CN112174872A - 荧光及光声成像剂吲哚苯醌类衍生物及其用途 - Google Patents
荧光及光声成像剂吲哚苯醌类衍生物及其用途 Download PDFInfo
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
一种吲哚苯醌类化合物，结构如式(I)和(II)所示：其中R1、R2、R3可表示相同或不同的基团，可以为H、烷基、烷氧基、卤素、脂肪环、芳香环、杂环、羧基、羟基、氨基、巯基以及碳酰化、硫酰化、磷酰化等酰化衍生物及一系列取代基衍生物，X为氯、溴、碘、羟基、巯基等，Y为氧、硫、硒、NH、N－。本发明化合物的性质稳定，通过药理实验证明具有良好的抗肿瘤活性。同时，该吲哚苯醌类化合物具有多环共轭的母核结构，其吸收波长较大且在近红外680nm处有较强的吸收，可在小动物光声成像仪中产生清晰良好的检测信号，并且能够准确定量地检测该类化合物在小动物的瘤内及全身的分布以及荧光成像。可作为荧光及光声显像剂。
Description
[技术领域]本发明涉及医药及显像技术领域，是一类吲哚苯醌类化合物，及该类化合物的用途。
[背景技术]
醌类化合物在天然产物、药物分子、染料和指示剂化合物中应用较多，尤其在植物中多见。天然药物如大黄、首乌、虎杖等有效成分中都包含醌类结构，醌类化合物具有诸多临床应用，例如泻下、利尿、抗菌、抗病毒、抗肿瘤等等，是一类具有良好生物活性和应用前景的化学结构。如唇形科鼠尾草属的红根草的根中，存在的有效成分红根草邻醌(saprorthoquinone)具有抗菌、抗肿瘤的作用，能明显有效地抑制白血病P388细胞，对革兰氏阳性菌、金黄色葡萄球菌都具有较强的抑制作用。
纵观文献，通过对萘醌、菲醌及蒽醌类化合物的拓展，可以发现较多天然或人工合成具有抗肿瘤细胞增殖活性的化合物，均具有包含醌类结构在内的三环结构模式，例如米托蒽醌(Mitoxantrone)，阿霉素(Doxorubicin)，匹杉琼(Pixantrone)等。
醌类衍生物表现出良好抗肿瘤生物活性的同时，也发现“2-苯基萘型”母核结构同样多表现出抗肿瘤活性，例如喜树碱(Camptothecin，CPT)及其衍生物10-羟基喜树碱(10-Hydroxy camptothecin，OPT)、伊立替康(Irinotecan)、拓扑替康(Topotecan)；另外还有棕霉素(Streptonigrin)(图1)等。
不仅如此，吲哚醌也是许多具有生物活性的天然产物如萜醌的核心结构(图2)。Kiriyama课题组证实了Asterriquinone(ASQ)(图2)能够通过嵌入DNA中，导致细胞周期G1期停滞，并进一步致使细胞凋亡，表明该类化合物的羟基苯醌部分能够与DNA有效结合。另外，双吲哚基苯醌还表现出一系列针对肿瘤和糖尿病的生物活性。Arai课题组曾报道过一类羟基苯醌衍生物，化合物2,5-二羟基-6-[2-(3-甲基-正丁基)吲哚-3-基]-3-(2-苯基吲哚-3-基)-1,4-醌(a)和2,5-二羟基-6-(2-甲基吲哚-3-基)-3-(2-苯基吲哚-3-基)-1,4-醌(b)(图2)，能够有效抑制皮肤鳞状细胞株A431的增殖。然而，吲哚苯醌结构与抗肿瘤活性的关系仍然仅处于探索阶段，吲哚基取代的卤代苯醌的细胞毒性及生物活性很少被研究。因此，选择双取代吲哚苯醌，作为适宜的抗肿瘤研究的骨架结构，有望获得新的抗肿瘤候选化合物。同时，由于该类衍生物为多环共轭的母核结构，其吸收波长较大且在近红外680nm处有较强的吸收，可用于荧光显像以及于小动物光声成像仪中产生清晰良好的检测信号，并能够准确地检测在小动物的瘤内及全身的分布。可实现活体动物肿瘤显像以及药物体内代谢动态分析，为肿瘤药物的研发建立基础。
本发明通过合成一系列吲哚苯醌类新结构化合物，并对其进行了抗肿瘤活性筛选，证明该类吲哚苯醌类化合物具有抗肿瘤活性。
[发明内容]
本发明目的在于合成一系列荧光及光声成像剂吲哚苯醌类衍生物，并通过实验筛选提供具有良好的抗肿瘤活性的药物，可将其应用癌症治疗和活体动物显像实验研究。
本发明提供了一种吲哚苯醌类化合物，结构如式(I)所示:
其中R1、R2、R3可表示相同或不同的基团，可以为H、烷基、烷氧基、卤素、脂肪环、芳香环、杂环、羧基、羟基、氨基、巯基以及碳酰化、硫酰化、磷酰化等酰化衍生物及一系列取代基衍生物，X为氯、溴、碘、羟基、巯基等，Y为氧、硫、硒、NH、N－。
进一步的，R1、R2、R3可表示相同或不同的基团，可以为H、烷基、烷氧基、卤素、脂肪环、芳香环、杂环、羧基、羟基、氨基、巯基以及碳酰化、硫酰化、磷酰化等酰化衍生物及一系列取代基，X为氯、溴、碘、羟基、巯基等等元素，Y为氧、硫、NH、N－，结构式如(II)所示：
更进一步的，R1、R2、R3表示相同或不同的基团，可以为H、烷基、烷氧基、卤素、脂肪环、芳香环、杂环、羧基、羟基、氨基、巯基以及碳酰化、硫酰化、磷酰化等酰化衍生物及一系列取代基，吲哚环可改为五元单杂环和六元单杂环。
经初步的体外肿瘤细胞生长抑制实验筛选，发现在上述通式(I)(II)的化合物中，X为氯和溴、Y为氧原子，具有较好的抗肿瘤活性(如式(III)所示)，本专利以其作为具体实例化合物之一。
综上所述，本发明为一类吲哚苯醌类化合物及该类化合物的显像用途。
[附图说明]
说明书附图1(基于“2-苯基萘型”的抗肿瘤化合物)
如图1所示，列举具有“2-苯基萘型”母核结构的化合物具有抗肿瘤活性的实例。
说明书附图2(以吲哚醌为母核的萜醌衍生物及吲哚羟基苯醌衍生物)
如图2所示，列举已成为药物的吲哚醌衍生物实例。
说明书附图3(药物在荷瘤小鼠肿瘤内的MSOT显像)
如图3所示，药物在荷瘤小鼠肿瘤内的MSOT显像，表明化合物III的吸收代谢变化随给药时间变化而变化。A为给药前光声成像，B为给药后0.5h光声成像，C为给药后2h光声成像，D为给药后6h的光声成像。
说明书附图4(药物在荷瘤小鼠肿瘤内及全身)
如图4所示，药物在荷瘤小鼠肿瘤内及全身药物分布结果，6小时已明显代谢分布于肝脏，给药24小时，48小时仍能监测到化合物III，证明其具有缓释作用。a为给药后6h荷瘤裸鼠药物分布于肝脏显像,b为给药后24h荷瘤裸鼠全身药物分布的MSOT显像。
说明书附图5(药物在肿瘤组织内的含量随时间变化的定量分析)
如图5所示，药物在肿瘤组织内的含量随时间变化的定量分析图，给药6小时后，药物慢慢代谢，持续时间至少24小时以上。
说明书附图6(荷瘤小鼠体内分布及代谢)
如图6所示，荷瘤小鼠体内分布及代谢荧光显像图，除在肿瘤部位明显可观察到外(图6，a)，在卵巢也显像清晰，说明化合物III可分布于卵巢(图6，b)。
[具体实施方式]
以下通过具体实施方式的实例再对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。在不脱离本发明上述技术思想情况下，根据本领域普通技术知识和惯用手段做出的各种替换或变更，均包括在本发明的范围内。
实施例1.体外肿瘤细胞抑制实验
实验方法：
将肺癌细胞系A549、人乳腺癌细胞MDA-BM-231和宫颈癌细胞系Hela常规地补充在有10％FBS,4mM谷氨酰胺，1mM丙酮酸钠,100IU/mL青霉素,100μg/mL链霉素和0.25μg/mL两性霉素的培养基里,置于37℃,5％CO2的培养箱内培养,以细胞每孔5×103的密度接种在96孔板中培养24h,分别按不同剂量浓度加入阳性对照药苯达莫司汀、伏立诺他及合成的目标化合物IV-IX,孵育72h后加入20mL刃天青钠处理2h，使用Victor微量滴定荧光计(Perkin-Elmer，USA)在560nm(激发),590nm(发射)记录荧光。IC50为与用最大量DMSO(0.25％)处理的细胞相比。
测试结果
各化合物抑制活性列表
实施例2.吲哚苯醌类化合物的光声成像
化合物III在波长680nm处有较强的吸收，小动物光声成像仪能够准确清晰地检测到代谢化合物III在裸鼠肿瘤及全身的代谢情况并进行定量。因此，作者于第7天，对已给药3次的注射组a(III/生理盐水)进行小动物光声成像，注射组a的测试时间点分别为给药前，给药后0.5h，给药后2h，给药后6h(图3)，给药后24h(图4)，给药48h后注射组a裸鼠的肿瘤组织内部依然有少量化合物III的存留。给药0.5h后，肿瘤组织内药物含量提高；给药后6h化合物III依然处于吸收的状态，其含量不断提高，但裸鼠除肿瘤外的其他部位，例如肝、肾等代谢器官也监测到化合物III，证明已经有较多化合物III被吸收代谢。给药后24h，肿瘤组织内的化合物III大幅减少，代谢器官处的化合物III依然存在(图3，图4)。对注射组a裸鼠肿瘤部位的化合物含量进行定量计算，结果如图5所示。
实施例3.吲哚苯醌类化合物的荧光成像
从荷鼠源乳腺瘤小鼠实验可知48小时肿瘤组织内部依然有化合物III留存(图6，a)，同时观察到经肝肾代谢过程。同时，观察到化合物III在卵巢有蓄积，有望成为治疗卵巢癌的候选化合物(图6，b)。
Claims (5)
1.一种荧光及光声成像剂吲哚苯醌类化合物，结构如式(I)所示
其特征在于R1、R2、R3可表示相同或不同的基团，可以为H、烷基、烷氧基、卤素、脂肪环、芳香环、杂环、羧基、羟基、氨基、巯基以及碳酰化、硫酰化、磷酰化等酰化衍生物及一系列取代基衍生物，X为氯、溴、碘、羟基、巯基等，Y为氧、硫、硒、NH、N－。
2.如权利要求1所述吲哚苯醌类化合物，其特征在于2，6-双吲哚取代以及R1、R2、R3可表示相同或不同的基团，可以为H、烷基、烷氧基、卤素、脂肪环、芳香环、杂环、羧基、羟基、氨基、巯基以及碳酰化、硫酰化、磷酰化等酰化衍生物及一系列取代基衍生物，X为氯、溴、碘、羟基、巯基等，Y为氧、硫、硒、NH、N－，结构式如(II)所示：
3.如权利要求1和2所述吲哚苯醌类化合物，其特征在于多环共轭的母核结构，其吸收波长较大且在近红外680nm处有较强的吸收，可以于小动物光声成像仪中产生清晰良好的检测信号，并且能够准确定量地检测该类化合物在小动物的瘤内及全身的分布以及荧光成像。
4.如权利要求1和2所述吲哚苯醌类化合物，其特征在于均可制成盐酸盐、硫酸盐、甲磺酸盐以及五元和六元单杂环等系列衍生物用于改善其活性。
5.权利要求1和2所述吲哚苯醌类化合物，其特征在于用于癌症治疗。
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| WO2001021589A2 (en) * | 1999-09-24 | 2001-03-29 | Sugen, Inc. | Mono- and bis-indolylquinones and prophylactic and therapeutic uses thereof |
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