CN116396270A - 一种苯并[b]硒吩类STING激动剂荧光探针分子及其用途 - Google Patents
一种苯并[b]硒吩类STING激动剂荧光探针分子及其用途 Download PDFInfo
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- CN116396270A CN116396270A CN202310321058.5A CN202310321058A CN116396270A CN 116396270 A CN116396270 A CN 116396270A CN 202310321058 A CN202310321058 A CN 202310321058A CN 116396270 A CN116396270 A CN 116396270A
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- 229940044665 STING agonist Drugs 0.000 title claims abstract description 46
- 239000007850 fluorescent dye Substances 0.000 title claims abstract description 27
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 125000006239 protecting group Chemical group 0.000 claims abstract description 7
- 230000008878 coupling Effects 0.000 claims abstract description 4
- 238000010168 coupling process Methods 0.000 claims abstract description 4
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- 238000002360 preparation method Methods 0.000 claims description 60
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- 239000001257 hydrogen Substances 0.000 claims description 42
- 150000002431 hydrogen Chemical class 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 15
- 230000037361 pathway Effects 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
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Abstract
本发明公开了一种苯并[b]硒吩类STING激动剂荧光探针分子，所述荧光探针分子为苯并[b]硒吩类单体或其二聚体STING激动剂与光激活保护基团偶联得到的化合物、立体异构体或其药学上可接受的盐。这些分子能通过特定波长的光照释放出STING激动剂，从而实现STING激活的时空可控。本发明还提供了这些化合物在制备诊断和治疗STING相关疾病药物中的用途，以及在制备活体荧光成像试剂中的用途。
Description
技术领域
本发明属于化学医药技术领域，涉及一种苯并[b]硒吩类STING激动剂荧光探针分子及其用途。
背景技术
免疫疗法的出现为治愈肿瘤提供了卓越的治疗效果以及全新的研究思路，被Science杂志评为2013年最重要的科学突破(Science 2013,342,1417)。环鸟苷酸-腺苷酸合酶(cyclic GMP-AMP synthase,cGAS)-干扰素基因刺激蛋白(stimulator ofinterferon genes,STING)通路是体内重要的固有免疫通路。cGAS作为模式识别受体，能捕捉、识别胞质异常DNA信号，催化第二信使环鸟腺苷酸(Cyclic GMP-AMP,cGAMP)的生成，从而激活内质网膜受体STING，进而启动下游转录因子的激活，最终促进I型干扰素和促炎因子的表达与分泌，增强固有免疫及获得性免疫应答(Drug Discov Today 2020,25,230-237)。近年来，cGAS-STING通路被认为是肿瘤免疫治疗的重要潜在靶点(J Hematol Oncol2019,12,35)。而在cGAS-STING通路中，跨膜受体STING又被认为是调控该通路最为关键的节点。在临床前小鼠肿瘤模型中，STING激动剂显示出高效的抗肿瘤活性，能够完全抑制肿瘤生长，使肿瘤完全清除(Nature.2018,564,439-443；Science.2020,369,eaba6098；Science.2020,369,993-999)。
到目前为止，国内外多家制药公司对STING激动剂的研发管线进行了布局，其中包括Aduro BioTech的ADU-S100，Merck的MK-1454等多个STING激动剂先后进入临床试验用于多种肿瘤的治疗。然而，STING激动剂全身给药具有引起全身炎症反应的风险，限制了该类药物的临床发展(J Clin Med 2020,9,3323)。因此，目前亟需新一代具有肿瘤选择性的STING激动剂。
通过光激活保护基团(Photoactivatable protecting groups,PPGs)使分子的药理活性被封闭，然后再利用光化学的非侵袭性及时空可控性释放出活性分子及荧光基团，可以完成对疾病的精准治疗及荧光成像，实现诊疗一体化。近年来，这种通过紫外-可见光-近红外光激活的PPGs已经得到了充分的发展(Chem Rev 2020,120,13135-13272)。其中，通过紫外-可见光激活的邻硝基苄基衍生物、香豆素衍生物和通过近红外光激活的七甲川花菁衍生物是应用较为广泛的几种PPGs。
为了克服目前STING激动剂全身给药带来的毒副作用问题，以及为了实现疾病的诊疗一体化，开发一种STING激动剂荧光探针分子具有重要意义。
发明内容
发明目的：本发明旨在通过利用光的时空可控性，提供了一系列苯并[b]硒吩类STING激动剂与PPGs相偶联得到的荧光探针分子，从而实现定时和定点释放以及具有良好成药性和药物代谢动力学性质。这些分子在特定波长的光照下能迅速释放出荧光基团及有效的STING激动剂，实现选择性的STING激活，从而实现疾病的诊疗一体化，克服目前STING激动剂全身给药带来的毒副作用问题。
本发明提供了一种苯并[b]硒吩类STING激动剂荧光探针分子，所述荧光探针分子为苯并[b]硒吩类单体或其二聚体STING激动剂与光激活保护基团偶联得到的化合物、立体异构体或其药学上可接受的盐。
所述光激活保护基团为邻硝基苄基衍生物X1、香豆素衍生物X2或七甲川花菁衍生物X3：
其中，
R1选自氢、甲基或烯丙基；
R2选自氢、羟基、甲基、叔丁基、甲氧基、OCH2CN、OCH2COOH、OCH2COOCH3或对位取代的苯乙烯基；
所述对位取代基包括但不局限于OH、OC1～C3烷基、OC1～C3卤代烷基、CHO和COOH)；
R3选自氢或甲氧基；
R4选自氢或甲基；
R5选自氢、卤素、甲氧基或氨基；
R6选自氢、羟基、甲氧基、N(CH2CH3)2、苄氧基、苯甲酰氧基或硼酸频哪醇酯基；
R7选自甲基、乙基、苄基、(CH2)mSO3H或(CH2)mCOOH；
R8选自氢、甲氧基、SO3H或COOH；
R9选自氢；或R9与R8相连形成苯环或C5～C6芳香杂环；
R10选自氢或甲基；
R11选自氢或甲基；
m选自3、4或5。
在某些优选实施方式中，
R1选自氢或甲基；
R2选自氢、羟基、甲基或甲氧基；
R5选自氢、溴或甲氧基；
R6选自氢、羟基、甲氧基或N(CH2CH3)2；
R7选自甲基、乙基、苄基或(CH2)mSO3H；
R8选自氢、甲氧基或SO3H；
m选自3或4。
本发明所述荧光探针分子优选具有如式(I)所示的结构：
其中，
X选自邻硝基苄基衍生物(X1)、香豆素衍生物(X2)或七甲川花菁衍生物(X3)。
本发明所述荧光探针分子优选具有如式(II)所示的结构：
其中，
Y选自氢、X1、X2或X3；且当一侧Y选自氢时，另一侧Y选自X1、X2或X3；或两侧Y同时选自X1、X2或X3。
本发明所述的苯并[b]硒吩类STING激动剂荧光探针分子，优选以下化合物：
本发明还提供了上述化合物的制备方法：
当化合物具有通式(I)所示结构，且X选自X1和X2时，由化合物BSP(根据专利CN113429387A制得)与邻硝基苄基衍生物1或者香豆素衍生物2通过酯缩合制得通式分别为(I-a)和(I-b)的化合物，其合成路线如下：
其中，R1、R2、R3、R4、R5和R6如上文所定义。
在一些更具体的实施例中，R1和R4选自氢或甲基，R2和R3选自氢或甲氧基，R5选自氢，R6选自氢或N(CH2CH3)2。
在一些更具体的实施例中，酯缩合反应使用的缩合剂选自HATU、HBTU、HOAT、HOBT、DCC、EDC或EDCI，所用碱选自TEA、DIPEA或DMAP，反应溶剂选自二氯甲烷、四氢呋喃或DMF。
当化合物具有通式(I)所示结构，且X选自X3时，由化合物BSP与化合物3通过酯缩合制得化合物4，化合物4再与化合物5反应制得Zincke盐6，化合物6最后与化合物7通过Zincke反应制备得到通式(I-c)的化合物，合成路线如下：
其中，R7、R8、R9、R10和R11如上文所定义。
在一些更具体的实施例中，R7选自甲基、乙基、(CH2)3SO3H或(CH2)4SO3H，R8选自氢或SO3H，R9选自氢，或者R8和R9可以相连形成苯环，R10选自氢或甲基，R11选自氢或甲基。
在一些更具体的实施例中，由化合物BSP制备化合物4的过程，反应物为化合物3，所用缩合剂选自HATU、HBTU、HOAT、HOBT、DCC、EDC或EDCI，所用碱选自TEA、DIPEA或DMAP，反应溶剂选自二氯甲烷、四氢呋喃或DMF。
在一些更具体的实施例中，由化合物4制备化合物6的过程，反应物为化合物5，反应溶剂选自甲苯、二甲苯或丙酮。
在一些更具体的实施例中，由化合物6制备通式化合物(I-c)的过程，反应物为化合物7，反应试剂选自苯胺或4-溴苯胺，所用碱选自碳酸钠、碳酸钾、乙酸钠或乙酸钾，反应溶剂选自甲醇、乙醇、二氯甲烷、四氢呋喃或DMF。
当化合物具有通式(II)所示结构时，合成路线如下：
其中，X如上文所定义。
通式(II)化合物一种具体的制备方法，包括以下步骤：
(1)化合物8与化合物9(溴化苄)在碱性条件下反应制得化合物10，反应试剂选自碳酸钾、碳酸钠、氢氧化钠或氢化钠，反应溶剂选自DMF或四氢呋喃；
(2)化合物10与化合物11(二甲基二硒醚)在碱性条件下反应制得化合物12，反应试剂选自DTT、巯基乙醇、DBU和碳酸钾，反应溶剂选自DMF或四氢呋喃；
(3)化合物12与化合物13(2-溴乙酸乙酯)经取代反应制得化合物14，反应溶剂为DMF；
(4)化合物14在碱性条件下环合制得化合物15，反应试剂选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠或氢氧化锂，反应溶剂选自DMF或乙腈；
(5)化合物15水解脱羧制得化合物16，反应试剂选自碳酸钾、氢氧化钠或强氧化锂，反应溶剂选自水、甲醇和四氢呋喃；
(6)化合物16与化合物17(丙二酸单甲酯钾盐)经缩合反应制得化合物18，反应试剂选自CDI和MgCl2，反应溶剂选自DMF或四氢呋喃；
(7)化合物18与化合物13(2-溴乙酸乙酯)在碱性条件经取代反应制得化合物19，反应试剂选自碳酸钾、甲醇钠、乙醇钠或氢化钠，反应溶剂选自DMF或四氢呋喃；
(8)化合物19同时发生水解和脱羧制得化合物20，反应试剂选自碳酸钾、氢氧化钠、氢氧化锂或盐酸，反应溶剂选自醋酸、水或四氢呋喃；
(9)化合物20通过乙酯保护制得化合物21，反应试剂选自二氯亚砜或草酰氯，反应溶剂选自乙醇；
(10)化合物21与化合物22(1,3-二溴丙烷)在碱性条件下经取代反应制得化合物23，反应试剂选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化锂、碘化钾或冠醚，反应溶剂选自DMF或四氢呋喃；
(11)化合物23与化合物21在碱性条件下经取代反应制得化合物24，反应试剂选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化锂、碘化钾或冠醚，反应溶剂选自DMF或四氢呋喃；
(12)化合物24在碱性条件下水解制得化合物diBSP，反应试剂选自碳酸钾、氢氧化钠或氢氧化锂，反应溶剂选自水、甲醇和四氢呋喃；
(13)化合物diBSP按照通式(I)化合物相同的合成方法制备得到通式(II)的化合物。
本发明还提供了所述的苯并[b]硒吩类STING激动剂荧光探针分子在制备激活cGAS-STING通路的药物中的用途。所述药物为STING激动剂，可以用来预防和/或治疗感染性疾病或肿瘤。
本发明还提供了所述的苯并[b]硒吩类STING激动剂荧光探针分子在制备预防和/或治疗与STING通路相关疾病药物中的用途。
本发明还提供了所述的苯并[b]硒吩类STING激动剂荧光探针分子在制备免疫佐剂中的用途。所述免疫佐剂可以用来预防和/或治疗感染性疾病或肿瘤。
本发明还提供了所述的苯并[b]硒吩类STING激动剂荧光探针分子在制备治疗一体化药物中的用途，所述药物可以用来同时对疾病进行诊断和治疗。
在某些优选实施方式中，所述疾病为肿瘤。所述的肿瘤包括但不限于肺癌、肝癌、胃癌、乳腺癌、黑色素瘤、结直肠癌、胰腺癌、前列腺癌、鳞状细胞癌、神经胶质瘤和白血病。
本发明的药物可以采用各种已知的方式施用，例如口服、胃肠外施用、通过吸入喷雾施用或经由植入的贮库施用。本发明的药物可单独给药也可与其他抗肿瘤药物联合用药。口服药物可以是任何口服可接受的剂型，包含但不限于片剂、胶囊剂、乳剂以及混悬剂、分散物和溶液。常用的药学上可接受的载体或赋形剂包括稳定剂、稀释剂、表面活性剂、润滑剂、抗氧化剂、粘合剂、着色剂、填充剂、乳化剂等。
无菌可注射组合物可按照本领域已知的技术使用适合的分散剂或润湿剂和助悬剂来配制。可以使用的药学上可接受的载体和溶剂包括水、甘露醇、氯化钠溶液等。
局部药物可被配制成油、洗剂、乳膏剂等。用于药物的载体包括植物油或矿物油、动物脂肪和高分子量醇等。药学上可接受的载体是活性成分在其中可溶的载体。
可以改变本发明的药物中活性成分的实际剂量水平以获得对特定患者、组合物和施用方式而言可以有效实现所需治疗响应、对患者无毒的活性成分的量。所选择的剂量水平取决于多种因素，包括所用的具体的本发明的化合物或其盐的活性、施用途径、施用时间、所用的具体药物的排泄速率、治疗的持续时间、与所用的具体药物组合使用的其它药物、化合物和/或材料、所治疗的患者的年龄、性别、体重、一般健康状况和既往病史以及医学领域中公知的类似因素。
本发明还提供了所述的苯并[b]硒吩类STING激动剂荧光探针分子在制备活体荧光成像试剂中的用途。
除非另外说明，在说明书和权利要求书中使用的以下术语具有下面讨论的含义：
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体。
术语“药学上可接受的盐”是指本发明通式(I)和(II)的化合物与药学上可接受的无毒碱包括有机碱或无机碱所制备出的盐。得自药学上可接受的有机碱的盐，包括伯胺、仲胺和叔胺的盐，取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂，例如甜菜碱、咖啡因、胆碱、N-乙基哌啶、N,N'-二苄基乙二胺、二乙胺、2-二甲基氨基乙醇、精氨酸、乙醇胺、乙二胺、N-乙基吗啉、葡萄糖胺、甲基葡萄糖胺、2-二乙基氨基乙醇、氨基葡萄糖、组氨酸、氨基乙醇、羟钴胺、赖氨酸、吗啉、哌嗪、哌啶、呱咤、多胺树脂、三乙胺、三甲胺、三丙胺、异丙基胺、氨基丁三醇等。得自药学上可接受的无机碱的盐，包括铝盐、铵盐、钙盐、锂盐、镁盐、钾盐、钠盐、锌盐等。
术语“烷基”是指具有指定范围内碳原子数的单价直链或支链饱和脂肪族烃基。烷基可以是取代的或未取代的。当是取代的烷基时，该取代基优选是一或多个，更优选1-3个，最优选1或2个取代基。
术语“卤素”或“卤代”是指氟、氯、溴或碘，或者氟代、氯代、溴代或碘代。
术语“卤代烷基”是指如上定义的烷基，其中一个或多个氢原子已被卤素替代。
术语“芳香杂环”表示5至6个环原子的环状基团，其中一个或两个环原子是选自N、O或S的杂原子，其余环原子是C，且环具有完全共轭的π电子系统。
有益效果：
本发明制备的苯并[b]硒吩类STING激动剂荧光探针分子在受到光照后，能脱除光保护基团，释放出原型药物即对应的STING激动剂，可以实现定时和定点释放，具有良好成药性和药物代谢动力学性质。因此本发明中的化合物可以用于制备激活cGAS-STING通路的药物、制备预防和/或治疗与STING通路相关疾病药物以及制备免疫佐剂。另外，本发明中的化合物带有荧光基团，可以用于制备荧光成像试剂。
附图说明
图1为代表化合物I-7和II-6分别在808nm和400nm波长光源照射下的光释放结果；
图2为代表化合物I-7和II-6的光依赖STING激动活性结果。
具体实施方式
下面通过具体实施例对本发明技术方案进行详细说明，但是本发明的保护范围不局限于所述实施例。
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
本发明实施例中TLC展开剂、柱层析洗脱剂比例均为体积比。
实施例1(R)-4-(5,6-二甲氧基苯并[b]硒吩-2-基)-2-乙基-4-氧代丁酸-2-硝基苄基酯(I-1)的制备
将化合物BSP(100mg,0.27mmol)、2-硝基苄醇(1a)(41mg,0.22mmol)、DCC(N,N'-二环己基碳二亚胺,84mg,0.41mmol)、DMAP(4-二甲氨基吡啶,1mg,0.01mmol)和二氯甲烷(4mL)加入到50mL反应瓶中，避光条件下，于室温下搅拌5h，TLC(二氯甲烷：甲醇＝20：1)检测原料反应完全后，反应液浓缩，所得残余物用乙酸乙酯(15mL)溶解，-10℃下降温搅拌约30min，过滤后使用冰乙酸乙酯(2mL)，滤液浓缩后获得粗品，粗品经硅胶柱层析(二氯甲烷：甲醇＝50：1)纯化得化合物I-1 81mg，浅黄色固体，收率59％。1H NMR(300MHz,DMSO-d6):δ＝8.12–8.06(m,1H),7.74(s,1H),7.63–7.54(m,3H),7.51(s,1H),7.14(s,1H),5.53–5.41(m,2H),3.82(s,6H),3.16-2.87(m,3H),1.65-1.50(m,2H),0.94(t,J＝8.8Hz,3H)ppm。13C NMR(75MHz,DMSO-d6):δ＝200.46,174.51,150.52,147.64,147.23,142.63,137.77,136.48,133.11,133.04,131.78,128.59,127.83,123.81,110.45,108.75,64.86,56.43,56.12,44.14,40.03,24.97,11.52ppm。HRMS(ESI+):计算值C23H24NO7Se+(M+H)+,506.0713；实测值506.0719。
实施例2(2R)-4-(5,6-二甲氧基苯并[b]硒吩-2-基)-2-乙基-4-氧代丁酸-1-(2-硝基苯基)乙基酯(I-2)的制备
参照实施例1所述的制备方法，将反应原料1a替换为1-(2-硝基苯基)乙醇制备得到化合物I-2。1H NMR(300MHz,DMSO-d6):δ＝8.05–7.97(m,1H),7.75(s,1H),7.68–7.62(m,1H),7.57–7.50(m,3H),7.14(s,1H),6.06(dq,J1＝6.2Hz,J2＝2.1Hz,1H),3.81(d,J＝2.9Hz,6H),3.21-3.03(m,2H),2.96-2.85(m,1H),1.64–1.56(m,5H),0.94(t,J＝6.4Hz,3H)ppm。13C NMR(75MHz,DMSO-d6):δ＝200.04,174.24,150.52,147.66,147.44,142.63,137.76,136.47,135.92,133.13,132.29,128.65,127.06,124.36,110.48,108.74,71.42,56.43,56.11,44.14,40.43,24.96,21.25,11.52ppm。HRMS(ESI+):计算值C24H26NO7Se+(M+H)+,520.0869；实测值520.0871。
实施例3(R)-4-(5,6-二甲氧基苯并[b]硒吩-2-基)-2-乙基-4-氧代丁酸-4,5-二甲氧基-2-硝基苄基酯(I-3)的制备
参照实施例1所述的制备方法，将反应原料1a替换为4,5-二甲氧基-2-硝基苯甲醇制备得到化合物I-3。1H NMR(300MHz,DMSO-d6):δ＝7.75(s,1H),7.52(d,J＝2.7Hz,2H),7.27(d,J＝2.5Hz,1H),7.14(s,1H),5.41(dq,J1＝11.3Hz,J2＝2.7Hz,2H),3.88(d,J＝2.8Hz,6H),3.83(d,J＝2.8Hz,6H),3.16-2.87(m,3H),1.64–1.52(m,2H),0.94(t,J＝6.3Hz,3H)ppm。13C NMR(75MHz,DMSO-d6):δ＝200.46,174.53,153.09,150.54,148.73,147.64,142.61,141.60,137.75,136.48,133.11,127.15,113.09,110.46,110.04,108.73,64.75,56.53,56.41,56.12,55.94,44.14,40.03,24.96,11.53ppm。HRMS(ESI+):计算值C25H28NO9Se+(M+H)+,566.0924；实测值566.0918。
实施例4(R)-4-(5,6-二甲氧基苯并[b]硒吩-2-基)-2-乙基-4-氧代丁酸-(2-氧代-2H-苯并吡喃-4-基)甲基酯(I-4)的制备
参照实施例1所述的制备方法，将反应原料1a替换为4-(羟基甲基)-2H-苯并吡喃-2-酮制备得到化合物I-4。1H NMR(300MHz,DMSO-d6):δ＝7.75(s,1H),7.66-7.56(m,2H),7.50(s,1H),7.44(dd,J1＝6.3Hz,J2＝2.9Hz,1H),7.23(dt,J1＝6.3Hz,J2＝2.9Hz,1H),7.15(s,1H),6.20(s,1H),5.43(s,2H),3.80(d,J＝2.9Hz,6H),3.13-2.87(m,3H),1.65–1.52(m,2H),0.94(t,J＝6.2Hz,3H)ppm。
13C NMR(75MHz,DMSO-d6):δ＝200.49,174.60,161.31,153.09,150.53,147.64,146.68,142.60,137.78,136.49,133.10,132.93,126.30,125.45,120.91,117.45,114.57,110.46,108.72,66.44,56.41,56.11,44.11,39.64,24.97,11.53ppm。
HRMS(ESI+):计算值C26H25O7Se+(M+H)+,529.0760；实测值529.0765。
实施例5(R)-4-(5,6-二甲氧基苯并[b]硒吩-2-基)-2-乙基-4-氧代丁酸-(7-(二乙基氨基)-2-氧代-2H-苯并吡喃-4-基)甲基酯(I-5)的制备
参照实施例1所述的制备方法，将反应原料1a替换为7-(二乙基氨基)-4-(羟基甲基)-2H-苯并吡喃-2-酮制备得到化合物I-5。1H NMR(300MHz,DMSO-d6):δ＝7.74(s,1H),7.52-7.46(m,2H),7.15(s,1H),6.63-6.57(m,2H),6.17(s,1H),5.43(s,2H),3.81(d,J＝2.9Hz,6H),3.50(q,J＝6.0Hz,4H),3.16-2.85(m,3H),1.63–1.52(m,2H),1.16(t,J＝6.3Hz,6H),0.94(t,J＝6.2Hz,3H)ppm。13C NMR(75MHz,DMSO-d6):δ＝200.49,174.61,161.35,154.35,151.97,150.52,147.66,146.56,142.63,137.79,136.48,133.11,126.90,115.54,114.37,110.47,110.10,108.73,99.65,66.71,56.41,56.10,44.40,44.12,39.66,24.96,12.36,11.53ppm。HRMS(ESI+):计算值C30H34NO7Se+(M+H)+,600.1495；实测值600.1491。
实施例6(2R)-4-(5,6-二甲氧基苯并[b]硒吩-2-基)-2-乙基-4-氧代丁酸-1-(7-(二乙基氨基)-2-氧代-2H-苯并吡喃-4-基)乙基酯(I-6)的制备
参照实施例1所述的制备方法，将反应原料1a替换为7-(二乙基氨基)-4-(1-羟基乙基)-2H-苯并吡喃-2-酮制备得到化合物I-6。1H NMR(300MHz,DMSO-d6):δ＝7.74(s,1H),7.52(s,1H),7.31(d,J＝8.9Hz,1H),7.16(s,1H),6.63(d,J＝2.7Hz,1H),6.49(dd,J1＝6.2Hz,J2＝2.7Hz,1H),6.19(s,1H),6.01(q,J＝6.0Hz,1H),3.82(d,J＝2.9Hz,6H),3.49(q,J＝6.0Hz,4H),3.22-2.84(m,3H),1.65–1.52(m,2H),1.42(d,J＝6.0Hz,3H),1.15(t,J＝6.0Hz,6H),0.94(t,J＝6.0Hz,3H)ppm。13C NMR(75MHz,DMSO-d6):δ＝200.08,174.11,161.53,154.30,153.45,152.02,150.52,147.65,142.63,137.78,136.49,133.10,126.00,114.50,113.41,110.48,108.83,108.70,100.03,75.05,56.41,56.09,44.40,44.10,39.96,25.07,20.66,12.34,11.52ppm。HRMS(ESI+):计算值C31H36NO7Se+(M+H)+,614.1652；实测值614.1645。
实施例7
步骤1：(2R)-4-(5,6-二甲氧基苯并[b]硒吩-2-基)2-乙基-4-氧代丁酸-1-(吡啶-4-基)乙基酯(4a)的制备
向100mL圆底烧瓶中加入BSP(500mg,1.36mmol)、4-(1-羟乙基)吡啶(3a,200mg,1.63mmol)、EDCI(1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐,390mg,2.03mmol)、DMAP(17mg,0.14mmol)和二氯甲烷(14mL)，所得反应混合物在室温下搅拌反应4h。TLC(二氯甲烷：甲醇＝20：1)检测反应完全后，向反应液中加入50mL水，分出有机层，用二氯甲烷萃取水层(20mL×2)。合并有机层，经饱和食盐水洗(20mL×2)、无水硫酸钠干燥、抽滤、减压浓缩后得粗品。粗品通过硅胶柱层析(二氯甲烷：甲醇＝40：1)纯化得中间体4a 490mg，黄色泡沫状固体，收率76％。1H NMR(300MHz,DMSO-d6):δ＝8.54-8.48(m,3H),7.71(d,J＝2.9Hz,1H),7.50(d,J＝1.1Hz,1H),7.38-7.32(m,2H),5.83-5.75(m,1H),3.85(s,3H),3.82(s,3H),3.50-3.40(m,1H),3.25(dt,J1＝17.3Hz,J2＝3.8Hz,1H),2.99-2.92(m,1H),1.73-1.61(m,2H),1.45(t,J＝6.5Hz,3H),0.97(dt,J1＝21.1Hz,J2＝7.3Hz,3H)ppm。HRMS(ESI+):计算值C23H26NO5Se+(M+H)+,476.0971；实测值476.0980。
步骤2：4-(1-(((R)-4-(5,6-二甲氧基苯并[b]硒吩-2-基)-2-乙基-4-氧代丁酰基)氧基)乙基)-1-(2,4-二硝基苯基)吡啶-1-鎓-4-甲基苯磺酸酯(6a)的制备
向50mL圆底烧瓶中加入中间体4a(490mg,1.03mmol)、4-甲基苯磺酸-2,4-二硝基苯基酯(5,419mg,1.24mmol)和丙酮(10mL)，所得反应混合物在50℃下搅拌反应24h，期间有固体析出。TLC(二氯甲烷：甲醇＝10：1)检测反应完全后，停止加热。待反应液冷却至室温后抽滤，滤饼用少量丙酮洗涤，干燥后得中间体6a 600mg，米白色固体，收率71％。1H NMR(300MHz,DMSO-d6):δ＝9.34(d,J＝6.6Hz,2H),9.10(d,J＝2.5Hz,1H),8.95(dd,J1＝8.7Hz,J2＝2.5Hz,1H),8.52(s,1H),8.39-8.36(m,3H),7.69(s,1H),7.54(s,1H),7.49(d,J＝8.0Hz,2H),7.14(d,J＝7.9Hz,2H),6.20(q,J＝6.4Hz,1H),3.85(s,3H),3.83(s,3H),3.54-3.44(m,1H),3.39(dd,J1＝17.6Hz,J2＝4.3Hz,1H),3.04-2.98(m,1H),2.29(s,3H),1.82-1.67(m,2H),1.62(d,J＝6.7Hz,3H),0.96(t,J＝7.4Hz,3H)ppm。HRMS(ESI+):计算值C29H28N3O9Se+(M)+,642.0985；实测值642.0982。
步骤3：2-((1E,3Z,5E)-4-(1-(((R)-4-(5,6-二甲氧基苯并[b]硒吩-2-基)-2-乙基-4-氧代丁酰基)氧基)乙基)-7-((E)-1,3,3-三甲基吲哚啉-2-亚基)庚-1,3,5-三烯-1-基)-1,3,3-三甲基-3H-吲哚-1-碘化物(I-7)的制备
向50mL圆底烧瓶中加入中间体6a(200mg,0.25mmol)、4-溴苯胺(51mg,0.30mmol)和甲醇(4mL)，所得反应混合物在室温下搅拌反应30min。加入1,2,3,3-四甲基-3H-吲哚鎓碘化物(7a,222mg,0.74mmol)和乙酸钠(121mg,1.45mmol)。反应液继续在室温下搅拌反应24h。TLC(二氯甲烷：甲醇＝10：1)检测反应完全后，减压浓缩除去反应溶剂，通过硅胶柱层析(二氯甲烷：甲醇＝30：1)纯化得化合物I-7 34mg，绿色固体，收率15％。1H NMR(300MHz,DMSO-d6):δ＝8.50(d,J＝13.2Hz,1H),8.10(t,J＝13.3Hz,2H),7.69(d,J＝14.1Hz,1H),7.61(t,J＝8.1Hz,2H),7.50(d,J＝10.1Hz,1H),7.45-7.37(m,4H),7.27(t,J＝7.3Hz,2H),6.66(t,J＝13.8Hz,2H),6.45(t,J＝12.5Hz,2H),6.19-6.13(m,1H),3.81-3.78(m,6H),3.61(s,3H),3.58(s,3H),3.47-3.41(m,1H),3.31-3.20(m,1H),2.96-2.85(m,1H),1.73-1.53(m,17H),1.02(dt,J1＝40.3Hz,J2＝7.3Hz,3H)ppm。13C NMR(75MHz,DMSO-d6):δ＝200.06,174.48,164.32,156.54,150.53,147.67,147.12,145.55,142.63,139.96,138.30,137.78,137.63,136.49,135.56,133.10,132.39,131.10,128.83,128.35,127.64,126.95,125.92,123.81,122.93,119.14,118.56,110.44,110.32,108.72,101.77,70.13,56.42,56.08,44.12,40.55,40.01,39.90,37.54,32.10,29.17,28.52,25.05,20.35,11.53ppm。HRMS(ESI+):计算值C47H53N2O5Se+(M)+,805.3114；实测值805.3115。
实施例8 2-((1E,3Z,5E)-4-(2-(((R)-4-(5,6-二甲氧基苯并[b]硒吩-2-基)-2-乙基-4-氧代丁酰基)氧基)丙基-2-基)-7-((E)-1,3,3-三甲基吲哚啉-2-亚基)庚-1,3,5-三烯-1-基)-1,3,3-三甲基-3H-吲哚-1-碘化物(I-8)的制备
参照实施例7所述的制备方法，将反应原料3a替换为2-(吡啶-4-基)丙烷-2-醇制备得到化合物I-8。1H NMR(300MHz,DMSO-d6):δ＝8.51(d,J＝13.2Hz,1H),8.12(t,J＝13.3Hz,2H),7.69(d,J＝13.9Hz,1H),7.59(t,J＝8.1Hz,2H),7.50(d,J＝10.1Hz,1H),7.48-7.36(m,4H),7.27(t,J＝7.2Hz,2H),6.67(t,J＝13.9Hz,2H),6.46(t,J＝12.1Hz,2H),3.81-3.78(m,6H),3.61(s,3H),3.58(s,3H),3.47-3.41(m,1H),3.31-3.20(m,1H),2.96-2.85(m,1H),1.74-1.51(m,20H),1.01(dt,J1＝40.3Hz,J2＝7.3Hz,3H)ppm。
13C NMR(75MHz,DMSO-d6):δ＝200.05,173.21,164.21,156.52,150.52,147.66,147.12,145.55,144.16,142.63,141.15,139.96,137.78,137.63,136.48,133.12,133.03,132.28,129.31,128.85,127.64,127.14,126.96,123.78,122.90,119.23,118.56,110.49,110.32,108.72,102.05,80.57,56.41,56.12,43.88,40.58,39.99,39.61,37.54,32.10,29.17,28.52,27.17,24.91,11.52ppm。
HRMS(ESI+):计算值C48H55N2O5Se+(M)+,819.3271；实测值819.3275。
实施例9 2-((1E,3Z,5E)-4-(1-(((R)-4-(5,6-二甲氧基苯并[b]硒吩-2-基)-2-乙基-4-氧代丁酰基)氧基)乙基)-7-((E)-5-甲氧基-1,3,3-三甲基吲哚啉-2-亚基)庚-1,3,5-三烯-1-基)-5-甲氧基-1,3,3-三甲基-3H-吲哚-1-碘化物(I-9)的制备
参照实施例7所述的制备方法，将反应原料7a替换为5-甲氧基-1,2,3,3-四甲基-3H-吲哚鎓碘化物制备得到化合物I-9。1H NMR(300MHz,DMSO-d6):δ＝8.50(d,J＝13.2Hz,1H),8.09(t,J＝13.2Hz,2H),7.70(d,J＝14.1Hz,1H),7.61(t,J＝8.1Hz,2H),7.51(d,J＝10.1Hz,1H),7.43-7.37(m,4H),7.27(t,J＝7.6Hz,2H),6.67(t,J＝13.9Hz,2H),6.45(t,J＝12.3Hz,2H),6.19-6.13(m,1H),3.83-3.78(m,12H),3.61(s,3H),3.58(s,3H),3.47-3.41(m,1H),3.31-3.19(m,1H),2.98-2.85(m,1H),1.73-1.53(m,17H),1.02(dt,J1＝39.9Hz,J2＝7.6Hz,3H)ppm。13C NMR(75MHz,DMSO-d6):δ＝200.08,174.47,164.09,156.03,155.25,154.77,150.52,147.65,143.93,142.63,139.59,138.66,138.31,137.79,137.55,136.48,135.57,133.11,131.10,128.35,125.94,121.15,119.22,118.71,113.53,111.40,110.63,110.45,108.90,108.72,101.95,70.12,56.42,56.11,55.65,44.13,41.00,39.99,39.88,37.57,32.12,29.18,28.55,25.05,20.36,11.53ppm。
HRMS(ESI+):计算值C49H57N2O7Se+(M)+,865.3326；实测值865.3321。
实施例10 3-(2-((1E,3Z,5E)-4-(1-(((R)-4-(5,6-二甲氧基苯并[b]硒吩-2-基)-2-乙基-4-氧代丁酰基)氧基)乙基)-7-((E)-3,3-二甲基-1-(3-磺丙基)吲哚啉-2-亚基)庚-1,3,5-三烯-1-基)-3,3-二甲基-3H-吲哚-1-鎓-1-基)丙烷-1-磺酸钠(I-10)的制备
参照实施例7所述的制备方法，将反应原料7a替换为3-(2,3,3-三甲基-3H-吲哚-1-鎓-1-基)丙烷-1-磺酸盐制备得到化合物I-10。1H NMR(300MHz,DMSO-d6):δ＝8.50(d,J＝13.4Hz,1H),8.09(t,J＝13.4Hz,2H),7.70(d,J＝14.2Hz,1H),7.62(t,J＝8.1Hz,2H),7.50(d,J＝10.1Hz,1H),7.45-7.37(m,4H),7.27(t,J＝7.3Hz,2H),6.66(t,J＝13.4Hz,2H),6.47(t,J＝12.5Hz,2H),6.18-6.13(m,1H),3.81-3.78(m,6H),3.67-3.55(m,4H),3.47-3.39(m,1H),3.32-3.20(m,1H),3.08-3.05(m,4H),2.96-2.85(m,1H),2.13-2.07(m,4H),1.75-1.53(m,17H),0.99(dt,J1＝40.1Hz,J2＝7.2Hz,3H)ppm。13C NMR(75MHz,DMSO-d6):δ＝200.05,174.47,169.22,155.65,150.52,147.65,144.19,144.10,142.64,140.47,137.81,137.77,137.23,136.49,135.54,133.10,132.00,131.28,128.99,128.05,127.55,125.95,124.92,124.06,122.99,119.76,117.74,111.13,110.45,108.74,102.24,70.11,56.43,56.11,51.51,50.06,45.18,44.11,43.65,42.60,41.44,39.90,29.05,28.45,25.06,23.41,20.36,18.84,11.50ppm。
HRMS(ESI-):计算值C51H59N2O11S2Se-(M)-,1019.2731；实测值1019.2737。
实施例11 2-((1E,3Z,5E)-4-(1-(((R)-4-(5,6-二甲氧基苯并[b]硒吩-2-基)-2-乙基-4-氧代丁酰基)氧基)乙基)-7-((E)-1-乙基-3,3-二甲基-5-磺酸吲哚啉-2-亚基)庚-1,3,5-三烯-1-基)-1-乙基-3,3-二甲基-3H-吲哚-1-鎓-5-磺酸钠(I-11)的制备
参照实施例7所述的制备方法，将反应原料7a替换为1-乙基-2,3,3-三甲基-3H-吲哚-1-鎓-5-磺酸盐制备得到化合物I-11。1H NMR(300MHz,DMSO-d6):δ＝8.52(d,J＝13.2Hz,1H),8.11(t,J＝13.1Hz,2H),7.82-7.78(m,1H),7.69(d,J＝14.1Hz,1H),7.50(d,J＝10.3Hz,1H),7.45-7.36(m,3H),7.23(t,J＝7.4Hz,2H),6.66(t,J＝13.5Hz,2H),6.45(t,J＝12.3Hz,2H),6.19-6.13(m,1H),3.81-3.78(m,6H),3.66-3.57(m,4H),3.47-3.42(m,1H),3.30-3.18(m,1H),2.96-2.84(m,1H),1.72-1.51(m,23H),1.00(dt,J1＝40.0Hz,J2＝7.4Hz,3H)ppm。13C NMR(75MHz,DMSO-d6):δ＝200.04,174.47,167.20,155.25,150.53,147.98,147.66,145.56,140.85,140.33,137.81,137.79,136.46,136.35,135.56,133.08,131.66,131.24,129.29,128.56,128.04,125.95,124.82,123.96,120.83,116.95,110.87,110.47,108.72,102.02,70.14,56.42,56.11,44.15,42.12,40.66,40.45,39.91,38.73,29.10,28.48,25.06,20.35,13.47,13.11,11.51ppm。
HRMS(ESI-):计算值C49H55N2O11S2Se-(M)-,991.2418；实测值998.2413。
实施例12 4-(2-((1E,3Z,5E,7E)-4-(1-(((R)-4-(5,6-5,6-二甲氧基苯并[b]硒吩-2-基)-2-乙基-4-氧代丁酰基)氧基)乙基)-7-(1,1-二甲基-3-(4-磺酸丁基)-1,3-二氢-2H-苯并[e]吲哚-2-亚基)庚-1,3,5-三烯-1-基)-1,1-二甲基-1H-苯并[e]吲哚-3-鎓-3-基)丁烷-1-磺酸钠(I-12)的制备
参照实施例7所述的制备方法，将反应原料7a替换为4-(1,1,2-三甲基-1H-苯并[e]吲哚-3-鎓-3-基)丁烷-1-磺酸盐制备得到化合物I-12。1H NMR(300MHz,DMSO-d6):δ＝8.67-8.63(m,1H),8.50(d,J＝13.2Hz,1H),8.31-8.25(m,2H),8.07-8.03(m,1H),7.83-7.74(m,3H),7.54-7.27(m,8H),7.16(s,1H),7.07(d,J＝8.7Hz,2H),6.87(dd,J1＝14.7Hz,J2＝6.1Hz,1H),6.74-6.70(m,1H),6.62-6.54(m,1H),6.14(dd,J1＝9.2Hz,J2＝2.9Hz,1H),5.42-5.34(m,1H),4.44-4.38(m,2H),3.84-3.72(m,8H),3.29-3.04(m,4H),2.98-2.79(m,3H),2.05-1.52(m,21H),1.35(d,J＝6.1Hz,3H),0.97(dt,J1＝40.0Hz,J2＝7.0Hz,3H)ppm。13CNMR(75MHz,DMSO-d6):δ＝200.08,174.47,165.42,154.94,150.51,147.66,142.62,141.65,140.52,137.77,137.60,136.55,136.48,135.57,133.82,133.15,133.09,132.64,131.88,131.28,129.24,128.75,128.04,127.81,127.69,127.22,126.83,126.45,126.10,125.94,123.17,122.82,120.42,117.14,110.47,108.77,108.72,101.75,70.14,56.41,56.11,55.26,52.95,45.44,44.69,44.13,43.67,41.02,39.92,30.92,30.38,25.69,25.06,23.58,23.30,20.35,19.78,11.52ppm。
HRMS(ESI-):计算值C61H67N2O11S2Se-(M)-,1147.3357；实测值1147.3352。
实施例13
步骤1：5-(苄基氧基)-2-溴-4-甲氧基苯甲醛(10)的制备
将2-溴-5-羟基-4-甲氧基苯甲醛(8,6.9g,30.0mmol)、K2CO3(8.3g,60.0mmol)和DMF(70mL)加入到250mL反应瓶中，加入溴化苄(9,6.1g,36.0mmol)。所得反应混合物加热至50℃并搅拌反应2h。TLC(石油醚：乙酸乙酯＝1：1)检测反应完全后停止加热，待反应液冷却至室温，将反应液倒入350mL冰水中，抽滤收集滤饼，滤饼经水洗后干燥。将干燥后的滤饼用石油醚(200mL)打浆20min，抽滤，滤饼用石油醚洗涤、干燥后得中间体10 9.24g，白色固体，收率96％。1H NMR(300MHz,CDCl3):δ＝10.16(s,1H),7.48(s,1H),7.46–7.30(m,5H),7.07(s,1H),5.16(s,2H),3.95(s,3H)ppm。HRMS(ESI+):计算值C15H14BrO3 +(M+H)+,321.0121；实测值321.0122。
步骤2：5-(苄基氧基)-4-甲氧基-2-(甲基硒基)苯甲醛(12)的制备
将中间体10(6.53g,20.3mmol)、DTT(DL-二硫苏糖醇,4.18g,27.1mmol)和DMF(70mL)加入到250mL反应瓶中，向其中加入二甲基二硒醚(11,2.55g,13.6mmol)和DBU(1,8-二氮杂双环[5.4.0]十一碳-7-烯,5.15g,33.9mmol)。在氮气保护和室温条件下搅拌27h后，反应液倒入250mL水中，析出沉淀。抽滤，滤饼经水洗后得粗品。粗品经硅胶柱层析(石油醚：乙酸乙酯＝8：1)纯化后得到中间体12 3.95g，淡黄色固体，收率87％。1H NMR(300MHz,CDCl3):δ＝10.08(s,1H),7.46–7.23(m,6H),6.97(s,1H),5.18(s,2H),3.99(s,3H),2.31(s,3H)ppm。HRMS(ESI+):计算值C16H17O3Se+(M+H)+,337.0337；实测值337.0334。
步骤3：2-((4-(苄基氧基)-2-甲酰基-5-甲氧基苯基)硒基)乙酸乙酯(14)的制备
将中间体12(3.95g,11.8mmol)和DMF(30mL)加入到100mL反应瓶中，加入2-溴乙酸乙酯(13,5.91g,35.4mmol)，反应液在150℃下加热搅拌4h。TLC(石油醚：乙酸乙酯＝4：1)检测原料反应完全后，将反应液逐渐冷却到室温。加入水(150mL)稀释并用乙酸乙酯(50mL)萃取三次。合并有机相，经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩得中间体14粗品，棕黄色固体。该粗品不经额外纯化直接用于下一步反应。HRMS(ESI+):计算值C19H21O5Se+(M+H)+,409.0549；实测值409.0548。步骤4：5-(苄基氧基)-6-甲氧基苯并[b]硒吩-2-甲酸乙酯(15)的制备
将上一步得到的中间体14和K2CO3(4.07g,29.5mmol)加入到100mL反应瓶中，向其中加入乙腈(40mL)。反应液在回流状态下搅拌4h。TLC(石油醚：乙酸乙酯＝4：1)检测原料反应完全后，将反应液逐渐冷却至室温。反应液浓缩后加入水(180mL)稀释，用乙酸乙酯(50mL)萃取三次。合并有机相，经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品经硅胶柱层析(石油醚：乙酸乙酯＝10：1)纯化得中间体15 3.48g，淡黄色固体，两步收率76％。1H NMR(300MHz,DMSO-d6):δ＝8.23(s,1H),7.75(s,1H),7.67(s,1H),7.49-7.32(m,5H),5.19(s,2H),4.32(q,J＝6.9Hz,2H),3.85(s,3H),1.33(t,J＝7.1Hz,3H)ppm。HRMS(ESI+):计算值C19H19O4Se+(M+H)+,391.0443；实测值391.0440。
步骤5：5-(苄基氧基)-6-甲氧基苯并[b]硒吩-2-甲酸(16)的制备
将中间体15(3.48g,8.94mmol)、甲醇(35mL)和四氢呋喃(35mL)加入到250mL反应瓶中，加入2N的NaOH水溶液(13mL)。反应液在60℃下搅拌1h。TLC(石油醚：乙酸乙酯＝4：1)检测原料反应完全后，反应溶剂通过减压方式移除，所得残余物用1N HCl调节pH至2～3。抽滤，滤饼经水洗、干燥后得中间体16 3.20g，米白色固体，收率99％。1H NMR(300MHz,DMSO-d6):δ＝8.13(s,1H),7.66(s,1H),7.62(s,1H),7.46–7.29(m,5H),5.09(s,2H),3.82(s,3H)ppm。HRMS(ESI-):计算值C17H13O4Se-(M-H)-,360.9985；实测值360.9991。
步骤6：3-(5-(苄基氧基)-6-甲氧基苯并[b]硒吩-2-基)-3-氧代丙酸甲酯(18)的制备将中间体16(3.20g,8.86mmol)、CDI(N,N-羰基二咪唑,4.31g,26.6mmol)和DMF(65mL)加入到250mL反应瓶中。所得反应液在室温下搅拌1h，加入MgCl2(2.53g,26.6mmol)和丙二酸单甲酯钾盐(17,4.15g,26.6mmol)。室温反应5h，TLC(石油醚：乙酸乙酯＝2：1)检测原料反应完全后，将反应液倒入水(300mL)中。抽滤，滤饼经水洗后得粗品，粗品经硅胶柱层析(石油醚：乙酸乙酯＝8：1)纯化得到中间体18 3.18g，黄色固体，收率86％。1H NMR(300MHz,CDCl3):δ＝8.01(s,1H),7.45–7.27(m,7H),5.19(s,2H),3.96(s,3H),3.97(s,2H),3.73(s,3H)ppm。HRMS(ESI+):计算值C20H19O5Se+(M+H)+,419.0392；实测值419.0393。
步骤7：2-(5-(苄基氧基)-6-甲氧基苯并[b]硒吩-2-羰基)丁二酸甲乙酯(19)的制备
将中间体18(3.18g,7.61mmol)、K2CO3(2.10g,15.2mmol)和DMF(30mL)加入到100mL反应瓶中，加入2-溴乙酸乙酯(13,1.52g,9.13mmol)。反应液在室温下搅拌4h，TLC(石油醚：乙酸乙酯＝2：1)检测原料反应完全后，反应液中加入水(150mL)，用乙酸乙酯(60mL)萃取三次。合并有机相，经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩和得中间体19粗品。该粗品不经过额外纯化直接用于下一步反应。HRMS(ESI+):计算值C24H25O7Se+(M+H)+,505.0760；实测值505.0759。
步骤8：4-(5-羟基-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸(20)的制备
将上一步得到的中间体19和醋酸(15mL)加入到100mL反应瓶中，缓慢加入浓盐酸(15mL)。所得反应液在90℃加热下搅拌2h，TLC(石油醚：乙酸乙酯＝2：1)检测原料反应完全后，将反应液自然冷却至室温，加入水(120mL)并用乙酸乙酯(50mL)萃取三次。合并有机相，经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品通过硅胶柱层析(二氯甲烷：甲醇＝30：1)纯化得中间体20 1.46g，淡黄色固体，两步收率59％。1H NMR(300MHz,DMSO-d6):δ＝12.16(s,1H),9.35(s,1H),8.21(s,1H),7.63(s,1H),7.36(s,1H),3.85(s,3H),3.26(t,J＝6.1Hz,2H),2.62(t,J＝6.5Hz,2H)ppm。HRMS(ESI-):计算值C13H11O5Se-(M-H)-,326.9777；实测值326.9782。步骤9：4-(5-羟基-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸乙酯(21)的制备
将中间体20(1.46g,4.47mmol)和无水乙醇(45mL)加入到100mL反应瓶中，置于冰浴中降温。0℃下，缓慢滴入SOCl2(1.59g,13.4mmol)，滴完后逐渐恢复至室温，在回流状态下搅拌1h。TLC(二氯甲烷：甲醇＝20：1)检测原料消耗完全后，将反应自然冷却至室温，反应液浓缩后，加水(180mL)并用乙酸乙酯(45mL)萃取三次。合并有机相，经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品经硅胶柱层析(石油醚：乙酸乙酯＝4：1)纯化得中间体21 1.51g，米白色固体，收率95％。1H NMR(300MHz,CDCl3):δ＝8.09(s,1H),7.40(s,1H),7.31(s,1H),4.22(q,J＝7.1Hz,2H),3.99(s,3H),3.34(t,J＝6.7Hz,2H),2.81(t,J＝6.9Hz,2H),1.29(t,J＝7.1Hz,3H)ppm。HRMS(ESI+):计算值C15H17O5Se+(M+H)+,357.0236；实测值357.0233。
步骤10：4-(5-(3-溴丙基)-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸乙酯(23)的制备
将中间体21(753mg,2.13mmol)、K2CO3(587mg,4.23mmol)和DMF(20mL)加入到100mL反应瓶中，加入1,3-二溴丙烷(22,4.29g,21.2mmol)，反应液在45℃加热下搅拌2h。TLC(石油醚：乙酸乙酯＝4：1)检测原料反应完全后，加入水(150mL)稀释，用乙酸乙酯(35mL)萃取三次。合并有机相，经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品经硅胶柱层析(石油醚：乙酸乙酯＝4：1)纯化得中间体23 768mg，淡黄色固体，收率76％。1H NMR(300MHz,CDCl3):δ＝8.10(s,1H),7.34(s,1H),7.33(s,1H),4.22–4.12(m,4H),3.94(s,3H),3.68(t,J＝6.3Hz,2H),3.34(t,J＝6.8Hz,2H),2.79(t,J＝6.7Hz,2H),2.45–2.37(m,2H),1.29(t,J＝7.1Hz,3H)ppm。HRMS(ESI+):计算值C18H22BrO5Se+(M+H)+,476.9810；实测值476.9814。
步骤11：4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸二乙酯)(24)的制备
将中间体23(758mg,1.61mmol)、中间体21(564mg,1.61mmol)、K2CO3(658mg,4.79mmol)、KI(27mg,0.15mmol)、18-冠醚-6(42mg,0.15mmol)和DMF(18mL)一起加入到50mL反应瓶中，所得反应液在50℃下搅拌8h。TLC(石油醚：乙酸乙酯＝2：1)检测原料反应完全后，加水(100mL)，用乙酸乙酯(40mL)萃取三次。合并有机相，经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品经硅胶柱层析(石油醚：乙酸乙酯＝2：1)纯化得中间体24 1040mg，黄色固体，收率87％。1H NMR(300MHz,DMSO-d6):δ＝8.42(s,2H),7.71(s,2H),7.58(s,2H),4.25(t,J＝5.8Hz,4H),4.09(q,J＝7.1Hz,4H),3.85(s,6H),3.31(t,J＝6.0Hz,4H),2.67(t,J＝5.9Hz,4H),2.30–2.25(m,2H),1.19(t,J＝7.1Hz,6H)ppm。HRMS(ESI+):计算值C33H37O10Se2 +(M+H)+,753.0712；实测值753.0714。
步骤12：4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(diBSP)的制备
将中间体24(900mg,1.20mmol)、甲醇(12mL)和四氢呋喃(12mL)加入到100mL反应瓶中，加入2N的NaOH水溶液(3.6mL)，反应液在55℃加热下搅拌1h。TLC(石油醚：乙酸乙酯＝1：1)检测原料反应完全后，反应液浓缩，所得残余物用1N HCl调节pH至2～3，用乙酸乙酯(40mL)萃取三次。合并有机相，经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品经硅胶柱层析(二氯甲烷：甲醇＝30：1)纯化得化合物diBSP 571mg，黄色固体，收率69％。1H NMR(300MHz,DMSO-d6):δ＝12.19(s,2H),8.40(s,2H),7.71(s,2H),7.59(s,2H),4.23(t,J＝5.9Hz,4H),3.85(s,6H),3.27(t,J＝5.9Hz,4H),2.61(t,J＝6.2Hz,4H),2.31–2.27(m,2H)ppm。13C NMR(75MHz,DMSO-d6):δ＝194.04,174.20,150.99,147.94,145.13,137.39,135.52,134.61,110.75,108.60,65.63,56.34,33.01,29.08,28.52ppm。HRMS(ESI-):计算值C29H27O10Se2 -(M-H)-,694.9940；实测值694.9945。
实施例14 4-(6-甲氧基-5-(3-((6-甲氧基-2-(4-((2-硝基苄基)氧基)-4-氧丁酰基)苯并[b]硒吩-5-基)氧基)丙氧基)苯并[b]硒酚-2-基)-4-氧代丁酸(II-1)的制备
将化合物diBSP(150mg,0.22mmol)、2-硝基苄醇(1a)(33mg,0.22mmol)、DCC(44mg,0.33mmol)、DMAP(1mg,0.01mmol)和二氯甲烷(4mL)加入到50mL反应瓶中，避光条件下，于室温下搅拌5h，TLC(二氯甲烷：甲醇＝20：1)检测原料反应完全后，反应液浓缩，所得残余物用乙酸乙酯(15mL)溶解，-10℃下降温搅拌约30min，过滤后使用冰乙酸乙酯(2mL)洗涤，滤液浓缩后获得粗品，粗品经硅胶柱层析(二氯甲烷：甲醇＝50：1)纯化得化合物II-1 106mg，浅黄色固体，收率59％。1H NMR(300MHz,DMSO-d6):δ＝11.62(s,1H),8.11–8.06(m,1H),7.76(s,2H),7.63–7.54(m,3H),7.52(s,2H),7.12(s,2H),5.51(d,J＝2.9Hz,2H),4.16(t,J＝3.1Hz,4H),3.84(s,6H),3.24-3.07(m,4H),2.69-2.58(m,4H),2.33–2.26(m,2H)ppm。13CNMR(75MHz,DMSO-d6):δ＝201.54,200.90,174.39,170.84,151.03,147.23,146.42,142.36,137.75,136.48,133.63,133.04,131.46,128.48,127.82,123.51,112.03,108.79,66.73,64.35,56.12,38.27,38.03,30.27,29.41,29.08ppm。HRMS(ESI-):计算值C36H32NO12Se2 -(M-H)-,830.0260；实测值830.0257。
实施例15 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)双(2-硝基)苄基酯(II-2)的制备
将化合物diBSP(150mg,0.22mmol)、2-硝基苄醇(1a)(99mg,0.65mmol)、DCC(88mg,0.66mmol)、DMAP(2mg,0.02mmol)和二氯甲烷(5mL)加入到50mL反应瓶中，避光，室温下搅拌6h，TLC(二氯甲烷：甲醇＝20：1)检测原料反应完全后，反应液浓缩，所得残余物用乙酸乙酯(15mL)溶解，-10℃下降温搅拌约30min，过滤后使用冰乙酸乙酯(2mL)洗涤，滤液浓缩后获得粗品，粗品经硅胶柱层析(二氯甲烷：甲醇＝100：1)纯化得化合物II-2 131mg，浅黄色固体，收率63％。1H NMR(300MHz,DMSO-d6):δ＝8.12–8.06(m,2H),7.79(s,2H),7.63–7.54(m,6H),7.52(s,2H),7.12(s,2H),5.50(d,J＝2.8Hz,2H),4.16(t,J＝6.0Hz,4H),3.84(s,6H),3.12(t,J＝3.3Hz,4H),2.62(t,J＝3.3Hz,4H),2.34–2.26(m,2H)ppm。13C NMR(75MHz,DMSO-d6):δ＝200.89,170.87,150.01,147.23,146.42,142.36,137.75,136.48,133.62,133.04,131.46,128.45,127.82,123.51,112.06,108.79,66.71,64.35,56.12,38.06,30.27,29.09ppm。HRMS(ESI+):计算值C43H39N2O14Se2 +(M+H)+,967.0726；实测值967.0724。
实施例16 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸酯)双(4,5-二甲氧基-2-硝基)苄基酯(II-3)的制备
参照实施例15所述的制备方法，将反应原料1a替换为4,5-二甲氧基-2-硝基苯甲醇制备得到化合物II-3。1H NMR(300MHz,DMSO-d6):δ＝7.78(s,2H),7.52(d,J＝3.0Hz,4H),7.26(t,J＝2.9Hz,2H),7.12(s,2H),5.50(d,J＝2.9Hz,4H),4.15(t,J＝6.1Hz,4H),3.88(d,J＝6.0Hz,12H)3.84(s,6H),3.12(t,J＝8.7Hz,4H),2.61(t,J＝5.9Hz,4H),2.34–2.25(m,2H)ppm。13C NMR(75MHz,DMSO-d6):δ＝200.89,170.88,153.07,151.01,148.73,146.42,142.36,141.60,137.73,136.49,133.62,127.04,113.10,112.06,110.04,108.79,66.71,64.23,56.52,56.11,55.95,38.06,30.25,29.10ppm。HRMS(ESI+):计算值C47H47N2O18Se2 +(M+H)+,1087.1149；实测值1087.1149。
实施例17 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸酯)双(2-氧代-2H-苯并吡喃-4-基)甲酯(II-4)的制备
参照实施例15所述的制备方法，将原料1a替换为4-(羟基甲基)-2H-苯并吡喃-2-酮得到化合物II-4。1H NMR(300MHz,DMSO-d6):δ＝7.76(s,2H),7.67–7.56(m,4H),7.50(s,2H),7.43(dd,J1＝5.9Hz,J2＝2.1Hz,2H),7.25–7.19(m,2H),7.11(s,2H),6.21(s,2H),5.42(s,4H),4.16(t,J＝6.0Hz,4H),3.84(s,6H),3.14(t,J＝8.1Hz,4H),2.61(t,J＝5.7Hz,4H),2.35–2.23(m,2H)ppm。13C NMR(75MHz,DMSO-d6):δ＝200.91,170.93,161.34,153.06,146.65,146.43,142.35,137.73,136.46,133.64,132.95,126.30,125.47,120.87,117.44,114.85,112.05,108.76,66.71,65.93,56.12,38.07,30.29,28.87ppm。HRMS(ESI+):计算值C49H41O14Se2 +(M+H)+,1013.0821；实测值1013.0822。
实施例18 4-(5-(3-((2-(4-((7-(二乙基氨基)-2-氧代-2H-苯并吡喃-4-基)甲氧基)-4-氧代丁酰基)-6-甲氧基苯并[b]硒吩-5-基)氧基)丙氧基)-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸(II-5)的制备
参照实施例14所述的制备方法，将反应原料1a替换为7-(二乙基氨基)-4-(羟基甲基)-2H-苯并吡喃-2-酮制备得到化合物II-5。1H NMR(300MHz,DMSO-d6):δ＝11.63(s,1H),7.76(s,2H),7.52–7.46(m,3H),7.12(s,2H),6.65–6.59(m,2H),6.15(s,1H),5.41(s,2H),4.15(t,J＝5.7Hz,4H),3.83(s,6H),3.50(q,J＝6.4Hz,4H),3.15–3.08(m,4H),2.68–2.58(m,4H),2.37–2.28(m,2H)ppm。13C NMR(75MHz,DMSO-d6):δ＝201.55,200.88,174.38,170.94,161.37,154.35,151.96,150.99,146.53,146.45,142.35,137.76,136.47,133.64,126.91,115.54,114.64,112.05,110.15,108.81,99.65,66.72,66.13,56.09,44.43,38.26,38.06,30.27,29.42,28.89,12.36ppm。HRMS(ESI-):计算值C43H42NO12Se2 -(M-H)-,924.1043；实测值924.1044。
实施例19 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸酯)双(7-(二乙基氨基)-2-氧代-2H-苯并吡喃-4-基)甲酯(II-6)的制备
参照实施例15所述制备方法，将原料1a替换为7-(二乙基氨基)-4-(羟基甲基)-2H-苯并吡喃-2-酮得到化合物II-6。1H NMR(300MHz,DMSO-d6):δ＝7.77(s,2H),7.53–7.46(m,4H),7.14(s,2H),6.63–6.56(m,4H),6.19(s,2H),5.43(s,4H),4.14(t,J＝8.9Hz,4H),3.86(s,6H),3.49(q,J＝8.3Hz,8H),3.12(t,J＝8.3Hz,4H),2.61(t,J＝8.5Hz,4H),2.34–2.26(m,2H),1.12(t,J＝6.1Hz,12H)ppm。13C NMR(75MHz,DMSO-d6):δ＝200.90,170.92,161.36,154.37,151.99,151.03,146.53,146.44,142.36,137.76,136.50,133.62,126.93,115.54,114.63,110.14,108.76,99.64,66.71,66.18,56.13,44.42,38.05,30.27,28.89,12.36ppm。HRMS(ESI+):计算值C57H59N2O14Se2 +(M+H)+,1155.2291；实测值1155.2288。
实施例20 4-(5-(3-((2-(4-(1-(7-(二乙基氨基)-2-氧代-2H-苯并吡喃-4-基)乙氧基)-4-氧代丁酰基)-6-甲氧基苯并[b]硒吩-5-基)氧基)丙氧基)-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸(II-7)的制备
参照实施例14所述的制备方法，将反应原料1a替换为7-(二乙基氨基)-4-(1-羟基乙基)-2H-苯并吡喃-2-酮制备得到化合物II-7。1H NMR(300MHz,DMSO-d6):δ＝11.63(s,1H),7.78(s,2H),7.53(s,2H),7.32(d,J＝8.7Hz,1H),7.12(s,2H),6.64(d,J＝2.8Hz,1H),6.50(dd,J1＝6.1Hz,J2＝2.9Hz,1H),6.18(s,1H),6.04(q,J＝5.9Hz,1H),4.15(t,J＝5.9Hz,4H),3.83(s,6H),3.51(q,J＝6.3Hz,4H),3.15–3.08(m,4H),2.68–2.58(m,4H),2.37–2.28(m,2H),1.43(d,J＝8.1Hz,3H),1.15(t,J＝6.5Hz,6H)ppm。13C NMR(75MHz,DMSO-d6):δ＝201.58,200.90,174.38,171.63,161.54,153.64,153.45,152.05,151.02,146.44,142.35,137.74,136.47,133.64,126.01,114.34,113.43,108.84,108.77,100.04,74.36,66.70,56.13,44.43,38.27,38.16,30.27,29.42,29.25,20.65,12.34ppm。HRMS(ESI-):计算值C44H44NO12Se2 -(M-H)-,938.1199；实测值938.1201。
实施例21 2-((1E,3Z,5E)-4-(1-((4-(5-(3-((2-(3-羧基丙酰基)-6-甲氧基苯并[b]硒吩-5-基)氧基)丙氧基)-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酰基)氧基)乙基)-7-((E)-1,3,3-三甲基吲哚啉-2-亚基)庚-1,3,5-三烯-1-基)-1,3,3-三甲基-3H-吲哚-1-碘化物(II-8)的制备
参照实施例7所述的制备方法，将反应原料BSP替换为diBSP制备得到化合物II-8。1HNMR(300MHz,DMSO-d6):δ＝11.64(s,1H),7.80(s,2H),7.73–7.46(m,7H),7.42–7.15(m,3H),7.10(s,2H),7.07–6.89(m,2H),6.75–6.66(m,2H),6.62–6.52(m,1H),6.24(dd,J1＝6.1Hz,J2＝2.7Hz,1H),5.55–5.34(m,1H),4.27(s,3H),4.17(t,J＝5.9Hz,4H),3.84(s,6H),3.55(s,3H),3.26–3.01(m,5H),2.69–2.56(m,4H),2.36–2.23(m,2H),1.71(dd,J1＝27.6Hz,J2＝15.2Hz,11H),1.28(d,J＝6.3Hz,3H)ppm。13C NMR(75MHz,DMSO-d6):δ＝201.59,200.92,174.39,171.83,164.32,156.60,151.03,147.15,146.42,145.54,142.35,139.94,138.83,137.74,137.61,136.46,135.33,133.63,132.26,131.10,128.86,128.27,127.63,126.94,125.96,123.81,122.92,119.11,118.58,112.06,110.32,108.81,101.76,69.46,66.72,56.11,40.56,39.98,38.25,38.14,37.55,32.11,30.27,29.45,29.25,29.17,28.53,20.33ppm。HRMS(ESI+):计算值C60H63N2O10Se2 +(M)+,1131.2808；实测值1131.2803。
实施例22 2-((1E,3Z,5E)-4-(1-((4-(5-(3-((2-(3-羧基丙酰基)-6-甲氧基苯并[b]硒吩-5-基)氧基)丙氧基)-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酰基)氧基)乙基)-7-((E)-5-甲氧基-1,3,3-三甲基吲哚啉-2-亚基)庚-1,3,5-三烯-1-基)-5-甲氧基-1,3,3-三甲基-3H-吲哚-1-碘化物(II-9)的制备
参照实施例7所述的制备方法，将反应原料BSP替换为diBSP，7a替换为5-甲氧基-1,2,3,3-四甲基-3H-吲哚鎓碘化物制备得到化合物II-9。1H NMR(300MHz,DMSO-d6):δ＝11.65(s,1H),7.79(s,2H),7.52–7.48(m,4H),7.42–7.33(m,2H),7.17–7.11(m,3H),7.01–6.90(m,3H),6.83(dd,J1＝6.2Hz,J2＝2.7Hz,1H),6.71(dt,J1＝6.4Hz,J2＝2.4Hz,1H),6.62–6.53(m,1H),6.23(dd,J1＝6.2Hz,J2＝2.7Hz,1H),5.44–5.34(m,1H),4.27(s,3H),4.26–4.11(m,7H),3.86–3.81(m,12H),3.56(s,3H),3.26–3.01(m,5H),2.71–2.53(m,4H),2.35–2.23(m,2H),1.68(dd,J1＝27.4Hz,J2＝15.3Hz,11H),1.29(d,J＝6.3Hz,3H)ppm。13CNMR(75MHz,DMSO-d6):δ＝201.56,200.90,174.39,171.83,164.11,156.02,155.26,154.77,151.02,146.44,143.95,142.35,139.59,138.70,138.31,137.75,137.53,136.48,135.33,133.62,131.13,128.27,125.97,125.96,121.16,119.21,118.72,113.52,112.08,111.43,110.61,108.91,108.78,101.96,69.43,66.71,56.11,55.67,40.97,39.99,38.26,38.12,37.57,32.14,30.26,29.45,29.23,29.18,28.52,20.33ppm。HRMS(ESI+):计算值C62H67N2O12Se2 +(M)+,1191.3019；实测值1191.3015。
实施例23 3-(2-((1E,3Z,5E)-4-(1-((4-(5-(3-((2-(3-羧基丙酰基)-6-甲氧基苯并[b]硒吩-5-基)氧基)丙氧基)-6-甲氧基苯并[b]硒吩-2-基)-4-丁酰基)氧基)乙基)-7-((E)-3,3-二甲基-1-(3-磺酰丙基)吲哚啉-2-亚基)庚-1,3,5-三烯-1-基)-3,3-二甲基-3H-吲哚-1-鎓-1-基)丙烷-1-磺酸钠(II-10)的制备
参照实施例7所述的制备方法，将反应原料BSP替换为diBSP，7a替换为3-(2,3,3-三甲基-3H-吲哚-1-鎓-1-基)丙烷-1-磺酸盐制备得到化合物II-10。1H NMR(300MHz,DMSO-d6):δ＝11.60(s,1H),7.77(s,2H),7.73–7.64(m,2H),7.60–7.51(m,4H),7.47–7.35(m,2H),7.28–7.09(m,4H),7.03(dt,J1＝6.3Hz,J2＝2.9Hz,1H),6.92–6.82(m,2H),6.74–6.69(m,1H),6.62–6.53(m,1H),6.14(dd,J1＝6.3Hz,J2＝2.9Hz,1H),5.44–5.31(m,1H),4.67–4.45(m,2H),4.13(dt,J1＝6.1Hz,J2＝2.9Hz,1H),4.06–3.93(m,2H),3.84(s,6H),3.45–3.23(m,2H),3.22–2.99(m,7H),2.69–2.54(m,4H),2.35–2.04(m,6H),1.66(dd,J1＝27.5Hz,J2＝15.2Hz,11H),1.31(d,J＝6.4Hz,3H)ppm。13C NMR(75MHz,DMSO-d6):δ＝201.53,200.88,174.39,171.81,169.23,155.66,151.03,146.45,144.18,144.10,142.35,140.47,137.83,137.72,137.22,136.46,135.32,133.65,132.03,131.25,129.02,128.07,127.57,125.96,124.94,124.03,122.99,119.78,117.76,112.05,111.11,108.75,102.23,69.56,66.72,56.11,51.50,50.04,45.16,43.66,42.63,41.42,38.27,38.14,30.27,29.42,29.23,29.06,28.48,23.42,20.34,18.85ppm。HRMS(ESI-):计算值C64H69N2O16Se2 -(M)-,1345.2424；实测值1345.2419。
实施例24代表化合物的光照释放实验
本发明制备的化合物含有两类光保护基团，一类是可以通过紫外-可见光照射脱除的邻硝基苄基和香豆素结构，另一类是可以通过近红外光照射脱除的七甲川花菁结构。
本发明选取化合物I-7和化合物II-6作为代表化合物，进行光照释放实验。上述代表化合物包含了这两个类型的光保护基团，且基本骨架相似，可以反映出本发明制备的化合物具有相同的光解性质。
化合物I-7和II-6溶解在DMSO中，配置为浓度为10mM的母液，保存于-20℃备用。化合物母液用甲醇：PBS＝1：1的混合溶剂稀释至终浓度为50μM，进行光照处理。对于化合物I-7，光照波长为808nm；对于化合物II-6，光照波长为400nm。在给定的时间分别取样进行HPLC分析和紫外吸收光谱图的测定。结果如图1所示。
图1中A和B分别表示化合物I-7在808nm光照射下的紫外吸收光谱变化及原型药物BSP的释放情况。C和D化合物II-6在400nm光照射下的紫外吸收光谱变化及原型药物diBSP的释放情况。从图1可以看出：两个化合物都具有良好的光解性质，能迅速且完全地转化为相应的原型药物。
因此，本发明制备的化合物具有较好的光解性质。
实施例25代表化合物在THP1-Lucia荧光素酶报告基因细胞中的光依赖的STING激动活性实验
本发明制备的化合物均需要通过光照释放其STING激动活性。在化合物具有优秀的光解性质基础上，本发明选取化合物I-7和化合物II-6作为代表化合物，进行光依赖STING激动活性实验。
将THP1-LuciaTMISG(Invivogen:thpl-isg)细胞使用培养基稀释并吸取100μL细胞悬液接种于96孔板，使得每孔含有1×105个细胞。随后将待测化合物100μL加入到96孔板中(化合物终浓度为25μM，每孔终体积为200μL)，并同时设置避光组和光照组，其中光照组的给药孔给予一定时间的光照处理。对于化合物I-7，光照波长为808nm，光照时间为5min；对于化合物II-6，光照波长为400nm，光照时间为1min。光照结束后，所有组在37℃的黑暗条件下继续孵育24h。随后吸取10μL上清液至新的96孔白板中，并加入50μL QUANT-Luc试剂。充分混匀后立刻使用酶标仪进行测定。实验设置3个复孔。测试结果以激动倍数(fold)表示，通过(测试孔-空白孔)/(阴性孔-空白孔)计算得到。空白孔为细胞培养介质，阴性孔为二甲基亚砜DMSO。测试结果如图2所示。(+代表光照组，﹣代表避光组，化合物diBSP为苯并[b]硒吩类二聚体STING激动剂，其STING激动活性数据见图2B。)
从图中可以得知，化合物I-7和II-6在避光条件下无法激活STING通路，而在对应的光照后能释放出原型药物，恢复STING激动活性。两个对应的原型药物在THP1荧光素酶报告基因测试中都表现出优秀的STING激动活性，是良好的STING激动剂。通过两个代表探针分子的光依赖STING激动活性，可以证明本发明制备的化合物均具有相似的作用。
本发明制备的化合物在受到光照后，能脱除光保护基团，释放出原型药物即对应的STING激动剂。因此本发明中的化合物可以用于制备激活cGAS-STING通路的药物、制备预防和/或治疗与STING通路相关疾病药物以及制备免疫佐剂。另外，本发明中的化合物带有荧光基团，可以用于制备荧光成像试剂。
Claims (10)
1.一种苯并[b]硒吩类STING激动剂荧光探针分子，其特征在于，所述荧光探针分子为苯并[b]硒吩类单体或其二聚体STING激动剂与光激活保护基团偶联得到的化合物、立体异构体或其药学上可接受的盐。
2.根据权利要求1所述的苯并[b]硒吩类STING激动剂荧光探针分子，其特征在于，所述光激活保护基团为邻硝基苄基衍生物X1、香豆素衍生物X2或七甲川花菁衍生物X3：
其中，
R1选自氢、甲基或烯丙基；
R2选自氢、羟基、甲基、叔丁基、甲氧基、OCH2CN、OCH2COOH、OCH2COOCH3或对位取代的苯乙烯基；
R3选自氢或甲氧基；
R4选自氢或甲基；
R5选自氢、卤素、甲氧基或氨基；
R6选自氢、羟基、甲氧基、N(CH2CH3)2、苄氧基、苯甲酰氧基或硼酸频哪醇酯基；R7选自甲基、乙基、苄基、(CH2)mSO3H或(CH2)mCOOH；
R8选自氢、甲氧基、SO3H或COOH；
R9选自氢；或R9与R8相连形成苯环或C5～C6芳香杂环；
R10选自氢或甲基；
R11选自氢或甲基；
m选自3、4或5。
3.根据权利要求2所述的苯并[b]硒吩类STING激动剂荧光探针分子，其特征在于，
R1选自氢或甲基；
R2选自氢、羟基、甲基或甲氧基；
R5选自氢、溴或甲氧基；
R6选自氢、羟基、甲氧基或N(CH2CH3)2；
R7选自甲基、乙基、苄基或(CH2)mSO3H；
R8选自氢、甲氧基或SO3H；
m选自3或4。
4.根据权利要求1-3任一项所述的苯并[b]硒吩类STING激动剂荧光探针分子，其特征在于，所述荧光探针分子具有如式(I)所示的结构：
其中，
X选自邻硝基苄基衍生物(X1)、香豆素衍生物(X2)或七甲川花菁衍生物(X3)。
5.根据权利要求1-3任一项所述的苯并[b]硒吩类STING激动剂荧光探针分子，其特征在于，所述荧光探针分子具有如式(II)所示的结构：
其中，
Y选自氢、X1、X2或X3；且当一侧Y选自氢时，另一侧Y选自X1、X2或X3；或
两侧Y同时选自X1、X2或X3。
6.根据权利要求1所述的苯并[b]硒吩类STING激动剂荧光探针分子，其特征在于选自：
7.权利要求1-6中任一项所述的苯并[b]硒吩类STING激动剂荧光探针分子在制备激活cGAS-STING通路的药物中的用途。
8.权利要求1-6中任一项所述的苯并[b]硒吩类STING激动剂荧光探针分子在制备预防和/或治疗与STING通路相关疾病药物中的用途。
9.权利要求1-6中任一项所述的苯并[b]硒吩类STING激动剂荧光探针分子在制备免疫佐剂中的用途。
10.权利要求1-6中任一项所述的苯并[b]硒吩类STING激动剂荧光探针分子在制备活体荧光成像试剂中的用途。
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