CN109180556B - 一种部花菁类荧光化合物及其制备方法和应用 - Google Patents
一种部花菁类荧光化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于特异性分子识别材料领域,公开了一种部花菁类荧光化合物及其制备方法和应用。所述部花菁类荧光化合物的结构通式如式(I)所示。本发明的荧光化合物,采用经典的花菁类染料结构,在R基位置引入电中性的吸电子基团,使其结构中的给电子基团和吸电子基团形成了推‑拉电子作用的共轭结构,并通过碳碳双键增加跃迁的共轭体系,使化合物分子产生的荧光向近红外区移动,同时引入的电中性基团解决了大部分带电荷的花菁类化合物无法通过血脑屏障的问题。该化合物分子对Aβ斑块具有亲和力,能够成功用于Aβ斑块的近红外荧光显像,具有安全无放射性、成本低廉、背景荧光干扰较低、在生物组织中穿透力强等优点。
Description
技术领域
本发明属于特异性分子识别材料领域,具体涉及一种部花菁类荧光化合物及其制备方法和应用。
背景技术
阿尔茨海默病(Alzheimer’s disease,AD),又称老年痴呆症,是一种多发于65岁以上人群的神经退行性疾病,影响着全球数百万人,每年新增5百万例。临床表现为进行性的记忆损伤、认知障碍、精神症状以及日常生活能力的丧失,这给病人、家属和社会带来了严重的精神压力和经济压力。然而,因为阿尔兹海默症的致病机理仍不明确,所以至今没有有效的药物可以诊断和治疗阿尔兹海默症。迄今为止,美国食品药品监督管理局(FDA)只批准了5种药物多奈哌齐(Aricept)、卡巴拉汀(Exelon)、加兰他敏(Reminyl)、他克林(Cognex)和美金刚(Namenda)用于AD的临床治疗,但这5种药物只能改善AD患者的症状,不能减缓AD的病情,不能从根本上治疗AD。
在AD患者脑中,β-淀粉样蛋白(Amyloid,Aβ)在脑中沉积是AD最为显著的病理性标志之一。Aβ斑块在AD发病前的5~10年已开始出现,是AD最早的神经组织退化标志和重要病理学特征,因此开发以Aβ蛋白沉积为靶点的小分子探针显像剂对AD的早期诊断具有重要意义。除了AD外,Aβ斑块也存在于其他疾病中,例如Down氏综合征、II型糖尿病胰岛瘤、脑淀粉样血管病、淀粉样心肌病、淀粉样多发性神经病、***性老年淀粉样变和伴有淀粉样变的遗传性脑出血等。
过去的数年间,用于体外和体内的检测Aβ蛋白的分子探针已经取得了显著的进步。已经应用的成像探针和方法,包括磁共振成像(MRI),正电子发射断层成像(PET),单光子发射计算机断层成像(SPECT)和光学成像技术。FDA已批准了三种PET探针[18F]FPIB,[18F]AV-45和[18F]AV-1,但这些PET成像剂在临床上的应用是有限的,因为它们不能用于确认性诊断AD,而且成本高,需要专门的设施用于放射性核素的回旋加速。相比较之下,光学成像具有安全无放射性、数据采集时间短以及成本低廉等诸多优势,近年在医学诊断等中的应用受到广泛重视。尤其是近红外荧光成像技术,因其背景荧光干扰较低,在生物组织中穿透力强,因此,研发对Aβ斑块具有亲和力的近红外荧光显像剂(分子探针),将具有重要的科学意义和实际价值。
因此,研发具有特异性结合Aβ斑块的Aβ分子探针引人关注。结合Aβ荧光探针和分子成像技术进行Aβ斑块的显像,可实现无创的、实时的Aβ斑块的体内示踪和检测,进而为AD等疾病患者进行早期诊断、疗效检测以及治疗药物的研究等提供极大便利。
发明内容
针对以上现有技术存在的缺点和不足之处,本发明的首要目的在于提供一种部花菁类荧光化合物。
本发明的另一目的在于提供上述部花菁类荧光化合物的制备方法。
本发明的再一目的在于提供上述部花菁类荧光化合物在制备Aβ沉积相关疾病的诊断试剂和治疗药物中的应用。
本发明目的通过以下技术方案实现:
一种部花菁类荧光化合物,其结构通式如式(I)所示:
上述部花菁类荧光化合物的制备方法,包括以下制备步骤:
(5)将中间体4溶解于乙腈中,加入碳酸钾和相应的R胺侧链进行反应,得到具有式(I)结构的部花菁类荧光化合物。
上述制备方法的合成路线图如图1所示。
优选地,步骤(1)中所述加热反应的温度为80℃。
优选地,步骤(2)中所述升温回流反应的温度为80℃。
优选地,步骤(3)中所述有机溶剂为正丁醇与甲苯的混合溶剂。
优选地,步骤(4)中所述有机溶剂为甲醇。
上述部花菁类荧光化合物在制备Aβ沉积相关疾病的诊断试剂和治疗药物中的应用。
进一步地,所述Aβ沉积相关疾病是指阿尔茨海默症或脑淀粉样血管病。
进一步地,所述诊断试剂和治疗药物包括式(I)结构的部花菁类荧光化合物与药学上可接受的载体。所述“药学上可接受的载体”是指各种赋形剂或稀释剂。如水、生理盐水、甘油或乙醇。
本发明提供Aβ斑块的显像方法。在本显像方法的第一步中,将可检测量的含有式(I)结构的部花菁类荧光化合物的诊断试剂和治疗药物通过本领域技术人员公知的方法引入组织或患者中,可检测量的式(I)所示的化合物引入患者并且在足以使化合物与Aβ斑块结合的时间之后,非创伤性地检测化合物。或将式(I)所示的化合物引入患者,经足量的时间以使化合物与Aβ斑块结合,自患者取组织样品,并脱离患者检测组织中的化合物。或自患者取组织样品并且将式(I)所示的化合物引入该组织样品。在足以使该化合物结合至Aβ斑块的时间之后,检测化合物。
可以通过整体的或局部的给药途径将式(I)所示的化合物给药至患者。例如,可以将化合物给药至患者以使其递送至全身。可选地,可以将化合物给药至关注的特定的器官或者组织。例如,为了诊断或追踪患者的AD的进程,需要定位和定量脑内的淀粉样斑块。
术语“患者”是指人类和其他动物。本领域技术人员也熟知如何确定足以使化合物与Aβ斑块结合的时间。通过将可检测量的式(I)所示的化合物引入患者,然后在给药后的各时间处检测化合物,可以容易地测定所需的时间。
术语“结合”是指化合物和Aβ斑块之间的化学相互作用。结合的实例包括共价键、离子键、亲水-亲水相互作用、疏水-疏水相互作用和络合物。
相对于现有技术,本发明的部花菁类荧光化合物及应用具有如下优点及有益效果:
本发明的荧光化合物,采用经典的花菁类染料结构,在R基位置引入电中性的吸电子基团,使其结构中的给电子基团和吸电子基团形成了推-拉电子作用的共轭结构,并通过碳碳双键增加跃迁的共轭体系,使化合物分子产生的荧光向近红外区移动,同时引入的电中性基团解决了大部分带电荷的花菁类化合物无法通过血脑屏障的问题;基于该骨架,引入给电子基团,增强荧光化合物的荧光量子产率,使其具备高荧光量子产率,而发射波长靠近近红外区。该类化合物在体外实验表现出对Aβ斑块具有亲和力,能够成功用于Aβ斑块的近红外荧光显像,具有安全无放射性、成本低廉、背景荧光干扰较低、在生物组织中穿透力强等优点。
附图说明
图1是本发明部花菁类荧光化合物制备方法的合成路线图;
图2~10分别为是本发明实施例所得的荧光化合物D1~D9与Aβ1-42聚集体作用后的荧光滴定光谱图。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述,但本发明的实施方式不限于此。
以下实施例对于未特别注明的参数,可参照常规技术进行。核磁谱采用德国Bruker公司Avance III 400MHz(600MHz)核磁共振仪测定,氘代氯仿或氘代DMSO做溶剂。
实施例1
本实施例的一种部花菁类荧光化合物的合成,具体合成步骤如下:
(1)合成中间体1
将4.77g的2,3,3-三甲基吲哚(30mmol)与3.22ml碘甲烷(7.08g,50mmol)在60ml乙醇中搅拌均匀,密封耐压容器,80℃反应12h。反应完成后,冷至室温,析出固体,抽滤,得到析出固体7.7g,即得淡紫色中间体1,产率85%。核磁数据如下:1H NMR(400MHz,DMSO)δ7.92-7.86(m,1H),7.85-7.78(m,1H),7.66-7.58(m,2H),3.96(s,3H),2.76(s,3H),1.52(s,6H)。
(2)合成中间体2
将17.5ml DMF(16.54g,225mmol)与18ml二氯甲烷混合均匀,冰浴并氮气保护下,逐滴慢慢滴加15ml三氯氧磷(24.68g,160mmol),搅拌20-40min后,加入4.6ml环己酮(4.37g,45mmol),升温到80℃回流反应4h后,冷至室温,将反应液缓慢倒入冰水中,析出固体,抽滤,得到7.5g黄色固体,即中间体2,产率:90.8%。核磁数据如下:1H NMR(400MHz,DMSO)δ2.51(s,1H),2.39-2.28(m,4H),1.62-1.52(m,2H)。
(3)合成中间体3
将7.5g中间体1(25mmol)和7g中间体2(40mmol)溶于140ml正丁醇与60ml甲苯混合溶剂中,升温到80-130℃反应4h后,除去溶剂,柱层析分离,得到2.5g红色中间体3,产率25%。核磁数据如下:1H NMR(400MHz,CDCl3)δ10.28(s,1H),7.85(d,J=12.5Hz,1H),7.23(t,J=3.5Hz,1H),7.22(d,J=3.7Hz,1H),6.96(t,J=7.3Hz,1H),6.75(d,J=7.7Hz,1H),5.48(d,J=12.6Hz,1H),3.25(s,3H),2.61(t,J=5.3Hz,2H),2.51(t,J=5.6Hz,2H),1.83-1.76(m,2H),1.68(s,6H)。
(4)合成中间体4
将400mg中间体3(1.2mmol)和800μL丙二腈(12mmol)溶于32ml甲醇中,再加入320μL饱和的碳酸钾甲醇溶液,室温搅拌过夜,抽滤,得到蓝色固体400mg,即得中间体4,产率88.9%。核磁数据如下:1H NMR(400MHz,DMSO)δ8.00(d,J=13.8Hz,1H),7.82(s,1H),7.48(d,J=6.9Hz,1H),7.33(t,J=7.7Hz,1H),7.20(d,J=7.6Hz,1H),7.10(t,J=7.4Hz,1H),5.90(d,J=12.9Hz,1H),3.47(s,3H),2.81(t,J=8.7Hz,2H),2.60(t,J=9.3Hz,2H),1.85–1.73(m,2H),1.60(s,6H)。
(5)合成荧光化合物D1
将190mg中间体3(0.5mmol)溶解于30mL无水乙腈中,加入3-5当量碳酸钾固体,再加入280μL N,N-二甲基乙二胺(2.5mmol),室温反应24h,抽滤除去固体碱,得到红色固体80mg,产率37%。核磁数据如下:1H NMR(400MHz,CDCl3)δ7.73(d,J=12.4Hz,1H),7.26–7.13(m,2H),6.94(t,J=7.3Hz,1H),6.87(s,1H),6.73(d,J=7.9Hz,1H),5.38(d,J=12.4Hz,1H),4.00(t,J=6.3Hz,2H),3.23(s,3H),2.68(t,J=6.3Hz,2H),2.56(t,J=6.5Hz,2H),2.30(s,6H),2.02(s,2H),1.81–1.71(m,2H),1.66(s,6H)。
(6)合成荧光化合物D2
将N,N-二甲基乙二胺替换为等当量的丁氨,由合成荧光化合物D1的方法得到D2,得到红色固体70mg,产率32%。核磁数据如下:1H NMR(400MHz,CDCl3)δ7.73(d,J=12.4Hz,1H),7.24–7.16(m,2H),6.93(t,J=6.4Hz,1H),6.80(s,1H),6.72(d,J=8.0Hz,1H),5.38(d,J=12.4Hz,1H),3.90(t,J=7.3Hz,2H),3.23(s,3H),2.56(t,J=6.6Hz,2H),2.30(t,J=8.0Hz,2H),1.82–1.71(m,4H),1.66(s,6H),1.39(t,J=7.7Hz,2H),0.97(t,J=7.3Hz,3H)。
(7)合成荧光化合物D3
由合成荧光化合物D1的方法得到D3,得到红色固体65mg,产率29%。核磁数据如下:1H NMR(400MHz,CDCl3)δ7.72(d,J=12.4Hz,1H),7.25–7.16(m,2H),6.93(t,J=7.4Hz,1H),6.91(s,1H),6.72(d,J=8.1Hz,1H),5.38(d,J=12.4Hz,1H),3.96(t,J=6.9Hz,2H),3.22(s,3H),2.56(t,J=6.7Hz,2H),2.30(t,J=6.4Hz,4H),2.22(s,6H),1.97–1.92(t,J=8.0Hz,2H),1.77(m,2H),1.66(s,6H)。
(8)合成荧光化合物D4
由合成荧光化合物D1的方法得到D4,得到红色固体78mg,产率39%。核磁数据如下:1H NMR(400MHz,CDCl3)δ7.75(d,J=12.4Hz,1H),7.26–7.15(m,2H),6.94(t,J=7.3Hz,1H),6.81(s,1H),6.73(d,J=8.0Hz,1H),5.39(d,J=12.4Hz,1H),3.87(t,J=8.0Hz,2H),3.23(s,3H),2.57(t,J=5.9Hz,2H),2.30(t,J=4.0Hz,2H),1.91–1.68(m,4H),1.66(s,6H),0.99(t,J=7.3Hz,3H)。
(9)合成荧光化合物D5
由合成荧光化合物D1的方法得到D5,得到红色固体80mg,产率32%。核磁数据如下:1H NMR(400MHz,CDCl3)δ7.73(d,J=12.4Hz,1H),7.20(dt,J=7.2,3.8Hz,2H),7.00–6.87(m,2H),6.72(d,J=8.0Hz,1H),5.38(d,J=12.4Hz,1H),3.97(t,J=6.7Hz,2H),3.75–3.68(m,4H),3.23(s,3H),2.57(t,J=6.0Hz,2H),2.43(s,4H),2.39(t,J=6.7Hz,2H),2.28(t,J=4.0Hz,2H),2.03–1.96(m,2H),1.79–1.73(m,2H),1.66(s,6H)。
(10)合成荧光化合物D6
由合成荧光化合物D1的方法得到D6,得到红色固体76mg,产率33%。核磁数据如下:1H NMR(400MHz,CDCl3)δ7.72(d,J=12.4Hz,1H),7.26–7.15(m,2H),6.93(t,J=7.3Hz,1H),6.85(s,1H),6.72(d,J=8.0Hz,1H),5.37(d,J=12.4Hz,1H),4.03(t,J=6.5Hz,2H),3.22(s,3H),2.85(t,J=6.5Hz,2H),2.62–2.54(m,6H),2.29(t,J=4.0Hz,2H),1.81–1.74(m,6H),1.66(s,6H)。
(11)合成荧光化合物D7
由合成荧光化合物D1的方法得到D7,得到有橙色固体50mg,产率25%。核磁数据如下:1H NMR(400MHz,CDCl3)δ7.78(d,J=12.5Hz,1H),7.26–7.18(m,2H),6.95(t,J=7.4Hz,1H),6.80(s,1H),6.75(d,J=8.0Hz,1H),5.39(d,J=12.5Hz,1H),4.11(t,J=4.0Hz,2H),4.96(t,J=4.0Hz,2H),3.25(s,3H),2.58(t,J=6.6Hz,2H),2.31(t,J=4.0Hz,2H),1.79–1.75(m,2H),1.66(s,6H)。
(12)合成荧光化合物D8
由合成荧光化合物D1的方法得到D8,得到红色固体80mg,产率32%。核磁数据如下:1H NMR(400MHz,CDCl3)δ8.42(s,1H),7.73(d,J=12.4Hz,1H),7.60(d,J=7.8Hz,1H),7.37(d,J=8.0Hz,1H),7.23–7.16(m,3H),7.10(t,J=7.2Hz,1H),6.98(s,1H),6.93(t,J=7.4Hz,1H),6.72(d,J=8.0Hz,1H),6.39(s,1H),5.36(d,J=12.4Hz,1H),4.18(t,J=6.8Hz,2H),3.26(t,J=6.8Hz,2H),3.22(s,3H),2.51(t,J=5.9Hz,2H),2.05–2.01(m,2H),1.68(s,6H),1.65–1.60(m,2H)。
(13)合成荧光化合物D9
由合成荧光化合物D1的方法得到D9,得到红色固体52mg,产率20%。核磁数据如下:1H NMR(400MHz,CDCl3)δ8.46(s,1H),7.73(d,J=12.4Hz,1H),7.25–7.17(m,3H),7.04(d,J=2.3Hz,1H),6.97–6.89(dd,J=9.2,5.3Hz,2H),6.83(dd,J=8.8,2.4Hz,1H),6.72(d,J=7.9Hz,1H),6.35(s,1H),5.36(d,J=12.4Hz,1H),4.16(t,J=6.7Hz,2H),3.83(s,3H),3.26–3.17(m,5H),2.50(t,J=7.3
Hz,2H),2.02–1.97(m,2H),1.67(s,6H),1.63–1.57(m,2H)。
实施例2
荧光化合物D1~D9探针在不同溶剂中的最大吸收波长(λabs)和最大发射波长(λem)实验:
实验方法:取荧光化合物D1~D9溶于二甲亚砜中,配制成10mM储备液。取上述溶液3μL,分别用不同极性的有机溶剂DCM、EtOH、ACN、MeOH、DMSO、PBS稀释至3mL,得到10μM的溶液,用紫外分光光度计(UV-2450,SHIMADZU)和荧光分光光度计(F-4500,Hitachi),测定并记录荧光化合物的最大吸收波长和最大发射波长。
本实施例中荧光化合物D9~D18在不同溶剂中的荧光光谱图见表1。
表1化合物D9~D18在不同溶剂中的最大吸收波长及发射波长
由表1可以看出,本发明的荧光化合物的发射波长随着溶剂极性的增大而发生红移,在PBS溶液中的发射波长基本靠近近红外区。
实施例3
荧光化合物D1~D9在DCM及PBS中的荧光量子产率测定实验;
实验方法:选取甲酚紫醋酸甲酚紫为参比化合物(在甲醇中,其荧光量子产率为0.54),分别在紫外可见分光光度计及荧光分光光度计上分别测出荧光化合物D1~D9以及参比化合物的紫外吸收光谱及荧光发射光谱,根据Yu=Ys*Fu/Fs*As/Au进行运算,得出荧光化合物的荧光量子产率。Yu、Ys为待测物质及参比标准物质的荧光量子产率,Fu、Fs为待测物质和参比物质的积分荧光强度,Au、As为待测物质和参比物质在该激发波长的入射光强度。
本实施例中荧光化合物D1~D9在DCM及PBS中的荧光量子产率见表2。
表2荧光化合物D1~D9在DCM及PBS中的荧光量子产率
由表2结果可以看出,本发明的荧光化合的荧光量子产率随着溶剂极性的减小,荧光量子产率增高。
实施例4
荧光化合物D1~D9探针与Aβ1-42聚集体的体外结合实验:
实验方法:取荧光化合物D1~D9溶于二甲亚砜中,配制成10mM储备液,用PBS溶液稀释成250nM的待测液。先测得探针的激发和发射光谱性质。选用Aβ1-42蛋白在37℃水浴中培育Aβ聚集体,用于模拟人脑内的Aβ蛋白聚集体。将探针与不同浓度的Aβ1-42聚集体混合,并用荧光分光光度计进行荧光检测。
本实施例中荧光化合物D1~D9探针与Aβ1-42聚集体混合前后的荧光滴定光谱图分别见图2~10,体外检出限(LOD)及体外结合常数(Kd)见表3。
表3荧光化合物D1~D9探针与Aβ1-42聚集体作用体外检出限及结合常数
由图2~10可以看出,本发明的荧光化合物与Aβ1-42聚集体结合后,荧光强度明显增强。由表3可以看出,本发明的荧光化合物体外检测Aβ1-42聚集体的检出限达到纳摩尔级别,基本低于10nM。本发明的荧光化合物与Aβ1-42聚集体的体外结合常数均达到纳摩尔级别,除了D7外,其他化合物的体外结合常数均低于百纳摩尔,具备中等结合力。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其它的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
3.根据权利要求2所述的一种部花菁类荧光化合物的制备方法,其特征在于:步骤(1)中所述加热反应的温度为80℃。
4.根据权利要求2所述的一种部花菁类荧光化合物的制备方法,其特征在于:步骤(2)中所述升温回流反应的温度为80℃。
5.根据权利要求2所述的一种部花菁类荧光化合物的制备方法,其特征在于:步骤(3)中所述有机溶剂为正丁醇与甲苯的混合溶剂。
6.根据权利要求2所述的一种部花菁类荧光化合物的制备方法,其特征在于:步骤(4)中所述有机溶剂为甲醇。
7.权利要求1所述的一种部花菁类荧光化合物在制备Aβ沉积相关疾病的诊断试剂和治疗药物中的应用。
8.根据权利要求7所述的一种部花菁类荧光化合物在制备Aβ沉积相关疾病的诊断试剂和治疗药物中的应用,其特征在于:所述Aβ沉积相关疾病是指阿尔茨海默症或脑淀粉样血管病。
9.根据权利要求7所述的一种部花菁类荧光化合物在制备Aβ沉积相关疾病的诊断试剂和治疗药物中的应用,其特征在于:所述诊断试剂和治疗药物包括式(I)结构的部花菁类荧光化合物与药学上可接受的载体。
10.根据权利要求9所述的一种部花菁类荧光化合物在制备Aβ沉积相关疾病的诊断试剂和治疗药物中的应用,其特征在于:所述药学上可接受的载体为水、生理盐水、甘油或乙醇。
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