CN117088858A - 一种正交电荷转移阳离子有机小分子在光疗中的应用 - Google Patents
一种正交电荷转移阳离子有机小分子在光疗中的应用 Download PDFInfo
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Abstract
本发明提供了一种单一近红外波段下可同时产生光热和光动力效果的正交电荷转移的阳离子有机小分子材料抗菌剂的制备和应用。提供了具有式(Ⅳ)所示结构或其异构体,药学上可接受的盐、水合物或溶剂化物等水溶性的分子结构,药物组合物的制备及其在抗菌和/或肿瘤协同光疗方面的应用。本发明提供的正交结构化合物可以实现分子内电荷转移,延长分子三重态寿命,在氧气存在的条件下将其转换成单线态氧,同时能够将光能转换成热能,实现光动力、光热联合治疗,弥补单一光疗的缺陷,增强光疗效果。
Description
技术领域
本发明涉及一类新型正交电荷转移阳离子有机小分子化合物在光疗中的应用,该类小分子在激光照射下兼具发光、发热以及产生活性氧效果,进而能够标记并杀死肿瘤细胞,同时对革兰氏阳性菌以及革兰氏阴性菌有一定的杀伤效果的一类正交电荷转移阳离子化合物在光疗中的应用,属于化学制药领域。
背景技术
随着癌症的发病率逐年上升,以及细菌感染对人类健康有着重大威胁,研究者们不断开创新的治疗手段,基于无创、副作用小等优点,光治疗逐渐走进人们的视野。光疗主要包括光热疗法(PTT)和光动力疗法(PDT)。光热疗法是化合物在激光照射下将光能转化成热能以产生高温,进而杀死细菌和癌细胞;对于光动力疗法是光敏剂在激光照射下产生活性氧,可诱导细胞凋亡。
由于在癌症治疗和细菌感染治疗中单一疗法的局限性,因此克服光热治疗和光动力治疗的缺陷,获得更好的治疗效果成为近年来许多研究者的重要目标。例如,将具有单一光热效果和光动力效果或化学治疗效果等的药物通过载体同时运输到病灶部位进行治疗,以实现协同治疗效果,尽管这种方法在肿瘤治疗中具有很高的潜力,但这种一体化方法也受到制备复杂、重复性低和药物动力学不稳定的限制,在临床开发和应用上同样具有一定的局限性。
因此,开发一种同时具有多种光治疗效果的小分子药物具有重要意义。在同一个分子中同时具有多诊断成像和协同治疗的有机小分子比一体式的光敏剂在制备上更加简单、结构更加明确、生物相容性提高以及具有更好的再现性。因此,基于光热治疗和光动力治疗的优势,制备一种同时具有多功能成像以及两种治疗效果的小分子药物的重要性和必要性显而易见。
发明内容
本发明针对上述现有技术中存在的问题,提供了一种新型阳离子有机小分子荧光化合物及其在光疗中的应用。该分子同时具有光热治疗和光动力治疗效果,可以与细菌结合,在激光照射下能够同时产生热量和活性氧,具有较高的光热转换效率和活性氧量子产率,易降解,可用于体内癌症治疗以及体外细菌感染治疗。
据此,本发明一方面提供一种具有式(Ⅰ)所示结构的化合物、其异构体、药学上可接受的盐、水合物等水溶性分子结构。
式(Ⅰ)中:
A为取代或非取代的杂环,优选地所述杂环不带电荷,更优选地所述杂环包含N,O,S,Cl,Br和I中的一个或多个杂原子;
L为取代或非取代的共轭碳链,优选地,所述共轭碳链中包含2-5个双键,更优选地,所述共轭碳链双键的个数为3个;
X1为O、N或-CR4R4’-,优选地,X1为O;
N为0或1,优选地,n为0;
R1、R1’、R2各自独立于具有吸电子能力的原子和基团,优选地所述R1、R1’、R2各自独立地选自于-CN、-CF3、-F、-SO2CF3、-NO2、-COOEt、-SO2ph、 和;更优选地,所述R1、R1’均为-CN;R2为-CN或/>
R3和R3’各自独立地选自于H、卤素原子、取代或非取代地烃基、取代或非取代的环烃基、取代或非取代的芳基、取代或非取代的杂芳基、取代或非取代的杂环基、取代或非取代的醇基、取代或非取代的醚基、取代或非取代的醛基、取代或非取代的羧基、取代或非取代的酰氨基、取代或非取代的酯基和取代或非取代的氨基;优选地,所述R3、R3’各自独立地选自于H,-(CH2)qCH3、-(CH2)qCF3、-(CH2)qCH=CH2、-(CH2)qCH≡CH、-(CH2)qOH、-(CH2)qCOOH、-(CH2)qNH2、-(CH2)qCH0、-(CH2)qCO(CH2)q’CH3、-(CH2)qO(CH2)q’CH3、 其中,q、q’各自独立地选自0-12的整数;
R4和R4’各自独立地选自于H、卤素原子、取代或非取代的烃基、取代或非取代的环烃基、取代或非取代的芳基、取代或非取代的杂芳基、取代或非取代的杂环基、取代或非取代的醇基、取代或非取代的醚基、取代或非取代的醛基、取代或非取代的羧基、取代或非取代的酰氨基、取代或非取代的酯基、取代或非取代的氨基;
当所述基团为取代的时,取代基为单取代或者多取代。
由式(Ⅰ)化合物在水溶液中具有高光热转换效率、优异的光热稳定性和易降解安全性高等优势。
在一些较佳的实施例中,所述A选自于取代或非取代的吡咯或氢化吡咯环、取代或非取代的呋喃或氢化呋喃环、取代或非取代的噻吩或氢化噻吩环、取代或非取代的吡唑或氢化吡唑环、取代或非取代的咪唑或氢化咪唑环、取代或非取代的噁唑或氢化噁唑环、取代或非取代的异噁唑或氢化异噁唑环、取代或非取代的噻唑或氢化噻唑环、取代或非取代的吲哚或氢化吲哚环、取代或非取代的苯并呋喃或氢化苯并呋喃环、取代或非取代的苯并咪唑或氢化苯并咪唑环、取代或非取代的咔唑或氢化咔唑环、取代或非取代的吡啶或氢化吡啶环、取代或非取代的吡喃或氢化吡喃环、取代或非取代的噻喃或氢化噻喃环、取代或非取代的苯并吡唑或氢化苯并吡唑环、取代或非取代的哒嗪或氢化哒嗪环、取代或非取代的嘧啶嗪或氢化嘧啶环、取代或非取代的吡嗪或氢化吡嗪环、取代或非取代的哌啶环、取代或非取代的吗啉环、取代或非取代的硫代吗啉环和取代或非取代的三唑环;
更佳地,所述A为
其中,R5、R6、R6’、R7各自独立地选自于H、卤素原子、取代或非取代的烃基、取代或非取代的环烃基、取代或非取代的芳基、取代或非取代的杂芳基、取代或非取代的杂环基、取代或非取代的醇基、取代或非取代的醚基、取代或非取代的醛基、取代或非取代的羧基、取代或非取代的酰氨基、取代或非取代的酯基和取代或非取代的氨基。
在另一些较佳的实施例中,所述L为其中
Y1为卤素原子、取代或非取代的氨基或烃氧基、取代或非取代的杂芳基;
M为0-5的整数,优选地,m为3;
R8各自独立地选自于H、卤素原子、取代或非取代的烃基、取代或非取代的环烃基、取代或非取代的芳基、取代或非取代的杂芳基、取代或非取代的杂环基、取代或非取代的醇基、取代或非取代的醚基、取代或非取代的醛基、取代或非取代的羧基、取代或非取代的酰氨基、取代或非取代的酯基和取代或非取代的氨基。
在特别优选的实施例中,m为3,Y1为Cl、Br、-NR9R9’、-OR9、并且R8为H、-CH3、/>R9和R9’各自独立地选自于H、取代或非取代的烃基、取代或非取代的环烃基、取代或非取代的芳基、取代或非取代的杂芳基、取代或非取代的杂环基、取代或非取代的醇基、取代或非取代的醚基、取代或非取代的醛基、取代或非取代的羧基、取代或非取代的酰氨基、取代或非取代的酯基、取代或非取代的氨基。
本发明另外提供一种由具有式(Ⅱ)所示结构的化合物、其异构体、药学上可接受的盐、水合物等水溶性结构,
式(Ⅱ)中,
Y2为Cl、Br、其中,q、q’各自独立地选自0-12的整数;
R10为-CN或
R11为-(CH2)m-、m为0-5的整数,优选地,R10为-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-,更优选地,R11为-(CH2)3-;
R12为
R13为
所述q、q’各自独立地选自0-12的整数;
更优选地,所述化合物(Ⅱ)为Ⅱ-1、Ⅱ-2、Ⅱ-3、Ⅱ-4、Ⅱ-5、Ⅱ-6、
Ⅱ-7、Ⅱ-8、Ⅱ-9、Ⅱ-10、Ⅱ-11、Ⅱ-12、Ⅱ-13、Ⅱ-14、Ⅱ-15、Ⅱ-16、Ⅱ-17、Ⅱ-18、Ⅱ-19、Ⅱ-20、Ⅱ-21、Ⅱ-22、Ⅱ-23、Ⅱ-24、Ⅱ-25、Ⅱ-26、Ⅱ-27、Ⅱ-28、Ⅱ-29、Ⅱ-30、Ⅱ-31、Ⅱ-32、Ⅱ-33、Ⅱ-34、Ⅱ-35、Ⅱ-36、Ⅱ-37、Ⅱ-38、Ⅱ-39、Ⅱ-40、Ⅱ-41、Ⅱ-42、Ⅱ-43、Ⅱ-44、Ⅱ-45、Ⅱ-46、Ⅱ-47、Ⅱ-48、Ⅱ-49或Ⅱ-50。
由于肿瘤(特别是实体瘤)组织的血管丰富,并缺失淋巴回流系统,会造成本发明所述的结构(自身或被聚合物包裹)在肿瘤位置被动高渗透性和滞留性。这种
结构在实体瘤组织的高通透效应和滞留效应被称为EPR效应(enhancedpermeability and retention effect)。这种被动靶向的能力,使这类小分子化合物,相对于其他报道的小分子光热转换试剂,具有明显的优势。
本发明提供了所述的结构在制备光治疗药物中的用途,优选地,所述光疗药物为光热治疗药物、光动力治疗药物或光声治疗药物。
本发明还提供所述的结构或者药物组合在制备诊断和/或治疗癌症的药物中的用途,优选地,所述癌症为食道癌、非小细胞肺癌、胆道癌、头颈癌、巴雷特食管癌、膀胱癌、结肠直肠癌、胰腺癌、卵巢癌、前列腺癌、脑肿瘤、乳腺癌或皮肤癌;所述皮肤癌包括黑色素瘤。
本发明还提供了所属结构在制备治疗皮肤病的药物中的用途,优选地,所述皮肤病为光化性角化病、基底细胞癌、皮肤T细胞淋巴瘤、博文氏病、鳞状细胞癌、外阴和肛门的上皮内瘤变或佩吉特病。
本发明还提供了一种在受试者的靶区域进行光治疗的方法,包括:
1)提供所述的结构;
2)将所述结构给予受试者;
3)等待所述结构在靶区域富集;
4)使用所述结构激发波段的光辐照受试者的靶区域,优选地,采用808nm的光波照射。
本发明另一方面提供了一种具有式(Ⅲ)所示结构的化合物、其异构体、药学上可接受的盐、水合物或溶剂化物。
X2选自于O、S或-CR21R21’-;
Y3、Y4、Y5各自独立地选自于H、羟基、卤素原子、取代或非取代的氨基和烃氧基及其衍生物;
t1、t2、t3各自独立地选自0-5的整数,优选地所述t1和t2均为1,t3为0;
R14、R14’、R15各自独立地选自于-CN,-CF3,F,-SO2CF3,-NO2,-COOEt,-SO2ph,优选地,R14、R14’均为-CN,R15为-CN或/>
R16为-(CH2)m-、 m为0-5的整数,优选地m为3;
R17和R18共同形成如下之一的连接: 或者R17、R18和X2共同形成如下连接/>其中,Ra、Rb、Rc、Rd、Re、Rf、Rg各自独立地选自于H、卤素原子、取代或非取代的烃基、取代或非取代的羧基、取代或非取代的羟基和取代或非取代的氨基;
R19、R19’R21和R21’各自独立地选自于H、卤素原子、取代或非取代的烃基、取代或非取代的环烃基、取代或非取代的芳基、取代或非取代的杂芳基、取代或非取代的杂环基、取代或非取代的醇基、取代或非取代的醚基、取代或非取代的醛基、取代或非取代的羧基、取代或非取代的酰氨基、取代或非取代的酯基和取代或非取代的氨基;优选地,R19、R19’各自独立地选自于H,-(CH2)qCH3、-(CH2)qCF3、-(CH2)qCHCH2、-(CH2)qCCH、-(CH2)qOH、-(CH2)qCOOH、-(CH2)qNH2、-(CH2)qCH0、-(CH2)qCO(CH2)q’CH3、-(CH2)qO(CH2)q’CH3、 其中q、q’各自独立地选自0-12的整数;
R20选自于H、Cl、Br等卤素原子;
当所述基团为取代时,取代基为单取代或者多取代。
在一个优选的实施例中,所述Y3和Y5均为H;
Y4为Cl、Br、-NR22R22’-或
t1、t2均为1,t3为0;
R22、R22’各自独立地选自于H、取代或非取代的烃基、取代或非取代的环烃基、取代或非取代的芳基、取代或非取代的杂芳基、取代或非取代的取代或非取代的杂环基、取代或非取代的醇基、取代或非取代的醚基、取代或非取代的醛基、取代或非取代的羧基、取代或非取代的酰氨基、取代或非取代的酯基和取代或非取代的氨基。
更优选地,所述化合物(Ⅲ)为Ⅱ-1、Ⅱ-2、Ⅱ-3、Ⅱ-4、Ⅱ-5、Ⅱ-6、
Ⅱ-7、Ⅱ-8、Ⅱ-9、Ⅱ-10、Ⅱ-11、Ⅱ-12、Ⅱ-13、Ⅱ-14、Ⅱ-15、Ⅱ-16、Ⅱ-17、Ⅱ-18、Ⅱ-19、Ⅱ-20、Ⅱ-21、Ⅱ-22、Ⅱ-23、Ⅱ-24、Ⅱ-25、Ⅱ-26、
Ⅱ-27、Ⅱ-28、Ⅱ-29、Ⅱ-30、Ⅱ-31、Ⅱ-32、Ⅱ-33、Ⅱ-34、Ⅱ-35、Ⅱ-36、Ⅱ-37、Ⅱ-38、Ⅱ-39、Ⅱ-40、Ⅱ-41、Ⅱ-42、Ⅱ-43、Ⅱ-44、Ⅱ-45、Ⅱ-46、Ⅱ-47、Ⅱ-48、Ⅱ-49或Ⅱ-50。
本发明另一方面提供了一种药物组合物包含
1)治疗有效剂量的式(Ⅲ)所示化合物、其异构体、药学上可接受的盐、水合物或溶剂化物,和
2)药学上可接受的载体;优选地,所述药学上可接受的载体包括稀释剂、崩解剂、赋形剂、粘合剂、稳定剂或其他组合。
本发明另一方面提供了具有式(Ⅳ)所示结构的化合物、其异构体、药学上可接受的盐、水合物或溶剂化物在制备光疗药物中的用途,
式(Ⅳ)中:
X2选自于N、O、S或-CR22R22’-;
Y3、Y4、Y5各自独立地选自于H、羟基、卤素原子、取代或非取代的氨基合烃氧基;
t1、t2、t3各自独立地选自0-5的整数,优选地,所述t1和t2均为1,t3为0;
R14、R14’、R15各自独立地选自于-CN,-CF3,F,-SO2CF3,-NO2,-COOEt,-SO2ph,优选地,R14、R14’均为-CN,R15为-CN或/>
R16为-(CH2)m-、 m为0-5的整数,优选地m为3;
R17和R18共同形成如下之一的连接: 或者R17、R18和X2共同形成如下连接/>其中,Ra、Rb、Rc、Rd、Re、Rf、Rg各自独立地选自于H、卤素原子、取代或非取代的烃基、取代或非取代的羧基、取代或非取代的羟基和取代或非取代的氨基;
R19、R19’、R20、R22和R22’各自独立地选自于H、卤素原子、取代或非取代的烃基、取代或非取代的环烃基、取代或非取代的芳基、取代或非取代的杂芳基、取代或非取代的杂环基、取代或非取代的醇基、取代或非取代的醚基、取代或非取代的醛基、取代或非取代的羧基、取代或非取代的酰氨基、取代或非取代的酯基和取代或非取代的氨基;优选地,R19、R19’、R20各自独立地选自于H,-(CH2)qCH3、-(CH2)qCF3、-(CH2)qCHCH2、-(CH2)qCCH、-(CH2)qOH、-(CH2)qCOOH、-(CH2)qNH2、-(CH2)qCH0、-(CH2)qCO(CH2)q’CH3、-(CH2)qO(CH2)q’CH3、 其中q、q’各自独立地选自0-12的整数;优选地,所述R20为-CH2CH3;
R21选自于H、Cl、Br、I等卤素原子;
当所述基团为取代时,取代基为单取代或者多取代。
在一个优选的实施例中,所述Y3和Y5均为H;
Y4为Cl、Br、-NR23R23’-或
t1、t2均为1,t3为0;
R23、R23’各自独立地选自于H、取代或非取代的烃基、取代或非取代的环烃基、取代或非取代的芳基、取代或非取代的杂芳基、取代或非取代的取代或非取代的杂环基、取代或非取代的醇基、取代或非取代的醚基、取代或非取代的醛基、取代或非取代的羧基、取代或非取代的酰氨基、取代或非取代的酯基和取代或非取代的氨基。
更优选地,所述化合物(Ⅳ)为Ⅱ-1、Ⅱ-2、Ⅱ-3、Ⅱ-4、Ⅱ-5、Ⅱ-6、
Ⅱ-7、Ⅱ-8、Ⅱ-9、Ⅱ-10、Ⅱ-11、Ⅱ-12、Ⅱ-13、Ⅱ-14、Ⅱ-15、Ⅱ-16、Ⅱ-17、Ⅱ-18、Ⅱ-19、Ⅱ-20、Ⅱ-21、Ⅱ-22、Ⅱ-23、Ⅱ-24、Ⅱ-25、Ⅱ-26、
Ⅱ-27、Ⅱ-28、Ⅱ-29、Ⅱ-30、Ⅱ-31、Ⅱ-32、Ⅱ-33、Ⅱ-34、Ⅱ-35、Ⅱ-36、Ⅱ-37、Ⅱ-38、Ⅱ-39、Ⅱ-40、Ⅱ-41、Ⅱ-42、Ⅱ-43、Ⅱ-44、Ⅱ-45、Ⅱ-46、Ⅱ-47、Ⅱ-48、Ⅱ-49或Ⅱ-50。
优选地,所述光治疗药物为光热治疗药物、光动力治疗药物或光声治疗药物。
本发明还提供式(Ⅳ)所示化合物、其异构体、药学上可接受的盐、水合物或溶剂化物作为光敏剂的用途,优选地,所述光敏剂用于制备光热治疗药物、光动力治疗药物或光声治疗药物。
本发明还提供式(Ⅳ)所示化合物、其异构体、药学上可接受的盐、水合物或溶剂化物在制备诊断和/或治疗癌症的药物中的用途,优选地,所述癌症为食道癌、非小细胞肺癌、胆道癌、头颈癌、巴雷特食管炎、膀胱癌、结肠直肠癌、胰腺癌、卵巢癌、前列腺癌、脑肿瘤、乳腺癌或皮肤癌;所述皮肤癌包括黑色素瘤。
本发明还提供式(Ⅳ)所示化合物、其异构体、药学上可接受的盐、水合物或溶剂化物在制备治疗皮肤病的药物中的用途,优选地,所述皮肤病为光化性角化病、基底细胞癌、皮肤T细胞淋巴瘤、博文氏病、鳞状细胞癌、外阴和肛门的上皮内瘤变或佩吉特病。
本发明的有益效果:
(1)本发明提供了式(Ⅰ)或式(Ⅱ)所示的化合物结构、其制备方法及应用。实验证明,该结构具有高光热转换效率、光热稳定性好、
光热效应和光动力效应好、易降解、安全性高的优势,且可以被动靶向肿瘤部位,在癌症和皮肤病的诊断和治疗方面具有广阔前景。
(2)本发明提供了式(Ⅲ)所示化合物,该化合物结构具有高光热转换效率、光热稳定性好、光热效应和光动力效应好、易降解、安全性高的优势。
(3)本发明还提供了式(Ⅳ)所示化合物用于制备光治疗药物、诊断和治疗癌症药物或治疗皮肤病药物的用途,其治疗效果好、创伤小,具备极大的市场价值和广阔的经济前景。
附图说明:
图1为本发明提供的化合物Ⅱ-1的合成路线图;
图2为化合物Ⅱ-1在不同溶剂中的紫外吸收光谱图;
图3为化合物Ⅱ-1在不同溶剂中的荧光发射图;
图4为不同浓度的化合物Ⅱ-1在808nm激光照射下的升温曲线;
图5为化合物Ⅱ在浓度为20μM时氮气鼓泡前后的光热升温曲线;
图6为不同浓度的化合物Ⅱ-1在808nm激光照射下的光热效率计算;
图7为化合物Ⅱ-1在水溶液中的光热稳定性图;
图8为化合物Ⅱ-1在808nm激光照射下,使用DPBF作为活性氧探针,检测活性氧产生的DPBF紫外吸收衰减光谱图;
图9为化合物Ⅱ-1被癌细胞吞噬后细胞共定位图像;
图10为化合物Ⅱ-1对Hela细胞Live-dead荧光成像图;
图11为化合物Ⅱ-1以及活性氧探针DCFH-DA进入Hela细胞后,用808nm激光照射后的细胞内活性氧产生的荧光成像图;
图12为化合物Ⅱ-1经尾静脉注射进小鼠后,不同时间点的小鼠全身的光声成像图;
图13为化合物Ⅱ-1经尾静脉注射进小鼠后,不同时间点的小鼠全身的光声成像信号强度图;
图14为化合物Ⅱ-1经尾静脉注射进小鼠后,96小时后的小鼠器官荧光成像图;
图15为化合物Ⅱ-1经尾静脉注射进小鼠后,96小时后的小鼠器官荧光成像信号强度图;
图16为化合物Ⅱ-1小鼠体内光热治疗中的光热成像;
图17为化合物Ⅱ-1小鼠体内光热成像升温曲线图;
图18为化合物Ⅱ-1小鼠的光治疗实验图;
图19为荷瘤小鼠尾静脉注射化合物Ⅱ-1并给予治疗后的肿瘤体积-时间图;
图20为荷瘤小鼠尾静脉注射化合物Ⅱ-1并给予治疗后的小鼠体重-时间图;
图21为荷瘤小鼠尾静脉注射化合物Ⅱ-1并给予治疗20天后的小鼠心、肝、脾、肺、肾的切片H&E染色图;
图22为荷瘤小鼠尾静脉是注射化合物Ⅱ-1并给予治疗后的小鼠肝功能和血常规情况;
具体实施方式:
本发明的方法于技术通常依据本领域已知的传统方法进行,除非另有说明。于本文中描述的生物学、药理学、及医学与医药化学相关的命名法,及实验方法与技术是本领域已知且常用的。化学合成法、化学分析法、医药制法、调配法与传送法,及检测或测试法均采用标准技术。
下面将结合附图和实施例对本发明作进一步的说明。
一些本发明的化合物的实例如下述化合物:
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上述化合物可通过以下反应通式进行合成:
主要合成步骤包括:
(1)分别提供化合物a、b、c的合成步骤;
化合物a的合成:
将化合物1’和化合物2’和乙醇镁溶于乙醇中,60℃反应24小时。真空下蒸去溶剂,所得固体经柱层析纯化得目标化合物a。
化合物b的合成:
将二氯甲烷和化合物4’冰浴下加入瓶中搅拌,恒压加入化合物5’搅拌,再加入化合物3’,80℃反应3小时;反应完全后将产物倒入碎冰中淬灭反应,在冰箱放置过夜。真空下蒸去溶剂得到粗产物化合物b,不进行提纯直接用于下一步反应。
化合物c的合成;
化合物6’和化合物7’加入到乙腈中。加热到110℃回流反应24小时。真空下蒸去溶剂,所得固体用乙醚洗涤3次得到化合物c。
(2)将化合物a和化合物b溶于乙醇中,加热回流,然后加入化合物c,加热回流,真空下蒸去溶剂,所得固体经柱层析纯化,得目标化合物Ⅱ。
实施例1化合物Ⅱ-1的合成及其荧光性质
如图1所示,化合物Ⅰ-1的合成包括以下步骤:
(1)化合物1的合成:1.46g丙二腈和0.93g乙醇镁加到15mL乙醇中,然后加入0.75mL的3-羟基-3-甲基丁烷-2-酮,加热到60℃反应12小时。真空旋蒸除去溶剂,所得固体经柱层析纯化得到目标产物1。1H NMR(400MHz,CDCl3):δ(ppm):2.36(s,3H),1.63(s,6H)。
(2)化合物2的合成:将30mL DCM和30mL DMF在冰浴下加入反应瓶中搅拌,恒压加入26.3mLPOCl3搅拌,再加入7.95mL的环己酮,加热到80℃反应3小时。反应结束后将产物倒入碎冰中,使反应淬灭,然后放置在冰箱中过夜,真空旋蒸除去溶剂,得到粗产物化合物2,直接进行下一步合成反应。
(3)化合物3的合成:4.5g的化合物1和3g的化合物2加入到50mL乙醇中。在90℃回流反应8小时。等冷却到室温后,抽滤获得粗产物化合物3,不进行提纯直接用于下一步反应。
(4)化合物4的合成:将0.5g 5-氯-2,3,3-三甲基吲哚和2.01g碘乙烷加入到50mL乙腈中。在110℃回流反应24小时。等冷却到室温后,用乙醚重结晶,抽滤获得粗产物4,不用提纯直接用于下一步。1H NMR(400MHz,CDCl3):δ(ppm):7.77(d,1H),7.56(m,2H),4.77(q,2H),3,15(s,3H),1.67(s,6H),1.61(t,3H).
(5)化合物Ⅱ-1的合成:0.4g的化合物3和0.44g的化合物4以及过量吡啶溶于5mL乙醇中,加热到90℃,回流6小时,抽滤得到纯的固体产物Ⅱ-1。1H NMR(400MHz,DMSO):δ(ppm):9.23(d,2H),8.99(t,1H),8.50(t,2H),7.55(d,1H),7.39(dd,1H),7.28(dd,1H),6.94(d,1H),6.42(d,J=14.4Hz,1H),6.15(d,1H),5.96(d,1H),4.07(q,2H),2.78(m,4H),1.98(t,2H),1.54(s,6H),1.17(t,3H),1.10(s,6H).
化合物Ⅱ-1在水和有机溶剂中的紫外吸收光谱图及荧光发射光谱图如图2和图3所示。
实施例2化合物Ⅱ-2至Ⅱ-15的合成
采用与实施例1类似的方法可以制备化合物Ⅱ-2至Ⅱ-15.
1.化合物Ⅱ-2的合成
以化合物6代替实施例1中的化合物1,其余所需试剂、制备方法同实施例1的步骤1-5,制备得到化合物Ⅱ-2;
1H NMR(400MHz,DMSO):δ(ppm):9.26(d,2H),9.16(t,2H),8.49(t,2H),7.86(s,2H),7.52(s,1H),7.20(d,1H),6.61(d,1H),6.51(s,1H),6.23(s,1H),5.21(s,1H),4.13(m,2H),3.18(m,2H),2.81(t,4H),1.79(s,6H),1.47(m,6H),1.31(t,3H),1.16(s,3H).
2.化合物Ⅱ-3的合成
以化合物7代替实施例1中的化合物1,其余所需试剂、制备方法同实施例1的步骤1-5,制备得到化合物Ⅱ-3;
1H NMR(400MHz,DMSO):δ(ppm):9.26(d,1H),9.16(t,1H),8.49(t,2H),7.52(s,1H),7.20(d,1H),6.61(d,1H),6.51(s,2H),6.23(s,1H),5.78(d,2H),5.21(s,1H),4.63(m,1H),4.13(m,2H),3.18(m,2H),2.81(m,6H),1.79(s,6H),1.47(m,6H),1.31(t,3H),1.58(s,3H),1.05(s,3H).
3.化合物Ⅱ-4的合成
以化合物8代替实施例1中的化合物1,其余所需试剂、制备方法同实施例1的步骤1-5,制备得到化合物Ⅱ-4;
1H NMR(400MHz,DMSO):δ(ppm):9.26(d,2H),9.16(t,1H),8.49(t,2H),7.52(s,1H),7.20(d,1H),6.61(d,1H),6.51(s,2H),6.23(s,1H),5.21(s,1H),
4.13(m,2H),3.80(t,2H),2.81(t,4H),1.79(s,6H),1.47(m,6H),1.31(t,3H),1.16(s,3H).
4.化合物Ⅱ-5的合成
以化合物9代替实施例1中的化合物1,其余所需试剂、制备方法同实施例1的步骤1-5,制备得到化合物Ⅱ-5;
1H NMR(400MHz,DMSO):δ(ppm):9.26(d,2H),9.16(t,1H),8.49(t,2H),7.52(s,1H),7.20(d,1H),6.61(d,1H),6.51(s,1H),6.23(s,1H),5.21(s,1H),4.13(m,2H),2.81(t,4H),1.79(s,6H),1.47(m,2H),1.31(t,3H),1.21(s,3H).
5.化合物Ⅱ-6的合成
以化合物10代替实施例1中的化合物4,其余所需试剂、制备方法同实施例1的步骤1-5,制备得到化合物Ⅱ-6;
1H NMR(400MHz,DMSO):δ(ppm):9.26(d,2H),9.16(m,1H),8.49(t,2H),7.34(d,1H),7.06(t,1H),6.72(t,1H),6.51(s,2H),6.36(d,1H),6.23(s,1H),5.21(s,1H),4.13(m,2H),2.81(t,4H),1.79(s,6H),1.47(m,2H),1.31(t,3H),1.16(s,6H).
6.化合物Ⅱ-7的合成
以化合物11代替实施例1中的化合物4,其余所需试剂、制备方法同实施例1的步骤1-5,制备得到化合物Ⅱ-7;
1H NMR(400MHz,DMSO):δ(ppm):9.26(d,2H),9.16(t,1H),8.49(t,2H),7.50(s,1H),7.32(d,1H),6.51(m,3H),6.23(s,1H),5.21(s,1H),4.13(m,2H),2.81(t,4H),1.79(s,6H),1.47(m,2H),1.31(t,3H),1.16(s,6H).
7.化合物Ⅱ-8的合成
以化合物12代替实施例1中的化合物4,其余所需试剂、制备方法同实施例1的步骤1-5,制备得到化合物Ⅱ-8;
1H NMR(400MHz,DMSO):δ(ppm):9.26(d,2H),9.16(t,1H),8.49(t,2H),7.87(s,1H),7.44(d,1H),6.51(m,3H),6.23(s,1H),5.21(s,1H),4.13(m,2H),2.81(t,4H),1.79(s,6H),1.47(m,2H),1.31(t,3H),1.16(s,6H).
8.化合物Ⅱ-9的合成
以化合物13代替实施例1中的化合物1,其余所需试剂、制备方法同实施例1的步骤1-5,制备得到化合物Ⅱ-9;
1H NMR(400MHz,DMSO):δ(ppm):9.26(d,2H),9.16(t,1H),8.49(t,2H),7.52(s,1H),7.41(m,3H),7.20(d,1H),6.61(d,2H),6.51(s,2H),6.23(s,1H),5.21(s,1H),4.13(m,2H),2.81(t,4H),1.79(s,6H),1.47(m,2H),1.31(t,3H),1.16(s,6H).
9.化合物Ⅱ-10的合成
以化合物14代替实施例1中的化合物2,其余所需试剂、制备方法同实施例1的步骤1-5,制备得到化合物Ⅱ-10;
1H NMR(400MHz,DMSO):δ(ppm):9.26(d,2H),9.16(t,1H),8.49(t,2H),7.52(s,1H),7.26(m,3H),6.79(d,2H),6.61(d,1H),6.51(s,2H),6.23(s,1H),6.06(m,1H),5.43(d,1H),5.31(d,1H),5.21(s,1H),4.67(d,2H),4.13(m,2H),2.84(m,1H),2.10(m,4H),1.79(s,6H),1.31(t,3H),1.16(s,6H).
10.化合物Ⅱ-11的合成
以化合物15代替实施例1中的化合物2,其余所需试剂、制备方法同实施例1的步骤1-5,制备得到化合物Ⅱ-11;
1H NMR(400MHz,DMSO):δ(ppm):9.26(d,2H),9.16(t,1H),8.49(t,2H),7.52(s,1H),7.39(d,2H),7.20(d,1H),6.86(d,2H),6.61(d,1H),6.51(s,2H),6.23(s,1H),5.21(s,1H),4.68(s,2H),4.13(m,2H),3.37(t,1H),2.84(m,1H),2.10(m,4H),1.79(s,6H),1.31(t,3H),1.16(s,6H).
11.化合物Ⅱ-12的合成
以化合物6和化合物10分别代替实施例1中的化合物1和化合物4,其余所需试剂、制备方法同实施例1的步骤1-5,制备得到化合物Ⅱ-12;
1H NMR(400MHz,DMSO):δ(ppm):9.26(d,2H),9.16(t,1H),8.49(t,2H),7.86(s,2H),7.34(d,1H),7.06(t,1H),6.72(t,1H),6.51(s,2H),6.36(d,1H),6.23(s,1H),5.21(s,1H),4.13(m,2H),3.18(m,2H),2.81(t,4H),1.79(s,6H),1.53(m,6H),1.31(t,3H),1.16(s,6H).
12.化合物Ⅱ-13的合成
以化合物7和化合物10分别代替实施例1中的化合物1和化合物4,其余所需试剂、制备方法同实施例1的步骤1-5,制备得到化合物Ⅱ-13;
1H NMR(400MHz,DMSO):δ(ppm):9.58(d,2H),9.07(m,1H),8.54(t,2H),7.34(d,1H),7.06(t,1H),6.72(t,1H),6.51(s,2H),6.36(d,1H),6.23(s,1H),5.78(m,4H),5.21(s,1H),4.63(m,1H),4.13(m,2H),3.18(t,2H),2.81(m,6H),1.79(s,6H),1.53(m,6H),1.31(t,3H),1.16(s,3H),1.05(s,3H).
13.化合物Ⅱ-14的合成
以化合物6和化合物11分别代替实施例1中的化合物1和化合物4,其余所需试剂、制备方法同实施例1的步骤1-5,制备得到化合物Ⅱ-14;
1H NMR(400MHz,DMSO):δ(ppm):9.26(d,2H),9.16(t,1H),8.49(t,2H),7.86(s,2H),7.34(d,1H),7.06(t,1H),6.51(s,2H),6.36(d,1H),6.23(s,1H),5.21(s,1H),4.13(m,2H),3.18(m,2H),2.81(t,4H),1.79(s,6H),1.53(m,6H),1.31(t,3H),1.16(s,6H).
14.化合物Ⅱ-15的合成
以化合物7和化合物11分别代替实施例1中的化合物1和化合物4,其余所需试剂、制备方法同实施例1的步骤1-5,制备得到化合物Ⅱ-15;
1H NMR(400MHz,DMSO):δ(ppm):9.58(d,2H),9.07(m,1H),8.54(t,2H),7.34(d,1H),7.06(t,1H),6.51(s,2H),6.36(d,1H),6.23(s,1H),5.78(m,4H),5.21(s,1H),4.63(m,1H),4.13(m,2H),3.18(t,2H),2.81(m,6H),1.79(s,6H),1.53(m,6H),1.31(t,3H),1.16(s,3H),1.05(s,3H).
实施例3化合物Ⅱ-1量子产率的计算
将化合物Ⅱ-1溶于DMSO中,配制成浓度为2mM的存储液,取10μL存储液加入到2mL去离子水中即可制备成测试所需的工作液。从2mM的DMSO存储液中取10μL到不同极性的溶剂中,测试其紫外吸收光谱,并用origin软件作图计算其荧光发射光谱的积分面积。通过所得数据计算荧光量子产率Φx,Φx=Φs(Fx/Fs)(As/Ax)(λexs/λexx)(nx/ns)2。
由表可以看出化合物Ⅱ-1在不同极性溶液中特征参数不同。
试验例1化合物Ⅱ-1体外光热效应及光热稳定性
共4组样品分别取3mL加到比色皿中,加盖并用密封膜封好。
1号样品是3mL去离子水;
2号样品是浓度为10μM的Ⅱ-1,具体配置方法为3mL去离子水加15μL的Ⅱ-1存储液(2mM,溶于DMSO);
3号样品是20μM的Ⅱ-1,具体配置方法为3mL去离子水加30μL的Ⅱ-1存储液;
4号样品是40μM的Ⅱ-1,具体配置方法为3mL去离子水加60μL的Ⅱ-1存储液。
5号样品是80μM的Ⅱ-1,具体配置方法为3mL去离子水加120μL的Ⅱ-1存储液。
用808nm激光器分别照射1-4组样品5分钟,同时用热成像仪每10秒记录一次温度,最后将时间-温度的数据在origin里作图,如图4。1号样品在10分钟内温度基本不变,仅上升1℃;2号样品温度从27.5℃上升至37.5℃,升温为10℃;3号样品从28.5℃上升至43.9℃,温度上升15.4℃;4号样品温度从28.5℃上升至51.7℃,升温23.2℃。
我们测试了化合物Ⅱ-1在除氧和不除氧的条件下的光热效果,如图5,结果显示,除氧之后其光热效果有了明显的提升,升温幅度增大,稳定性变好,其原因是该化合物能够将氧气转换成单线态氧,生成的单线态氧会破坏小分子共轭结构,导致其浓度降低,光热效果变差。
我们也计算了化合物Ⅱ-1的光热转换效率,如图6,4号样品的的光热转换效率为40.5%,这都说明了化合物Ⅱ-1具有极其优异的光热效应。
选取5号样品进行光热稳定性测试。图7表明5号样品在808nm激光照射5分钟后温度从26.6℃升至53.4℃,然后关闭激光器,使其自然降温冷却10分钟,然后再次打开激光器照射5分钟,自然降温,这样重复5次,在这5次光热升降温测试中5号样品每次都可以升到50℃左右,最小升温幅度为12.9℃,这表明化合物Ⅱ-1具有较好的光热稳定性。
试验例2化合物Ⅱ-1体外光动力效应
在测试前首先配制浓度为20mM的DPBF存储液,溶于DMF;浓度为2mM的ICG存储液,溶于DMSO.
共3组样品,1-3号分别取3mL加到比色皿中,加盖并用密封膜封好。
1号样品加3mL去离子水和7.5μL的DPBF存储液(20mM,溶于DMF);
2号样品加3mL去离子水,7.5μL的DPBF存储液(20mM,溶于DMF)以及15μL的ICG存储液(2mM,溶于DMSO);
3号样品加3mL去离子水,7.5μL的DPBF存储液(20mM,溶于DMF)以及15μL的Ⅱ-1存储液(2mM,溶于DMSO);
打开激光器,用808nm激光分别照射1-3号魅族样品5分钟,并且每30秒记录一次样品的紫外吸收光谱图,最后将每组样品的紫外吸收光谱图在origin软件中作图查看DPBF紫外吸收的衰减情况。如图8所示,1号样品和2号样品DPBF的紫外吸收曲线衰减程度很小,而3号样品在808nm激光照射后,DPBF的紫外吸收随时间延长出现明显的衰减。这说明样品中产生了活性氧,并且将ICG作为参比物(单线态氧产率为0.2%),经过计算,其单线态氧产率为1.82%,表明化合物Ⅱ-1具有优异的光动力效果。
试验3细胞成像实验
将细胞核染料Hoechst33342(100nM)、溶酶体染料Lyso-Green(75nM)和Ⅰ-1(10μM)加入到细胞培养基中进行细胞染色,30分钟后,用PBS冲洗两遍后在共聚焦荧光显微镜下观察拍照,如图9所示,化合物Ⅱ-1进入细胞后,与溶酶体部分几乎完全重合,说明化合物Ⅰ-1能有效的被细胞摄入。
试验4细胞内光毒性和暗毒性测试
将HeLa细胞培养在96孔板中,每个孔1×104细胞,24h后向每个孔中加入不同浓度的Ⅰ-1(0.2μM~100μM),检测暗毒性的细胞孔板在培养箱中放置24小时后,加入活细胞染料Calcein-AM和死细胞染料EthD-I染色30分钟。随后在荧光显微镜下观察,发现细胞几乎全部存活,证明化合物Ⅱ-1本身的毒性极小。
如图10所示,将检测光毒性的每个细胞孔板在808nm激光器下照射6分钟,激光照射完后,在荧光显微镜下观察拍照,发现当浓度大于15μM时细胞死亡率接近100%,这表明化合物Ⅱ-1具有良好的光毒性,对肿瘤细胞具有良好的杀伤效果。
如图11所示,检测细胞内活性氧生成的细胞孔板分为两组,使用DCFH-DA作为细胞内活性氧检测剂,分别加入5μM的DCFH-DA;5μM的DCFH-DA和40μM的化合物Ⅱ-1。用808nm激光照射6分钟,然后在荧光显微镜下拍照,加入5μM的DCFH-DA和40μM化合物Ⅱ-1的细胞孔板在激光照射后荧光强度明显高于对照组。对比表明,化合物Ⅱ-1被Hela细胞吞噬后经过808nm激光照射,能显著生成活性氧,进一步说明化合物Ⅱ-1具有优异的光动力效果。
试验例5小鼠肿瘤光声成像测试
首先构建小鼠肿瘤模型。向6周龄雌性裸鼠胸前注射4×106 4T1细胞,等肿瘤体积生长到75mm3,通过尾静脉注射将200μg化合物Ⅱ-1注射进小鼠体内。在不同的时间点用三维光声层析成像系统监测。如图11所示,注射后,2-8小时内小鼠肿瘤部位荧光随时间增加逐渐增强。如图13柱状图所示,随时间的延长,在24小时内,肿瘤部位一直有光声信号。此实例证明化合物Ⅱ-1有优异的光声信号。而且,在24小时内裸鼠身体没有发生痉挛、抽搐等异常,证明化合物Ⅱ-1毒性小,安全性较高。
试验例6小鼠肿瘤荧光成像实验
首先构建小鼠肿瘤模型。向6周龄雌性裸鼠胸前注射4×106 4T1细胞,等肿瘤体积生长到75mm3,通过尾静脉注射将200μg化合物Ⅱ-1注射进小鼠体内。注射后,在不同的时间点用活体成像仪监测。96小时后,对其进行解剖,将心、肝、脾、肺、肾、肿瘤进行荧光成像,如图14和图15所示,发现肿瘤部位荧光较强,肝和肾中也有一定强度的荧光,肝肾属于代谢器官,说明药物可以被良好的代谢。由此证明化合物Ⅱ-1具有一定的靶向性。而且,在24小时内裸鼠身体没有发生痉挛、抽搐等异常,证明化合物Ⅱ-1毒性小,安全性较高。
试验例7小鼠体内光热治疗中的光热成像实验
实验组小鼠尾静脉注射200μL化合物Ⅱ-1(200μg),用808nm激光器照射小鼠肿瘤部位10分钟,同时用光热成像仪持续拍照。从图16和图17可以看出,肿瘤部位温度可以上升到59.1℃,并且肿瘤周围组织温度并没有升高,说明化合物Ⅱ-1在光治疗中具有对肿瘤附件组织损伤低的优点。
试验例8小鼠体内光治疗实验
将裸鼠分为4组。第4组裸鼠注射生理盐水,不加激光照射;第3组裸鼠注射生理盐水并使用808nm激光照射10分钟;第2组裸鼠注射200μL化合物Ⅱ-1(200μg),不加激光照射;第1组裸鼠将200μL化合物Ⅱ-1(200μg)通过尾静脉注射进小鼠体内,用808nm激光器照射小鼠肿瘤部位10分钟。每天用游标卡尺测量每组裸鼠的肿瘤体积,持续记录20天。
如图18,第1组激光照射进行联合光疗后的裸鼠,治疗前肿瘤体积为50mm3左右,对其进行治疗后,第二天肿瘤破溃,随着时间增长,未见明显的肿瘤生长,并且肿瘤破溃处开始愈合,第18天时破溃处yi3完全愈合,有一个小伤疤。肿瘤体积变化情况如图19,实验组(第1组)小鼠在激光照射后肿瘤消除,而对照组(第2、3、4组)小鼠肿瘤的体积持续上升。小鼠体重变化情况如图20,实验组和对照组小鼠体重皆未有异常变化,未见Ⅱ-1的明显副作用。如图21,将实验20天后的实验组小鼠进行解剖,将肿瘤、心、肝、脾、肺、肾进行切片H&E染色观察。发现肿瘤细胞发生凋亡,其余器官未见明显损伤。证明化合物Ⅱ-1有优异的光治疗能力,并且不损伤内脏,副作用小,相对安全可靠。
以上实验说明化合物Ⅱ-1在808nm激光照射下,产生的光热和光动力效果对肿瘤具有优异的杀伤作用,且安全性较高,在临床癌症光疗中有着广阔的应用前景。经验证明本发明的其他化合物也有类似的光治疗效果。
试验例9化合物Ⅱ-1在小鼠体内安全性实验
选用10只雌性裸鼠,5只通过尾静脉注射200μL化合物Ⅱ-1(200μg),另外5只尾静脉注射生理盐水,24小时后取小鼠的血液进行血常规和肝功能的检测。如图22所示,红细胞分布宽度,平均血小板体积和淋巴细胞数目这些血常规指标均在正常范围之内,白蛋白、丙氨酸转氨酶、碱性磷酸酶和血糖这些肝功能指标均在正常范围之内。结果表明,化合物Ⅱ-1有较高的生物安全性,短期内不损伤肝脏,相对安全可靠。
上述说明仅为本发明的优选实例,并非时对本发明的限制,尽管参照前述实施例对本发明进行了详细的说明,对于本领域技术人员来说,其依然可以对前述各实例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改型等,均应包含在本发明的保护范围之内。
Claims (6)
1.一种用于抗菌和/或肿瘤协同光疗的正交电荷转移阳离子有机小分子化合物,所述化合物具有式(Ⅳ)所示结构或其异构体、药学上可接受的盐、水合物或溶剂化物等水溶性的分子结构:
在上述式(Ⅳ)中:
X2选自于N、O、S或-CR22R22’-;
Y3、Y4、Y5各自独立地选自于H、羟基、卤素原子、取代或非取代的氨基合烃氧基;
t1、t2、t3各自独立地选自0-5的整数;
R14、R14’、R15各自独立地选自于-CN,-CF3,F,-SO2CF3,-NO2,-COOEt,-SO2ph,
R16为-(CH2)m-、
m为0-5的整数;
R17和R18共同形成如下之一的连接:
或者R17、R18和X2共同形成如下连接/>其中,Ra、Rb、Rc、Rd、Re、Rf、Rg各自独立地选自于H、卤素原子、取代或非取代的烃基、取代或非取代的羧基、取代或非取代的羟基和取代或非取代的氨基;
R19、R19’、R20、R22和R22’各自独立地选自于H、卤素原子、取代或非取代的烃基、取代或非取代的环烃基、取代或非取代的芳基、取代或非取代的杂芳基、取代或非取代的杂环基、取代或非取代的醇基、取代或非取代的醚基、取代或非取代的醛基、取代或非取代的羧基、取代或非取代的酰氨基、取代或非取代的酯基和取代或非取代的氨基;
R21选自于H、Cl、Br、I等卤素原子;
R23、R23’各自独立地选自于H、取代或非取代的烃基、取代或非取代的环烃基、取代或非取代的芳基、取代或非取代的杂芳基、取代或非取代的取代或非取代的杂环基、取代或非取代的醇基、取代或非取代的醚基、取代或非取代的醛基、取代或非取代的羧基、取代或非取代的酰氨基、取代或非取代的酯基和取代或非取代的氨基。
2.根据权利要求1所述的化合物,其特征在于,式(Ⅳ)中,所述t1和t2均为1,t3为0;
所述Y3和Y5均为H,Y4为
所述R21为H、Cl、Br、I;
所述R14,R14’均为CN,R15为-CN或
3.根据权利要求1所述的化合物,其特征在于,所属化合物Ⅱ-1、Ⅱ-2、Ⅱ-3、Ⅱ-4、Ⅱ-5、Ⅱ-6、Ⅱ-7、Ⅱ-8、Ⅱ-9、Ⅱ-10、Ⅱ-11、Ⅱ-12、Ⅱ-13、Ⅱ-14、Ⅱ-15、Ⅱ-16、Ⅱ-17、Ⅱ-18、Ⅱ-19、Ⅱ-20、Ⅱ-21、Ⅱ-22、Ⅱ-23、Ⅱ-24、Ⅱ-25、Ⅱ-26、Ⅱ-27、Ⅱ-28、Ⅱ-29、Ⅱ-30、Ⅱ-31、Ⅱ-32、Ⅱ-33、Ⅱ-34、Ⅱ-35、Ⅱ-36、Ⅱ-37、Ⅱ-38、Ⅱ-39、Ⅱ-40、Ⅱ-41、Ⅱ-42、Ⅱ-43、Ⅱ-44、Ⅱ-45、Ⅱ-46、Ⅱ-47、Ⅱ-48、Ⅱ-49或Ⅱ-50。
4.一种药物组合物,其特征在于,包括权利要求1-3任一项所述的化合物,和药学上可接受的载体。
5.权利要求1-3任一项所述的化合物具有正交电荷转移特征、在制备用于肿瘤和/或抗菌光热光动力协同光疗和/或诊断药物中的应用。
6.根据权利要求5所述的应用,其特征在于,所述癌症包括食道癌、非小细胞肺癌、胆道癌、头颈癌、巴雷特食管炎、膀胱癌、结肠直肠癌、胰腺癌、卵巢癌、前列腺癌、脑肿瘤、乳腺癌或皮肤癌;所述细菌感染疾病包括葡萄球菌性烫伤样皮肤综合征、猩红热、脓疱病、毛囊炎、疖、痈、蜂窝织炎、丹毒及麻风,所述光治疗药物为光热治疗药物、光动力治疗药物,光热光动力协同治疗药物、光声治疗药物。
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