CN108379591A - 免疫激动剂靶向化合物的合成及其应用 - Google Patents
免疫激动剂靶向化合物的合成及其应用 Download PDFInfo
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- CN108379591A CN108379591A CN201810331582.XA CN201810331582A CN108379591A CN 108379591 A CN108379591 A CN 108379591A CN 201810331582 A CN201810331582 A CN 201810331582A CN 108379591 A CN108379591 A CN 108379591A
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
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Abstract
本发明发现系列小分子免疫激动剂偶联靶向药物,形成新的具有免疫激活功能的靶向化合物药物,在体外体内产生了有利于提高靶向药的免疫激活效果和抗肿瘤及其它疾病的效果,赋予了所述靶向药双功能(双功能靶向药),这种提高的效果是由具有免疫抗肿瘤因素(如IFN‑γ)和对致病性靶向位点的抑制二个功能协同作用产生,一种功能合二为一的新型高效靶向药物。
Description
技术领域
本发明涉及一系列同系物的小分子免疫激动剂及其用途,属于药物化学和免 疫学的交叉学科领域。
技术背景
Toll样受体(TLR)是生物体防御体系的第一道防线(Kaisho,T.&Akira,S. Toll-like receptor function and signaling.J.Allergy Clin.Immunol.117,979–987(2006);Miyake,K.Innate immune sensing of pathogens and danger signals by cellsurface Toll-like receptors.Semin.Immunol.19,3–10(2007));其中TLR7的激活天 然配体是ssRNA,在ssRNA系列病毒侵袭的防御中具有重要作用(Blasius,A.L.& Beutler,B.Intracellular toll-like receptors.Immunity 32,305–315(2010));此外 TLR7能够被人工合成的小分子化合物激活诱导机体的免疫调节,在抗病毒和抗 肿瘤方面具有重要作用(Huju Chi,Chunman Li,Flora Sha Zhao,Li Zhang,Tzi Bun Ng,Guangyi Jin andOu Sha.Anti-tumor Activity of Toll-Like Receptor 7Agonists. FrontPharmacol.2017May 31;8:304.doi:10.3389/fphar.2017.00304)。
以TKI(tyrosine kinase inhibitor)为代表的抗肿瘤靶向药延长了患者的生命,但是大部分在一年左右或更短时间内产生耐药。为了解决TKI的耐药性,我们 在前期研究中探索将TKI和TLR7免疫激动剂联合应用,以期产生靶向免疫协同作 用。然而实验结果显示TKI拮抗了TLR7激动剂的免疫细胞激活作用,抑制了免疫 激活细胞因子的产生(Scientific Reports,2016Dec 21;6:39598.doi: 10.1038/srep39598)。但是我们将TKI靶向药和TLR7小分子免疫激动剂共价化合 偶联后,意外发现这类共价偶联化合物不但保持或提高了小分子免疫激动剂的免 疫激活细胞因子的产生,而且也提高了TKI的抗肿瘤效果。这种免疫激活靶向抗 肿瘤作用对于肿瘤的长期高效治疗具有重要意义。
发明内容
本发明的内容为在一系列具有免疫激活作用的小分子免疫激动剂基础上,与 靶向药物链接成为新型的免疫靶向药。
本发明中的所述的免疫激动剂链接靶向药通式表达如下:
其中TLA代表小分子免疫激动剂(TLR7Agonists),Tar表示靶向药,其代表同 说明中的靶向药或抗体,如TKI(tyrosine kinase inhibitor),EGFR抑制剂, KRAS抑制剂,BRAF抑制剂,BTK抑制剂,BRD4抑制剂,PD-L1抑制剂,PD-1 抑制剂,OX40激动剂,PARP抑制剂,以及CDK4/6抑制剂等;n、m可以是一 个或者几个,一般为1---5之间的数值。L代表连接链(Linker),可以是各种直 链和支链的烷烃或者聚乙二醇链,包括可能需要降解的功能链,或者增加溶解性 的链。包括如下链:
链中包括了增加溶解性的聚乙二醇基团,也包括了2个叔胺的碱性基团可以形成各种盐。连接链的两端可以是酰胺、烷氧键、烷硫键、取代胺基、季胺盐、cilck 反应形成的杂环、可以蛋白酶(Cathepsin)解离的氨基酸基团、脲基团和硫脲基 团等。
上述具有免疫激活用途的小分子免疫激动剂及免疫靶向化合物如下:
酸式系列
α,β-不饱和羰基系列
免疫靶向激动剂系列
其它免疫激动剂系列
其中的α,β-不饱和羰基系列化合物可与含巯基的多肽形成加成产物,例如可以与谷胱甘肽(glutathione,GSH)形成加成物(能够靶向谷胱甘肽转移酶,协同 化疗药物、不可逆TKI靶向药物和其它不可逆靶向药物提高疾病治疗效果,消 除抗药性)同时激活免疫效果,例如:
这些α,β-不饱和羰基系列化合物(SZU-114、SZU-117、SZU-122、SZU-127、 SZU-133、SZU-138、SZU-144)可以和特异靶点的靶向药(如TKI)形成偶联物, 达到免疫靶向的双功能作用:
免疫激动剂偶联靶向药物方法路线之一:
这些类型的α,β-不饱和羰基系列化合物免疫激动剂中的含羧基化合物的双 功能基团能够多种用途,例如SZU-138可以通过加成反应和偶联反应形成可溶 性的功能蛋白多肽偶联体,解决偶联产物的溶解度问题:
抗体偶联SZU-158形成的新抗体由于带有了二甲氨基基团可以成盐,形成 离子化的正电荷,有利于提高治疗效果和水溶解性。
由SZU-158也可以偶联靶向药(如TKI等)形成免疫靶向药物,克服耐药 性,提高治疗效果:
免疫激动剂偶联靶向药物方法路线之二:
上述同样的方法可以由SZU-144或者SZU-133形成,linker也可以是简单的 直链烷烃,也可以由各种需要而代替。
由上述的α,β-不饱和羰基系列化合物免疫激动剂中的含羧基化合物,也可 以偶联2个不同的靶向药,形成双靶向免疫药物:
免疫激动剂偶联靶向药物方法路线之三:
由上述的α,β-不饱和羰基系列化合物免疫激动剂和谷胱甘肽形成的产物, 也可以偶联化合2个靶向药,以提高疗效。如SZU-114-GSH:
免疫激动剂偶联靶向药物方法路线之四:
其中的靶向药可以是各种TKI药物以及各种肿瘤靶向药,也可以是抗体, 如CD3抗体、PD-1抗体、OX40抗体,CD19抗体、CD20抗体,HER2抗体, MUC1抗体,以及各种肿瘤蛋白抗体和致病原的抗体等。其中的链接链可以是各 种烷烃链或者烷氧基链等,根据溶解和代谢优化需要可以调整。
上述双偶联靶向药物优点是可以形成2个正离子氨基基团(氨基盐-HN+-、 -NH+ 3),溶解性高,双靶可以根据需要调整优化;比如靶向1为T细胞的CD3 抗体或CD122抗体,靶向2为靶向肿瘤细胞HER2抑制剂,可以推动T细胞向 肿瘤微环境的浸润,加强抗肿瘤效果的同时,激活免疫TLR7受体,产生靶向免 疫记忆。
在本说明的免疫激动剂偶联靶向药物方法路线五中,SZU-166做为独特的异 氰酸酯小分子免疫激动剂,具有和氨基化合物温和定量偶联加成的优势:
免疫激动剂偶联靶向药物方法路线之五:
酸系列的激动剂赖氨酸衍生化合物SZU-104、SZU-105、SZU-112、SZU-113 为具有免疫激动剂活性的氨基酸衍生物,在制备免疫抗原多肽中,可以按照需要 插入多肽(或抗体)的定点位置达到定位偶联的目的:
SZU-161和SZU-162作为偶联蛋白药物的小分子免疫激动剂,具有特异性 紫外吸收峰(342nM),可以作为测定免疫激动剂偶联蛋白药物偶联度的通用方 法:
紫外光法偶联度测定
测定方法,1)在不同浓度下测定SZU-161在紫外342nM的光吸收强度, 做出浓度和吸光度的标准曲线,得出浓度-吸光度关系式;2)偶联蛋白后测定偶 联蛋白在一定浓度的342nM的吸光度,代入关系式即可得出偶联物中的SZU-161 的相对浓度既得偶联度。SZU-162具有同样的应用效果。
SZU-115和SZU-160是具有click反应基团的新型小分子免疫激动剂,其功 能基本包括二点,1)在与大分子和生物活性物质偶联后,利用click反应接上发 色指示剂对偶联产物进行光学示踪,例如在偶联蛋白后或者靶向药后,观察蛋白 或靶向药的细胞吸收和体内分布情况:
免疫激动剂偶联靶向药物方法路线之六:
2)SZU-115也可以同时连接抗体和靶向药,减小抗体的脱靶效应,增强靶向药 效,激活抗肿瘤免疫:
化合物SZU-136和化合物SZU-160具有相似的作用和应用效果。
本发明中的SZU-139由SZU-136与核糖click反应生成:
免疫激动剂偶联核糖
同样方法可以应用于免疫激动剂偶联小分子RNA(microRNA),例如microRNA 21(miRNA21)在肿瘤发生和发展中具有重要作用(Cell Death Dis.2018Feb 13;9(2):219.doi:10.1038/s41419-017-0243-9;Proc Natl Acad Sci U S A.2015Jun 30;112(26):E3355-64.doi:10.1073/pnas.1504630112;Cancer Lett.2017May 1;393:86-93.doi:10.1016/j.canlet.2017.02.019;
https://en.wikipedia.org/wiki/MIRN21),应用免疫激动剂偶联致病的miRNA可以 引导免疫系统切断疾病的发生源头,阻断相关蛋白的变化和相关疾病的发生:
免疫激动剂偶联靶向药物方法路线之七:
叠氮化microRNA的合成可参考文献(Bioconjug Chem.2003 May-Jun;14(3):697-701)合成:
炔基免疫激动剂可用SZU-115代替,SZU-115的羧基可以与Argonaute偶联成 复合物,干扰miRNA和Argonaute复合物的形成,并在TLR7激动剂的作用下 引导到免疫细胞内涵体,导致免疫消除和记忆:
近期研究证实肿瘤外泌体释放致病性的miRNA是导致肿瘤耐药扩散的重要 原因(Proc Natl Acad Sci U S A.2018Feb 12.pii:201717363.doi: 10.1073/pnas.1717363115;J Clin Invest.2016Apr 1;126(4):1163-72.doi: 10.1172/JCI81130);人体自身产生的microRNA,特别是肿瘤细胞释放的microRNA一般没有免疫诱导能力,外源的反义寡核苷酸RNA虽然可以特异识 别目标miRNA,但是大都具有免疫原性而被清除,或者在体内极快的被降解。 应用上述方法可将致病性自身miRNA形成天然免疫能够识别的免疫原性 miRNA。相同的方法同样适用于其它的致病性miRNA如miRNA30c等。
miRNA的一个重要作用是引导相应的Argonaute蛋白到目标mRNA切割或 者进行转录抑制(https://en.wikipedia.org/wiki/Argonaute)。因此TLR7免疫激动 剂和人体自身miRNA偶联的创新作用之一是免疫靶向干扰Argonaute蛋白的结 合,消除其有关的致病作用,该作用示意图请参见图73。综上所述,本发明发 现系列小分子免疫激动剂偶联靶向药物,形成新的具有免疫激活功能的靶向化合 物药物,在体外体内产生了有利于提高靶向药的免疫激活效果和抗肿瘤及其它疾 病的效果,赋予了所述靶向药双功能(双功能靶向药),这种提高的效果是由具 有免疫抗肿瘤因素(如IFN-γ)和对致病性靶向位点的抑制二个功能协同作用产 生,一种功能合二为一的新型高效靶向药物。
本发明中所述免疫靶向药物的一个合理作用是通过免疫途径清除病原性靶 点(蛋白),如图74所示。免疫激动剂偶联靶向药后形成的免疫靶向药,由靶向 药引导至病原性蛋白,导致靶向细胞死亡,释放病原性蛋白,进而由免疫激动剂 引导至抗原递呈细胞(如DC,antigen presenting cell),在细胞内对病原性蛋白 进行切割处理,导致这些蛋白降解。
本发明说明中的靶向药选择包括至少一种以下的各类靶向药:EGFR抑制剂,TKI(tyrosine kinase inhibitor),BRD4抑制剂,KRAS通路相关靶点抑制剂,BRAF 抑制剂,BTK抑制剂,PARP抑制剂,PD-L1抑制剂(包括抗体,小分子),PD-1 抑制剂(包括抗体,小分子),OX40激动剂(包括抗体,小分子),CD122抗体, CD3抗体,CD19抑制剂,CD20抑制剂,MUC1抑制剂,MUC16抑制剂,CDK4/6 抑制剂,TGF-β抑制剂,CXCR抑制剂,CCL和CXCL趋化因子抑制剂,以及miRNA等,其中的小分子靶向药至少是如下的一个:
Dasatinib,Imatinib,Saracatinib,Ponatinib,Nilotinib,Danusertib,AT9283Degrasyn, Bafetinib,kw-2449,nyp-bhg712,dcc-2036,GZD824.,GNF-2,PD173955,GNF-5, Bosutinib,Gefitinib,Erlotinib,Sunitinib,Ruxolitinib,Tofacitinib,Lapatinib, Vandetanib,Sorafenib,Sunitinib,Axitinib,Nintedanib,Regorafenib,Pazopanib, Lenvatinib,Crizotinib,Ceritinib,Cabozantinib,DWF,Afatinib.Ibrutinib,Niraparib, Palbociclib,B43,KU004,Foreinib,KRCA-0008,PF-06439015,PF-06463922, Canerlinib,GSA-10,GW2974,GW583340,W24002,CP-380736,D2667, Mubritinib,PD153035,PD168393,Pelitinib,PF-06459988,PF06672131, PF-6422899,PKI166,ReveromycinA,Tyrphostin 1,tyrphostin23,lyrphostin51,Tyrphostin,AG528,Tyrphostin,AG658,Tyrphostin,AG825,Tyrphostin,AG835,Tyrphostin,AG1478,Tyrphostin,RG13022,Tyrphostin,RG14620,B178, GSK1838705A,PD-161570,PD173074,SU-5402,Roslin2,Picropodophyllotoxin, PQ401,i-ome-tyrphostin,AG538,GNF5837,GW441756,Tyrphostin,AG879, DMPQ,jnj-10198409,PLX647,Trapidil,TyrphostinA9,Tyrhostin,AG370, Lestaurtinib,DMH4,Eldanamvcin,Genistein,Gw2580,HerbimycinA,Lavendustin, CMidostaurin,nvp-bhg712,PD158780,pd-166866,pf-0627334,PP2,RPL, SU11274,SU5614,Symadex,Tyrphostin,AG34,Tyrphostin,AG974,Tyrphostin, AG1007,UNC2881,Honokiol,SU1498,SKLB1002,cp-547632,jk-p3,KRN633,sc-1,ST638,SU 5416,Sulochrin,Tyrphostin,SU1498,rociletinib,Dacomitinib,Tivantinib,Neratinib,Masitinib,Vatalanib,Icotinib,xl-184,osi-930,AB1010,Quizartinib,AZD9291,Tandutinib,HM61713,Brigantinib,Vemurafenib(plx-4032),Semaxanib,AZD2171,Crenolanib,Damnacanthal,Fostamatinib,Motesanib, Radotinib,osi-027,Linsitinib,BIX02189,PF-431396,PND-1186,PF-03814735, PF-431396,sirollmus,temsirolimus,everolimus,deforolimus,Zotarolimus, BEZ235,INK128,Omipalisib,AZD8055,MHY1485,PI-103,KU-0063794, ETP-46464,GDC0349,XL388,WYE-354,WYE-132,GiSK1059615,WAY-600, PF-04691502,wYE-687,PP121,BGT226,AZD2o014,PP242,CH5132799, P529,GDC0980,GDC-0994,XMD82,Ulixertinib,FR180204,SCH772984,Trametinib,PD184352,PD98059,Selumetinib,PD325901,U0126,Pimasertinib, tak-733,AZD8330,Binimetinib,PD318088,SL-327,Refametinib,gdc-0623, Cobimetinib,b1-847325,Adaphostin,GNF2,PPYA,aim-100,ASP 3026,LFM, Toceranib,JQ1,Niraparib,Fuzuopali,palbociclib,ARS-853,ARS-1620, Chlorazol-violet N(直接紫N),miRNA-21,PreS,Zidovudine,Lenvatinib, ARS-1620,Reparixin等。
附图说明
以下各图图例中的“免疫细胞因子”表示Cytokine(包括IFN-γ,IL-12,IL-6,
TNF-α等),代表了免疫细胞激活效应。
图1示出了SZU-GSH系列化合物免疫激活效果。
图2示出了荧光标记的SZU-116在细胞内的分布。
图3示出了SZU-102、103、106、107、108、110、111、114、115、116、117、 118的免疫细胞因子激活效果。
图4示出了SZU-143、144、146、147、149的的免疫细胞因子(IFNγ)激活效 果。
图5示出了SZU-143、144、146、147、149的的免疫细胞因子(IL-12)激活效 果。
图6示出了SZU-143、144、146、147、149的的免疫细胞因子(TNFα)激活效 果。
图7示出了SZU-143、144、146、147、149的的免疫细胞因子(IL-6)激活效果。
图8示出了SZU-145、158、104、109、112、124、126的免疫细胞因子(IFNγ) 激活效果。
图9示出了SZU-145、158、104、109、112、124、126的免疫细胞因子(IL-12) 激活效果。
图10示出了SZU-145、158、104、109、112、124的免疫细胞因子(TNFα)激 活效果。
图11示出了SZU-145、158、104、109、112、124的免疫细胞因子(IL-6)激活 效果。
图12示出了SZU-125的免疫细胞因子激活效果。
图13示出了SZU-105的免疫细胞因子激活效果。
图14示出了SZU-105的免疫细胞因子激活效果。
图15示出了SZU-113的免疫细胞因子激活效果。
图16示出了SZU-113的免疫细胞因子激活效果。
图17示出了SZU-119的免疫细胞因子激活效果。
图18示出了SZU-119的免疫细胞因子激活效果。
图19示出了SZU-120的免疫细胞因子激活效果。
图20示出了SZU-120的免疫细胞因子激活效果。
图21---图58示出了本发明中部分SZU系列免疫激动剂的免疫细胞因子激发效果。
图59示出了SZU-119、125、146、147、169、174、175、168、176、177、179 激活免疫细胞产生IFN-γ的效果。
图60示出了SZU-119、125、146、147、169、174、175、168、176、177、179 激活免疫细胞产生IL-12的效果。
图61示出了新型靶向免疫药物体内抗肿瘤(CT26)活性效果:Veh(未给药对照), A(SZU-177),B(SZU-175),C(SZU-174),D(SZU-147),E(SZU-176)。
图62示出了新型靶向免疫药物体内抗肿瘤(B16)活性效果:Veh(未给药对照), G(PD-L1抗体),H(SZU-178),I(SZU-158-PD-L1),J(SZU-158-OX40),K (PD-1抗体),L(SZU-158-PD-1)。
图63示出了JQ1抑制SZU-101的TLR7激动剂活性;SZU-119保持了TLR7激 动剂的免疫细胞因子激发活性。
图64示出了JQ1抑制SZU-101的TLR7激动剂活性;SZU-119保持了TLR7激 动剂的免疫细胞因子激发活性。
图65示出了SZU-119保持了JQ1对B16细胞的CD274(PD-L1)抑制活性。
图66示出了SZU-163和SZU-166激活免疫细胞产生IFN-γ的效果。
图67示出了SZU-180和SZU-136-miRNA21激活免疫细胞产生IFN-γ的效果。
图68示出了PD-1抗体、PD-L1抗体、OX40抗体、和它们的SZU-158偶联物以 及SZU-178的抗肿瘤(4T1)存活率效果。
图69示出了PD-1抗体、PD-L1抗体和OX40抗体和它们的SZU-158偶联物及SZU-178激活免疫细胞产生IFN-γ的效果。
图70示出了SZU-181激活免疫细胞产生IFN-γ的效果。
图71示出了SZU-106、SZU-158、SZU-160激活免疫细胞产生IFN-γ的效果。
图72示出了SZU-106、SZU-158、SZU-160激活免疫细胞产生IL-6的效果。
图73示出了TLR7免疫激动剂和人体自身miRNA偶联以免疫靶向干扰 Argonaute蛋白的结合,消除其有关的致病作用的作用示意图。
图74示出了本发明中所述免疫靶向药物通过免疫途径清除病原性靶点(蛋白) 的作用示意图。
具体实施方式
本发明有关的化合物合成举例如下,举例方法可以启示本领域技术人员实现本发明中新型化合物的合成,但是可以不局限于举例中的合成方法:
SZU-112
将1g SZU-101,311mg NHS和518mg EDC溶于12mL无水DMF,氮气保护条 件下室温反应2h,TLC监测反应。反应结束后,将反应液倒入水中,析出沉淀, 过滤干燥,得SZU-009T粗品,直接进行下一步反应。
将500mg SZU-009T与339mg Fmoc-D-赖氨酸溶于10mL无水DMF中,室温搅 拌1h。反应完成后,加水析出固体,抽滤。经氯仿:甲醇=3:1柱层析分离, 得白色固体576mg,产率78.9%,ESI-MS:m/z=795.3[M+H]+
SZU-113
称取50mg SZU-112溶于1mL二乙胺中,室温搅拌1h,TLC监测反应进程。反 应完成后,减压除去二乙胺。加入1mL二氯甲烷洗涤,10,000rpm离心5min, 移除上清,沉淀重复洗涤一次。减压干燥,得白色固体32mg,产率90%,ESI-MS: m/z=573.2[M+H]+
SZU-115
将108mg SZU-009T溶于2mL无水DMF中,依次加入31mg SZU-013T和100μL DIEA,室温搅拌过夜,LC-MS监测反应。反应结束后,经制备液相分离,得白 色固体65mg,产率56%,ESI-MS:m/z=582.2[M+H]+
SZU-116
将264mg SZU-017T,324mg HBTU,119mg HOBt溶于5mL无水DMF中,滴加 256μLDIEA,室温搅拌10min。加入5mL SZU-020T(230mg)的无水DMF溶 液后,室温搅拌过夜。将反应液到入100mL 5%HCl中,30mL二氯甲烷萃取3 次,合并有机层,分别用饱和碳酸氢钠溶液,5%HCl,饱和氯化钠溶液洗涤, 经无水硫酸钠干燥,减压除去溶剂,柱层析分离(二氯甲烷:甲醇=50:1),得 紫红色半固体SZU-021T 180mg,产率51.6%。
将28mg SZU-021T溶于0.1mL DMSO中,与0.5mL,97mg TCEP水溶液,0.1mL, 18mgTBTA的DMSO溶液和0.5mL、54mg无水硫酸铜的水溶液混合,加入20mg SZU-115的甲醇/水混合溶液2mL,室温搅拌2h。经柱层析分离得紫红色固体 31mg,产率66%,ESI-MS:m/z=1393.7[M+H]+
SZU-119
称取SZU-009T 667mg,溶于2mL无水DMF中,加入300mg SZU-020T,室温 搅拌过夜。反应完成后,将反应液倒入水中,析出白色固体,干燥得SZU-030T 粗品。
将上一步所得SZU-030T溶于10mL无水THF中,冰浴下加入484mg三苯基膦, 转入室温继续搅拌过夜,LC-MS监测反应。反应毕,加入20mL水,继续搅拌 30min,减压抽滤,水洗两次,干燥得SZU-031T 625mg,两步合并收率79%。 取71mg SZU-031T,42mg(+)-JQ-1-COOH(JQ1活性体),46mg HBTU溶于 2mL无水DMF中,加入催化量的DMAP和DIPEA,室温搅拌24h,LC-MS监 测反应。经制备液相分离,冻干得淡黄色固体27mg,产率27%,ESI-MS:m/z=1001.2[M+H]+
SZU-124
制备方法同SZU-116,只是用FITC替代SZU-017T,得草绿色半固体,两步合 并收率31%,ESI-MS:m/z=1199.5[M+H]+
SZU-125
将34mg SZU-008T溶于500μL无水DMF中,依次加入53mg PD-1/PD-L1 inhibitor(CAS#:1675203-84-5),43mg HBTU,42μL三乙胺以及催化量的DMAP, 室温搅拌5h。反应完成后,经制备液相分离,冻干,得白色固体45mg,产率56%, ESI-MS:m/z=802.3[M+H]+
SZU-127
制备方法同SZU-125,只是用维甲酸替代PD-1/PD-L1inhibitor,得黄色固体,ESI-MS:m/z=627.4[M+H]+
SZU-134
制备方法同SZU-125,只是用戊二酸酐替代PD-1/PD-L1inhibitor,得白色固体,ESI-MS:m/z=459.1[M+H]+
SZU-138
制备方法同SZU-125,只是用衣康酸酐替代PD-1/PD-L1inhibitor,得白色固体,ESI-MS:m/z=457.1[M+H]+
SZU-140
制备方法同SZU-125,只是用乙酸酐替代PD-1/PD-L1inhibitor,得白色固体,ESI-MS:m/z=387.1[M+H]+
SZU-103-GSH(SZU-141)
将SZU-103和等当量谷胱甘肽(Glutathione,GSH)溶于无水DMF中,室温搅拌过夜,LC-MS监测反应。反应结束后,经制备液相分离,得白色固体,产率85%, ESI-MS:m/z=936.2[M+H]+
SZU-142
将5g SZU-005T置于圆底烧瓶中,加入浓盐酸,反应12h,反应毕,低温下用氢 氧化钠调节pH至3~4,析出白色固体4.56g,产率95%,ESI-MS:m/z=345.2[M+H]+
SZU-145
将20mg SZU-138溶于2mL无水DMF中,依次加入8.7mg D-葡糖胺,9.2mg EDC,6.5mg HOBt,室温搅拌2h。反应结束后,经制备液相分离,得白色固体12mg, 产率44%,ESI-MS:m/z=618.2[M+H]+
SZU-114-GSH(SZU-156)
制备方法同SZU-141,只是用SZU-114替代SZU-103,得白色固体,ESI-MS:m/z=763.3[M+H]+
SZU-117-GSH(SZU-157)
制备方法同SZU-141,只是用SZU-117替代SZU-103,得白色固体,ESI-MS:m/z=874.3[M+H]+
SZU-158
制备方法同SZU-141,只是用SZU-138替代SZU-103,2-甲胺乙硫醇替代谷胱甘 肽,得白色固体,ESI-MS:m/z=562.2[M+H]+
SZU-161
制备方法同SZU-141,只是用SZU-138替代SZU-103,SZU-033T替代谷胱甘肽, 得白色固体,ESI-MS:m/z=708.4[M+H]+
SZU-162方法同SZU-161,ESI-MS:m/z=695.81[M+H]+
SZU-160
制备方法同SZU-115,只是用SZU-032T替代SZU-013T,得白色固体,ESI-MS: m/z=599.3[M+H]+
SZU-114:
实验操作:在0℃下,向TL-008的无水DMF溶液中加入HBTU、DMAP和TEA。 室温搅拌0.5h后,在0℃下加入反式-4-二甲氨基巴豆酸盐酸盐。室温反应24h。 将反应液倒入水中,抽滤得到粗品,后经液相分离纯化得纯品(ESI-MS: m/z=456.6[M+H]+)。
实验操作,SZU-001S:
在0℃下,向SZU-101的无水DMF溶液中加入EDCI、HOBt和DIPEA。室温 搅拌0.5h后,在0℃下加入N-Boc哌嗪。室温反应24h。反应液倒入水中,抽 滤得到粗品,后经液相分离纯化得纯品(ESI-MS:m/z=613.4[M+H]+)。
实验操作,SZU-130:
向SZU-001S的二氯甲烷溶液中滴加三氟乙酸。搅拌2h后,减压浓缩反应液。 加入5mL乙醇及2N HCl溶液得到其盐酸盐。减压除去溶剂后,加入乙醚或二 氯甲烷再次减压出除去溶剂,重复多次后得到固体得纯品(ESI-MS:m/z=513.5 [M+H]+)。
实验操作,SZU-117:
在0℃下,向SZU-130的无水DMF溶液中依次加入TEA和丙烯酰氯。室温搅 拌2h后,将反应液倒入水中,抽滤得到粗品,后经液相分离纯化得纯品(ESI-MS: m/z=567.7[M+H]+)。
SZU-118:
实验操作:向SZU-101的无水DMF溶液中加入EDCI和HOBt。搅拌15m后, 在0℃下加入DIPEA。室温反应0.5h后,在0℃下加入盐酸羟胺,室温反应 过夜。将反应液倒入水中,抽滤得到粗品,后经液相分离纯化得纯品(ESI-MS: m/z=460.4[M+H]+)。
SZU-120:
实验操作:向SZU-101的无水DMF溶液中加入EDCI和HOBt。搅拌15m后, 在0℃下加入DIPEA。室温反应0.5h后,在0℃下加入吗啉,室温反应过夜。 将反应液倒入水中,抽滤得到粗品,后经液相分离纯化得纯品(ESI-MS: m/z=514.5[M+H]+)。
SZU-122:
实验操作:在0℃下,向SZU-142的无水DMF溶液中依次加入TEA和丙烯酰 氯。室温搅拌2h后,将反应液倒入水中,抽滤得到粗品,后经液相分离纯化得 纯品(ESI-MS:m/z=399.4[M+H]+)。
SZU-128:
实验操作:向SZU-101的无水DMF溶液中加入EDCI和HOBt。搅拌15m后, 在0℃下加入DIPEA。室温反应0.5h后,在0℃下加入1-甲基哌嗪,室温反 应过夜。将反应液倒入水中,抽滤得到粗品,后经液相分离纯化得纯品(ESI-MS: m/z=527.7[M+H]+)。
SZU-129:
实验操作:向SZU-101的无水DMF溶液中加入EDCI和HOBt。搅拌15m后, 在0℃下加入DIPEA。室温反应0.5h后,在0℃下加入硫吗啉,室温反应过 夜。将反应液倒入水中,抽滤得到粗品,后经液相分离纯化得纯品(ESI-MS: m/z=530.6[M+H]+)。
SZU-131:
实验操作:向SZU-101的无水DMF溶液中加入EDCI和HOBt。搅拌15m后, 在0℃下加入DIPEA。室温反应0.5h后,在0℃下加入1-乙酰基哌嗪,室温 反应过夜。将反应液倒入水中,抽滤得到粗品,后经液相分离纯化得纯品 (ESI-MS:m/z=555.6[M+H]+)。
SZU-132:
实验操作:向SZU-101的无水DMF溶液中加入EDCI和HOBt。搅拌15m后, 在0℃下加入DIPEA。室温反应0.5h后,在0℃下加入吡咯烷,室温反应过 夜。将反应液倒入水中,抽滤得到粗品,后经液相分离纯化得纯品(ESI-MS: m/z=498.5[M+H]+)。
SZU-133:
实验操作:向SZU-142的无水DMF溶液中加入马来酸酐。反应过夜后,将反应 液倒入水中,抽滤得到粗品,后经液相分离纯化得纯品(ESI-MS:m/z=443.3[M +H]+)。
SZU-143:
实验操作:向富马酸单甲酯的无水DMF溶液中加入EDCI和HOBt。搅拌15m 后,在0℃下加入DIPEA。室温反应0.5h后,在0℃下加入SZU-142,室温 反应过夜。将反应液倒入水中,抽滤得到粗品,后经高效液相HPLC分离纯化得 纯品(ESI-MS:m/z=457.4[M+H]+)。
SZU-144:
实验操作:向SZU-143的甲醇/水(1:1)混合溶液中加入氢氧化钠(1.1eq)。室温搅拌8小时反应完成后用1N HCl溶液中和反应液,经抽滤、水洗得到粗品,后经 高效液相HPLC分离纯化得纯品(ESI-MS:m/z=443.5[M+H]+)。
SZU-146:
实验操作:向SZU-101的无水DMF溶液中加入EDCI和HOBt。搅拌15m后, 在0℃下加入DIPEA。室温反应0.5h后,在0℃下加入3-(三氟甲基)-5,6,7,8- 四氢-[1,2,4]三唑并[4,3-a]吡嗪(Fuzuopali中间体),室温反应过夜。将反应液倒 入水中,抽滤得到粗品,后经液相分离纯化得纯品(ESI-MS:m/z=619.6[M+H]+)。 SZU-147:
实验操作:向SZU-101的无水DMF溶液中加入等摩尔的EDCI和HOBt。搅拌 15m后,在0℃下加入DIPEA。室温反应0.5h后,在0℃下加入等摩尔的 Niraparib,室温反应过夜。将反应液倒入水中,抽滤得到粗品,后经高效液相 HPLC分离纯化得纯品SZU-147(ESI-MS:m/z=747.77[M+H]+)。
SZU-148:
实验操作:将1:1的氢氧化锂和SZU-101加入水中,搅拌2-3h,后冻干除去溶 剂得纯品。
SZU-150,151,152and 153:
实验操作,SZU-151:向N,N-二甲基乙醇胺中加入金属Na,形成钠盐后,向反 应液中加入起始原料,加热至95℃反应3h。减压除去溶剂后加入水,抽滤得 到固体,水洗至pH值7-8后,减压干燥得纯品SZU-151。
实验操作,SZU-152:向SZU-151的乙酸溶液中缓慢滴加溴素。搅拌过夜后,用NaHCO3中和反应液。向所得粘性化合物中加如少许乙醇。后加入硫代硫酸钠溶 液除去剩余溴。抽滤并干燥所得固体后,加入10%NaOH溶液,再次抽滤后减 压干燥。制备液相纯化得溴化物。
向甲醇中加入金属Na,搅拌后加入起始原料,加热至80℃反应2h。减压除去 甲醇,用HCl中和。抽滤并减压干燥所得固体SZU-152。
实验操作,SZU-150和SZU-153:将SZU-152加入HCl并搅拌12h。减压除去 溶液,经液相制备分离后得到化合物SZU-150(ESI-MS:354.5[M+H]+)和 SZU-153(ESI-MS:m/z=372.4[M+H]+)。
SZU-154:
实验操作:向SZU-152的乙醇/水(1:1)混合溶液中加入NaOH,回流过夜。减压 浓缩,调pH至3。液相制备纯化得纯品SZU-154(ESI-MS:m/z=387.5[M+H]+)。
SZU-155:
实验操作:将SZU-154溶解于浓HCl并搅拌过夜。减压除去溶剂,制备液相纯 化得纯品SZU-155(ESI-MS:m/z=373.5[M+H]+)。
SZU-104:
SZU-104实验操作:将50mg SZU-102溶于0.5mL DMSO中,加入41mg Boc 保护的赖氨酸,室温搅拌过夜。反应结束后,冻干除去DMSO,经制备液相分 离,得到白色固体69mg,收率85%,ESI-MS:m/z=633.7[M+H]+。
SZU-105:
SZU-105实验操作:将50mg SZU-102溶于0.5mL DMSO中,加入47mg Boc 保护的赖氨酸,室温搅拌过夜。反应结束后,冻干除去DMSO,经制备液相分 离,得到白色固体68mg,收率83%,ESI-MS:m/z=533.6[M+H]+。
SZU-108:
SZU-108实验操作:将109mg SZU-102溶于1mL DMSO中,加入50mg PEG2, 室温搅拌过夜。反应结束后,冻干除去DMSO,经制备液相分离,得到白色固 体125mg,收率79%,ESI-MS:m/z=564.6[M+H]+。
SZU-109:
SZU-109实验操作:将87mg SZU-102溶于0.9mL DMSO中,加入50mg PEG3, 室温搅拌过夜。反应结束后,冻干除去DMSO,经制备液相分离,得到白色固 体105mg,收率77%,ESI-MS:m/z=608.7[M+H]+。
SZU-110:
SZU-110实验操作:将193mg羧基化合物溶于2mL DMSO中,依次加入100mg EDCI和59mg NHS,室温搅拌两小时后,向反应液中加入50mg PEG2,室温搅 拌过夜。反应结束后,冻干除去DMSO,经制备液相分离,得到白色固体203mg, 收率73%,ESI-MS:m/z=519.5[M+H]+。
SZU-111:
SZU-111实验操作:将155mg羧基化合物溶于1.5mL DMSO中,依次加入79mg EDCI和47mg NHS,室温搅拌两小时后,向反应液中加入50mg PEG3,室温搅 拌过夜。反应结束后,冻干除去DMSO,经制备液相分离,得到白色固体174mg, 收率72%,ESI-MS:m/z=563.6[M+H]+。
SZU-149和SZU-163的合成
将100毫升的无水正丁醇中,与0℃下缓慢加入0.5克的金属钠。30分钟后, 加入3克的反应物a,反应物于100℃搅拌8小时,冷却到室温,倾倒大量水中, 析出黄色固体过滤,用四氢呋喃洗三次,干燥得产物b 2.5克。
将2.5克b与100毫升的氯仿混合搅拌均匀,加入10毫升的溴素,室温反应24 小时,过滤得产物c 2.2克。将产物c与二氧六环60毫升混合,加入浓盐酸10 毫升,混合物于110℃反应12小时,反应物倾入600毫升水中,析出固体粗品, 产物过滤,溶解于60毫升的1N NaOH中,冷却下用盐酸中和到pH4,析出纯品, 干燥后得SZU-149:1克,收率55%。MS(ESI):m/z:[M+Na]381.42。
将0.5克SZU-149溶解于无水甲醇,加入蓝尼镍0.5克,于氢气压力3个大 气压下氢化反应24小时,过滤,减压蒸馏得SZU-163纯品,0.4克收率89%; MS(ESI):m/z:[M+H]329.41。
SZU-166、SZU-181的合成
取SZU-163 1.5克溶解在30毫升的DMSO中,加入1毫升三乙胺,0.5克的氯 甲酸乙酯;混合物室温搅拌2小时。混合物真空蒸馏至少量体积,冷却至室温, 加入30毫升乙酸乙酯,析出固体,过滤,乙酸乙酯洗,干燥得到SZU-166纯品 0.75克,收率46%,MS(ESI):m/z:[M+H]355.40.
SZU-181的合成:
免疫激动剂偶联靶向乙肝PreS抗原表位的合成
取SZU-166(10mg)与PreS-Peptide(90mg)混合溶液与3毫升的DMF中, 加入0.2毫升的三乙胺,混合物于20℃搅拌反应24小时。加入3毫升的二氯甲 烷,产品沉淀离心分离,粗品HPLC分离纯化,冷冻干燥得SZU-181,65mg。质 谱确定分子量:3512.80:(1756.3x2),(1170.9x3)。
SZU-136和:SZU-139的合成
步骤1:将EDCI和HOBt加入等摩尔数的4-戊炔酸的DMF溶液中,15分钟后 加入三乙胺,反应与0℃搅拌15分钟后,继续室温搅拌反应30分钟,然后加入 等摩尔的TL-008与室温反应过夜。反应也倾倒与水中,析出的产品过滤,真空 干燥后得SZU-136收率87%,MS(ESI):m/z:[M+1]425.51.
步骤2:将SZU-136、叠氮化合物2、抗坏血酸钠以等摩尔加入DMSO和水的 1:1溶液中,于室温搅拌过夜,加入10倍体积的水,过滤,HPLC纯化,干燥得 SZU-139,收率77%,MS(ESI):m/z:[M+1]654.72.
SZU-169的合成
OX40agonist synthesis
将SZU-134溶解于DMSO中,加入等摩尔的NHS和EDCI,搅拌10分钟后, 加入等摩尔的直接紫N(OX40agonist)。反应物室温密闭反应3天。反应物加入 20倍的水,析出的固体过滤,加入2N的NaOH与10℃搅拌30分钟,过滤, 滤液用2N盐酸酸化到PH1,析出固体产品SZU-169,收率52%,MS(ESI):m/z: [M+2Na]1611.64
SZU-136-阿法替尼偶联合成(SZU-174):
将a反应物溶解于少量DMF中,加入一倍当量的叠氮化钠,于室温搅拌反应24 小时,反应物中加入10倍量体积的水,用乙酸乙酯提取,提取相用水洗三次, 减压蒸馏除去溶剂,得产物b,收率90%。
将阿法替尼(Afatinib)100毫克和50毫克b溶解于15毫升的DMF中,加入微 量的NaI,于60℃反应24小时;向反应混合物加入正丁醇100毫升,混合物减 压蒸馏至少量体积(约5毫升),冷却至室温,加入50毫升的乙酸乙酯,析出固 体产品c,真空干燥得118毫克产物c,MS(ESI):m/z:[M+H]688.21。
将产物c 100毫克、60毫克SZU-136、10毫克硫酸铜、30毫克微生素C加入DMSO 和水的1:1溶液中,于室温搅拌过夜,加入10倍体积的水,过滤,HPLC纯化, 干燥得SZU-174,105毫克,收率65%,MS(ESI):m/z:[M+1]1112.70.
SZU-158偶联PD-1抗体反应(制备SZU-158-PD-1):
取5毫克的SZU-158,溶解于0.5毫升的DMSO中,加入等摩尔的NHS和EDCI, 室温搅拌4小时。将PD-1抗体20毫克(购自Bioxcell,J43)的0.5毫升PBS 溶液加入,混合物于密闭15℃搅拌过夜。混合反应液用滤膜过滤,得
SZU-158-PD-1偶联产物,冷冻干燥得白色固体SZU-158-PD-1,18毫克。质谱 检测偶联度为n=4.(SZU-158-PD-1的免疫细胞因子活性和抗体功能见图69、 62和68)。
SZU-158偶联OX40抗体反应(制备SZU-158-OX40):
取5毫克的SZU-158,溶解于0.5毫升的DMSO中,加入等摩尔的NHS和EDCI, 室温搅拌4小时。将OX40抗体20毫克(购自Bioxcell,OX-86)的0.5毫升PBS 溶液加入,混合物于密闭15℃搅拌过夜。混合反应液用滤膜过滤,得
SZU-158-OX40偶联产物,冷冻干燥得白色固体SZU-158-OX40,17毫克。质谱 检测偶联度为n=4.(SZU-158-OX40的免疫细胞因子活性和抗体功能见图69、 62和68)。
SZU-158偶联PD-L1抗体反应(制备SZU-158-PD-L1):
取5毫克的SZU-158,溶解于0.5毫升的DMSO中,加入等摩尔的NHS和EDCI, 室温搅拌4小时。将PD-L1抗体20毫克(购自Bioxcell,10F.9G2)的0.5毫升 PBS溶液加入,混合物于密闭15℃搅拌过夜。混合反应液用滤膜过滤,得 SZU-158-PD-L1偶联产物,冷冻干燥得白色固体SZU-158-PD-L1,15毫克。质 谱检测偶联度为n=4.(SZU-158-PD-L1的免疫细胞因子活性和抗体功能见图69、 62和68)。
SZU-168、SZU-175的合成:
Vemu-1是Vemurafenib的前体,购自药明康德公司。
将Vemu-1溶解于DMF中,加入2倍摩尔的三乙胺,冷却至0℃,加入1倍摩 尔的乙烯基磺酰氯,混合物缓慢升至室温搅拌8小时,混合物加入10倍体积的 冰水,充分搅拌1小时,饱和Na2CO3调节pH至8,析出固体,过滤,水洗2 次,干燥得Vemu-2。将1克Vemu-2溶解在30毫升的DMF中,加入0.33克的 巯基乙胺,混合物室温搅拌12小时,反应物减压蒸馏除溶剂,得Vemu-3粗品, 硅胶柱层析分离得Vemu-3纯品0.98克,收率85%,MS(ESI):m/z:[M+1]552.04。 将0.3克Vemu-3溶解在10毫升的DMSO中,加入0.2克的SZU-166,混合物 于40℃搅拌反应8小时,加入100毫升水,离心沉淀得粗品,粗品溶解在20 毫升的冰醋酸中,过滤后,滤液加入100毫升的水,析出纯品SZU-168,干燥得 0.33克,MS(ESI):m/z:[M+1]906.41。
将1克SZU-158溶解在10毫升的DMSO中,加入0.2克NHS (N-hydroxysuccinimide)、0.33克的EDCI(1-(3-Dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride),混合物室温搅拌过夜得SZU-137。加入0.9 克Vemu-3,室温继续搅拌12小时,混合物加入100毫升水,过滤,得粗品,用 乙酸重结晶,得SZU-175醋酸盐1.22克,MS(ESI):m/z:[M+1]1095.81。
SZU-176合成:
Osimertinib中间体购自药明康德公司。
将1克SZU-144溶解在10毫升的DMSO中,加入0.26克NHS、0.4克的EDCI, 混合物室温搅拌过夜。加入1克Osimertinib中间体,室温继续搅拌12小时,混 合物加入100毫升水,过滤,得粗品,用乙酸重结晶,得SZU-176醋酸盐1.5 克,MS(ESI):m/z:[M+1]870.81。
SZU-177合成:
将100毫克Erlotinib、150毫克SZU-160、20毫克硫酸铜、20毫克微生素C加 入DMSO和水的1:1溶液中(10毫升),于室温搅拌过夜,加入10倍体积的水, 过滤,HPLC纯化,干燥得SZU-177,176毫克,收率70%,MS(ESI):m/z:[M+1] 993.10。
SZU-160-Erlotinib-PD-L1抗体(SZU-178)的制备:
取3.5毫克的SZU-160,溶解于0.5毫升的DMSO中,加入等摩尔的NHS和EDCI, 室温搅拌4小时。将PD-L1抗体20毫克(购自Bioxcell,10F.9G2)的0.5毫升 PBS溶液加入,混合物于密闭15℃搅拌过夜。混合反应液用滤膜过滤,得 SZU-160-PD-L1抗体偶联产物溶液;将2.5毫克的Erlotinib、2毫克的抗坏血酸 钠、2毫克的硫酸铜加入,混合物室温搅拌反应12小时,反应液用滤膜过滤,冷 冻干燥得白色固体SZU-160-Erlotinib-PD-L1抗体(SZU-178),12毫克。质谱检 测偶联度为n=4.(SZU-178的激发免疫细胞因子和抗肿瘤功能见附图)。
SZU-136-miRNA21的合成:
将71毫克的miRNA21(购自苏州吉玛基因股份有限公司)溶于10毫升的乙腈 和水1:1的溶剂中,加入14毫克的Ag2CO3,混合物于室温搅拌12小时,减压 蒸除溶剂得Ag-miRNA21,69毫克(96%)。将此Ag-miRNA21与氯化叠氮物5 毫克混合于20毫升的乙腈,混合物加热回流4小时,冷却到室温,加入50毫升 水,搅拌15分钟后,过滤。滤液减压蒸馏至少量体积(10毫升),加入50毫升 的四氢呋喃,搅拌10分钟后,离心沉淀,沉淀真空干燥得N3-miRNA21,45毫 克(收率61%)。MS(ESI):m/z:[M+Na]7307.42。
取40毫克的N3-miRNA21、3毫克的SZU-136、2毫克的硫酸铜,2毫克的维生 素C,混合加入DMSO和水的1:1溶液中(10毫升),于室温搅拌过夜,产物 HPLC纯化,冷冻干燥,真空干燥得SZU-136-miRNA21,14毫克,收率33%, MS(ESI):m/z:[M+Na]7731.86。
SZU-179合成:
取580毫克的SZU-115、267毫克的Zidovudine,25毫克的硫酸铜,25毫克的抗 坏血酸钠,混合加入DMSO和水的1:1溶液中(25毫升),于室温搅拌过夜,加 入10倍体积的水,真空蒸馏至较少体积(约10毫升),加入30毫升水,混合液 用5%NaOH调节到pH10,过滤,滤液用冰乙酸调节为pH5,析出产物,过滤出 产品,真空干燥得SZU-179,728毫克,收率86%,MS(ESI):m/z:[M+Na]871.42。
SZU-115偶联PD-L1抗体和靶向药的制备(制备SZU-115-PD-L1-靶向药):
SZU-180制备方法:
偶联PD-L1抗体方法与SZU-178制备中相同、click反应方法与SZU-179制备中 相同。可用于治疗艾滋病。
检测本发明SZU系列免疫激动剂和新型免疫靶向药对脾淋巴细胞的免疫激发作用方法(Elisa法):
(一)、脾淋巴细胞的提取
(1)取BALB/c或者C57BL/6小鼠脾,用含小鼠淋巴细胞分离液的小皿内研磨, 经0.22μm滤膜过滤后得到细胞悬液。经离心处理得到淋巴细胞。将取出的淋巴细 胞放入15ml离心管内并加入10ml1640培养基,混匀。转速250g离心10min,弃上 清。
(2)用1ml红细胞裂解液重悬细胞,裂解1分钟后加4ml1640完全培养基终止。 转速1000rpm,离心5分钟,弃上清。
(3)用2ml1640完全培养基重悬细胞并计数,将细胞按照1X106个/孔种于24 孔板内。
(二)获取样品
用不同浓度的发明SZU系列免疫激动剂和新型免疫靶向药刺激接种于24孔板 内的脾淋巴细胞,将24孔板移入孵箱,刺激24小时候轻轻吸取上清,即为Elisa 检测的样品。浓度和浓度梯度由各个测定样品的需要而定。
(三)Elisa检测
(1)包被:10X包被缓冲液稀释到1X后,用于稀释capture antibody。96孔酶 标板内加入稀释后的capture antibody,每孔100μl,用保鲜膜封好放置在37℃2-4 小时或者4℃冰箱过夜。吸去酶标板内的液体,用洗涤缓冲液(PBST:PBS溶液 加千分之五Tween-20)洗板三次,拍干。
(2)封闭:每孔加入μl 200已稀释的封闭液,用保鲜膜封好,室温封闭一小 时。用PBST洗板三次,拍干。
(3)加样品:设置12个标准品,每个标准品浓度设立2个复孔。标准品最高 浓度为2000pg/mL,用稀释缓冲液倍比稀释至所需浓度。标准品浓度依次为:2000 pg/mL,1000pg/mL,500pg/mL,250pg/mL,125pg/mL,62.5pg/mL,31.5pg/mL,15.75pg/mL,7.875pg/mL,3.9375pg/mL,1.96875pg/mL,0pg/mL。将不同浓 度的药物刺激脾淋巴细胞得到的上清样品加入到对应的孔内,每个样品设置三个 复孔,另需设置空白对照孔和阴性对照孔,并作好相应的标记。将加好标准品和 样品的96孔酶标板用保鲜膜封好,室温孵育2小时或者4℃冰箱过夜。吸去板内液 体,用PBST洗板三次,拍干。
(4)二抗:用稀释缓冲液将detection antibody稀释到所需浓度,每孔加入100 μl,室温孵育1小时。吸去板内液体,用PBST洗涤五次,拍干。
(5)加酶标抗体:用稀释缓冲液将Avidin-HRP稀释到所需浓度,每孔加入 100μl,室温孵育30分钟。吸去板内液体,用PBST洗板五次,拍干。
(6)显色:每孔加入100μl TMB显色液,室温避光孵育15分钟。
(7)终止:显色完成后,每孔加入50μl终止液,终止液为1mol/L H2SO4。
(8)检测:将终止后的96孔酶标板放入全波长酶标仪内,在450nm波长处 读取吸光度值。将数据导出,用软件作出标准曲线图,并得出线性回归方程。计 算出免疫细胞产生免疫因子(INF-γ、IL-6等)的浓度。
本发明免疫靶向药的抗肿瘤效果实验方法:
1、小鼠种瘤protocol:
(1)将6—8周龄的BALB/c或者C57BL/6小鼠称重,按50mg/kg i.p.戊巴比妥麻 醉,种植瘤部位(背部)剃毛,胶带固定。
(2)用棉签蘸取75%酒精在手术部位消毒,在种植瘤部位开1cm左右小口,向里 注入100ul肿瘤细胞悬液(5*104个,CT26细胞、B16细胞或4T1细胞)。用手术 线缝合,消毒。术后连续3天腹腔注射5万单位氨苄青霉素/100μL/只。
2、给药:
分别用PBS空白对照、免疫激动剂、或靶向药(或抗体)对照给药。对照药和新 型靶向免疫药物的给药剂量为按照实际需要而定(有效、安全剂量原则),溶解 在适当的溶剂,每次给药体积100μL;各组给药方式为腹腔注射。在种植肿瘤后 的第7天,第15、22、29天各组分别给药;并定期量瘤大小。当肿瘤达到1500立 方毫米或者大于体重的15%时将小鼠安乐死。肿瘤抑制和存活率结果见附图。可 见本发明中新型免疫靶向药处理组具有显著提高的抗肿瘤效应。
说明:本说明中的新型免疫激动剂和新型免疫靶向药物的生物活性测试方法不局限于上述的测试方法,也可使用其它相关公知或公认的活性测试方法。同理本发 明中的有关活性示意图也不局限于所表示的一种图示方法,图示方法可以启示本 领域技术人员实现本发明中新型化合物的应用效果。
Claims (15)
1.本发明中的所述的免疫激动剂链接靶向药形成免疫靶向化合物通式表达如下:
其中TLA代表小分子免疫激动剂(TLR7 Agonists),Tar表示靶向药,其代表同说明中的靶向药或抗体,如TKI(tyrosine kinase inhibitor),EGFR抑制剂,KRAS抑制剂,BRAF抑制剂,BTK抑制剂,BRD4抑制剂,PD-L1抑制剂,PD-1抑制剂,OX40激动剂,PARP抑制剂,以及CDK4/6抑制剂等;n、m可以是一个或者几个,一般为1---5之间的数值。L代表连接链(Linker),可以是各种直链和支链的烷烃或者聚乙二醇链,包括可能需要降解的的功能链,或者增加溶解性的链。包括如下链:
链中包括了增加溶解性的聚乙二醇基团,也包括了2个叔胺的碱性基团可以形成各种盐。连接链的两端可以是酰胺、烷氧键、烷硫键、取代胺基、季胺盐、cilck反应形成的杂环、可以蛋白酶(Cathepsin)解离的氨基酸基团、脲基团和硫脲基团等。通式中的TLA和Tar都和L共价键链接。
2.根据权利要求1所述的免疫靶向化合物(通式),其代表化合物为如下所示的SZU系列化合物:
SZU-116,SZU-119,SZU-124,SZU-125,SZU-147,SZU-168,SZU-169,SZU-174,SZU-175,SZU-176,SZU-177,SZU-178,SZU-179,SZU-180,SZU-181,SZU-158-PD-L1抗体,SZU-158-OX40抗体,SZU-158-PD-1抗体,SZU-136-miRNA21。
3.根据权利要求1所述的小分子免疫激动剂(TLA),代表化合物为如下SZU-XYZ(或SZUXYZ)的系列化合物,其中的XYZ代码如下:
104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、142、143、144、145、146、147、158、160、161、162、163、166;
TLA也代表以下α,β-不饱和羰基系列免疫激动剂与谷胱甘肽(GSH)加成产物:SZU-103-GSH,SZU-114-GSH,SZU-117-GSH,SZU-122-GSH,SZU-127-GSH,SZU-133-GSH,SZU-138-GSH,SZU-144-GSH。
4.根据权利要求1中所述的靶向药(Tar),选择包括至少一种以下的各类靶向致病靶点的药:EGFR抑制剂,TKI(tyrosine kinase inhibitor),BRD4抑制剂,KRAS通路相关靶点抑制剂,BRAF抑制剂,BTK抑制剂,PARP抑制剂,PD-L1抑制剂(包括抗体,小分子),PD-1抑制剂(包括抗体,小分子),OX40激动剂(包括抗体,小分子),CD122抗体,CD3抗体,CD19抑制剂,CD20抑制剂,MUC1抑制剂,MUC16抑制剂,CDK4/6抑制剂,TGF-β抑制剂,CXCR抑制剂,CCL和CXCL趋化因子抑制剂,以及miRNA等,其中的小分子靶向药至少是如下的一个:
Dasatinib,Imatinib,Saracatinib,Ponatinib,Nilotinib,Danusertib,AT9283Degrasyn,Bafetinib,kw-2449,nyp-bhg712,dcc-2036,GZD824.,GNF-2,PD173955,GNF-5,Bosutinib,Gefitinib,Erlotinib,Sunitinib,Ruxolitinib,Tofacitinib,Lapatinib,Vandetanib,Sorafenib,Sunitinib,Axitinib,Nintedanib,Regorafenib,Pazopanib,Lenvatinib,Crizotinib,Ceritinib,Cabozantinib,DWF,Afatinib.Ibrutinib,Niraparib,Palbociclib,B43,KU004,Foreinib,KRCA-0008,PF-06439015,PF-06463922,Canerlinib,GSA-10,GW2974,GW583340,W24002,CP-380736,D2667,Mubritinib,PD153035,PD168393,Pelitinib,PF-06459988,PF06672131,PF-6422899,PKI166,ReveromycinA,Tyrphostin 1,tyrphostin23,lyrphostin51,Tyrphostin,AG528,Tyrphostin,AG658,Tyrphostin,AG825,Tyrphostin,AG835,Tyrphostin,AG1478,Tyrphostin,RG13022,Tyrphostin,RG14620,B178,GSK1838705A,PD-161570,PD173074,SU-5402,Roslin2,Picropodophyllotoxin,PQ401,i-ome-tyrphostin,AG538,GNF5837,GW441756,Tyrphostin,AG879,DMPQ,jnj-10198409,PLX647,Trapidil,TyrphostinA9,Tyrhostin,AG370,Lestaurtinib,DMH4,Eldanamvcin,Genistein,Gw2580,HerbimycinA,Lavendustin,CMidostaurin,nvp-bhg712,PD158780,pd-166866,pf-0627334,PP2,RPL,SU11274,SU5614,Symadex,Tyrphostin,AG34,Tyrphostin,AG974,Tyrphostin,AG1007,UNC2881,Honokiol,SU1498,SKLB1002,cp-547632,jk-p3,KRN633,sc-1,ST638,SU 5416,Sulochrin,Tyrphostin,SU1498,rociletinib,Dacomitinib,Tivantinib,Neratinib,Masitinib,Vatalanib,Icotinib,xl-184,osi-930,AB1010,Quizartinib,AZD9291,Tandutinib,HM61713,Brigantinib,Vemurafenib(plx-4032),Semaxanib,AZD2171,Crenolanib,Damnacanthal,Fostamatinib,Motesanib,Radotinib,osi-027,Linsitinib,BIX02189,PF-431396,PND-1186,PF-03814735,PF-431396,sirollmus,temsirolimus,everolimus,deforolimus,Zotarolimus,BEZ235,INK128,Omipalisib,AZD8055,MHY1485,PI-103,KU-0063794,ETP-46464,GDC0349,XL388,WYE-354,WYE-132,GiSK1059615,WAY-600,PF-04691502,wYE-687,PP121,BGT226,AZD2o014,PP242,CH5132799,P529,GDC0980,GDC-0994,XMD82,Ulixertinib,FR180204,SCH772984,Trametinib,PD184352,PD98059,Selumetinib,PD325901,U0126,Pimasertinib,tak-733,AZD8330,Binimetinib,PD318088,SL-327,Refametinib,gdc-0623,Cobimetinib,b1-847325,Adaphostin,GNF2,PPYA,aim-100,ASP 3026,LFM,Toceranib,JQ1,Niraparib,Fuzuopali,palbociclib,ARS-853,ARS-1620,Chlorazol-violet N(直接紫N),miRNA-21,PreS,Zidovudine,Lenvatinib,LY-364947,ARS-1620,Reparixin等。
5.根据权利要求1---3中的免疫激动剂和免疫靶向化合物及其它们的盐,在制备免疫调节药物中的应用。
6.根据权利要求1---3中的免疫激动剂和免疫靶向化合物及其它们的盐,在制备抗肿瘤药物,抗病毒药物和靶向清除蛋白的药物中的应用。
7.根据权利要求3中的免疫激动剂及其它们的盐,在偶联靶向药和抗体、及其偶联和联合其它化合物药物中应用。
8.根据权利要求1---3中的免疫激动剂和免疫靶向化合物及其它们的盐,在制备各种药物用途的制剂中的应用,包括各种固体制剂,液体制剂,及其与各种载体形成的复合物,或结晶水复合物。
9.根据权利要求1---3中的免疫激动剂,其中的SZU-116和SZU-124具有免疫激动剂发色指示剂的光学示踪特性,根据此特性偶联蛋白或者靶向药,在观察研究蛋白或靶向药的细胞吸收和体内分布中的应用。
10.根据权利要求1---3中的免疫激动剂,SZU-161和SZU-162作为具有的特异紫外吸收小分子免疫激动剂,在测定免疫激动剂偶联蛋白药物和细胞的偶联度中的应用。
11.根据权利要求1---3中的免疫激动剂,其中的α,β-不饱和羰基系列化合物SZU-114、SZU-117、SZU-122、SZU-127、SZU-133、SZU-138、SZU-143在和靶向药偶联形成免疫靶向双功能药物中的应用。
12.根据权利要求1---3中的免疫激动剂,其中的SZU-166作为异氰酸酯类小分子免疫激动剂,在和多肽、抗体、靶向药物、氨基化合物偶联加成制备药物中的应用。
13.根据权利要求1---3中的免疫激动剂,其中的SZU-115、SZU-136和SZU-160作为具有click反应基团的新型小分子免疫激动剂,在形成和制备免疫靶向药物中的应用。
14.根据权利要求1---3中的免疫激动剂,其中的SZU-136-miRNA21及其类似物作为免疫靶向的小分子RNA在制备免疫靶向RNA药物中的应用。
15.根据权利要求1---3中的免疫激动剂,其中的SZU-179、SZU-180和SZU-181作为抗病毒免疫激动剂在制备抗艾滋病和抗乙肝药物中的应用。
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