CN114790215B - 基于喹喔啉的d-a-d近红外二区荧光分子及其制备方法和应用 - Google Patents
基于喹喔啉的d-a-d近红外二区荧光分子及其制备方法和应用 Download PDFInfo
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- CN114790215B CN114790215B CN202210079357.8A CN202210079357A CN114790215B CN 114790215 B CN114790215 B CN 114790215B CN 202210079357 A CN202210079357 A CN 202210079357A CN 114790215 B CN114790215 B CN 114790215B
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- 125000000217 alkyl group Chemical group 0.000 claims description 78
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- 150000002367 halogens Chemical class 0.000 claims description 35
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 34
- -1 hydroxy, amino, carboxyl Chemical group 0.000 claims description 33
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
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- 125000003545 alkoxy group Chemical group 0.000 claims description 18
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 4
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- 125000000542 sulfonic acid group Chemical group 0.000 claims description 2
- PIILXFBHQILWPS-UHFFFAOYSA-N tributyltin Chemical group CCCC[Sn](CCCC)CCCC PIILXFBHQILWPS-UHFFFAOYSA-N 0.000 claims description 2
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical group O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims 1
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- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
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Abstract
本发明涉及一种基于喹喔啉的D‑A‑D近红外二区荧光分子及其制备方法和应用。所述基于喹喔啉的D‑A‑D近红外二区荧光分子选自通式I‑1和I‑2所示的化合物及它们的盐,可以用于制备显影剂,用于在生物组织及样品中进行体外定量检测和体内成像以及非生物组织的指示定量。
Description
技术领域
本发明属于有机荧光探针领域,涉及一类喹喔啉类化合物,其制备方法及应用。
背景技术
生物成像技术在临床诊断、手术导航、治疗效果的评估及预后发挥着重要作用。传统的成像技术,如计算机X射线断层成像(CT)、超声扫描仪(US)、正电子发射断层成像(PET)、单电子发射断层成像(SPECT)和磁共振成像(MRI)等,广泛应用于临床,以提供解剖学和功能学信息。然而,与有害的电离辐射(CT、PET和SPECT)和低时间分辨率(CT、MRI和PET)[Nature,2008,452,580;Nat.Biomed.Eng.2017,1,0008]相比,荧光成像具有成像范围广、成本低、操作简单、无创、灵敏度与时空分辨率高、可视化效果好、细胞内动力学实时分析、亚细胞水平生物分子实时定位等独特优势[Chem.Soc.Rev.2018,47,4258;Adv.Mater.2018,30,1802394;Nat.Biomed.Eng.2017,1,0010;Nat.Biotechnol.2017,35,1102;Adv.Optical Mater.2019,1900917]。
尽管荧光成像具有诸多优势,但穿透深度差仍然是荧光成像应用于临床的主要障碍[ACS Nano.2018,12,9654]。传统的可见光(Vis,400-700nm)荧光成像只有约2mm的生物组织穿透深度。在过去几十年中,近红外一区(NIR-I,700-900nm)的荧光成像经历了爆炸式发展。与可见光谱相比,它在生理和病理信息输出方面具有更大优势[Adv.HealthcareMater.2018,7,1800497;Chem.Soc.Rev.2018,47,4258]。目前,吲哚菁绿(ICG,λex max=789nm,λem max=814nm)和亚甲基蓝(MB,λex=665nm,λem=686nm)已被FDA批准应用于临床[Nat.Rev.Clin.Oncol.2013,10,507-518]。与传统的可见-近红外一区(Vis-NIR-I,400-900nm)荧光成像相比,近五年来出现的近红外二区生物成像窗口(NIR-II,1000-1700nm)极大地减少了组织的光子散射、吸收和自荧光[Proc.Natl.Acad.Sci.USA 2018,115,4465;Nat.Nanotechnol.2009,4,710],提供更高的信噪比和更深的组织穿透性(约11mm的生物组织穿透深度)[ChemBioChem.2018,19,2522],提高检测的灵敏度和特异性,显示出疾病诊断及手术导航治疗的极大潜力(Nat.Biomed.Eng.2017,1,0010)。特别地,近红外二区荧光探针的开发广泛应用于生物医学领域。例如,监测生理及病理条件下血流变化、实时精确的淋巴结显影及肿瘤成像,以及术中前哨淋巴结/肿瘤组织的手术切除。此外,将荧光分子作为报告基团连接至药物分子或特异性靶向配体,可追踪药物分子在体内的分布代谢性质以及靶向相关受体,实现受体高表达的相关疾病诊断(Adv.Funct.Mater.2017,1700995;Adv.Mater.2016,28,6872–6879;Chem.Sci.,2017,8,3489;Adv.Mater.2017,29,1605497)。
无机纳米颗粒(碳纳米管、量子点及稀土纳米颗粒等)由于其在NIR-II波长处固有的荧光发射广泛应用于二区荧光成像。然而无机近红外-II荧光团较差体内代谢动力学、潜在的长期毒性极大限制该类成像剂在临床应用[Nat.Biomed.Eng.2017,1,0008]。与无机纳米颗粒相比,有机NIR-II荧光剂,特别是近年来开发的供体-受体-供体(D-A-D)结构的小分子,因其良好的生物相容性、明确的化学结构和可定制的光学性质而得到了广泛的研究。目前为止,报道的D-A-D型有机荧光团主要以苯并[1,2-c:4,5-c']双([1,2,5]噻二唑)(BBTD)、噻二唑苯并三唑(TBZ)、6,7-二苯基噻二唑喹啉(PTQ)等作为强电子受体(Nat.Mater.2016,15(2),235-242;Adv.Funct.Mater.2017,27,1700995;ACS Nano 2017,11,12276-12291;Nat.Commun.2017,8,15269;Adv.Mater.2018,30,1705799;Adv.Mater.2018,30,1706856;ACS Nano 2017,11,7177-7188;ChemicalScience.2020.DOI:10.1039/d0sc03160g)。然而,BBTD、TBZ在碱性条件下极不稳定,且对苛刻的合成条件敏感,限制了NIR-II荧光分子的开发。此外,现有基于PTQ为电子受体的荧光分子皆为包载纳米材料或聚合物,其生物安全性仍有待考究(Polymer,2015:12-20.)。
因此,寻找新一代稳定的受体结构单元,改善上述电子受体缺陷,为NIR-II有机分子的开发提供更多的设计策略显得尤为紧要。
发明内容
6,7-二(芳杂基)-[1,2,5]噻二唑[3,4-g]喹喔啉受体单元结构多用于有机光电材料领域。本发明目的是以其为电子受体单元,合成一类喹喔啉类近红外二区荧光分子,同时提供其制备方法及应用。
本发明的一方面提供了一种基于喹喔啉的D-A-D近红外二区荧光分子,其选自通式I-1和I-2所示的化合物及它们的盐:
其中:
X为S、O、Se、NR5;特别为S;
Y为S、O、Se、NR5;特别为S、O、NR5;
R1和R2各自独立地选自R6和R9各自独立地为H、C1-C8烷基、C1-C8烷氧基、取代或未取代的C6-C10芳基或5-10元杂芳基;R7和R8各自独立地为H、C1-C8烷基、C1-C8烷氧基、或卤素,或者R7和R8与和其相连接的C一起形成5-10元杂环基;Y1为Se、S、O或NR5,特别为S或O,更特别为S;
R3和R4各自独立地选自H、C1-C12烷基、C1-C12烷氧基、C1-C8烷基硅基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、巯基C1-C8烷基、卤代C1-C8烷基、酰氧基C1-C8烷基、氨基、卤素、羧基C1-C6烷基、取代或未取代的C6-C10芳基或5-10元杂芳基、-(CH2)n1-COOCH2CH2Si(CH3)3,其中n1为0~10的整数;-(CH2)n2-(OCH2CH2)n3-R,其中n2为1~10的整数,n3为1~500的整数,R选自H、C1-C8烷基、羟基、氨基、羧基、磺酸基、卤素、巯基、及
当C6-C10芳基或5-10元杂芳基被取代时,取代基选自C1-C8烷基、C1-C8烷氧基、C1-C8烷基硅基、羟基C1-C8烷基、氨基C1-C8烷基、巯基C1-C8烷基、卤代C1-C8烷基、羧基C1-C6烷基;
R5选自H、C1-C8烷基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、巯基C1-C8烷基、卤代C1-C8烷基、酰氧基C1-C8烷基、-(CH2)n2-(OCH2CH2)n3-R,其中n2为1~10的整数,n3为1~500的整数,R选自H、C1-C8烷基、羟基、氨基、羧基、磺酸基、卤素、巯基、及/>
D1和D2各自独立地选自如下基团:
其中,R10-R48各自独立地选自H、取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基、取代或未取代的C1-C8烷基硅基、氨基、卤素、-(CH2)n1-COOCH2CH2Si(CH3)3,其中n1为0~10的整数;式-(CH2)n2-(OCH2CH2)n3-R,其中n2为1~10的整数,n3为1~500的整数,R选自H、C1-C8烷基、羟基、氨基、羧基、磺酸基、卤素、巯基、及/>-(CH2)n4-CONHCH2CH2SO3H,其中n4为0~10的整数;
所述取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基或取代或未取代的C1-C8烷基硅基的取代基选自羟基、氨基、C1-C4炔基、叠氮基、巯基、醛基、羧基、磺酸基、卤素、RaOC(=O)-、RaC(=O)O-、RaNC(=O)-和吡咯烷二酮-N-,其中Ra各自独立地选自C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、醛基C1-C6烷基、巯基C1-C6烷基、卤代C1-C6烷基、炔基C1-C6烷基、叠氮基C1-C6烷基、羧基C1-C6烷基、磺酸基C1-C6烷基和吡咯烷二酮-N-;
或者,R10-R48各自独立地选自式其中,R’和R”各自独立地选自C1-C8亚烷基,“A”选自环状RGD肽基团,例如c(RGDyk)、c(RGDfk);单糖基团;二糖基团及多糖基团,所述单糖优选选自葡糖糖、半乳糖、果糖、阿拉伯糖、鼠李糖、核糖;所述二糖优选选自乳糖及麦芽糖;所述多糖优选选自环糊精;“B”为含有Fv段的分子基团,例如可以选自单抗、双抗及单链Fv段基团;
或者,R10-R48各自独立选自
在一些实施方式中,R1和R2各自独立地选自其中,R6为H、C1-C4烷基或C1-C4烷氧基;R7和R8各自独立地为H、C1-C4烷基、C1-C4烷氧基或卤素,或者R7和R8与和其相连接的C一起形成5-7元杂环基,特别是二氧杂环己烷基;Y为S或O,特别是S。在一些实施方式中,R1和R2彼此相同。在另一些实施方式中,R1和R2彼此相同,选自其中,R6为H、C1-C2烷基或C1-C2烷氧基;R7和R8各自独立地为H、C1-C2烷基、C1-C2烷氧基或卤素,或者R7和R8与和其相连接的C一起形成5-7元杂环基,特别是二氧杂环己烷基;Y1为S。
在一些实施方式中,D1和D2各自独立地选自如下基团:
特别是/> 在另一些实施方式中,D1和D2彼此相同。
在一些实施方式中,
X为S;
Y为S、O或NR5;
R1和R2彼此相同,为其中,R7和R8为H或者R7和R8与和其相连接的C一起形成二氧杂环己烷基;Y1为S;以及
D1和D2彼此相同,选自如下基团:
其他基团定义与上述相同。
在一些实施方式中,
X为S;
Y为S;
R1和R2彼此相同,为其中,R6为H、C1-C4烷基或C1-C4烷氧基,特别为H;
D1和D2彼此相同,为R10和R11定义与上述相同。
在一些实施方式中,R3和R4各自独立地选自H、C1-C4烷基、C1-C4烷氧基、羟基C1-C4烷基、氨基C1-C4烷基、醛基C1-C4烷基、巯基C1-C4烷基、卤代C1-C4烷基、氨基、卤素、-(CH2)n1-COOCH2CH2Si(CH3)3,其中n1为0~10的整数。在一些实施方式中,R3和R4彼此相同。
在一些实施方式中,R5选自H、C1-C4烷基、羟基C1-C4烷基、氨基C1-C4烷基、醛基C1-C4烷基、巯基C1-C4烷基、卤代C1-C4烷基,特别是H或C1-C4烷基。
在一些实施方式中,上述R10-R48各自独立地选自H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷基硅基、氨基、卤素、-(CH2)n2-(OCH2CH2)n3-R,其中n2为1~10的整数,n3为1~500的整数,R选自H、C1-C8烷基、羟基、氨基、羧基、磺酸基、卤素、巯基、及/>特别地,上述R10-R48各自独立地选自H、C1-C6烷基、卤素。所述的取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基或取代或未取代的C1-C6烷基硅基的取代基选自羟基、氨基、乙炔基、叠氮基、醛基、羧基、磺酸基、卤素、RaOC(=O)-、RaNC(=O)-、吡咯烷二酮-N-,其中Ra各自独立地选自C1-C4烷基、羟基C1-C4烷基、氨基C1-C4烷基、醛基C1-C4烷基、巯基C1-C4烷基、卤代C1-C4烷基、羧基C1-C4烷基、磺酸基C1-C4烷基和吡咯烷二酮-N-。
在一些实施方式中,R10-R48各自独立地选自式其中,R’选自C1-C6亚烷基,“A”选自单糖基团,所述单糖选自葡糖糖、半乳糖、果糖、阿拉伯糖、鼠李糖、核糖、乳糖及麦芽糖。
在一些实施方式中,R10-R48各自独立选自
在一些实施方式中,上述R10和R11彼此相同,选自H,C1-C6烷基,和被羟基、氨基、醛基、羧基、磺酸基、RaNC(=O)-取代的C1-C6烷基,其中Ra选自C1-C4烷基、羟基C1-C4烷基、氨基C1-C4烷基、醛基C1-C4烷基、巯基C1-C4烷基、卤代C1-C4烷基、羧基C1-C4烷基、磺酸基C1-C4烷基或单糖基团,所述单糖选选自葡糖糖、半乳糖、果糖、阿拉伯糖、鼠李糖及核糖。
在一些实施方式中,上述R12和R13彼此相同,选自H,C1-C6烷基,和被选自羟基、氨基、乙炔基、叠氮基、醛基、羧基、磺酸基、卤素、RaOC(=O)-、RaNC(=O)-、吡咯烷二酮-N-的取代基取代的C1-C6烷基,其中Ra各自独立地选自C1-C4烷基、羟基C1-C4烷基、氨基C1-C4烷基、醛基C1-C4烷基、巯基C1-C4烷基、卤代C1-C4烷基、羧基C1-C4烷基、磺酸基C1-C4烷基和吡咯烷二酮-N-。
在一些实施方式中,上述R14选自H,C1-C6烷基,和被选自羟基、氨基、乙炔基、叠氮基、醛基、羧基、磺酸基、卤素、RaOC(=O)-、RaNC(=O)-的取代基取代的C1-C6烷基,其中Ra各自独立地选自C1-C4烷基、羟基C1-C4烷基、氨基C1-C4烷基、醛基C1-C4烷基、巯基C1-C4烷基、卤代C1-C4烷基、羧基C1-C4烷基、磺酸基C1-C4烷基;和
R15选自H,C1-C6烷基,和被选自羟基、氨基、乙炔基、叠氮基、醛基、羧基、磺酸基、卤素、RaOC(=O)-、RaNC(=O)-的取代基取代的C1-C6烷基,其中Ra各自独立地选自C1-C4烷基、羟基C1-C4烷基、氨基C1-C4烷基、醛基C1-C4烷基、巯基C1-C4烷基、卤代C1-C4烷基、羧基C1-C4烷基、磺酸基C1-C4烷基;或者
R15选自
在一些实施方式中,上述R16和R17彼此相同,选自C1-C6烷基,和被选自羟基、氨基、醛基、羧基、磺酸基、RaOC(=O)-、RaNC(=O)-的取代基取代的C1-C6烷基,其中Ra各自独立地选自C1-C4烷基、羟基C1-C4烷基、氨基C1-C4烷基、醛基C1-C4烷基、巯基C1-C4烷基、卤代C1-C4烷基、羧基C1-C4烷基、磺酸基C1-C4烷基;和R18为H。
在一些实施方式中,上述R38选自H、C1-C6烷基、被选自羟基、氨基、乙炔基、叠氮基、醛基、羧基、磺酸基、卤素的取代基取代的C1-C6烷基。
在一些实施方式中,本发明的基于喹喔啉的D-A-D近红外二区荧光分子选自下列化合物或其盐:
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术语“卤素”是指氟、氯、溴或碘。
术语“C1-C12烷基”是指链上具有1至12个碳原子的直链或支链饱和烃基,非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基等。C1-C8烷基、C1-C6烷基、C1-C4烷基的含义以此类推。
术语“烷氧基”是指上述烷基末端连接氧所得的基团,例如,甲氧基、乙氧基、正丙氧基、仲丁氧基、叔丁基、正己氧基等。
术语“C1-C8烷基硅基”为结构RaRbRcSi-,其中,Ra、Rb和Rc中至少有一个为C1-C8烷基,其余为氢的基团,例如,三甲基硅烷、三乙基硅烷。
术语“磺酸基”是指-SO3H。
术语“氨基”是指-NH2。
术语“羧基”是指-COOH。
术语“酰氧基”是指被结构-OC(=O)Rd,其中,Rd选自H、“C1-C8烷基”、“C2-C8烯基”、“C2-C8炔基”、“杂环烷基”、“芳基”、“杂芳基”、“C1-C8烷基芳基”、“C1-C8烷基杂芳基”。
术语“酰氧基C1-C8烷基”是指被上述酰氧基取代的C1-C8烷基,特别地,“酰氧基C1-C8烷基”非限制地包括2-(乙酰氧基)乙基。
术语“C6-C10芳基”是指具有6至10个碳原子的芳基,非限制性地包括苯基、萘基等。
术语“5-10元杂环基”是指含有一个或多个饱和和/或部分饱和环,其包括5至10个环原子,其中一个或多个环原子选自氮、氧或硫的杂原子,其余环原子为碳;例如,环氧丙烷、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基等。
“C6-C10芳基”和“5-10元杂环基”在被取代时,取代基可以选自C1-C8烷基、C1-C8烷氧基、C1-C8烷基硅基、羟基C1-C8烷基、氨基C1-C8烷基、巯基C1-C8烷基、卤代C1-C8烷基、羧基C1-C8烷基。
本发明的另一方面提供了制备通式I-1或I-2所示的喹喔啉类化合物的方法,所述方法包括以下步骤:
其中,各取代基的定义如上所述,
R’为硼酸基或硼酸酯基或三正丁基锡基;
a、化合物1经还原反应得到中间体2;
b、中间体2与化合物3-1或3-2经缩合反应得到中间体4-1或4-2;
c、中间体4-1或4-2与化合物5经Suzuki偶联反应得到中间体6-1或6-2;
d、中间体6-1或6-2与化合物7经Suzuki偶联反应得到化合物I-1或I-2。
特别地,反应条件例如可以如下:
a、取化合物1、Zn粉于反应容器中,氮气或惰性气体保护下,加入二氯甲烷-90%甲醇混合溶液,其中,二氯甲烷和90%甲醇的体积比为15~3:1;向反应液中通入氮气或惰性气体,排除反应液中的氧气,再加入氯化铵,继续向反应液中通入氮气或惰性气体,室温反应4~48h,反应结束后进行提纯,即得到中间体2;
b、取中间体2、化合物3-1或3-2加入到反应容器中,溶于乙酸溶液,向反应液中通入氮气或惰性气体,加热回流反应10~72h,反应结束后进行提纯,即得到中间体4-1或4-2;
c、取中间体4-1或4-2、化合物5、碳酸钾加入到反应容器中,氮气或惰性气体保护下,加入甲苯-水混合液,其中,甲苯和水的体积比为10~3:1,向反应液中通入氮气或惰性气体,排除反应液中的氧气,再加入四(三苯基膦)钯,继续向反应液中通入氮气或惰性气体,加热回流反应10~96h,反应结束后进行提纯,即得到中间体6-1或6-2;
d、取中间体6-1或6-2、化合物7、碳酸钾加入到反应容器中,氮气或惰性气体保护下,加入甲苯-水混合液,其中,甲苯和水的体积比为10~3:1,向反应液中通入氮气或惰性气体,排除反应液中的氧气,再加入四(三苯基膦)钯,继续向反应液中通入氮气或惰性气体,加热回流反应10~96h,反应结束后进行提纯,即得到化合物I-1或I-2。
步骤a所述的化合物1、Zn粉、氯化铵的摩尔比为1:120:36,所述的二氯甲烷和90%甲醇的体积比为10:1;步骤b所述的中间体2和化合物3的摩尔比为1:2;步骤c和步骤d所述的中间体4、化合物5、碳酸钾、四(三苯基膦)钯的摩尔比为1:1:5:0.1,所述的甲苯和水的体积比为3:1。
步骤a所述的化合物1的反应时间为4~6h。
步骤b所述的中间体2与化合物3的反应时间为10~48h,所述的回流温度为100~120℃。
步骤c所述的中间体4与化合物5的反应时间为10~96h,所述的回流温度为100~120℃。
步骤d所述的中间体6与化合物7的反应时间为10~96h,所述的回流温度为100~120℃。
本发明另一方面涉及上述近红外二区荧光报告分子用于制备显影剂的用途。
本发明又一方面涉及一种显影剂,其包含上述近红外二区荧光报告分子。
所述显影剂可以用于在生物组织及样品中进行体外定量检测和体内成像以及非生物组织的指示定量。例如,所述显影剂可以用于活体荧光成像指导肿瘤切除,例如龋齿类动物活体成像及荧光成像指导荷瘤鼠肿瘤切除;所述显影剂可用于龋齿类动物血液循环系统成像、淋巴管及淋巴结成像、肿瘤血管成像、血栓成像及脑血管成像;所述显影剂可用于坏死组织成像,例如龋齿类动物无水乙醇诱导的肌肉坏死组织成像。
附图说明
图1为6,7-二(噻吩基)-[1,2,5]噻二唑[3,4-g]喹喔啉(TTQ)、BBTD、TBZ在有无三乙胺存在下的高效液相色谱图。图中可见,BBTD及TBZ在三乙胺(TEA)条件下,发生分解,TTQ则稳定存在。
图2为TTQ及PTQ的紫外吸收图谱。图中可见,TTQ发生吸收红移。
图3为染料Ia至Ip的最大发射波长图。
图4为静脉注射染料(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)、(Ig)、(Ih)、(Ii)、(Ij)进入正常小鼠体内近红外二区1100nm生物分布图。
图5为染料Iu导航外科手术前后评价的图像,可辅助外科手术,提高外科手术准确度。
具体实施方式
下面结合具体实施例对本发明做进一步阐述。这些实施例仅是出于解释说明的目的,而不限于本发明的范围和实质。
实施例
实施例1化合物(Ia)的合成
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取化合物1a(1g,1.8mmol)溶于50mL二氯甲烷-90%甲醇混合溶液中(体积比为1:1),加入锌粉(14.3g,219mmol),氮气保护下,加入氯化铵(65.2mmol,3.49g)溶成5毫升水溶液,室温搅拌4小时。反应结束后,二氯甲烷萃取,合并有机相,得黄色粗产品2a 800mg,粗产率90%,未进行纯化,直接进行下步反应;
取化合物3a(109.3mg,0.49mmol),中间体2a(200mg,0.41mmol)溶于5mL的乙酸中,100℃加热搅拌过夜。次日,反应液中有大量沉淀,二氯甲烷反复萃取,合并有机相,得墨绿色固体4a 236mg,粗产率85%。1H NMR(400MHz,CDCl3)δ8.78(m,2H),7.70(m,2H),7.53(m,2H),7.12(m,2H),5.32(m,2H).;
取中间体4a(100mg,0.15mmol),化合物5a(72mg,0.3mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(15mg,0.015mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Ia 50mg。产率:45%。1H NMR(400MHz,DMSO-d6)δ11.31(s,2H),8.79(dd,J=24,4.0Hz,2H),8.04–7.92(m,4H),7.61–7.35(m,10H),7.15–7.02(m,2H),6.57(s,2H).13C NMR(126MHz,DMSO-d6)δ151.42,151.28,145.50,141.18,136.41,134.88,133.82,133.47,132.23,132.04,128.72,128.16,126.99,125.74,122.38,119.98,119.31,117.70,112.63,102.34.MALDI-TOF/TOF理论值:C40H22N6S5[M]:746.05,实测值[M]:745.912.
实施例2化合物(Ib)的合成
取化合物3b(95mg,0.49mmol),中间体2a(200mg,0.41mmol)溶于5mL的乙酸中,100℃加热搅拌过夜。次日,反应液中有大量沉淀,二氯甲烷反复萃取,合并有机相,得墨绿色固体4b 200mg,粗产率75%,1H NMR(400MHz,CDCl3)δ8.90(d,J=4.0Hz,2H),7.74(dd,J=4.0Hz,0.4Hz,2H),7.26(d,J=4.0Hz,2H),7.22(dd,J=3.6,0.4Hz,2H),6.73(m,2H);
取中间体4b(100mg,0.15mmol),化合物5b(132mg,0.3mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(15mg,0.015mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Ib 60mg。产率:36%。1H NMR(400MHz,DMSO-d6)δ11.27(s,2H),8.86(d,J=4.0Hz,2H),8.01(s,2H),7.98(s,2H),7.57–7.47(m,6H),7.42(t,J=4.0Hz,2H),7.11(d,J=2.8Hz,2H),6.82–6.77(m,2H),6.55(t,J=4.0Hz,2H),4.16(t,J=7Hz,4H),2.91(t,J=7Hz,4H),1.84-1.74(m,8H).13C NMR(126MHz,DMSO-d6)δ151.71,151.35,150.95,146.36,140.57,136.44,135.00,134.12,133.51,128.73,126.98,125.74,122.51,119.97,119.56,117.66,116.10,113.18,112.65,102.33,54.74,31.62,31.0,6.5.MALDI-TOF/TOF理论值C48H36I2N6O2S3[M]:1078.015,实测值[M]:1077.976.
实施例3化合物(Ic)的合成
取化合物3c(93mg,0.43mmol),中间体2a(200mg,0.41mmol)溶于5mL的乙酸中,100℃加热搅拌过夜。次日,反应液中有大量沉淀,二氯甲烷反复萃取,合并有机相,得墨绿色固体4c 150mg,粗产率52%,未经纯化,直接进行下步反应;
取中间体4c(20mg,0.03mmol),化合物5a(8mg,0.03mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(3.44mg,0.003mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得中间体6a 10mg。产率:47%;
取中间体6a(20mg,0.03mmol),化合物5c(17mg,0.03mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(3.44mg,0.003mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得中间体Ic 8mg。产率:38%。1H NMR(500MHz,CDCl3)δ9.75(d,J=8.1Hz,1H),8.04(dd,J=9.5,7.5Hz,1H),7.88–7.80(m,1H),7.73–7.59(m,3H),7.40(dd,J=17.0,7.5Hz,1H),7.21(t,J=7.7Hz,1H),7.14–7.08(m,1H),6.91(dt,J=7.3,1.3Hz,2H),6.23(t,J=7.5Hz,1H),3.81(s,3H),3.50–3.41(m,1H),3.45(s,3H),3.44–3.38(m,1H),3.19(s,1H),2.60–2.50(m,7H).13C NMR(126MHz,DMSO-d6)δ178.34,172.44,160.20,160.12,146.15,146.07,139.87,139.81,137.55,137.20,135.80,135.71,134.69,134.60,132.09,131.49,131.40,130.88,130.85,130.37,129.60,128.91,126.19,126.12,126.09,125.24,125.15,122.91,122.51,122.46,121.54,119.83,119.75,118.54,115.62,115.55,114.90,114.84,113.69,111.49,111.08,105.12,58.25,57.38,53.15,53.08,53.03,52.97,52.92,40.06,35.55,35.48,26.09.MALDI-TOF/TOF理论值:C56H52N12O5S3[M]:1068.335,实测值[M]:1068.115。
实施例4化合物(Id)的合成
取中间体4a(100mg,0.15mmol),化合物5d(90mg,0.3mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(15mg,0.015mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Id 60mg。产率:45%。1H NMR(400MHz,CDCl3)δ8.94(s,1H),8.14(d,J=45.0Hz,4H),7.68(dd,J=53.8,4.1Hz,6H),7.41(d,J=8.5Hz,4H),7.25(s,2H),7.13–7.08(m,2H),3.87(s,4H).13C NMR(126MHz,CDCl3)δ172.02,145.37,141.87,131.39,130.88,127.39,123.86,121.01,111.55,109.26,63.23,31.54,17.43,-0.01,-1.51.MALDI-TOF/TOF理论值:C44H26N6O4S5[M]:862.062,实测值[M]:862.143.
实施例5化合物(Ie)的合成
取化合物1b(1g,1.5mmol)溶于50mL二氯甲烷-90%甲醇混合溶液中(体积比为1:1),加入锌粉(11.8g,181mmol),氮气保护下,加入氯化铵(2.89g,54mmol)溶成5毫升水溶液,室温搅拌4小时。反应结束后,二氯甲烷萃取,合并有机相,得黄色粗产品2b 800mg,粗产率93%,未经纯化,直接进行下步反应;
取化合物3a(88mg,0.39mmol),中间体2b(200mg,0.33mmol)溶于5mL的乙酸中,100℃加热搅拌过夜。次日,反应液中有大量沉淀,二氯甲烷反复萃取,合并有机相,得黑色固体4d 220mg,粗产率84%,未经纯化,直接进行下步反应;
取中间体4d(100mg,0.12mmol),化合物5e(180mg,0.24mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(14mg,0.012mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Ie 40mg。产率:32%。1H NMR(400MHz,CDCl3)δ8.24(m,2H),8.05(m,2H),7.67(m,2H),7.36(m,2H),7.22(m,2H),4.35(s,4H),4.29(m,4H),4.28–4.22(m,4H),2.68(t,J=7Hz,4H),2.53(t,J=7Hz,4H),2.03(m,4H).13C NMR(126MHz,CDCl3)δ172.14,152.62,143.16,142.65,136.50,135.70,127.59,126.16,123.96,123.82,121.70,119.49,117.55,111.47,109.20,101.77,64.54,64.47,41.6,32.8,22.1.MALDI-TOF/TOF理论值:C50H40N8O4S5[M]:976.178,实测值[M]:978.264.
实施例6化合物(If)的合成
取中间体4a(100mg,0.15mmol),化合物5f(150mg,0.3mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(15mg,0.015mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物If 100mg。产率:53%。1H NMR(500MHz,DMSO-d6)δ7.99(d,J=7.3Hz,1H),7.70(d,J=7.5Hz,1H),7.50(dd,J=7.4,1.6Hz,1H),7.42–7.36(m,2H),7.36–7.33(m,1H),7.20–7.12(m,3H),7.07–6.97(m,8H),2.77(tt,J=7.1,1.1Hz,4H),2.55(t,J=7.1Hz,4H).13C NMR(126MHz,DMSO-d6)δ176.66,156.47,145.48,144.98,143.11,141.99,141.80,136.53,135.29,134.02,130.85,130.29,129.19,128.79,128.52,127.62,126.31,121.56,121.52,121.51,120.16,35.47,29.54.MALDI-TOF/TOF理论值:C72H54N6O8S5[M]:1290.261,实测值[M]:1290.345。
实施例7化合物(Ig)的合成
取中间体4a(00mg,0.15mmol),化合物5g(220mg,0.3mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(15mg,0.015mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Ig 120mg。产率:46%。1H NMR(500MHz,DMSO-d6)δ9.05(s,0H),7.42–7.33(m,1H),7.20–7.12(m,1H),7.07–6.97(m,2H),4.42(t,J=7.1Hz,1H),3.01(t,J=7.1Hz,1H),2.85(tt,J=7.1,1.1Hz,1H),2.62(t,J=7.1Hz,1H).13C NMR(126MHz,DMSO-d6)δ172.98,146.76,146.05,144.16,144.08,143.31,141.61,135.21,131.86,129.39,128.80,127.85,127.22,127.14,127.01,126.68,124.26,119.19,113.57,63.54,52.34,35.41,30.21.MALDI-TOF/TOF理论值:C80H70N6O20S9[M]:1722.213,实测值[M]:1722.415。
实施例8化合物(Ih)的合成
取中间体4a(100mg,0.15mmol),化合物5h(220mg,0.3mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(15mg,0.015mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Ih 100mg。产率:38%。1H NMR(500MHz,DMSO-d6)δ8.73(s,2H),8.12(d,J=7.5Hz,1H),7.79–7.72(m,3H),7.68(d,J=7.5Hz,1H),7.62–7.55(m,1H),7.54(dd,J=7.4,1.6Hz,1H),7.50(dd,J=7.4,1.6Hz,1H),7.46–7.36(m,4H),7.33–7.26(m,1H),7.17(t,J=7.5Hz,1H),3.48(ddt,J=12.5,8.1,7.1Hz,2H),3.36(ddt,J=12.4,8.2,7.1Hz,2H),2.79(dt,J=12.5,7.1Hz,2H),2.60(dt,J=12.5,7.1Hz,2H),2.16(t,J=6.9Hz,4H),1.92(dt,J=12.4,7.1Hz,2H),1.82(dt,J=12.4,7.0Hz,2H),1.65–1.28(m,13H).13C NMR(126MHz,DMSO-d6)δ175.28,146.05,144.16,144.08,143.31,141.61,141.55,136.79,135.38,135.09,131.93,131.59,128.80,127.85,127.46,127.41,127.22,127.16,127.14,126.68,124.52,124.26,124.24,122.04,120.81,72.12,50.21,39.29,36.29,33.88,27.88,26.08,25.68.MALDI-TOF/TOF理论值:C82H88N8O16S9[M]:1728.38,实测值[M-1]:1727.33。
实施例9化合物(Ii)的合成
取中间体4d(100mg,0.12mmol),化合物5h(200mg,0.24mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(14mg,0.012mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Ii 100mg。产率:43%。1H NMR(500MHz,DMSO-d6)δ7.92–7.89(m,4H),7.88–7.81(m,6H),7.63(brs,4H),7.52–7.47(m,4H),7.38–7.34(m,4H),7.8(t,J=5.0Hz,2H),4.58(brs,4H),4.41(brs,4H),3.25(t,J=8.0Hz,8H),2.55(t,J=8.0Hz,8H),2.03(t,J=8.0Hz,,8H),1.85(t,J=7.4Hz,8H),1.26(p,J=7.4Hz,8H),1.04(p,J=7.5Hz,8H),0.67(m,8H).13CNMR(126MHz,DMSO-d6)δ172.14,152.54,151.17,150.79,146.22,142.78,141.74,140.55,140.16,138.89,135.66,132.28,132.01,131.46,128.59,127.88,127.54,125.27,123.44,120.89,120.37,120.08,108.18,65.32,64.95,55.15,51.05,35.92,35.79,29.54,25.43,23.92.MALDI-TOF/TOF理论值:C86H92N8O20S9[M]:1846.25,实测值[M-1]:1845.37。
实施例10化合物(Ij)的合成
取化合物3d(109.3mg,0.4mmol),中间体2a(200mg,0.41mmol)溶于5mL的乙酸中,100℃加热搅拌过夜。次日,反应液中有大量沉淀,二氯甲烷反复萃取,合并有机相,得墨绿色固体4e 236mg,粗产率83%,未经纯化,直接进行下步反应;
取中间体4e(100mg,0.15mmol),化合物5i(150mg,0.3mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(15mg,0.015mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Ij 80mg。产率:34%。1H NMR(500MHz,DMSO-d6)δ9.70(t,J=6.2Hz,1H),7.99(d,J=7.5Hz,1H),7.70(d,J=7.5Hz,1H),7.51(dd,J=7.4,1.6Hz,1H),7.44–7.33(m,3H),7.20–7.12(m,7H),7.10–6.99(m,5H),3.39(t,J=7.1Hz,2H),2.97(t,J=7.1Hz,1H),2.78(s,4H),2.67–2.54(m,6H),2.44(t,J=7.1Hz,2H),1.87(dp,J=27.4,7.1Hz,4H),1.70(p,J=7.0Hz,2H).13C NMR(126MHz,DMSO-d6)δ202.15,168.76,168.74,146.76,146.05,145.39,144.16,144.08,143.31,142.88,141.61,141.42,140.83,138.35,136.31,135.21,129.48,129.39,128.80,127.85,127.47,127.22,127.14,127.04,127.01,126.68,124.26,119.19,112.85,40.11,36.86,35.14,34.49,33.39,32.43,30.94,29.64,27.73,27.58.MALDI-TOF/TOF理论值:C87H74Br2O9S5[M]:1692.25,实测值[M]:1692.33。
实施例11化合物(Ik)的合成
取中间体4d(100mg,0.12mmol),化合物5j(128mg,0.24mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(14mg,0.012mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Ik 80mg。产率:44%。1H NMR(400MHz,CDCl3)δ7.95(d,J=8.0Hz,2H),7.83(s,2H),7.79-7.72(m,4H),7.56(d,J=5.0Hz,2H),7.52(d,J=3.5Hz,2H),7.39–7.30(m,6H),7.07(t,J=4.4Hz,2H),4.63-4.57(m,4H),4.45–4.38(m,4H),1.99-2.09(m,8H),1.43(p,J=7.5Hz,8H),1.14(p,J=7.3Hz,8H),1.00–0.89(m,8H),0.62–0.81(m,8H),.13C NMR(126MHz,DMSO-d6)δ173.92,150.72,150.63,145.98,142.11,140.93,138.28,132.16,130.65,130.29,127.60,127.06,126.92,125.45,122.79,122.35,120.70,120.46,119.87,119.72,64.84,64.67,62.27,55.04,29.56,24.67,23.49,17.30.MALDI-TOF/TOF理论值:C78H72N4O12S5[M]:1416.38,实测值[M]:1416.54。
实施例12化合物(Il)的合成
取化合物1c(1g,2.6mmol)溶于50mL二氯甲烷-90%甲醇混合溶液中(体积比为1:1),加入锌粉(20g,312mmol),氮气保护下,加入氯化铵(1.96g,93.7mmol)溶成5毫升水溶液,室温搅拌4小时。反应结束后,二氯甲烷萃取,合并有机相,得黄色粗产品2c 800mg,粗产率94%,未进行纯化,直接进行下步反应;
取化合物3a(164mg,0.74mmol),中间体2c(200mg,0.62mmol)溶于5mL的乙酸中,100℃加热搅拌过夜。次日,反应液中有大量沉淀,二氯甲烷反复萃取,合并有机相,得墨绿色固体4e 250mg,粗产率80%,未经纯化,直接进行下步反应;
取中间体4e(100mg,0.2mmol),化合物5g(280mg,0.4mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(22mg,0.02mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Il 100mg。产率:32%。1H NMR(400MHz,DMSO-d6)δ7.90(d,J=4.9Hz,2H),7.87–7.83(m,6H),7.41(d,J=3.7Hz,2H),7.22(d,J=8.3Hz,8H),7.15–7.11(m,2H),7.08(d,J=8.2Hz,10H),3.33(m,8H),2.81(t,J=7.8Hz,8H),2.56(t,J=7.7Hz,8H),2.38(t,J=7.7Hz,8H).13C NMR(126MHz,DMSO-d6)δ171.45,153.03,148.01,146.29,145.32,142.15,137.12,135.36,134.50,132.04,130.98,129.95,128.38,127.97,127.70,125.20,120.58,51.13,37.61,36.01,31.03.MALDI-TOF/TOF理论值:C72H70N10O16S7[M]:1555.83,实测值[M]:1555.282.
实施例13化合物(Im)的合成
取中间体4e(100mg,0.2mmol),化合物5f(320mg,04mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(22mg,0.02mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Im 95mg。产率:43%。1H NMR(400MHz,CDCl3)δ7.93(d,J=8.5Hz,4H),7.55(d,J=4.2Hz,2H),7.50(d,J=3.4Hz,2H),7.28-7.26(m,5H),7.20-7.13(m,15H),7.05–7.01(m,2H),2.95(t,J=8.0Hz,8H),2.64(t,J=8.0Hz,8H).13C NMR(126MHz,DMSO-d6)δ172.69,152.79,147.63,145.46,145.28,142.34,135.16,133.55,130.08,129.93,127.46,127.36,127.07,124.66,120.91,62.24,29.99.MALDI-TOF/TOF理论值:C64H50N6O8S3[M]:1126.29,实测值[M]:1126.375.
实施例14化合物(In)的合成
取中间体4e(100mg,0.2mmol),化合物5k(320mg,0.4mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(22mg,0.02mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物In 120mg。产率:34%。1H NMR(400MHz,CDCl3)δ1H NMR(400MHz,CDCl3)δ7.93(d,J=8.5Hz,4H),7.55(d,J=4.2Hz,2H),7.50(d,J=3.4Hz,2H),7.28-7.26(m,5H),7.20-7.13(m,15H),7.05–7.01(m,2H),4.2-3.62(m,20H),3.57(m,5H),2.95(t,J=8.0Hz,8H),2.64(t,J=8.0Hz,8H),13C NMR(126MHz,CDCl3)δ173.0,150.7,145.1,144.8,143.1,139.9,138.8,135.7,130.9,128.8,128.6,128.0,127.9,127.6,123.2,110.6,95.5,71.0,70.6,65.1,62.2,61.1,35.9,31.1.MALDI-TOF/TOF理论值:C88H94N10O24S3[M]:1771.95,实测值[M-1]:1770.449.
实施例15化合物(Io)的合成
取化合物3e(109.3mg,0.35mmol),中间体2a(200mg,0.41mmol)溶于5mL的乙酸中,100℃加热搅拌过夜。次日,反应液中有大量沉淀,二氯甲烷反复萃取,合并有机相,得墨绿色固体4f 236mg,粗产率88%,未经纯化,直接进行下步反应;
取中间体4f(100mg,0.15mmol),化合物5l(70mg,0.3mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(15mg,0.015mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Io 40mg。产率:35%。1H NMR(500MHz,DMSO-d6)δ8.52(d,J=7.5Hz,1H),8.07(d,J=7.5Hz,1H),7.83(d,J=7.5Hz,1H),7.47–7.41(m,3H),7.08(dd,J=16.1,7.5Hz,1H),3.82–3.69(m,1H),3.12(td,J=6.5,1.1Hz,1H),3.08–2.99(m,1H),2.99–2.93(m,2H),2.93–2.87(m,2H),2.85–2.78(m,2H),2.17(t,J=3.0Hz,1H).13C NMR(126MHz,DMSO-d6)δ161.79,161.71,154.22,154.16,145.90,145.83,143.76,142.96,142.69,142.61,141.32,141.27,140.60,140.40,139.68,139.64,135.94,135.86,133.37,133.29,130.13,130.10,129.95,129.87,129.82,125.76,124.53,124.50,121.53,121.47,120.77,120.72,119.50,119.41,84.20,84.18,70.76,70.74,60.90,41.30,36.62,35.65,34.05,33.98,17.96,17.87.MALDI-TOF/TOF理论值:C46H35N7OS5[M]:861.151,实测值[M]:861.174.
实施例16化合物(Ip)的合成
取中间体4a(100mg,0.15mmol),化合物5m(160mg,0.3mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(15mg,0.015mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Ip 110mg。产率:49%。1H NMR(500MHz,CDCl3)δ7.63(d,J=7.5Hz,1H),7.40(dd,J=7.5,1.5Hz,1H),7.34(dd,J=7.5,1.5Hz,1H),7.24–7.10(m,13H),7.03(d,J=7.5Hz,1H),6.67(s,1H),3.78(t,J=7.1Hz,2H),3.01–2.95(m,2H),2.58(qt,J=7.0,1.1Hz,4H),1.83–1.60(m,8H).13C NMR(125MHz,CDCl3)δ166.02,150.65,148.95,148.23,145.12,144.65,141.63,138.78,136.50,136.01,135.58,129.65,129.24,129.14,128.59,127.99,125.92,125.80,124.54,124.13,122.67,48.39,46.26,34.23,31.49,31.42,31.10,28.51.MALDI-TOF/TOF理论值:C84H70N14O4S5[M]:1498.431,实测值[M-1]:1497.236。
实施例17化合物(Iq)的合成
取化合物3f(268mg,0.49mmol),中间体2b(200mg,0.33mmol)溶于5mL的乙酸中,100℃加热搅拌过夜。次日,反应液中有大量沉淀,二氯甲烷反复萃取,合并有机相,得黑色固体4g 300mg,粗产率82%,未经纯化,直接进行下步反应;
取中间体4g(100mg,0.09mmol),化合物5h(130mg,0.18mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(12mg,0.009mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Iq 90mg。产率:46%。1H NMR(400MHz,CDCl3)δ7.99(s,2H),7.77(d,J=36.4Hz,6H),7.44(d,J=3.5Hz,2H),7.35(d,J=26.1Hz,6H),6.90(d,J=3.7Hz,2H),4.61(m,4H),4.43(m,4H),4.32–4.26(m,4H),4.15–4.08(m,8H),3.89(s,3H),2.12(t,J=7.6Hz,8H),2.04(m,8H),1.38(s,8H),1.21–1.02(m,12H),0.94(m,8H),0.62(m,8H),0.06(s,18H),0.04(s,36H).13C NMR(126MHz,CDCl3)δ175.34,171.48,154.40,152.14,152.05,147.04,143.54,143.33,142.36,142.02,141.42,139.79,137.54,133.62,132.08,128.75,128.46,128.32,126.95,124.22,123.63,122.08,121.70,121.27,121.11,110.00,105.24,66.29,66.16,65.19,63.69,56.48,41.63,37.51,35.87,31.12,30.96,26.07,24.89,18.79,18.71,-0.05,-0.08.MALDI-TOF/TOF理论值:C112H148N4O6S5Si6[M]:2132.81,实测值[M]:2132.56。
实施例18化合物(Ir)的合成
取中间体4e(100mg,0.2mmol),化合物5g(140mg,0.2mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(23mg,0.02mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得中间体6b 100mg。产率:50%;
取中间体6b(100mg,0.1mmol),化合物7b(24mg,0.1mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(12mg,0.01mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Ir 35mg。产率:34%。1H NMR(400MHz,CDCl3)δ7.53-7.37(m,10H),7.18-7.15(m,6H),7.03–6.92(m,6H),3.64(t,J=8.0Hz,4H),3.29(t,J=8.0Hz,4H),3.02(s,6H),2.68(t,J=8.0Hz,4H),2.34(t,J=8.0Hz,4H).13C NMR(126MHz,CDCl3)δ173.3,154.2,150.7,145.2,144.8,143.1,139.9,138.8,135.7,130.9,128.8,128.6,128.0,127.9,127.6,126.0,123.2,112.7,110.6,47.8,41.3,37.4,35.6,31.1.MALDI-TOF/TOF理论值:C52H48N8O8S5[M]:1072.22,实测值[M]:1072.06。
实施例19化合物(Is)的合成
取化合物1d(1g,1.4mmol)溶于50mL二氯甲烷-90%甲醇混合溶液中(体积比为1:1),加入锌粉(10.8g,167mmol),氮气保护下,加入氯化铵(41.8mmol,2.24g)溶成5毫升水溶液,室温搅拌4小时。反应结束后,二氯甲烷萃取,合并有机相,得黄色粗产品2d 800mg,粗产率87%,未进行纯化,直接进行下步反应;
取化合物3b(87mg,0.45mmol),中间体2d(200mg,0.30mmol)溶于5mL的乙酸中,100℃加热搅拌过夜。次日,反应液中有大量沉淀,二氯甲烷反复萃取,合并有机相,得墨绿色固体产物4g 200mg,粗产率81%,
取中间体4g(100mg,0.12mmol),化合物5n(135mg,0.3mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(15mg,0.015mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Is 50mg。产率:32%。1H NMR(500MHz,CDCl3)δ7.96(dd,J=7.0,2.0Hz,1H),7.77(d,J=1.4Hz,1H),7.58(dd,J=7.5,1.7Hz,1H),7.54(dd,J=7.5,1.5Hz,1H),7.47(d,J=7.5Hz,1H),7.42–7.36(m,1H),7.33–7.24(m,2H),6.97(s,1H),6.76(dd,J=7.5,1.6Hz,1H),6.68(t,J=7.4Hz,1H),4.27(t,J=7.0Hz,2H),3.74(t,J=7.1Hz,2H),3.68–3.54(m,9H),3.38(s,2H),2.75(t,J=7.1Hz,2H),1.61(p,J=7.1Hz,2H),1.35–1.24(m,6H),0.92–0.84(m,3H).13C NMR(125MHz,CDCl3)δ156.74,147.14,146.74,144.06,141.97,141.21,138.44,137.69,135.76,130.76,129.90,129.50,126.40,125.55,125.34,124.11,123.45,122.00,120.69,120.64,113.47,112.89,111.78,110.76,70.75,70.49,69.49,69.37,69.23,58.97,44.76,31.26,30.72,29.62,28.52,23.39,14.25.MALDI-TOF/TOF理论值:C74H28N6O8S3[M]:1275.65,实测值[M]:1275.34.
实施例20化合物(It)的合成
取中间体4b(100mg,0.15mmol),化合物5o(10mg,0.3mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(15mg,0.015mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物It 50mg。产率:48%。1H NMR(500MHz,CDCl3)δ9.05(dd,J=7.3,1.1Hz,2H),8.54–8.49(m,2H),8.22(d,J=7.5Hz,1H),7.88(dd,J=4.9,4.1Hz,1H),6.89(d,J=7.5Hz,1H),6.71–6.64(m,2H),4.37(d,J=0.9Hz,3H).13C NMR(126MHz,DMSO-d6)δ157.7,150.3,146.8,146.5,144.3,142.9,139.8,137.9,128.4,119.5,112,110.2,107.1,49.MALDI-TOF/TOF理论值:C36H24N6O2S3[M]:668.80,实测值[M]:668.54.
实施例21、化合物(Iu)的合成
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取中间体4e(100mg,0.2mmol),化合物5f(140mg,0.2mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(23mg,0.02mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得中间体6c 100mg。产率:50%。1H NMR(500MHz,CDCl3)δ7.75–7.69(m,1H),7.51(ddd,J=7.3,4.6,1.5Hz,1H),7.42–7.37(m,1H),7.29–7.23(m,1H),7.17(t,J=7.5Hz,1H),7.05–6.97(m,4H),2.81–2.74(m,2H),2.55(t,J=7.1Hz,2H).
取中间体6c(100mg,0.1mmol),化合物7c(136mg,0.1mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(12mg,0.01mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应16h。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Iu 35mg。产率:16%。MALDI-TOF/TOF理论值:C91H89N15O15S3[M]:1728.98,实测值[M]:1728.82。
实施例22、化合物(Iv)的合成
取中间体4e(100mg,0.2mmol),化合物5p(246mg,0.4mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(20mg,0.02mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应过夜。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Iv 110mg。产率:55%。1H NMR(500MHz,CDCl3)δδ7.98(d,J=7.5Hz,2H),7.54–7.47(m,4H),7.42–7.14(m,34H).13C NMR(126MHz,CDCl3)δ160.12,148.14,143.93,143.43,140.97,140.56,137.40,136.26,134.41,132.84,131.31,130.61,129.39,129.34,129.15,129.10,129.06,129.01,128.97,128.76,128.63,128.56,128.34,126.36,119.75.MALDI-TOF/TOF理论值:C64H40N4S5[M]:1025.35,实测值[M]:1025.12.
实施例23、化合物(Iw)的合成
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取中间体4b(100mg,0.2mmol),化合物5p(246mg,0.4mmol)加入25mL圆底烧瓶中。氮气保护下,加入甲苯/1M碳酸钾水混合液(v/v,3:1)4mL。向反应液中通入氮气,排除反应液中的氧气20min,再加入四(三苯基膦)钯(20mg,0.02mmol),继续向反应液中通入氮气10min。氮气保护下,加热回流反应过夜。反应结束后,加入乙酸乙酯(EA)(15mL×3)萃取三次,合并有机相,水(10mL×2)洗两次。有机相用无水硫酸镁干燥,过滤,滤液旋干过硅胶柱得产物Iw 110mg。产率:55%。1H NMR(500MHz,CDCl3)δ7.98(d,J=7.5Hz,2H),7.57–7.49(m,4H),7.38–7.22(m,22H),7.24–7.18(m,8H),6.76(dd,J=7.5,1.6Hz,2H),6.68(t,J=7.4Hz,2H).13C NMR(126MHz,CDCl3)δ160.12,148.14,147.14,144.06,143.93,142.42,140.46,137.54,136.38,134.30,133.18,131.31,130.61,129.63,129.58,129.53,129.48,129.43,129.39,129.34,128.43,128.36,120.20,113.47,113.23.MALDI-TOF/TOF理论值:C64H40N4O2S3[M]:993.23,实测值[M]:992.91.
实施例24 BBTD、TTQ及TBZ在三乙胺碱性条件下稳定性测试
将苯并[1,2-c:4,5-c']双([1,2,5]噻二唑)(BBTD)、噻二唑苯并三唑(TBZ)及6,7-二(噻吩基)-[1,2,5]噻二唑[3,4-g]喹喔啉(TTQ)分别溶于10v%二甲基甲酰胺(DMF)-甲醇(MeOH)溶液中,配制成20μM。然后分别将这三种化合物溶液平均分成两份,其中一份加入1μL甲醇,另外一份加入1μL三乙胺(TEA),充分混合后,利用高效液相监测其稳定性情况。高效液相色谱参数:检测波长:254nm;流动相体系:甲醇:水(含0.1%三氟乙酸)75:25;监测时间:20min。
如图1所示,BBTD及TBZ加入三乙胺后,发生不同程度分解,表明其在碱性条件下稳定性差;TTQ加入三乙胺后,仍稳定存在,表明其在碱性条件下稳定。本发明根据电子受体TTQ耐碱的特性,对其进行碱性条件下的结构修饰,扩大并建立以其为电子受体的荧光分子库。
实施例25、PTQ及TTQ紫外吸收图谱。
将6,7-二苯基噻二唑喹啉(PTQ)及TTQ分别溶于50v%二甲基乙酰胺(DMAC)-水中,配制成20μM。分别取2mL用1cm常量比色皿测吸收光谱。吸收检测波长范围:300-1000nm;仪器名称:安捷伦Cary60紫外-可见分光光度计。
结果如图2所示,TTQ较PTQ紫外吸收发生红移,表明TTQ较PTQ吸电子能力更强。因此,以TTQ为电子受体,构建D-A-D型荧光探针,可使发射波长更加红移,提供信噪比更高,穿透深度更好的成像质量。
实施例26、化合物Ia至Ip的荧光发射图谱。
将Ia至Ip荧光分子溶于50V%DMAC-水中,配制成20μM。分别取2mL用1cm常量比色皿测近红外二区荧光光谱。荧光光谱参数:808激光器,功率:2W,激发狭缝宽度:5nm,发射狭缝宽度:10nm,收集波长:850-1500nm。仪器名称:爱丁堡FLS980荧光光谱仪。
结果如图3所示,Ia至Ip荧光分子的最大二区荧光发射峰在950nm至1100nm之间。
实施例27、化合物Ia至Ij在正常小鼠体内生物分布图
5至7周龄BALB/c小鼠(15-20g,♀)购自中国科学院上海实验动物中心。饲养环境为25℃,12小时明暗交替,所有动物自由饮水和进食。所有与动物实验相关的操作都遵循中国科学院上海物质医学研究所机构动物护理与使用委员会(IACUC)的相关要求。
探针Ia至Ij分别溶于5v%DMAC-磷酸缓冲液PBS(pH=7.4)中,配成浓度为100μM,将其对小鼠进行尾静脉注射100μL,1h后进行荧光成像。荧光光谱参数:808激光器,功率:100mW/cm2,激发狭缝宽度:5nm,发射狭缝宽度:10nm,长通滤光片:1100nm。
结果如图4所示,探针在小鼠体内不同的生物分布。实验结果显示,Ia-Ij主要分布于小鼠肝脏区域,揭示探针通过肝脏代谢。其中,If-Ih在胫骨有明显吸收,可用于小鼠正常骨成像及相关骨疾病的成像,如骨质疏松等。Ib,Ic,If及Ii明显小鼠后肢血管吸收,可用于成像血管及淋巴管相关疾病的诊断,如血栓等。该实验初步探究了荧光探针在体内分布及代谢性质,为筛选性质优良的荧光分子提供了理论依据及实验基础。
实施例28、染料Iu导航外科手术前后评价
5至7周龄裸鼠(15-20g,♀)购自中国科学院上海实验动物中心。裸鼠右前肩接种1000万个CT26细胞,接种于150μL无血清培养基中。在成像之前,肿瘤生长大约20天。饲养环境为25℃,12小时明暗交替,所有动物自由饮水和进食。所有与动物实验相关的操作都遵循中国科学院上海物质医学研究所机构动物护理与使用委员会(IACUC)的相关要求。
将100μL浓度为200μM的Iu荧光分子在1v%DMSO-PBS(pH=7.4)中的溶液静脉注入到CT26肿瘤鼠中,24h后进行荧光成像。然后利用成像引导手术切除,成功将肿瘤组织取出。荧光光谱参数:808激光器,功率:100mW/cm2,激发狭缝宽度:5nm,发射狭缝宽度:10nm,长通滤光片:1100nm。
结果如图5所示,左图显示外科手术前探针在小鼠肿瘤组织呈现高吸收,右图显示已经利用成像引导手术切除,成功将肿瘤组织取出。
荧光成像具有实时性,可实时成像进行肿瘤切除,特别是与正常组织浸润边缘的切除,极大提高切除手术的成功率,减小对正常组织创伤。
上述结果表明,本发明的化合物可以作为荧光分子进行荧光成像。
Claims (17)
1.一种基于喹喔啉的D-A-D近红外二区荧光分子,其为通式I-1所示的化合物及它们的盐:
其中:
X为S;
Y为S、O、NR5;
R1和R2各自独立地选自R6为H、C1-C8烷基、C1-C8烷氧基;R7和R8各自独立地为H、C1-C8烷基、C1-C8烷氧基、或卤素,或者R7和R8与和其相连接的C一起形成5-10元杂环基;Y1为S;
R3和R4各自独立地选自H、C1-C12烷基、C1-C12烷氧基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、巯基C1-C8烷基、卤代C1-C8烷基、氨基、卤素、-(CH2)n1-COOCH2CH2Si(CH3)3,其中n1为0~10的整数;
R5选自H、C1-C8烷基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、巯基C1-C8烷基、卤代C1-C8烷基;
D1和D2各自独立地选自如下基团:
其中,R10-R18、R37、R38各自独立地选自H、取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基、取代或未取代的C1-C8烷基硅基、氨基、卤素、-(CH2)n1-COOCH2CH2Si(CH3)3,其中n1为0~10的整数;式-(CH2)n2-(OCH2CH2)n3-R,其中n2为1~10的整数,n3为1~500的整数,R选自H、C1-C8烷基、羟基、氨基、羧基、磺酸基、卤素、巯基、及/>-(CH2)n4-CONHCH2CH2SO3H,其中n4为0~10的整数;
所述取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基或取代或未取代的C1-C8烷基硅基的取代基选自羟基、氨基、C1-C4炔基、叠氮基、巯基、醛基、羧基、磺酸基、卤素、RaOC(=O)-、RaC(=O)O-、RaNC(=O)-和吡咯烷二酮-N-,其中Ra各自独立地选自C1-C6烷基、羟基C1-C6烷基、氨基C1-C6烷基、醛基C1-C6烷基、巯基C1-C6烷基、卤代C1-C6烷基、炔基C1-C6烷基、叠氮基C1-C6烷基、羧基C1-C6烷基、磺酸基C1-C6烷基和吡咯烷二酮-N-;
或者,R10-R18、R37、R38各自独立地选自式其中,R’和R”各自独立地选自C1-C8亚烷基,“A”选自环状RGD肽基团,所述环状RGD肽基团选自c(RGDyk)、c(RGDfk);单糖基团;二糖基团及多糖基团;所述单糖选自葡萄糖、半乳糖、果糖、阿拉伯糖、鼠李糖、核糖;所述二糖选自乳糖及麦芽糖;所述多糖选自环糊精;“B”为含有Fv段的分子基团,选自单抗、双抗及单链Fv段基团。
2.根据权利要求1所述的基于喹喔啉的D-A-D近红外二区荧光分子,其中,
R1和R2各自独立地选自其中,R6为H、C1-C4烷基或C1-C4烷氧基;R7和R8各自独立地为H、C1-C4烷基、C1-C4烷氧基或卤素,或者R7和R8与和其相连接的C一起形成5-7元杂环基。
3.根据权利要求2所述的基于喹喔啉的D-A-D近红外二区荧光分子,其中,
R1和R2彼此相同。
4.根据权利要求2所述的基于喹喔啉的D-A-D近红外二区荧光分子,其中,
R1和R2彼此相同,选自其中,R6为H、C1-C2烷基或C1-C2烷氧基;R7和R8各自独立地为H、C1-C2烷基、C1-C2烷氧基或卤素,或者R7和R8与和其相连接的C一起形成5-7元杂环基。
5.根据权利要求4所述的基于喹喔啉的D-A-D近红外二区荧光分子,其中,R7和R8与和其相连接的C一起形成二氧杂环己烷基。
6.根据权利要求1所述的基于喹喔啉的D-A-D近红外二区荧光分子,其中,
R1和R2彼此相同,为其中,R7和R8为H或者R7和R8与和其相连接的C一起形成二氧杂环己烷基;
其他基团定义与权利要求1中相同。
7.根据权利要求1所述的基于喹喔啉的D-A-D近红外二区荧光分子,其中,
X为S;
Y为S;
R1和R2彼此相同,为其中,R6为H、C1-C4烷基或C1-C4烷氧基;
D1和D2彼此相同,为R10和R11定义与权利要求1相同。
8.根据权利要求7所述的基于喹喔啉的D-A-D近红外二区荧光分子,其中,R6为H。
9.根据权利要求1所述的基于喹喔啉的D-A-D近红外二区荧光分子,其中,
R3和R4各自独立地选自H、C1-C4烷基、C1-C4烷氧基、羟基C1-C4烷基、氨基C1-C4烷基、醛基C1-C4烷基、巯基C1-C4烷基、卤代C1-C4烷基、氨基、卤素、-(CH2)n1-COOCH2CH2Si(CH3)3,其中n1为0~10的整数;
和/或
R5选自H、C1-C4烷基、羟基C1-C4烷基、氨基C1-C4烷基、醛基C1-C4烷基、巯基C1-C4烷基、卤代C1-C4烷基;
和/或
R10-R18、R37、R38各自独立地选自H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷基硅基、氨基、卤素、-(CH2)n2-(OCH2CH2)n3-R,其中n2为1~10的整数,n3为1~500的整数,R选自H、C1-C8烷基、羟基、氨基、羧基、磺酸基、卤素、巯基、及/>其中,所述的取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基或取代或未取代的C1-C6烷基硅基的取代基选自羟基、氨基、乙炔基、叠氮基、醛基、羧基、磺酸基、卤素、RaOC(=O)-、RaNC(=O)-、吡咯烷二酮-N-,其中Ra各自独立地选自C1-C4烷基、羟基C1-C4烷基、氨基C1-C4烷基、醛基C1-C4烷基、巯基C1-C4烷基、卤代C1-C4烷基、羧基C1-C4烷基、磺酸基C1-C4烷基和吡咯烷二酮-N-;或者
R10-R18、R37、R38各自独立地选自式其中,R’选自C1-C6亚烷基,“A”选自单糖基团,所述单糖选自葡萄糖、半乳糖、果糖、阿拉伯糖、鼠李糖、核糖、乳糖及麦芽糖。
10.根据权利要求9所述的基于喹喔啉的D-A-D近红外二区荧光分子,其中,
R3和R4彼此相同。
11.根据权利要求9所述的基于喹喔啉的D-A-D近红外二区荧光分子,其中,
R5为H或C1-C4烷基。
12.根据权利要求9所述的基于喹喔啉的D-A-D近红外二区荧光分子,其中,
R10-R18、R37、R38各自独立地选自H、C1-C6烷基、卤素。
13.根据权利要求1-5中任一项所述的基于喹喔啉的D-A-D近红外二区荧光分子,其中,
R10和R11彼此相同,选自H,C1-C6烷基,和被羟基、氨基、醛基、羧基、磺酸基、RaNC(=O)-取代的C1-C6烷基,其中Ra选自C1-C4烷基、羟基C1-C4烷基、氨基C1-C4烷基、醛基C1-C4烷基、巯基C1-C4烷基、卤代C1-C4烷基、羧基C1-C4烷基、磺酸基C1-C4烷基;
R12和R13彼此相同,选自H,C1-C6烷基,和被选自羟基、氨基、乙炔基、叠氮基、醛基、羧基、磺酸基、卤素、RaOC(=O)-、RaNC(=O)-、吡咯烷二酮-N-的取代基取代的C1-C6烷基,其中Ra各自独立地选自C1-C4烷基、羟基C1-C4烷基、氨基C1-C4烷基、醛基C1-C4烷基、巯基C1-C4烷基、卤代C1-C4烷基、羧基C1-C4烷基、磺酸基C1-C4烷基和吡咯烷二酮-N-;
R14选自H,C1-C6烷基,和被选自羟基、氨基、乙炔基、叠氮基、醛基、羧基、磺酸基、卤素、RaOC(=O)-、RaNC(=O)-的取代基取代的C1-C6烷基,其中Ra各自独立地选自C1-C4烷基、羟基C1-C4烷基、氨基C1-C4烷基、醛基C1-C4烷基、巯基C1-C4烷基、卤代C1-C4烷基、羧基C1-C4烷基、磺酸基C1-C4烷基;
R15选自H,C1-C6烷基,和被选自羟基、氨基、乙炔基、叠氮基、醛基、羧基、磺酸基、卤素、RaOC(=O)-、RaNC(=O)-的取代基取代的C1-C6烷基,其中Ra各自独立地选自C1-C4烷基、羟基C1-C4烷基、氨基C1-C4烷基、醛基C1-C4烷基、巯基C1-C4烷基、卤代C1-C4烷基、羧基C1-C4烷基、磺酸基C1-C4烷基;
R16和R17彼此相同,选自C1-C6烷基,和被选自羟基、氨基、醛基、羧基、磺酸基、RaOC(=O)-、RaNC(=O)-的取代基取代的C1-C6烷基,其中Ra各自独立地选自C1-C4烷基、羟基C1-C4烷基、氨基C1-C4烷基、醛基C1-C4烷基、巯基C1-C4烷基、卤代C1-C4烷基、羧基C1-C4烷基、磺酸基C1-C4烷基;和R18为H;
R38选自H、C1-C6烷基、被选自羟基、氨基、乙炔基、叠氮基、醛基、羧基、磺酸基、卤素的取代基取代的C1-C6烷基。
14.基于喹喔啉的D-A-D近红外二区荧光分子,其选自下列化合物或其盐:
15.一种制备通式I-1所示的喹喔啉类化合物的方法,所述方法包括以下步骤:
其中,X、Y、R1、R2、R3、R4、D1和D2的定义如权利要求1中所述,
R’为硼酸基或硼酸酯基或三正丁基锡基;
a、化合物1经还原反应得到中间体2;
b、中间体2与化合物3-1经缩合反应得到中间体4-1;
c、中间体4-1与化合物5经Suzuki偶联反应得到中间体6-1;
d、中间体6-1与化合物7经Suzuki偶联反应得到化合物I-1。
16.根据权利要求1-14中任一项所述的基于喹喔啉的D-A-D近红外二区荧光分子用于制备显影剂的用途。
17.一种显影剂,其包含根据权利要求1-14中任一项所述的基于喹喔啉的D-A-D近红外二区荧光分子。
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