CN108997404B - 一种光敏剂、制备方法及其应用 - Google Patents
一种光敏剂、制备方法及其应用 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 claims abstract description 6
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- 238000000034 method Methods 0.000 claims description 7
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
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- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
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- 229910015900 BF3 Inorganic materials 0.000 description 1
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- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
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- -1 dichloromethane Alkane Chemical class 0.000 description 1
- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
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- 229910052763 palladium Inorganic materials 0.000 description 1
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- ZFJMTDFOGDGPTF-UHFFFAOYSA-N phosphanium;chloride;hydrochloride Chemical compound P.Cl.Cl ZFJMTDFOGDGPTF-UHFFFAOYSA-N 0.000 description 1
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- 238000010189 synthetic method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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Abstract
本发明涉及光动力治疗技术领域,具体涉及一种光敏剂、制备方法及其应用。本发明提供了一种光敏剂,为具有式I所示结构的化合物。本发明还提供了一种光敏剂的制备方法,将具有式II与式III所示结构的化合物通过sonogashira偶联反应,制备得到具有式I所示结构的化合物。本发明提供一种光敏剂、制备方法及其应用,解决了现有的光敏剂治疗效果差、对人体毒害大且价格昂贵不易合成的技术问题。
Description
技术领域
本发明涉及光动力治疗技术领域,具体涉及一种光敏剂、制备方法及其应用。
背景技术
光动力治疗是一种以非手术的方式治疗癌症的一种方法,利用光敏剂在光照条件下吸收光子到达激发态,后通过系间窜越到达三重态,与同样处于三重态的基态氧原子发生三重态—三重态能量转移过程,将能量传递给氧气获得单线态氧实现杀死癌细胞的目的,故而设计合成一种性能优良的光敏剂对于光动力治疗而言尤为重要。
目前而言,用于光动力治疗的光敏剂多为过渡金属复合物,碘原子或溴原子取代的光敏剂等,利用过渡金属,碘或溴原子发挥重原子效应,促进光敏剂的系间窜越过程,提高单线态氧量子产率。然而,在实际应用中,过渡金属价格昂贵,对人体正常组织毒害作用较大,且过渡金属复合物难以合成,摩尔消光系数低,而碘原子或溴原子在光照条件下易脱落降低了治疗效果,使得这些光敏剂在实际应用中效果并不理想。
因此现有的光敏剂治疗效果差、对人体毒害大且价格昂贵不易合成成为了本领域技术人员亟待解决的技术问题。
发明内容
有鉴于此,本发明提供一种光敏剂、制备方法及其应用,解决了现有的光敏剂治疗效果差、对人体毒害大且价格昂贵不易合成的技术问题。
本发明提供了一种光敏剂,为具有式I所示结构的化合物:
本发明还提供了一种光敏剂的制备方法,将具有式II与式III所示结构的化合物通过sonogashira偶联反应,制备得到具有式I所示结构的化合物;
优选的,式II所示结构的化合物与式III所示结构的化合物的摩尔比为1:2-1:6。
优选的,式II所示结构的化合物与式III所示结构的化合物的摩尔比为1:2。
优选的,所述sonogashira偶联反应的温度为40-110℃。
更优选的,所述sonogashira偶联反应的温度为60℃。
优选的,将炔基化合物溶于四氢呋喃溶液后,将四丁基氟化铵的四氢呋喃溶液加入到反应体系中,过夜得到式II所示结构的化合物。
优选的,所述炔基化合物为
本发明还提供了一种光敏剂作为光动力治疗光敏剂的应用。
本发明实施例提供的光敏剂通过引入硒元素,可发挥重原子效应,提高光敏剂的系间窜越效率,并且硒为人体组成元素之一,因此在传统光敏剂的基础上引入硒吩,可极大限度地降低光敏剂的生物毒性以及得到较高的单线态氧量子产率。此外由于本发明中的光敏剂具有高摩尔消光系数、较高的系间窜越效率、能够有效到达三重态并具有较长的三重态寿命,其在低功率光源激发下,能够高效敏化空气中的三线态氧原子产生大量单线态氧,提高了光动力治疗的效果。
本发明实施例制备的光敏剂其最大吸收波长位于540nm处,而其最大发射波长为640nm,其斯托克斯位移达到了100nm,能够有效的抑制该分子的自吸收,减少能量损失。此外将该光敏剂和单线态氧捕获剂DPBF混合于有机溶剂,测得其具有较高的单线态量子产率。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动性的前提下,还可以根据这些附图获得其它的附图。
图1为本发明实施例1中光敏剂的紫外可见吸收光谱测试以及荧光发射光谱测试图;
图2为本发明实施例1中步骤4所得产物的核磁共振氢谱;
图3为本发明实施例1中步骤3所得产物的核磁共振氢谱;
图4为本发明实施例1中步骤6所得产物的核磁共振氢谱。
具体实施方式
下面对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
本发明提供一种光敏剂、制备方法及其应用,解决了现有的光敏剂治疗效果差、对人体毒害大且价格昂贵不易合成的技术问题。
为了进一步理解本发明,下面结合实施例对本发明提供的一种光敏剂、制备方法及其应用进行具体的描述。
实施例1
步骤1:将硒吩(1.0g,7.6mmol)溶于氯仿(10mL)中,氮气保护下,,将NBS加入到反应体系中,混合物在室温下搅拌反应一天。反应结束后,加入去离子水淬灭反应,用二氯甲烷进行萃取,后分别加入饱和硫代硫酸钠溶液、去离子水进行洗涤,无水硫酸钠干燥后,旋蒸干溶剂,用纯石油醚作为展开剂进行柱层析提纯,得浅绿色液体1.852g,即得到测定其产率为84.4%,其核磁数据为1H NMR(400MHz,Chloroform-d)δ7.00(s,2H).
步骤2:将(3.46mmol,1.0g)、碘化亚铜(0.692mmol,0.131g)、双三苯基膦二氯化钯(0.346mmol,0.242g)溶于三乙胺(10mL)/THF(20mL)的混合溶液中,在氮气保护下,加入三甲基硅乙炔基(17.3mmol,1.18mL),反应物在60℃下搅拌反应10h,反应停止后,待反应液冷却至室温后,旋蒸除走溶剂,用石油醚作为展开剂提纯,得到黄色固体产物0.9g,即测定其产率为86.9%,其核磁数据为1H NMR(400MHz,Chloroform-d)δ7.25(s,2H),0.26(s,18H).
步骤3:将(93.5mg,0.289mmol)溶解在四氢呋喃中。加入四丁基氟化铵的四氢呋喃溶液,将反应混合物在室温下搅拌过夜,再将反应混合物依次用二氯甲烷萃取,有机层用盐水洗涤。用Na2SO4干燥,真空除去溶剂,得到黄棕色固体。即得到测定其产率为40%,其核磁数据为1H NMR(400MHz,Chloroform-d)δ7.31(s,1H),3.51(s,1H).
步骤4:将苯甲酰氯(1.14g,11mmol),2,4-二甲基吡咯(2.0mL,20mmol)溶于150ml无水二氯甲烷中。在氮气保护下,室温下搅拌反应10h。冰浴条件下,逐滴滴加三乙胺(10mL)、三氟化硼乙醚(10mL),搅拌反应10h,反应结束后,旋蒸除去溶剂,用体积比为2:1的二氯甲烷和石油醚混合溶液过柱提纯。得到橙色固体产物1.8g,即得到测定其产率为51%,其核磁数据为1H NMR(400MHz,Chloroform-d)δ7.48(dd,J=5.1,2.1Hz,1H),7.31–7.27(m,1H),5.98(s,1H),2.56(d,J=1.2Hz,2H),1.37(s,2H).
步骤5:将(86mg,0.265mmol)溶于20mL无水乙醇中,将碘单质(33.6mg,0.265mmol)和碘酸饱和溶液(37.3mg)。在氮气保护下,抽真空。室温下搅拌反应10min,旋蒸后,用体积比为2:1的二氯甲烷和石油醚混合溶液过柱提纯后得到红色固体产物93.2mg,即测定其产率为78.1%,其核磁数据为1H NMR(400MHz,CDCl3)δ7.55–7.46(m,1H),7.27(m,1H),7.25(s,1H),6.04(s,1H),2.63(s,3H),2.57(s,3H),1.38(s,6H).
步骤6:将(128.32mg,0.2851mmol)、碘化亚铜(5.43mg,0.02851mmol)、双三苯基磷二氯化钯(10mg,0.01426mmol)、三苯基膦(14.95mg,0.05702mmol)溶解于三乙胺(5mL)和10mL的THF(四氢呋喃)的混合溶液中,氮气保护下抽真空,室温下搅拌15min,在氮气保护下加入(46.1mg,0.14255mmol),加热至60℃,搅拌12h,旋蒸后,用体积比为1:1的二氯甲烷和石油醚混合溶液进行柱层析提纯后得到黄褐色固体产物10.7mg,即得到测定其产率为9.1%。
核磁数据:1H NMR(400MHz,Methylene Chloride-d2)δ7.59–7.46(m,6H),7.31(dd,J=6.5,2.8Hz,4H),7.22(s,2H),6.09(s,2H),2.62(s,5H),2.55(s,5H),1.47(s,6H),1.42(s,6H).
HRMS(ESI):m/z calcd for C46H38B2F4N4Se([M+H]+):825.24567,found:825.24591.
将本实施例1制备得到的光敏剂进行紫外可见吸收光谱测试以及荧光发射光谱测试,如图1所示。该化合物的最大吸收波长位于540nm处,而其最大发射波长为640nm,其斯托克斯位移达到了100nm,能够有效的抑制该分子的自吸收,减少能量损失。同时,相较于传统三重态光敏剂,该分子具有9.2μs的长三重态寿命及高达52%的单线态氧量子产率。
将本发明实施例制得的光敏剂和和单线态氧捕获剂DPBF混合于二氯甲烷中,其中DPBF在414nm处的紫外可见吸光度为1,光敏剂在540nm处紫外可见吸光度在0.2~0.3之间。在测试单线态氧量子产率时,配制样品使其紫外可见吸光度为1,用540nm波长激发光敏剂,每隔一段时间测试样品吸光度,通过计算得到光敏剂的单线态氧量子产率。而对于利用活性氧杀死癌细胞的光动力治疗而言,光敏剂的单线态氧量子产率高则是提高治疗效果的关键因素。
对比例1
分子1是在BODIPY(氟硼二吡咯)基础上通过单键引入噻吩基团得到,该分子具有摩尔消光系数大,斯托克斯位移大(在甲苯中达到79nm),三重态寿命长(389.9μs)等特点,但其单线态氧量子产率非常低,杀死癌细胞效率大大降低,不利于光动力治疗。
分子1的合成方法:利用发生Suzuki偶联反应反应,得到具有分子1所示结构的光敏剂;
由该对比例可知,噻吩基团能够代替过渡金属及卤素原子发挥重元素效应,促进分子的系间窜越过程,利于分子到达三重态,与氧气分子作用产生单线态氧杀死癌细胞,而Se与S是同族元素,并且Se的相对原子质量较S大,重元素效应较S明显,并且作为人体需要摄入的元素之一—Se,引入S和Se有利于降低光敏剂对于有机体的毒害作用,得到对正常组织损害较小的三重态光敏剂用于光动力治疗。
但同时,对比式I与分子1的光物理参数可知,虽然式I的三重态寿命较分子1短,但是其单线态氧量子产率明显高于分子1,说明式I能够有效敏化空气中的基态氧生成对细胞有杀伤作用的单线态氧,更加适用于光动力治疗。
以上所述仅是本发明的优选实施方式,应当指出,对于使本技术领域的专业技术人员,在不脱离本发明技术原理的前提下,是能够实现对这些实施例的多种修改的,而这些修改也应视为本发明应该保护的范围。
Claims (7)
1.一种光敏剂,其特征在于,为具有式I所示结构的化合物:
2.一种光敏剂的制备方法,其特征在于,将具有式II与式III所示结构的化合物通过sonogashira偶联反应,制备得到具有式I所示结构的化合物;
3.根据权利要求2所述的光敏剂的制备方法,其特征在于,式II所示结构的化合物与式III所示结构的化合物的摩尔比为1:2-1:6。
4.根据权利要求3所述的光敏剂的制备方法,其特征在于,式II所示结构的化合物与式III所示结构的化合物的摩尔比为1:2。
5.根据权利要求2所述的光敏剂的制备方法,其特征在于,所述sonogashira偶联反应的温度为40-110℃。
6.根据权利要求2所述的光敏剂的制备方法,其特征在于,式II所示结构的化合物通过以下方法制备:
将溶于四氢呋喃溶液后,将四丁基氟化铵的四氢呋喃溶液加入到反应体系中,过夜得到式II所示结构的化合物。
7.根据权利要求1所述的一种光敏剂或根据权利要求2~6任一项所述的一种光敏剂的制备方法制得的光敏剂作为光动力治疗光敏剂的应用;所述应用不属于疾病诊断和治疗方法。
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