半乳糖-(1→3)-2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-脱氧-6-硝基-β-D-葡萄糖呱喃糖苷(化合物30)
(5-aminopentylβ-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-deoxy-6-nitro-β-D-glucopyranoside(Compound 30))
1H NMR(600MHz,D2O)δ4.93(d,J=6.9Hz,1H)、4.70(t,J=9.1Hz,1H)、4.60-4.51(m,2H)、4.47(d,J=7.8Hz,1H)、4.43-4.28(m,2H)、4.27(d,J=2.4Hz,1H)、4.20(d,J=2.6Hz,1H)、4.17(d,J=2.5Hz,1H)、4.07-3.97(m,3H)、3.97-3.49(m,22H)、3.41-3.28(m,1H)、3.01(t,J=7.2Hz,2H)、2.04(s,3H)、1.86-1.55(m,4H)、1.63-1.25(m,3H)。13C NMR(150MHz、D2O)δ175.10、104.79、103.45、102.91、102.09、100.36、79.83、79.54、78.67、77.06、75.53、74.98、74.59、74.24、72.71、72.43、72.08、71.15、71.09、70.78、70.61、70.57、70.26、68.89、68.54、67.96、67.58、60.97、60.93、60.34、60.23、51.47、39.29、28.19、26.35、22.26、22.01。以HRMS(ESI-TOF,MH+)计算得C37H65N3O27H+984.3878,可得984.3864。
5-胺戊基α-L-吡喃海藻糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-脱氧-6-氟-β-D-葡萄糖呱喃糖苷(化合物2)
(5-aminopentylα-L-fucopyranosyl-(1→2)-β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-deoxy-6-fluoro-β-D-glucopyranoside(Compound 2))
1H NMR(600MHz,D2O)δ5.25(d,J=2.6Hz,1H)、4.92(d,J=3.7Hz,2H)、4.84-4.74(m,1H)、4.65(d,J=7.6Hz,1H)、4.56(d,J=7.6Hz,1H)、4.55(d,J=9.8Hz,1H)、4.52(d,J=7.7Hz,1H)、4.41(t,J=6.5Hz,1H)、4.28(m,2H)、4.07(d,J=3.1Hz,1H)、4.13-3.64(m,32H)、3.34(t,J=8.5Hz,1H)、2.99(t,J=7.5Hz,2H)、2.07(s,3H)、1.75-1.64(m,4H)、1.55-1.43(m,2H)。19F NMR(470MHz、CDCl3)δ-234.87(td、J=47.0、32.9Hz).13C NMR(150MHz、D2O)δ174.28、103.95、103.33、102.15、102.04、100.45、99.27、81.94、81.72、80.83、78.23、77.49、77.46、77.21、76.36、76.11、75.46、75.07、74.63、74.31、73.58、73.36、73.24、72.91、72.10、71.85、70.83、70.29、70.16、69.52、69.18、69.11、68.48、68.02、67.83、66.79、60.98、60.96、60.36、51.65、39.43、28.21、26.84、22.25、22.10、15.31。利用HRMS(ESI-TOF,MH+)计算得C43H75FN2O29H+1103.4512,可得1103.4549。
5-胺戊基α-L-吡喃海藻糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-叠氮基-6-脱氧-β-D-葡萄糖呱喃糖苷(化合物3)
(5-aminopentylα-L-fucopyranosyl-(1→2)-β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-azido-6-deoxy-β-D-glucopyranoside(Compound 3))1HNMR(600MHz,D2O)δ5.26(d,J=4.1Hz,1H)、4.92(d,J=4.0Hz,1H)、4.64(d,J=7.7Hz,1H)、4.57(d,J=7.8Hz,1H)、4.55(d,J=8.1Hz,1H),4.50(d,J=7.7Hz,1H)、4.41(t,J=6.6Hz,1H)、4.34-4.23(m,2H)、4.13(d,J=2.5Hz,1H)、4.09-3.57(m,31H)、3.35(t,J=8.5Hz,1H)、3.06-2.99(m,2H)、2.07(s,3H)、1.77-1.63(m,4H)、1.53-1.41(m,2H)、1.24(d,J=6.6Hz,3H)。13C NMR(150MHz、D2O)δ177.02、106.70、106.20、104.79、104.72、103.18、102.02、82.42、80.99、79.88、79.11、78.85、78.27、77.81、77.37、77.07、76.44、76.33、75.66、74.84、74.59、73.57、72.96、72.89、72.26、71.91、71.85、71.22、70.77、70.56、69.53、63.73、63.70、63.10、54.39、53.13、42.09、30.94、29.17、24.99、24.85、18.05。以HRMS(ESI-TOF,MH+)计算得C43H75N5O29H+1126.4620,可得1126.4639。
5-胺戊基α-L-吡喃海藻糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-O-苯基-β-D-葡萄糖呱喃糖苷(化合物4)
(5-aminopentylα-L-fucopyranosyl-(1→2)-β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-O-phenyl-β-D-glucopyranoside(Compound 4))
1H NMR(600MHz,D2O)δ7.43(t,J=8.0Hz,2H)、7.11(t,J=8.0Hz,3H)、5.26(d,J=4.1Hz,1H)、4.89(d,J=4.0Hz,1H)、4.64(d,J=7.7Hz,1H)、4.57(d,J=7.6Hz,1H)、4.55(d,J=8.0Hz,1H)、4.48(d,J=10.1Hz,1H)、4.45-4.34(m,3H)、4.27-4.24(m,2H)、4.13(d,J=2.1Hz,1H)、4.06-3.62(m,27H)、3.58-3.50(m,2H)、3.39(dd,J=9.3,8.2Hz,1H)、2.91(t,J=7.4Hz,2H)、2.07(s,3H)、1.73-1.60(m,4H)、1.51-1.39(m,2H)、1.24(d,J=6.6Hz,3H)。13CNMR(150MHz、D2O)δ174.28、157.80、129.93、121.82、115.08、103.95、103.24、102.23、102.05、100.40、99.28、78.22、77.85、77.14、76.36、76.11、75.54、75.07、74.62、74.42、73.58、73.09、73.04、72.05、71.85、70.64、70.28、70.13、69.52、69.17、69.11、68.48、68.02、67.81、66.78、65.91、60.98、60.95、60.38、60.35、51.64、39.56、28.27、27.49、22.25、22.13、15.31。以HRMS(ESI-TOF,MH+)计算得C49H80N2O30H+1177.4869,可得1177.4918。
5-胺戊基α-L-吡喃海藻糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-O-对硝基苯基-β-D-葡萄糖呱喃糖苷(化合物5)
(5-aminopentylα-L-fucopyranosyl-(1→2)-β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-O-p-nitrophenyl-β-D-glucopyranoside(Compound 5))
1H NMR(600MHz,D2O)δ8.30(d,J=8.8Hz,2H)、7.21(d,J=8.8Hz,2H)、5.26(d,J=4.1Hz,1H)、4.89(d,J=3.6Hz,1H)、4.65(d,J=7.6Hz,1H)、4.60(m,3H)、4.39(m,2H)、4.25-4.21(m,1H)、4.13(s,1H)、4.01-3.65(m,28H)、3.59-3.56(m,3H)、3.45-3.35(m,1H)、2.94(t,J=6.9Hz,2H)、2.07(s,3H)、1.66-1.62(m,4H)、1.44-1.42(m,2H)、1.24(d,J=6.3Hz,3H)。13C NMR(150MHz、D2O)δ177.03、166.29、144.26、128.97、117.83、106.69、106.25、104.98、104.79、103.15、102.02、80.94、79.82、79.10、78.85、78.31、77.81、77.37、77.16、76.32、75.73、75.56、74.82、74.78、74.59、73.40、72.97、72.88、72.26、71.91、71.86、71.22、70.77、70.55、69.53、69.12、65.21、63.73、63.70、63.09、54.39、42.19、30.97、24.99、24.86、18.05。HRMS(ESI-TOF,MH+)计算得C49H79N3O32H+1222.4719,可得1222.4729。
5-胺戊基α-L-吡喃海藻糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-脱氧-6-硝基-β-D-葡萄糖呱喃糖苷(化合物6)
(5-aminopentylα-L-fucopyranosyl-(1→2)-β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-deoxy-6-nitro-β-D-glucopyranoside(Compound 6))
1H NMR(600MHz,D2O)δ5.26(s,1H)、4.91(s,1H)、4.69-4.52(m,5H)、4.42(d,J=6.4Hz,1H)、4.34(d,J=7.5Hz,1H)、4.26(m,2H)、4.13(s,1H)、4.12-3.62(m,28H)、3.57(m,1H)、3.34(t,J=8.3Hz,1H)、3.02(t,J=6.1Hz,2H)、2.07(s,3H)、1.80-1.62(m,4H)、1.47(dt,J=22.4,7.5Hz,2H)、1.24(d,J=6.4Hz,3H)。利用HRMS(ESI-TOF,MH+)计算得C43H75N3O31H+1130.4457,可得1130.4438。
5-胺戊基α-L-吡喃半乳糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-β-D-葡萄糖呱喃糖苷(化合物7)
(5-aminopentylα-L-galactopyranosyl-(1→2)-β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-β-D-glucopyranoside(Compound 7))
1H NMR(600MHz,D2O)δ5.40(d,J=3.9Hz,1H)、4.92(d,J=3.7Hz,1H)、4.65(d,J=7.7Hz,1H)、4.61(d,J=7.4Hz,1H)、4.53(d,J=7.7Hz,1H)、4.50(d,J=8.0Hz,1H)、4.41(t,J=6.4Hz,1H)、4.34-4.24(m,2H)、4.15-3.56(m,34H)、3.33(t,J=8.3Hz,1H)、2.97(t,J=7.5Hz,2H)、2.09(s,3H)、1.74-1.66(m,4H)、1.49-1.42(m,2H)。13C NMR(150MHz、D2O)δ174.45、103.70、103.30、102.02、101.95、100.42、98.45、78.77、78.40、77.16、76.09、75.47、75.15、74.79、74.58、74.52、74.50、73.71、72.93、72.09、70.85、70.24、70.14(2C)、69.44、69.20、69.17、69.06、68.43、68.28、67.75、61.76、60.96、60.89、60.33、60.03、51.49、39.47、28.20、27.12、22.30、22.12。利用HRMS(ESI-TOF,MH+)计算得C43H76N2O31H+1117.4505,可得1117.4488。
5-胺戊基6-叠氮基-6-脱氧-α-L-吡喃半乳糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-β-D-葡萄糖呱喃糖苷(化合物8)
(5-aminopentyl 6-azido-6-deoxy-α-L-galactopyranosyl-(1→2)-β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-β-D-glucopyranoside(Compound 8))
1H NMR(600MHz,D2O)δ5.46(d,J=3.8Hz,1H)、4.92(d,J=3.5Hz,1H)、4.65(d,J=7.5Hz,1H)、4.60(d,J=8.3Hz,1H)、4.53(d,J=7.7Hz,1H)、4.53(d,J=8.0Hz,1H)、4.41(t,J=6.4Hz,1H)、4.34-4.24(m,2H)、4.18(s,1H)、4.09-3.59(m,32H)、3.33(t,J=8.1Hz,2H)、2.99(t,J=7.4Hz,2H)、2.08(s,3H)、1.78-1.64(m,4H)、1.55-1.44(m,2H)。13C NMR(150MHz、D2O)δ174.36、103.87、103.30、102.29、101.95、100.42、98.41、78.79、78.35、77.17、76.95、75.48、75.11、74.79、74.67、74.53、74.43、73.85、72.93、72.09、70.85、70.15、70.12、69.67、69.61、69.14、69.08、69.05、68.56、68.02、67.78、60.95、60.91、60.33、60.04、51.40、51.25、39.44、28.19、26.96、22.32、22.10。以HRMS(ESI-TOF,MH+)计算得C43H75N5O30H+1142.4570,可得1142.4569。
5-胺戊基6-脱氧-6-氟-α-L-吡喃半乳糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-β-D-葡萄糖呱喃糖苷(化合物9)
(5-aminopentyl 6-deoxy-6-fluoro-α-L-galactopyranosyl-(1→2)-β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-β-D-glucopyranoside(Compound 9))
1H NMR(600MHz,D2O)δ5.40(d,J=3.9Hz,1H)、4.91(d,J=3.9Hz,1H)、4.69(m,1H)、4.64-4.60(m,2H)、4.57(d,J=8.2Hz,1H)、4.52(d,J=7.8Hz,1H)、4.49(d,J=8.0Hz,1H)、4.39(m,2H)、4.26(d,J=2.4Hz,1H)、4.12(d,J=2.7Hz,1H)、4.09-3.56(m,31H)、3.32(t,J=8.5Hz,1H)、2.99(t,J=7.4Hz,2H)、2.07(s,3H)、1.71-1.66(m,4H)、1.49-1.44(m,2H)。13CNMR(150MHz、D2O)δ174.38、103.84、103.30、102.05、101.95、100.43、98.98、83.96、82.86、78.79、78.27、77.16、76.69、75.65、75.48、75.09、74.79、74.52、74.47、73.65、72.93、72.09、70.85、70.14、70.12、69.11、68.96、68.36、68.05、67.80、60.95、60.90、60.34、60.03、51.45、39.43、28.18、26.89、22.28、22.10。以HRMS(ESI-TOF,MH+)计算得C43H75FN2O30H+1119.4461,可得1119.4459。
5-胺戊基6-乙炔基-6-脱氧-α-L-吡喃半乳糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙酰胺基-2-脱氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-β-D-葡萄糖呱喃糖苷(化合物10)
(5-aminopentyl 6-acetylenyl-6-deoxy-α-L-galactopyranosyl-(1→2)-β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-β-D-glucopyranoside(Compound 10))
1H NMR(600MHz,D2O)δ5.32(d,J=4.0Hz,1H)、4.91(d,J=3.0Hz,2H)、4.64(d,J=7.7Hz,1H)、4.59(d,J=8.4Hz,1H)、4.53(d,J=7.7Hz,1H)、4.50(d,J=8.0Hz,1H)、4.40(t,J=6.5Hz,1H)、4.26(d,J=2.8Hz,1H)、4.17-4.13(m,2H)、4.05-3.58(m,32H)、3.32(t,J=8.5Hz,1H)、3.02(m,2H)、2.07(s,3H)、1.77-1.64(m,4H)、1.53-1.43(m,2H)。13C NMR(150MHz、D2O)δ177.06、106.53、106.04、104.69、104.60、103.17、102.13、81.52、80.89、79.91、79.26、78.87、78.79、78.22、77.88、77.54、77.27、77.19、76.13、75.67、74.83、74.77、73.69、73.59、72.89、72.81、71.86、71.83、71.28、71.19、70.59、70.21、65.69、65.19、63.68、63.64、63.08、62.77、54.26、42.06、30.89、29.13、25.00、24.81。以HRMS(ESI-TOF,MH+)计算得C44H74N2O30H+1111.4399,可得1111.4397。
实施例5:GH衍生物的DT-共轭物的免疫分析
为了解GH衍生物的DT-共轭物(1-DT至10-DT)的免疫性,以肌肉注射方式将含2微克GH衍生物的GH衍生物的DT-共轭物及2微克的糖脂佐剂C34投予至5只BALB/c母鼠体内,双周间隔共投予三次。先前研究指出,在仅投予GH蛋白共轭物而不投予佐剂的情况下,仅能得到低效价的抗GH抗体。13b在第三次投予后10天,取得各抗原的抗血清,再利用包含94种化学合成聚糖(包含GH 1、GH衍生物2-10、GH衍生物片段11-30及其他肿瘤相关糖类抗原)的聚糖微数组进行分析测试。由于聚糖具有某些化学修饰,该聚糖微数组亦包含该多个功能性链接子,以测试交互反应。
由GH衍生物DT-共轭物(1-DT到10-DT)所引发产生的抗体可专一辨识GH、GH衍生物及GH片段,却不会结合至其他TACAs及功能性链接子。选取GH、Gb5及SSEA4作为DT-共轭物的标准抗原(图1A:GH,图1B:Gb5,图1C:SSEA4)。由复合糖体所引发的高IgG抗体效价分离的血清可知,其是为一种与T细胞相关的免疫反应。有趣的是,不论是GH-乳糖或是海藻糖衍生物皆不会引发显著的IgM产生。在IgG对抗GH方面,相较于天然形式的GH-DT共轭物(1-DT),GH-N3-DT(3-DT)及N3-GH-DT(8-DT)会引发更高的抗体效价,由GH-F-DT(2-DT)及GH-苯基-DT(4-DT)引发的抗体效价则与天然形式的GH-DT共轭物(1-DT)相当。由GH-N3-DT(3-DT)及N3-GH-DT(8-DT)所产生的高效价可推知,叠氮基可作为一种免疫调节剂。用以增加免疫性的机致目前尚不明确,然相较于天然的GH,位于GH-N3 3或N3-GH 8的聚糖的N3特性可能扮演着重要的角色。由GH氟基团所产生的免疫性调节具有位向选择性(regioselective)。19c,33位于GH还原端的葡萄糖的C-6位置的氟基团可引发与天然GH相当的价效,而由GH非还原端海藻糖的C-6位置的氟基团所引发的效价则与GH具有低反应性。有趣的是,由GH-苯基-DT(4-DT)所引发的免疫反应可与GH产生交互反应。该交互反应与先前报导所述的在利用N-苯乙酰基(N-phenylacetyl)GM3或STn作为疫苗时,天然GM3与STn并不会产生交互反应的结果并不相符。19a,20抗原GH-苯基NO2-DT(5-DT)、GH-NO2-DT(6-DT)、OH-GH-DT(7-DT)、F-GH-DT(9-DT)及乙炔基-GH-DT(10-DT)仅能产生微弱的免疫反应以对抗GH。此外,GH-苯基NO2-DT(5-DT)及GH-NO2-DT(6-DT)虽可对苯基NO2及NO2糖类相似物产生强烈的免疫反应,却不会对天然形式的GH相似物产生免疫反应。该结果亦与先前报导所述的TNF-α单一对苯基NO2突变可引发大量辨识野生型TNF-α的抗体产生的结果不符。21a有趣的是,由该多个复合糖体所引发的抗体对Gb5及SSEA4亦具有相同的辨识功效(第1B-C图)。因此,该多个结果指出,以氟、叠氮基或苯基来修饰Globo H还原端的C-6位置可引发大量IgG抗体免疫,据以专一地辨识Globo H、Gb5及SSEA。然而,唯有利用叠氮基修饰Globo H非还原端海藻糖的C-6位置可产生强烈的IgG免疫反应。可参照Lee et al.,J.Am.Chem.Soc.2014,136,16844-16853。
进一步利用聚糖微数组来分析该多个疫苗所产生的抗血清中IgG次类别的抗体类型;结果指出,抗体具有显著量的IgG1、IgG2b、IgG2c及IgG3,以及少量的IgG2a。此外,在具有高量IgG3抗体的抗血清中,IgG1次类别具有最高的含量,其是为一种典型的抗糖类反应且与T细胞所产生的免疫反应相关。
利用流式细胞仪来检测由GH-DT(1-DT)、GH-F-DT(2-DT)、GH-N3-DT(3-DT)、GH-苯基-DT(4-DT)及N3-GH-DT(8-DT)所产生的小鼠抗血清于辨识GH表现MCF7人类乳癌细胞株的能力(图2)。可预期地,相较于未经处理的小鼠,由GH-DT(1-DT)所引发的抗血清可与GH表现MCF7细胞产生显著的反应。由GH衍生物-DT(2-DT、3-DT、4-DT及8-DT)所引发的抗血清亦可辨识MCF7细胞。
实施例6:GH衍生物DT共轭物的与补体相关的细胞毒杀
利用具有GH表现的MCF7癌细胞株来分析与补体相关的细胞毒杀(Complement-dependent cytoxicity,CDC)(图3)。将MCF-7细胞种植于96孔洞细胞培养盘中,每孔洞的细胞数量为104细胞。于37℃放置至隔日后,将细胞培养液置换为100微升的抗血清/补体混合液,再于37℃的环境中培养2小时。为制备抗血清/补体混合液,以包含20%兔子补体(LifeTechnologies)的细胞培养液20倍稀释抗血清。培养后,利用CytoTox非放射活化细胞毒杀试剂套组(CytoToxNon-Radioactive Cytotoxicity Assay kit,Promega,Fitchburg,WI)并依据其使用说明来分析由抗血清所引发的细胞毒杀反应。利用未经处理的Blab/c小鼠的血清标准化由抗血清引发的细胞毒杀,并以相对倍数来表示结果。
相较于未经处理的小鼠的血清,由GH-DT(1-DT)、GH-F-DT(2-DT)、GH-N3-DT(3-DT)、GH-苯基-DT(4-DT)及N3-GH-DT(8-DT)刺激免疫反应所得的抗血清可显著地诱发癌细胞产生细胞毒杀反应。由GH-苯基-DT(4-DT)及N3-GH-DT(8-DT)所得的抗血清所引发的细胞毒杀反应与天然形式的GH-DT(1-DT)相当。有趣的是,相较于GH-DT(1-DT),由GH-F-DT(2-DT)或GH-N3-DT(3-DT)疫苗所得的抗血清可诱发更高量(15%)的癌细胞毒杀反应;该结果显示,该多个衍生物可作为更具治疗功效的疫苗。
本发明建立了一套用以化学酶合成GH衍生物及其免疫共轭物的策略。利用聚糖微数组来评估相较于天然形式的GH-DT(1-DT),GH衍生物共轭物的免疫特性。结果指出,以氟、叠氮基或苯基来修饰Globo H的还原端可引发大量IgG抗体免疫,据以专一地辨识Globo H、Gb5及SSEA,而唯有Globo H的叠氮基-海藻糖衍生物可产生强烈的IgG免疫反应。此外,由GH-DT(1-DT)、GH-F-DT(2-DT)、GH-N3-DT(3-DT)、GH-苯基-DT(4-DT)及N3-GH-DT(8-DT)所产生的抗体可辨识具有GH表现的肿瘤细胞(MCF-7),且可引发可对抗肿瘤细胞的与补体相关的细胞毒杀反应。相较于GH-DT(1-DT),GH-F-DT(2-DT)及GH-N3-DT(3-DT)疫苗具有更高的癌细胞毒杀功效,可作为新一代修饰糖抗原结构的疫苗。
方法、材料及仪器
所有的化学药品及试剂皆是购买自Acros,Echo chemical,Merck Sigma-Aldrich,Fluka,且无需进一步纯化即可直接使用。所有对空气或湿度敏感的试剂或中间物皆是于含氩环境中操作使用。在高真空中加热干燥分子筛(Acros)。以位于硅胶60F254盘(2毫米,Merck)的薄层色谱分析检测反应的进行,并利用紫外光照射及以酸铈钼酸铵(acid ceric ammonium molybdate)或对茴香醛(p-anisaldehyde)染色后进行观测。于硅胶(40-63微米,Merck)或LiChroprep RP-18(40-63微米,Merck)进行快速管柱色谱分析。透析膜(纤维素酯,MCCO=10,000)在使用前先以二次水洗涤。NMR光谱是以Brüker Advance600记录位于600MHz(1H NMR)及150MHz(13C HMR)的光谱。以ppm(δ标)来标记化学位移(chemical shift),其是以相对于氘代氯仿(deuterated chloroform,δ=4.80ppm)、氘代水(δ=4.80ppm)或氘代甲醇(δ=3.31ppm)的残基质子及碳讯号进行校正。以1H NMR或光谱的化学位移来计算Hz的耦合常数(Coupling constant)。以下列方式来表述结果:化学位移、多重性(multiplicity,s=单、d=双、t=三、q=四、m=多、br=广)、Hz的整合及耦合常数(intergration and coupling constant,J)。以APEX-ultra 9.4T FTICR-MS(BrukerDaltonics)记录高解析ESI质谱。利用Bruker Ultraflex II TOF/TOF200光谱仪,并以芥子酸(sinapinic acid)作为基质,来计录MALDI-TOF光谱。与Alexa Fluor 647结合的山羊抗-小鼠IgG抗体、与DyLight 649结合的山羊抗-小鼠IgM抗体、与Alexa Fluor 488结合的山羊抗-小鼠IgG1抗体、与Alexa Flour 594结合的山羊抗-小鼠IgG2a抗体、与Cy3结合的山羊抗-小鼠IgG2b抗体、与R-PE结合的抗-小鼠IgG2c抗体及与Alexa Fluor 647结合的山羊抗-小鼠IgG3抗体皆是购买自Jackson Immunoresearch。利用微数组荧光片读取器(GenePix4300A;Molecular Devices Corporation)以635纳米、594纳米、532纳米或488纳米的波长来扫瞄微数组玻片。以GenePix Pro-6.0软件(Axon Instruments,Union City,CA,USA)分析荧光资料。白喉类毒素CRM 197是购买自PFenex公司。
所有的核苷酸、糖类、糖核苷酸及化学物质皆购买自Sigma-Aldrich(St.Louis,MO)。依据已知步骤来进行转殖、过量表现、纯化及检测酶活性。3
用以合成GH-衍生单酯的方法
将GH衍生物(2-3毫克,1等量)溶于无水二甲基甲酰胺(anhydrousdimethylformamide,DMF)溶液中。再加入对硝基苯基酯类连结子(5-6毫克,5等量),并于室温搅拌1-5小时。利用薄层色谱分析,并以3:2:2的比例的正丁醇/乙酸/水作为显影溶剂来检测反应进行。取得最佳产量后,以真空且不加热的方式浓缩反应混合物以移除DMF。以反相(C18)管柱层析法来纯化,且逐渐以包含1%醋酸的水及甲醇:水=7:3的冲提液来冲提产物。冷冻干燥溶液,直到产生淡黄色的固态GH-衍生物单酯(1.5-2毫克,60~80%)。
GH-衍生物复合糖体的制备方法
将DT溶于100mM的磷酸盐缓冲液(pH 7.9,每毫升5毫克)中,再加入30-40等量的GH-衍生物单酯。于室温缓慢搅拌混合液24小时。以水稀释混合液,再利用Amicon Ultra-0.5(10kDa)以10次去离子水离心产物。冷冻干燥溶液,直到得到白色粉末。以MALDI-TOF(正模式,基质芥子酸,水)来分析所得GH-衍生物DT共轭物中寡糖的嵌合数量。
微阵列制备及检测
为制备微数组,将化合物1-30、9种功能性链接子及55种具有胺戊基的寡糖溶于10mM的打印缓冲液(300mM磷酸缓冲液,0.005%妥文20,pH 8.5)。以机器探头(SMP3;TeleChem International)自96孔洞盘取得约0.6奈升的溶液后,将聚糖打印(BioDot;Cartesian Technologies)至具有NHS涂布的玻璃片(Nexterion H slide;SCHOTT NorthAmerica)上。微数组玻片共具16个网格,其中各网格皆是由20列×10栏所组成。打印出的玻片在80%湿度的环境中反应1小时后,再干燥至隔日。将该多个玻片保存于室温的干燥箱中,以供后续使用。
细胞株及流式细胞仪分析
将人类乳癌细胞株MCF-7培养于包含10%胎牛血清、1倍抗生素-抗真菌(Antimycotic,Life Technologies)及胰岛素(每毫升50毫克)的DMEM细胞培养液(LifeTechnologies,Carlsbad,CA)中。为进行流式细胞仪分析,收集细胞后,以500g的转速离心3分钟,再将细胞悬浮于FACS染色/洗涤缓冲液(1%胎牛血清、溶于磷酸盐缓冲液的0.1%NaN3)。将细胞(2.5x105)培养于经GH衍生物处理的Balb/c小鼠的抗血清(1/10稀释于50微升的FACS染色/洗涤缓冲液)中,于4℃反应2小时。将未经处理的Balb/c小鼠的血清作为实验对照组。以1毫升的FACS染色/洗涤缓冲液洗涤2次后,将细胞培养于以FITC标记的抗-小鼠IgG/IgM抗体(1/20稀释,BD Biosciences,San Jose,CA),于4℃作用30分钟。再次以1毫升的FACS染色/洗涤缓冲液洗涤2次后,利用流式细胞仪进行分析。利用FACSCanto(BectonDickinson,Franklin Lakes,NJ)、FACSDiva软件(Becton Dickinson)及FlowJo(TreeStar,Ashland,OR)来分析各样品。
小鼠剂量及免疫方法
为比较GH衍生物疫苗(1-DT到10-DT),以肌肉注射方式将糖脂C34注入10组小鼠体内(每组5只,8周大的Balb/c母鼠,购买自台湾BioLASCO)。每2周投予一次疫苗,共3次。各疫苗包含2微克的GH衍生物及2微克的C34。将投予磷酸盐缓冲液的小鼠作为对照组。在首次注射前及第3次注射后10天,采取小鼠血液。以4,000×g的转速离心10分钟,以取得血清。以聚糖微数组分析各血清反应。
以聚糖微阵列分析血清
以1%BSA/PBST缓冲液(PBST缓冲液:磷酸盐缓冲液及0.05%妥文-20,pH 7.4)稀释小鼠血清。将Superblock阻断缓冲液(Pierce)加入聚糖微数组,并于4℃反应1小时;之后,以PBST缓冲液洗涤3次。将稀释后的血清加入聚糖微数组中,并于4℃反应1小时。洗涤移除过量的血清抗体,再分别加入与Alexa Fluor 647结合的山羊抗-小鼠IgG抗体或与DyLight 649结合的山羊抗-小鼠IgM抗体(作为第二抗体),于避光的环境中,置于4℃作用1小时。以PBST洗涤3次后,利用微数组荧光片读取器(GenePix 4300A;Molecular DevicesCorporation)以635纳米的波长进行扫瞄,再以GenePix Pro-6.0分析软件(AxonInstruments,Union City,CA,USA)分析扫瞄影像。
抗体次类别分析
如上述方式分析抗体的次类别。分别将与Alexa Flour 594结合的山羊抗-小鼠IgG2a抗体、与Cy3结合的山羊抗-小鼠IgG2b抗体、与R-PE结合的抗-小鼠IgG2c抗体及与Alexa Fluor 647结合的山羊抗-小鼠IgG3抗体以400倍稀释比例加入微数组中,再进行反应及洗涤。
其他实施方式
可以任何组合方式组合本说明书所揭示的技术特征。亦可以能产生相同、等量或相似功效的替代性技术来取代本说明书所揭示的各技术特征。因此,除非另有定义,否则本揭示内容中各技术特征仅作为能产生等量或相似特征的范例。
虽然上文实施方式中揭示了本发明的具体实施例,然其并非用以限定本发明,本发明所属技术领域中具有通常知识者,在不悖离本发明的原理与精神的情形下,当可对其进行各种更动与修饰,因此本发明的保护范围当以附随申请专利范围所界定者为准。
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Claims (19)
2.如权利要求1所述的免疫组合物,其特征在于,该载体可以是一蛋白、一脂质、一脂质化蛋白、一病毒、一多肽或一糖肽的树枝状聚合物(dendrimer)。
3.如权利要求2所述的免疫组合物,其特征在于,该载体蛋白是选自由破伤风类毒素(tetanus toxoid,TT)、白喉类毒素(diphtheria toxoid,DT)、白喉类毒素交互反应物质197(diphtheria toxin cross-reacting material 197,CRM197)、破伤风类毒素的片段C(fragment C of TT)、键孔血蓝蛋白(Keyhole limpet hemocyanin,KLH)、胎牛血清白蛋白(bovine serum albumin,BSA)、蛋白D(protein D)、外膜蛋白(outer-membrane protein,OMP)及肺炎球菌溶血素(pneumolysin)所组成的群组。
5.如权利要求1所述的免疫组合物,其特征在于,该连接子是一异-(hetero-)或同-(homo-)双功能连接子。
6.如权利要求5所述的免疫组合物,其特征在于,该连接子是一胺基活化(amino-active)的同-双功能连接子,具有2-20个的碳原子,可分别与该至少一种聚糖及该载体蛋白形成酰胺键(amide bond)。
7.如权利要求1所述的免疫组合物,其特征在于,该佐剂是一能与树突细胞的CD1d分子结合的糖脂。
8.如权利要求1所述的免疫组合物,其特征在于,该佐剂是C34、7DW8-5、C17、C23、铝盐、鲨烯(Squalene)、MF59或QS-21。
9.一种癌症疫苗,包含如权利要求1所述的免疫组合物及一药学上可接受的赋形剂。
10.一种如权利要求1所述的免疫组合物的用途,其是用于制备一治疗一个体的癌症的药物,其中该免疫组合物可诱发癌细胞产生细胞毒杀反应、引发对抗该癌症的免疫反应、产生可专一结合至或中和一或多种癌细胞表面抗原的抗体,其中该一或多种癌细胞表面抗原是选自由Globo H、SSEA-3及SSEA-4所组成的群组。
11.如权利要求10所述的用途,其特征在于,该抗体是IgG抗体。
12.如权利要求10所述的用途,其特征在于,该癌症是选自由脑癌、肺癌、乳腺癌、口腔癌、食道癌、胃癌、肝癌、胆管癌、胰腺癌、大肠直肠癌、肾癌、骨癌、皮肤癌、子宫颈癌、卵巢癌及前列腺癌所组成的群组。
13.如权利要求10所述的用途,其特征在于,该癌症会表现Globo H、SSEA-3或SSEA-4抗原。
14.一种用以制备如权利要求1所述的免疫组合物的方法,包含:提供该载体;以及利用一共轭反应(conjugation reaction)将该至少一种聚糖经由该连接子与该载体形成共轭。
15.如权利要求14所述的方法,其特征在于,该连接子包含至少一硫原子、羧酸酯基(carboxylate group)、酰胺基(amide group)、氨基甲酸酯基(carbamate group)、碳酸基(carbonate group)、硫代氨基甲酸酯基(thiocarbamate group)、硫碳酸基(thiocarbonate group)、硫醚基(thioether group)、丁二酰胺基(succinamide group)、正-羟基丁二酰胺基(n-hydroxy succinamide group)或其组合物。
18.如权利要求17所述的方法,其特征在于,该胺基活化的双功能连接子是一具有4到6个碳原子的二羧酸(dicarboxylic acid)。
19.如权利要求17所述的方法,其特征在于,该载体是一蛋白、一脂质、一脂质化蛋白、一病毒、一多肽或一糖肽的树枝状聚合物。
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