CN114671751B - 一种邻羟基苯基酮类化合物及其制备方法和应用 - Google Patents
一种邻羟基苯基酮类化合物及其制备方法和应用 Download PDFInfo
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- CN114671751B CN114671751B CN202210193088.8A CN202210193088A CN114671751B CN 114671751 B CN114671751 B CN 114671751B CN 202210193088 A CN202210193088 A CN 202210193088A CN 114671751 B CN114671751 B CN 114671751B
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Abstract
本发明公开了一种邻羟基苯基酮类化合物及其制备方法和应用,属于医药技术领域,具体提供了一种邻羟基苯基酮类化合物或其异构体或其药学上可接受的盐或其酯或其溶剂合物或其前药对醛缩酶B的调控作用,从而可以用于预防或治疗肿瘤,如结直肠癌、肝癌、胃癌、肾透明细胞癌等,以及化疗药物耐药性、高血糖等。
Description
技术领域
本发明涉及医药技术领域,具体涉及到一种邻羟基苯基酮类化合物及其制备方法和应用。
背景技术
细胞的能量供应主要通过氧化磷酸化和糖酵解两种方式,正常细胞在有氧条件下主要通过氧化磷酸化获取能量,无氧条件下才会选择糖酵解进行糖代谢和能量摄取,但在肿瘤细胞中,即使是有氧环境,细胞依然会采用糖酵解的方式进行糖代谢和能量摄取,肿瘤这一代谢异常现象被称为瓦博格效应(Warburg效应)。Warburg效应不仅影响ATP的快速合成,还参与肿瘤细胞其他的生物合成,如氨基酸合成,脂肪酸合成等。
醛缩酶(Aldolase,ALDO)是一个在糖酵解通路中起着重要作用的酶,参与糖酵解途径的第四步,主要负责将果糖1,6-二磷酸(fructose-1,6-biphosphate,FBP)转化为三磷酸甘油醛(glyceraldehyde-3-phosohate,G3P)和磷酸二羟丙酮(dihydroxyacetonephosphate,DHAP)或其逆反应。此步反应产生的糖酵解中间产物对肿瘤细胞是有益的。哺乳动物醛缩酶由三种不同基因编码三种亚型:ALDOA、ALDOB和ALDOC。其中,ALDOB又称为肝型醛缩酶,主要在肝脏和肾脏中表达。ALDOB不仅可以催化一分子FBP转化为G3P和DHAP,还可以逆向催化一分子G3P和一分子DHAP生成一分子FBP,促进糖异生和磷酸戊糖途径。ALDOB不仅是糖酵解过程中的重要酶,也是值得关注的肿瘤治疗靶点。
在结直肠癌中,通过癌症病人组织的微阵列分析发现,ALDOB过表达的癌症病人有更低的存活率,ALDOB的上调通过调控上皮-间质转化(epithelial-mesenchymaltransition,EMT)促进结直肠癌转移。在结肠癌肝转移中,转移性细胞通过转录调节因子GATA6上调ALDOB的表达,进而引发结肠癌细胞在新的微环境下的代谢重编程,为肿瘤细胞在新环境中的快速增殖所需的中心碳代谢提供燃料。
在肝癌中,ALDOB下调与肝癌预后不良密切相关,ALDOB在肝癌组织的缺乏会促进葡萄糖代谢,促进肿瘤生长,其主要是通过导致ALDOB/Akt/PP2A蛋白复合物稳态被破坏,进而激活AKT,促进肝癌的发展。此外,研究发现ALDOB可以通过上调Ten-Eleven转运基因1(ten-eleven translocation 1,TET1)抑制肝癌细胞的侵袭迁移和小鼠体内肿瘤细胞的肺转移和肝内转移。在蛋白互作方面发现ALDOB可以通过直接与G6PD结合并抑制其活性,抑制磷酸戊糖途径,肝脏ALDOB通过在肝癌的葡萄糖代谢中起代谢转换的作用而达到抑制肝癌的效果,而ALDOB的下调则可使G6PD从ALDOB–G6PD–p53复合物中脱离下来恢复G6PD活性以增强PPP通量,来维持肿瘤的快速生长,从而重新编程了中心碳代谢。
在肾透明细胞癌(clear cell renal cell carcinoma,ccRCC)中,ALDOB下调和FBP的蓄积对癌症发展有促进作用。肾透明细胞癌细胞通过下调ALDOB维持高水平的FBP,与正常肾组织相比,肾透明细胞癌组织中的FBP增加了三倍;FBP通过抑制NADPH氧化酶亚型NOX4的活性,部分调控氧化还原状态。ALDOB的下调和FBP的积累,通过抑制氧化应激促进ccRCC的生长。并且,ALDOB下调可以降低毒性甲基乙二醛的产生,这对癌细胞有利。此外,越来越多的证据表明,抑制氧化应激可以保护癌细胞免受化疗损伤;将ALDOB异位表达的Caki-1细胞和对照组细胞植入裸鼠体内,并给予低剂量紫杉醇;与对照组细胞相比,ALDOB的表达明显延缓了肿瘤的生长。ALDOB可能作为肾透明细胞癌和紫杉醇等化疗药物耐药性的潜在治疗靶点。
在胃癌中,ALDOB可能是其预后生物标志物和治疗靶点。根据微阵列分析,与邻近的非肿瘤组织相比,ALDOB在胃癌组织中显著下调(超过7倍)。采用QRT-PCR和免疫组织化学方法检测其差异表达,结果表明,在转录和翻译水平上,胃癌组织上的ALDOB均明显低于非肿瘤组织。此外,还发现ALDOB的表达与胃癌患者的肿瘤浸润深度、淋巴结转移、远转移、TNM分期呈负相关。此外,ALDOB低表达的患者的长期生存时间要短于高表达的患者。这提示着ALDOB可能是胃癌的预后生物标志物和治疗靶点。
在高血糖症中,人类胰岛中ALDOB的表达与胰岛素分泌呈负相关,人类胰岛β细胞ALDOB表达水平上调,并可能抑制胰岛素分泌。从器官捐赠者得到的人类胰岛长期暴露于高糖,其ALDOB蛋白水平会上调。并且,成熟β细胞中ALDOB的长期上调可能会减少葡萄糖代谢中ATP的产生,这种效应可能会抑制葡萄糖诱导的胰岛素分泌(glucose-inducedinsulinsecretion,GIIS)。正常血糖和高血糖患者相比,ALDOB和肥胖相关基因FAIM2的基因表达差异明显,并且这两种基因的mRNA水平与胰岛素分泌呈负相关、与糖化血红蛋白呈正相关。ALDOB可能作为高血糖症的潜在治疗靶点。
以上这些结果证实ALDOB的功能变化是众多疾病的病理机制,ALDOB调控剂已成为以上相关疾病的治疗靶点。因此,以ALDOB为靶点的药物发现已成为相关领域的研究热点。现已发现了几种与其他醛缩酶亚型有关的候选化合物。自然界的醛缩酶根据催化过程是否需要金属离子参与分为两大类,其中主要存在于动物及高等植物中的为Ⅰ型醛缩酶,主要存在于细菌及真菌中的为Ⅱ型醛缩酶。Ⅱ型醛缩酶多作为抗真菌药物的靶点,目前发现的此靶点的抑制剂大部分为FBP或DHAP类似物,但它们结构中含有高极性的磷酸基团而很难穿透细胞膜,难以表现出体内活性。因此,研发新的ALDOB调控剂对于以上相关疾病的治疗具有重要意义。
发明内容
针对现有技术的不足,本发明的目的是提供一种ALDOB调控剂—邻羟基苯基酮类化合物及其制备方法和应用。
为达上述目的,本发明采取如下的技术方案:
本发明提供一种邻羟基苯基酮类化合物,其化学通式如式(I)所示:
其中,R1为氢原子、羟基、卤素、6~14元芳基、C1-10烷酸基、C1-10烷基、C3-10环烷基、氰基、氨基、硝基、-O-(C1-6烷基)、-NH-6~14元芳基、-C(O)1-10-6~14元芳基或-NHSO2-6~14元芳基;
R2为氢原子、羟基、卤素、苄基、6~14元芳基、C1-10烷基、C3-10环烷基、氰基、氨基、硝基、-O-(C1-6烷基)、-NH-6~14元芳基、-C(O)1-10-6~14元芳基或-NHSO2-6~14元芳基。
进一步地,R1为氢原子、6~14元芳基、C1-10烷酸基或C1-6烷基。
进一步地,R2选自:氢原子、羟基、氨基、苯基或甲氧基。
进一步地,邻羟基苯基酮类化合物的优选结构式如下所示:
更优选为:
最优选为:
本发明还提供上述邻羟基苯基酮类化合物的制备方法,包括以下步骤:将化合物A和化合物B进行酰基化反应,分离纯化,制得邻羟基苯基酮类化合物;
化合物A的结构通式如下所示:
其中,R2为氢原子、羟基、卤素、苄基、6~14元芳基、C1-10烷基、C3-10环烷基、氰基、氨基、硝基、-O-(C1-6烷基)、-NH-6~14元芳基、-C(O)1-10-6~14元芳基或-NHSO2-6~14元芳基;优选为氢原子、羟基、氨基、苯基或甲氧基等;
化合物B的结构通式如下所示:
其中,R1为氢原子、羟基、卤素、6~14元芳基、C1-10烷酸基、C1-10烷基、C3-10环烷基、氰基、氨基、硝基、-O-(C1-6烷基)、-NH-6~14元芳基、-C(O)1-10-6~14元芳基或-NHSO2-6~14元芳基;优选为氢原子、6~14元芳基、C1-10烷酸基或C1-6烷基。
进一步地,上述邻羟基苯基酮类化合物的制备方法,具体包括以下步骤:将化合物A和化合物B溶于溶剂中,加入三氯化铝,25~45℃下搅拌反应1~5h,反应结束后对反应体系进行分离纯化,制得邻羟基苯基酮类化合物;其中,化合物A、化合物B和三氯化铝的摩尔比为1:1~2:0.05~0.2。
进一步地,溶剂包括N,N-二甲基甲酰胺、二甲亚砜、1,3-二甲基-2-咪唑啉酮、乙腈、甲醇、二氯甲烷、氯仿、乙酸乙酯和四氢呋喃中的至少一种;优选为二氯甲烷。
进一步地,化合物A、化合物B和三氯化铝的摩尔比为1:1.1:0.1。
本发明还提供上述邻羟基苯基酮类化合物或其异构体或其药学上可接受的盐或其酯或其溶剂合物或其前药在用作和/或制备ALDOB调控剂的药物中的应用。
本发明还提供一种ALDOB调控剂,包括上述邻羟基苯基酮类化合物或其异构体或其药学上可接受的盐或其酯或其溶剂合物或其前药。
本发明还提供上述邻羟基苯基酮类化合物或其异构体或其药学上可接受的盐或其酯或其溶剂合物或其前药在制备用于预防或治疗肿瘤、高血糖、提高化疗药物耐药性等的药物中的应用。
进一步地,上述肿瘤包括直肠癌、肝癌、胃癌、肾透明细胞癌等;其中,肝癌包括但不限于:肝细胞癌、肝内胆管癌、肝细胞癌-肝内胆管癌混合型肝癌。
本发明还提供一种药物组合物,包括上述邻羟基苯基酮类化合物或其异构体或其药学上可接受的盐或其酯或其溶剂合物或其前药以及药学上可接受的辅料。
进一步地,上述药物组合物的剂型可以为片剂、丸剂、胶囊剂、颗粒剂、散剂、糖浆剂、膜剂、软膏剂、栓剂、混悬剂、注射剂、脂质体、凝胶剂、气(粉)雾剂、喷雾剂。
本发明中的药物组合物可以用本领域已知的方式配制成临床或药学上可接受的任一剂型,以口服、舌下、胃肠外、直肠、皮肤或经肺给药等方式用于需要预防或治疗的患者。用于口服给药时,可制成片剂、丸剂、胶囊剂、颗粒剂、散剂、膜剂、糖浆剂、混悬剂。用于舌下给药时,可制成片剂、丸剂、颗粒剂、膜剂、散剂。用于胃肠外给药时,可制成注射剂,包括注射液、注射用无菌粉末、注射用浓溶液、脂质体注射液等。用于直肠给药时,可制成栓剂。用于皮肤给药时,可制成软膏剂、凝胶剂、膜剂等。用于经肺给药时,可制成气(粉)雾剂、喷雾剂等。
本发明上述的“卤素”是指作为取代基的氟、氯、溴或碘。当卤原子作为取代基的时候,其取代的数目为一个以上,包括1个、2个或3个等。
本发明上述的“6~14元芳基”是指环原子为6~14元碳原子的环状芳香基团,包括6~8元单环芳基和8~14元稠环芳基。6~8元单环芳基是指全部不饱和的芳基,8~14元稠环芳基是指由两个或两个以上环状结构彼此共用两个相邻的碳原子所形成的,至少有一个环全部不饱和的芳香环的环状基团。所述芳基可任选地被1~5个适当取代基,如羟基、硝基、磺酸基、卤素、氰基、三氟甲基、三氟甲氧基或二氟甲氧基取代。
本发明上述的“C3-10环烷基”是含有3至10个碳原子的由单、双或三环构成的完全氢化的非芳香族环。因此,环烷基可为典型地含有3至7个环原子的单环。实例包括但不限于环丙基、环丁基、环戊基及环己基。可替代地,2或3个环可一起稠合,诸如双环癸烷基和十氢萘基。同时,“环烷基”也包括桥联双环烷基系统,诸如但不限于双环[2.2.1]庚烷和双环[1.1.1]戊烷。所述环烷基可任选地被1至5个适当取代基,如羟基、硝基、磺酸基、卤素、氰基、三氟甲基、三氟甲氧基或二氟甲氧基取代。
本发明所述的“盐”是指药学上可接受的盐,“药学上可接受的盐”指通式(I)的化合物与酸或碱结合而制备的盐,所述酸的阴离子或所述碱的阳离子通常被认为适于人体使用。所述盐通常通过适当的无机酸或有机酸与游离碱反应而制备。包括衍生自无机酸(如氢氯酸、氢溴酸、氢氟酸、硼酸、氟硼酸、磷酸、偏磷酸、硝酸、碳酸、磺酸及硫酸)和有机酸(诸如乙酸、苯磺酸、苯甲酸、柠檬酸、乙磺酸、反丁烯二酸、葡萄糖酸、乙醇酸、2-羟乙磺酸、乳酸、乳糖酸、顺丁烯二酸、苹果酸、甲磺酸、三氟甲磺酸、丁二酸、甲苯磺酸、酒石酸及三氟乙酸)的盐。适当的有机酸通常包括例如脂族、环脂族、芳香族、芳脂族、杂环、羧酸及磺酸类有机酸。
适当的有机酸盐的特定实例包括乙酸盐、三氟乙酸盐、甲酸盐、丙酸盐、丁二酸盐、乙醇酸盐、葡萄糖酸盐、二葡萄糖酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、葡萄糖醛酸盐、顺丁烯二酸盐、反丁烯二酸盐、丙酮酸盐、天冬氨酸盐、谷氨酸盐、苯甲酸盐、邻氨基苯甲酸盐、硬脂酸盐、水杨酸盐、对羟基苯甲酸盐、苯乙酸盐、扁桃酸盐、双羟萘酸盐(扑酸盐)、甲磺酸盐、乙磺酸盐、苯磺酸盐、泛酸盐、甲苯磺酸盐、2-羟基乙磺酸盐、对氨基苯磺酸盐、环己基氨基磺酸盐、海藻酸盐、β-羟基丁酸盐、粘酸盐、半乳糖醛酸盐、己二酸盐、藻酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、十二烷基硫酸盐、葡糖庚酸盐、甘油磷酸盐、庚酸盐、己酸盐、烟酸盐、2-萘磺酸盐、草酸盐、果胶酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、硫氰酸盐及十一酸盐。
当本发明的化合物带有酸性基团时,其适当的药学上可接受的盐可包括碱金属盐(如钠盐或钾盐)、碱土金属盐(如钙盐或镁盐)及与适当的有机配体形成的盐(如季铵盐)。另外还有其他形式碱盐,包括铝盐、精氨酸盐、苄星青霉素(benzathine)盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、葡甲胺盐、胆胺盐、氨丁三醇盐及锌盐。有机盐可由仲胺、叔胺或季胺(如氨丁三醇、二乙胺、N,N’-二苄基乙二胺、氯普罗卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺及普罗卡因)。
本发明所述的“酯”是指本发明所提供的化合物中存在的羟基与适当的酸(如羧酸或含氧无机酸)形成的酯。适宜的酯基团包括但不限于,甲酸酯、乙酸酯、丙酸酯、丁酸酯、丙烯酸酯、乙基琥珀酸酯、硬脂肪酸酯或棕榈酸酯。
本发明所述的“异构体”包括化合物的顺式和反式异构体、光学异构体(诸如R和S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体及互变异构体,包括显示超过1种异构现象的化合物;及其混合物(如外消旋物和非对应异构体)。同时也包括化合物盐的形式,比如D-乳酸盐或L-赖氨酸;或外消旋形式的,例如DL-酒石酸盐或DL-精氨酸。
需要说明的是,本发明中若无特殊限定和具体说明的实验步骤,可采用本领域的常规步骤;本发明中若无特殊限定和具体说明的使用试剂,可采用本领域现有方法制备或直接购买市售产品。
综上所述,本发明具有以下优点:
本发明首次提供了一种邻羟基苯基酮类化合物或其异构体或其药学上可接受的盐或其酯或其溶剂合物或其前药对醛缩酶B的调控作用,从而可以用于预防或治疗肿瘤,如结直肠癌、肝癌、胃癌、肾透明细胞癌等,以及化疗药物耐药性、高血糖等。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明,即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。
因此,以下对提供的本发明的实施例的详细描述并非旨在限制要求保护的本发明的范围,而是仅仅表示本发明的选定实施例。基于本发明的实施例,本领域技术人员在没有做出创造性劳动的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。
本发明中邻羟基苯基酮类化合物的制备方法,具体包括以下步骤:
将化合物A和化合物B溶于二氯甲烷中,加入三氯化铝,25~45℃下搅拌反应1~5h,TLC监测反应完全;加入蒸馏水淬灭反应,乙酸乙酯萃取三次,收集有机相,经无水Na2SO4干燥过夜、过滤、减压浓缩,经柱层析纯化,制得邻羟基苯基酮类化合物;其中,化合物A、化合物B和三氯化铝的摩尔比为1:1~2:0.05~0.2;
化合物A的结构通式如下所示:
其中,R2为氢原子、羟基、卤素、苄基、6~14元芳基、C1-10烷基、C3-10环烷基、氰基、氨基、硝基、-O-(C1-6烷基)、-NH-6~14元芳基、-C(O)1-10-6~14元芳基或-NHSO2-6~14元芳基;
化合物B的结构通式如下所示:
其中,R1为氢原子、羟基、卤素、6~14元芳基、C1-10烷酸基、C1-10烷基、C3-10环烷基、氰基、氨基、硝基、-O-(C1-6烷基)、-NH-6~14元芳基、-C(O)1-10-6~14元芳基或-NHSO2-6~14元芳基。
上述为本发明中邻羟基苯基酮类化合物的通用制备方法,因加入反应原料化合物A和化合物B的不同而各有差异(如反应温度和反应时间),但在上述反应条件下均可相应顺利制得本发明所述的目标产物-邻羟基苯基酮类化合物(所有目标产物的收率在20~80%之间)。需要说明的是,上述中若无特殊限定和具体说明的实验步骤,可采用本领域的常规步骤;上述中若无特殊限定和具体说明的使用试剂,可采用本领域现有方法制备或直接购买市售产品。
下面对本发明中邻羟基苯基酮类化合物的制备列举一些实施例,进行更加具体说明,但不以任何形式构成对本发明的限制。
实施例1:1-(2,6-二羟基-4-甲氧基苯基)-3-苯丙-1-酮(化合物1-1)的制备
步骤1:5-甲氧基间苯二酚的制备
往150mL DMF中加入均苯三酚(12.0g,95.24mmol),K2CO3(26.3g,190.48mmol),降温到0℃,缓慢加入碘甲烷(13.6g,95.24mmol)。反应液在0℃搅拌5小时,减压蒸干DMF,加入乙酸乙酯和水分层萃取,收集乙酸乙酯层,无水硫酸钠干燥,旋干,过柱,乙酸乙酯:石油醚=1:1,得到1.8g产物,收率13.5%。
步骤2:1-(2,6-二羟基-4-甲氧基苯基)-3-苯丙-1-酮(化合物1-1)的制备
在0℃下,往75mL二氯甲烷中加入上一步产物(6g,42.8mmol),再加入苯丙酰氯(14.43g,85.6mmol),AlCl3(11.42g,85.7mmol)。加完后反应液升到室温搅拌过夜。反应结束后,将反应液倒入冰水中,分层,收集二氯甲烷层,二氯甲烷层用1M HCl(2×50mL)洗涤,分层,收集二氯甲烷层,用无水硫酸钠干燥,旋干过柱,乙酸乙酯:石油醚=1:10,得到2.5g化合物1-1,收率21.4%。
分子式:C16H16O4;分子量:272,ESI-MS m/z:273.1[M+H]+;1H NMR(400MHz,CD3OD)δ:7.27-7.11(m,5H),5.92(s,2H),3..76(s,3H),3.34(t,J=13.3Hz,2H),2.94(t,J=10.1Hz,2H);13C NMR(100MHz,CD3OD)δ:204.99,166.13,164.23,163.46,141.74,128.05,127.97,125.49,104.59,92.92,54.44,45.61,30.64.
实施例2:1-(2,6-二羟基-4-甲氧基苯基)-4-苯基丁烷-1-酮(化合物2-1)的制备
在0℃下,往75mL甲苯中加5-甲氧基苯-1,3-二酚(5.47g,39.0mmol),再加入苯丁酰氯(14.1g,78.0mmol),AlCl3(10.39g,78.0mmol)。加完后反应液升到120℃搅拌过夜。反应结束后,将反应液倒入冰水中,分层,收集甲苯层,用1M HCl(2×50mL)洗涤,合并有机相,用无水硫酸钠干燥,旋干过柱,乙酸乙酯:石油醚=1:10,得到3.40g产物,收率30.4%。
分子式:C17H18O4;分子量:286,ESI-MS m/z:287.1[M+H]+;1H NMR(500MHz,CDCl3)δ:7.24-7.19(m,5H),6.06(q,2H),3.80(s,3H),2.96(d,2H),2.63(d,2H),1.61(d,2H);13C NMR(125MHz,CDCl3)δ:205.4,166.6,164.2,142.0,128.8,128.1,126.0,104.0,95.8,55.8,51.8,40.1,35.2,24.4.
实施例3:1-(2,4-二羟基-6-甲氧基苯基)-3-苯基丁-1-酮(化合物3-1)的制备
在0℃下,往75mL甲苯中加5-甲氧基苯-1,3-二酚(5.47g,39.0mmol),再加入2-苄基丙酰氯(14.20g,78.0mmol),AlCl3(10.39g,78.0mmol)。加完后反应液升到120℃搅拌过夜。反应结束后,将反应液倒入冰水中,分层,收集甲苯层,用1M HCl(2×50mL)洗涤,合并有机相,用无水硫酸钠干燥,旋干过柱,乙酸乙酯:石油醚=1:10,得到3.10g产物,收率27.8%。
分子式:C17H18O4;分子量:286,ESI-MS m/z:287.1[M+H]+;1H NMR(500MHz,CDCl3)δ:7.32(s,2H),7.22-7.21(m,3H),6.06(q,2H),3.81-3.55(m,5H),3.41(t,1H),1.25(d,1H);13CNMR(125MHz,CDCl3)δ:205.7,166.6,164.2,146.1,128.4,126.1,125.9,104.0,95.8,55.8,51.8,40.9,20.6.
实施例4:1-(2-羟基-4-甲氧基-6-甲基苯基)-4-苯基丁-1-酮(化合物4-1)的制备
在0℃下,往75mL甲苯中加3-甲氧基-5-甲基苯酚(5.00g,36.2mmol),再加入苯丁酰氯(13.18g,72.4mmol),AlCl3(9.65g,72.4mmol)。加完后反应液升到120℃搅拌过夜。反应结束后,将反应液倒入冰水中,分层,收集甲苯层,用1M HCl(2×50mL)洗涤,合并有机相,用无水硫酸钠干燥,旋干过柱,乙酸乙酯:石油醚=1:10,得到2.70g产物,收率26.2%。
分子式:C18H20O3;分子量:284,ESI-MS m/z:285.1[M+H]+;1H NMR(500MHz,CDCl3)δ:7.24(m,4H),7.19(s,1H),6.49(q,1H),6..40(q,1H),3.80(s,3H),2.96(d,2H),2.63(d,2H),2.27(s,3H),1.61(d,2H);13C NMR(125MHz,CDCl3)δ:200.1,166.3,165.3,143.8,142.0,128.8,128.1,126.0,111.4,110.2,100.2,55.8,40.1,35.2,24.4,22.6.
实施例5:2-羟基-4-甲氧基苯乙酮(化合物5-1)的制备
用20mL甲苯溶解3-甲氧基-1-苯酚(1.56g,10.0mmol),乙酰氯(0.86g,11.0mmol)以及AlCl3(0.15g,1.1mmol),加热至120℃反应6h。冷却至室温后,用少量水淬灭反应。加入乙酸乙酯,分层萃取,收集乙酸乙酯层,无水硫酸钠干燥,旋干,过柱,得到1.40g产物,收率为76.0%。
分子式:C9H10O3;分子量:166,ESI-MS m/z:167.1[M+H]+;1H NMR(400MHz,CD3OD)δ:6.41(1H,d,J=2.4Hz),6.50(1H,dd,J1=8.8Hz,J2=2.4Hz),7.78(1H,d,J=8.8Hz),2.55(3H,s),3.84(3H,s);13C NMR(100MHz,CD3OD)δ:202.64,166.46,165.55,131.22,114.17,106.88,103.21,55.83,26.60.
实施例6:1-(2,6-二羟基-4-甲氧基苯基)辛基-1-酮(化合物6-1)的制备
在0℃下,往75mL甲苯中加5-甲氧基苯-1,3-二酚(6.00g,42.8mmol),再加入正辛酰氯(13.89g,85.7mmol),AlCl3(11.42g,78.0mmol)。加完后反应液升到100℃搅拌过夜。反应结束后,将反应液倒入冰水中,分层,收集甲苯层,用1M HCl(2×50mL)洗涤,合并有机相,用无水硫酸钠干燥,旋干过柱,乙酸乙酯:石油醚=1:10,得到2.95g产物,收率25.9%。
分子式:C15H22O4;分子量:266,ESI-MS m/z:267.1[M+H]+;1H NMR(500MHz,CDCl3)δ:6.06(q,2H),3.80(s,3H),2.96(d,2H),1.53(d,2H),1.33-1.26(m,8H),0.89(t,3H);13C NMR(125MHz,CDCl3)δ:205.4,166.6,164.2,104.0,95.8,55.8,43.1,31.8,29.2,29.1,29.0,22.7,14.1.
实验例1:本发明化合物与ALDOB的结合能力
采用微量热泳动法(MST法)测定本发明化合物(以实施例1-5所得化合物为例)与ALDOB的结合能力。方法如下:
蛋白溶液的配制:ALDOB蛋白干粉用ddH2O稀释至3.76μM作为储备浓度;化合物1-1、化合物2-1、化合物3-1、化合物4-1和化合物5-1作为配体,按照化合物相对分子质量称取相应质量的化合物,用ddH2O溶解,加1%DMSO使其充分溶解,配置成1mL,1mM初始浓度的样品溶液。
荧光标记:按照Monolith TM Series Protein Labeling Kit说明书对目标蛋白ALDOB进行标记,具体操作为交换柱离心去除乙醇后,小心滴加300μL Labelling buffer,离心(3000rpm,30s)弃去残留液体;再次加入Labelling buffer,离心(3000rpm,30s),吸取30μL ALDOB(浓度为3.76μM)小心滴加入A柱,离心(3000rpm,30s),蛋白纯化完成;7μLLabellingbuffer与纯化后的ALDOB混匀,加3μL荧光染料,避光孵育半小时,得40μL混合液;先用PBS加满纯化柱B,平衡B柱3次,将与染料混合好的ALDOB蛋白加入B柱,加入蛋白buffer进行洗脱,用不同1.5mL EP管分管收集洗脱液,EP管做好标记,得到荧光标记的ALDOB,浓度约为0.2μM,-80℃储存待用。
荧光强度预测试:打开MST和NT control软件,输入蛋白名称,原液浓度,毛细管类型等信息,用毛细管(型号MO-K022)吸取上一步荧光标记ALDOB蛋白,开始荧光信号扫描,观察测得的的蛋白标记荧光值是否在200~1500之间。
亲和力测试:将1mM样品母液等浓度梯度1:1稀释为16个浓度,每个浓度的体积为10μL,第1个浓度为1mM,剩下浓度依次降级。取荧光标记蛋白ALDOB与样品梯度浓度溶液各5μL混匀,用毛细管吸取混合好的样品,注意混合液体积要达到毛细管一半以上位置,将毛细管放置在托盘凹槽内进行亲和力检测。观察荧光强度是否在正常范围内,荧光强度是否稳定均一,是否存在样品粘附现象,收集数据,启动MO.Affinity软件进行分析得到拟合曲线和KD值。
实验结果:MST结果显示,化合物1-1与ALDOB的KD值为36.7μM,化合物2-1与ALDOB的KD值为76.4μM,化合物3-1与ALDOB的KD值为90.3μM,化合物4-1与ALDOB的KD值为96.1μM,化合物5-1与ALDOB的KD值为180.8μM。以上表明本发明化合物可直接结合ALDOB蛋白,且化合物1-1具有更强的ALDOB结合能力。
需要说明的是,上述实验例1仅是列举本发明中邻羟基苯基酮类化合物与ALDOB的结合能力的一些实施例;参照实验例1的实验步骤,本发明中其他邻羟基苯基酮类化合物可与ALDOB蛋白进行不同程度的结合。
实验例2:本发明化合物体外抑制不同肿瘤细胞的增殖
采用四甲基偶氮唑盐微量酶反应比色法(MTT法)测定本发明化合物(以实施例1-5所得化合物为例)体外影响不同肿瘤细胞增殖的能力。方法如下:
细胞加药处理:取对数生长期人肝癌细胞SMMC7721,人肾透明细胞癌细胞Caki-1,人肾癌细胞OSRC-2,人结肠癌细胞SW480,胰酶消化后离心,重悬并以3×104个/mL的细胞密度接种于96孔板,每孔100μL细胞悬液;调零孔不加细胞,只加入细胞培养液;待细胞培养12h贴壁后进行加药处理。化合物5-1实验组加入100μL/孔的含药培养液,使每组终浓度为100μM,300μM,1mM,3mM;其余实验组每组分别加入100μL/孔的含药培养液,使每组终浓度为10μM,30μM,100μM,300μM;对照组加入不含药培养液;每组设8个复孔,继续培养48h,72h。
吸光度值测定:到达药物作用时间后,加入PBS溶解配制好的浓度为5mg/mL的MTT溶液每孔加20μL,孵育4h弃去上层培养液,每孔加入DMSO 150μL,摇床振荡10min,于酶标仪检测570nm波长处的吸光度值。重复实验3次
数据处理:计算各组不同浓度含药培养液对细胞的抑制率,抑制率(%)=(OD对照组-OD实验组)/(OD对照组-OD空白组)×100%。
实验结果:实验结果(表1、2)显示,在10μM~3mM浓度范围内,本发明化合物对人肝癌细胞SMMC7721,人肾透明细胞癌细胞Caki-1,人肾癌细胞OSRC-2,人结肠癌细胞SW480增殖均有一定抑制作用,且对人肝癌细胞SMMC7721的细胞增殖抑制作用最为明显。
表1本发明化合物对不同肿瘤细胞增殖的抑制作用(48h)
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表2本发明化合物对不同肿瘤细胞增殖的抑制作用(72h)
需要说明的是,上述实验例2仅是列举本发明中邻羟基苯基酮类化合物体外抑制不同肿瘤细胞的增殖的一些实施例;参照实验例2的实验步骤,本发明中其他邻羟基苯基酮类化合物均可不同程度上体外抑制不同肿瘤细胞的增殖。
实验例3:本发明化合物体外抑制肝癌细胞的增殖
采用四甲基偶氮唑盐微量酶反应比色法(MTT法)测定本发明化合物(以实施例1-5所得化合物为例)体外影响不同肝癌细胞增殖的能力。方法如下:
细胞加药处理:取对数生长期人肝癌细胞SMMC7721、MHCC97L、MHCC97H、HCCLM3、HepG2、HHCC和人正常肝细胞HL7702,胰酶消化后离心,重悬并以3×104个/mL的细胞密度接种于96孔板,每孔100μL细胞悬液;调零孔不种细胞,只加入细胞培养液;待细胞培养12h贴壁后进行加药处理。化合物5-1实验组加入100μL/孔的含药培养液,使终浓度为100μM,300μM,1000μM,3000μM;其余化合物实验组每组分别加入100μL/孔的含药培养液,使每组终浓度为10μM,30μM,100μM,300μM;对照组加入不含药培养液;每组设8个复孔,继续培养48h。
吸光度值测定:到达药物作用时间后,加入PBS溶解配制好的浓度为5mg/mL的MTT溶液每孔加20μL,孵育4h弃去上层培养液,每孔加入DMSO 150μL,摇床振荡10min于酶标仪检测570nm波长处的吸光度值。重复实验3次。
数据处理:计算各组不同浓度含药培养液对细胞的抑制率,抑制率(%)=(OD对照组-OD实验组)/(OD对照组-OD空白组)×100%。
实验结果:实验结果(表3、4)显示,化合物1-1、化合物2-1、化合物3-1、化合物4-1和化合物5-1对肝癌细胞增殖的抑制作用均大于对正常肝细胞增殖的抑制作用。
表3本发明化合物对肝癌细胞HCCLM3、MHCC97H和MHCC97L增殖的抑制作用
表4本发明化合物对正常肝细胞HL7702和肝癌细HepG2和HHCC增殖的抑制作用
需要说明的是,上述实验例3仅是列举本发明中邻羟基苯基酮类化合物体外抑制肝癌细胞的增殖的一些实施例;参照实验例3的实验步骤,本发明中其他邻羟基苯基酮类化合物均可不同程度上体外抑制不同肿瘤细胞的增殖。
实验例4:本发明化合物抑制肝癌细胞的迁移
采用划痕实验测定本发明化合物(以实施例1-5所得化合物为例)影响肝癌细胞迁移能力的作用。方法如下:
接种细胞:用marker笔在24孔板背后横穿过孔均匀画出直线,每孔穿过3条线。取对数生长期肝癌细胞SMMC7721,胰酶消化后离心,重悬并以1×105个/mL的细胞密度接种于24孔板细胞用含2.5%FBS的低血清培养基饥饿培养。
划痕及加药处理:待第二天细胞贴壁铺满后,用枪头尽量垂至于背后的横线划痕,划痕后弃去上清,用PBS洗去漂浮细胞,对照组加入含2.5%FBS的低血清培养基,实验组分别加入含2.5%FBS的低血清培养基溶解的25μM,50μM,75μM的化合物1-1、2-1、3-1、4-1和5-1的含药溶液,共分为16组。
拍照与数据分析:加药后分别于0h,24h,48h拍照,注意各个时间点的拍照位置要一致,用Image J计算划痕面积,与对照组进行比较。
实验结果:实验结果(表5)显示,与对照组相比,化合物1-1、化合物2-1、化合物3-1、化合物4-1和化合物5-1在孵育48h后肝癌细胞SMMC7721划痕愈合能力明显减弱。
表5本发明化合物抑制肝癌细胞迁移能力的作用
需要说明的是,上述实验例4仅是列举本发明中邻羟基苯基酮类化合物体外抑制肝癌细胞的迁移的一些实施例;参照实验例4的实验步骤,本发明中其他邻羟基苯基酮类化合物均可不同程度上体外抑制肝癌细胞的迁移。
实验例5:本发明化合物抑制肝癌细胞的侵袭
采用Transwell法测定本发明化合物(以实施例1-5所得化合物为例)影响肝癌细胞侵袭能力的作用。方法如下:
小室准备:将冷冻在-20℃Matrigel固态基质胶(50mg/L)置于4℃条件下融化为液态,按1:8比例用1640培养基稀释后加入50μL包被小室,置于37℃条件下静置30min至胶凝,每孔加入50μL含10g/L BSA的无血清培养基,37℃条件下孵育箱静置30min水化基底膜。
接种细胞:肝癌细胞SMMC7721提前12h用含2.5%FBS的低血清培养基进行饥饿处理,胰酶消化离心收集细胞,使用含10g/L BSA的无血清培养基重悬细胞,使其密度为2×105个/mL,取200μL细胞重悬液加入上室,下室分别加入500μL含10%FBS的完全培养基(对照组),或10%FBS的完全培养基溶解的75μM的化合物1-1、2-1、3-1、4-1、5-1溶液(实验组),注意小室与下层培养液之间不能有气泡,于孵育箱培养48h后拍照。
结晶紫染色、拍照与数据分析:用棉签擦去基质胶和上室内的细胞,4%多聚甲醛固定30min,PBS洗两次,甲醇透化1h,适当风干。用稀释后的0.1%的结晶紫染色20min,再用PBS洗至无色,于显微镜下拍照并用Image J进行计数,比较对照组与实验组差异。
实验结果:75μM化合物1-1、化合物2-1、化合物3-1、化合物4-1和化合物5-1处理后肝癌细胞SMMC7721的侵袭能力,与对照组相比,分别降低29.6%、22.4%、21.7%、18.3%和16.4%。表明本发明化合物在高浓度条件下,有抑制肝癌细胞侵袭的作用。
需要说明的是,上述实验例5仅是列举本发明中邻羟基苯基酮类化合物体外抑制肝癌细胞的侵袭的一些实施例;参照实验例5的实验步骤,本发明中其他邻羟基苯基酮类化合物均可不同程度上体外抑制肝癌细胞的侵袭。
实验例6:本发明化合物对肝癌细胞周期的影响
采用流式细胞术测定本发明化合物(以实施例1-5所得化合物为例)对肝癌细胞周期的影响。方法如下:
细胞样品制备:待SMMC7721、MHCC97L细胞生长汇合至70%左右时,按之前的分组给药处理,即对照组:不加药的低血清培养基;实验组:25μM、50μM、75μM化合物1-1,2-1,3-1,4-1,5-1的低血清培养基。药物作用24h后进行胰酶消化,终止消化离心后收集细胞,用预冷的PBS重悬,再次离心,吸出上清,1mL冰浴预冷的PBS重悬。
细胞固定:吸取4mL冰浴预冷的95%乙醇于10mL离心管,低速涡旋振荡,同时逐滴加入细胞悬液,混匀后于4℃条件下固定24h以上。随后将固定好的细胞1000rpm离心5min,弃上清,加入5mL冰浴预冷PBS重悬,再次离心沉淀细胞,弃去上清。
细胞染色:按试剂盒说明书配制碘化丙啶(PI)染色液,每个样品加入新鲜配制的碘化丙啶染色液0.4mL,吹打混匀,37℃条件下避光孵育30min。染色完成后上机检测。
流式检测:用流式细胞仪测定并分析细胞DNA含量分布情况,进而分析细胞周期,将对照组与实验组进行差异比较。
实验结果:实验结果(表6、7)显示,与对照组相比,化合物1-1、化合物2-1、化合物3-1、化合物4-1和化合物5-1能浓度依赖性地使肝癌细胞SMMC7721的S期细胞数目增多,G1期细胞数目减少,差距均具有统计学意义(p<0.05)。同样地,与对照组相比,化合物1-1、化合物1-1、化合物3-1、化合物4-1和化合物5-1在浓度为75μM时,能使肝癌细胞MHCC97L细胞的S期细胞数目增多。
表明:本发明化合物能不同程度显著地抑制肝癌细胞SMMC7721和MHCC97L细胞周期,使其发生S期阻滞。
表6本发明化合物对肝癌细胞SMMC7721细胞周期的影响
表7本发明化合物对肝癌细胞MHCC97L细胞周期的影响
实验例7:本发明化合物对裸鼠皮下瘤的抑瘤作用
构建裸鼠皮下移植瘤模型,测定本发明化合物(以实施例1所得化合物1-1为例)体内抗癌活性。方法如下:
裸鼠皮下移植瘤模型的建立:对数生长期的SMMC7721肝癌细胞于125cm2培养瓶中扩增培养,胰酶消化离心后收集细胞,调整细胞浓度为5×107个/mL,0.2mL/只接种于裸鼠右背部皮下。待接种5-7天可见明显瘤块凸起出现即可进行分组。接种第7天将18只雄性裸鼠随机分为3组,分别为模型组(6只,生理盐水),化合物1-1高浓度组(6只,100mg/kg),化合物1-1低浓度组(6只,50mg/kg),用1%DMSO助溶。灌胃给药,每天一次,第28天处死动物。
抑瘤率的测定:裸鼠隔天测量并计算瘤体积,称量裸鼠体重,动物处死解剖脏器及瘤块拍照,观察裸鼠心肝脾肺肾有无累及损伤,瘤块称重后计算抑瘤率。肿瘤体积计算公式:肿瘤体积=最小直径2×最大直径×0.5;抑瘤率(%)=(给药组肿瘤平均质量/模型组肿瘤平均质量)×100%。
实验结果:与生理盐水组比较,化合物1-1对裸鼠的体重没有明显影响,但对肿瘤体积有明显的抑制作用,表明化合物1-1对裸鼠整体毒性较小,对肿瘤生长具有抑制作用。化合物1-1低浓度组(50mg/kg)抑瘤率为42.85%,化合物1-1高浓度组(100mg/kg)对肿瘤的抑制作用更强,抑瘤率可达76.69%。说明化合物1-1对裸鼠皮下瘤生长有一定抑制作用,并且高浓度的化合物1-1对裸鼠皮下瘤的生长抑制效果更显著。表明本发明化合物具有抑制裸鼠皮下瘤生长的作用。
以上内容仅仅是对本发明所作的举例和说明,所属本领域的技术人员不经创造性劳动即对所描述的具体实施例做的修改或补充或采用类似的方式替代仍属本专利的保护范围。
Claims (1)
1.如式(I)所示的邻羟基苯基酮类化合物在制备通过调控ALDOB来治疗肝癌、肾透明细胞癌和结肠癌SW480的药物中的应用,
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