CN111646933B - 一类小分子化合物在制备抗肿瘤转移药物中的应用 - Google Patents
一类小分子化合物在制备抗肿瘤转移药物中的应用 Download PDFInfo
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Abstract
本发明属于医药技术领域，具体涉及一类小分子化合物在制备抗肿瘤转移药物中的应用。本发明的通过邻甲基苯甲酸出发，制备得到了小分子化合物，小分子化合物影响肿瘤细胞转移时骨架蛋白的重组，对肿瘤细胞转移具有显著的抑制作用。
Description
技术领域
本发明属于医药技术领域，具体涉及一类小分子化合物在制备抗肿瘤转移药物中的应用。
背景技术
恶性肿瘤除在原发部位浸润生长、累及相邻器官外，还可通过淋巴管、血管等方式扩散到身体其他部位，这个过程称为肿瘤转移。近年，恶性肿瘤的患病率和病死率呈逐年上升的趋势。且因恶性肿瘤易发生转移，而给临床用药、手术治疗等都带来极大困难，以致超过90％的恶性肿瘤患者死于肿瘤转移。同时，肿瘤转移的发生可以在原发肿瘤还很小的“早期”状态。越来越多的证据显示：在原发肿瘤尚处于微小的状态，已经可以发生肿瘤细胞的远处播散。因此，阻止肿瘤转移成为了恶性肿瘤治疗的关键点。
目前，FDA已了批准超过200余款抗癌药物，而细胞毒性药物依然是抗肿瘤的基础和主要途径，但临床仍缺少确能达到高效低毒目标的药物，其中能抑制肿瘤转移的更少。细胞毒性药物在杀死肿瘤细胞的同时往往对正常细胞也造成伤害，且不能有效抑制肿瘤细胞转移，临床上常见肿瘤原发病灶有所减轻，但出现多处转移灶，最终致病情恶化。因此，对于现代肿瘤治疗来说，提供一种具有能够抑制肿瘤细胞转移的药物具有十分重要的意义。
发明内容
本发明旨在提供一类小分子化合物在制备抗肿瘤转移药物中的应用，本发明制备得到了小分子化合物，小分子化合物对肿瘤细胞转移具有显著的抑制作用。
为了达到上述目的，本发明采用以下技术方案：
一类小分子化合物，结构式为(Ⅰ)的化合物，
其中，所述R1、R2、R3、R4、R5、R6、R7、R8分别选自H、F、Cl、 Br、I、NH2、NO2、D、CH3、
中的一种。
优选地，所述小分子化合物包括
本发明提供所述小分子化合物的制备方法，其特征在于，包括以下步骤：
优选地，具体包括以下步骤：
S1)将邻甲基苯甲酸和N，N-二甲基甲酰胺加入圆底烧瓶，塞好瓶塞，用注射器加入无水二氯甲烷，在氩气的保护下滴加草酰氯，于室温下反应；反应后将反应液旋干，得到邻甲基苯甲酰氯；
S2)在步骤S1的邻甲基苯甲酰氯中加入化合物S2，塞好瓶塞，加入无水二氯甲烷和三乙胺，于室温下反应；用TLC点板监控反应完全后，得到产物；
S3)将步骤S2的产物用硅胶柱纯化，得到小分子化合物。
优选地，所述硅胶柱纯化过程中以乙酸乙酯/石油醚为洗脱剂。
优选地，所述乙酸乙酯和石油醚的体积比为1：10。
本发明提供上述小分子化合物在制备抗肿瘤转移药物中的应用。
优选地，所述肿瘤包括乳腺癌、肺癌、胃癌、鼻咽癌、胰腺癌和膀胱癌。
所述肿瘤包括鼻咽癌细胞S18和鼻咽癌细胞5-8F所引起的鼻咽癌，乳腺癌细胞MDA-MB-231所引起的乳腺癌、非小细胞肺癌细胞A549和非小细胞肺癌H1299所引起的肺癌，胃癌细胞MKN45、胃癌细胞MGC803和胃癌细胞MGC803所引起的胃癌，胰腺癌细胞PANC-1所引起的胰腺癌，以及膀胱癌细胞UM-UC-3，膀胱癌细胞J82，膀胱癌细胞T24，膀胱癌细胞SW780和膀胱癌细胞BIU87所引起的膀胱癌。
本发明还提供了一种小分子化合物制剂，包含权利要求1所述小分子化合物及药学上可用的辅料。
优选地，所述的辅料包括但不限于填充剂、黏结剂、润滑剂、分散剂、助流剂、润湿剂、崩解剂、香料或色料。
优选地，所述填充剂包括但不限于天然来源的高分子聚合物、糖类、纤维素及其衍生物、淀粉及其衍生物、环糊精及其衍生物、聚合物、无机盐、PH调节剂。
优选地，天然来源的高分子聚合物包括但不限于：虫胶、桃胶、阿拉伯胶、黄原胶、刺槐豆胶、愈创胶、帚叉藻聚糖胶、果胶、角叉菜胶、明胶、刺梧桐胶、印度胶、白芨胶、田菁胶、红藻胶、西黄芪胶、西黄耆胶、卡拉胶、塔拉胶、刺槐豆胶、瓜尔豆胶、洋菜胶、古阿树胶、英豆胶、梧桐胶、鹿角菜胶、海藻酸及其盐、杏胶、琼脂、葡聚糖、甲壳素及其衍生物、玉米朊、干酪素等。
优选地，糖类包括但不限于：葡萄糖、果糖、蔗糖、红糖、黄糖、白糖、冰糖、淀粉糖、麦芽糖、毛蕊糖、乳糖、糊精、赤藓糖醇、木糖醇、果糖醇、甘露糖醇、山梨糖醇、乳糖醇、半乳糖醇、麦芽糖醇、异麦芽酮糖醇、异麦芽糖醇、帕拉金糖醇、益寿糖、低聚异麦芽糖醇、阿拉伯糖醇、低聚异麦芽糖、大豆低聚糖、低聚半乳糖、低聚甘露糖、低聚果糖、低聚麦芽糖、低聚木糖、低聚葡甘糖、低聚乳果糖、低聚乳糖、低聚蔗果糖、分枝低聚果糖、牛乳低聚糖、海藻糖棉子糖、潘糖、葡萄糖基蔗糖、偶合糖、乳果糖、乳果低聚糖、乳酮糖、水苏糖、异构乳糖、蔗糖低聚糖、纤维低聚糖、低聚乳蔗糖、氢化淀粉水解物、阿拉伯糖、木糖、普鲁蓝等。
优选地，纤维素及其衍生物包括但不限于：低取代羟丙基纤维素、甲基纤维素、羧甲基纤维素钠、羧甲基纤维素、苯二甲酸醋酸纤维素、微晶纤维素、乙基纤维素、乙基甲基纤维素、交联羧甲基纤维素钠、醋酸纤维素等。
优选地，淀粉及其衍生物包括但不限于：变性淀粉、羧甲基淀粉、羟甲基淀粉、羟基淀粉丙酸酯、预胶化淀粉、糊精等。
优选地，环糊精及其衍生物包括但不限于：环糊精、甲基环糊精、羟丙基环糊精、羟乙基环糊精、聚合物环糊精、乙基环糊精、支链环糊精等。
优选地，聚合物包括但不限于：聚乙烯吡咯烷酮、聚乙烯醇、聚乙烯醇缩丁醛、苯乙烯—乙烯吡啶共聚物、丙烯酸树脂、交联聚丙烯酸树脂(卡波姆)、交联聚维酮、聚维酮、聚醋酸乙烯酯、丙烯酸甲酯共聚物、聚乳酸、聚氨基酸、聚羧乙酸、聚乙二醇、聚醚、离子交换树脂等。
优选地，无机材料包括但不限于：滑石粉、碳酸钙、碳酸镁、硫酸钙、磷酸氢钙、磷酸钙、氧化镁、氢氧化铝、二氧化硅、活性炭、活性白土、氧化铝、氯化钠、二氧化钛等。
优选地，PH调节剂包括但不限于：碳酸氢钠、碳酸氢钾、磷酸氢二氢钠、磷酸氢二氢钾、柠檬酸、酒石酸、琥珀酸、富马酸、己二酸、苹果酸等。
优选地，黏结剂包括但不限于：蒸馏水、乙醇。
优选地，润滑剂包括但不限于：硬脂酸镁、硬脂酸。
优选地，分散剂包括但不限于：水溶性分散剂和油性分散剂。
优选地，助流剂包括但不限于：二氧化硅或滑石粉。
优选地，崩解剂包括但不限于：低取代羟丙纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠、交联聚维酮。
优选地，所述剂型为口服剂。
优选地，所述口服剂的形式为：片剂、硬或软胶囊、锭剂、滴丸、微丸、水性或油混悬剂、乳剂、可分散的散剂或颗粒剂、口服液、糖浆剂或酏剂。
优选地，所述剂型为注射剂。
优选地，所述注射剂的形式为：灭菌的水性或油性溶液、无菌粉末、脂质体、乳剂或微囊。
本发明制备得到了一种小分子化合物，同时对小分子化合物是否对肿瘤细胞起到制肿瘤转移的作用进行研究。具有转移特性的肿瘤细胞在进行细胞迁移的时候，必须进行骨架蛋白的重组，以实现肿瘤细胞的空间转移。而在本发明的实验中，通过实验“Transwell侵袭实验测定药物对细胞侵袭能力的影响”后发现，小分子化合物能够显著抑制鼻咽癌细胞S18、乳腺癌细胞MDA-MB-231、非小细胞肺癌细胞A549、非小细胞肺癌细胞H1299、非小细胞肺癌细胞H1975和胃癌细胞MGC803为代表的肿瘤细胞的迁移与侵袭。由此，推测小分子化合物是通过破坏肿瘤细胞骨架蛋白的重组而实现抗肿瘤转移的作用。
与现有技术相比，本发明具有以下有益效果：
(1)本发明从邻甲基苯甲酸出发，制得了一种小分子化合物，从而提供了一种新的抗肿瘤转移药物。
(2)本发明的小分子化合物经过实验后发现，小分子化合物对肿瘤细胞转移起到显著的抑制作用，为抗肿瘤转移药物提供一种全新的方向。
附图说明
图1为本发明小分子化合物的核磁谱图。
图2为本发明小分子化合物对不同肿瘤细胞的生长作用。
图3为本发明小分子化合物对鼻咽癌细胞S18体外侵袭的抑制影响。
图4为本发明小分子化合物对乳腺癌细胞MDA-MB-231体外侵袭的抑制影响。
图5为本发明小分子化合物对非小细胞肺癌细胞A549体外侵袭的抑制影响。
图6为本发明小分子化合物对非小细胞肺癌细胞H1299体外侵袭的抑制影响。
图7为本发明小分子化合物对非小细胞肺癌细胞H1975体外侵袭的抑制影响。
图8为本发明小分子化合物对胃癌细胞MGC803体外侵袭的抑制影响。
图中，inhibition rate为抑制率，concentration为浓度，invaded cell perfiled 为侵袭细胞，Negative为阴性对照，Positive为阳性对照，H03为小分子化合物。
具体实施方式
以下通过实施例形式的具体实施方式，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实施例。
小分子化合物的制备
包括以下步骤：
具体为：
S1)将邻甲基苯甲酸(950mg)和一滴N，N-二甲基甲酰胺加入圆底烧瓶，塞好瓶塞，用注射器加入无水二氯甲烷(10mL)，在氩气的保护下滴加草酰氯(710μL)，于室温下反应1h；反应后将反应液旋干，得到邻甲基苯甲酰氯；
S2)在步骤S1的邻甲基苯甲酰氯中加入化合物S2，邻甲基苯甲酰氯和化合物S2的摩尔比为1：1，塞好瓶塞，加入无水二氯甲烷和三乙胺各两滴，于室温下反应3h；用TLC点板监控反应完全后，得到产物；
S3)将步骤S2的产物用硅胶柱纯化，以乙酸乙酯/石油醚＝1:10为洗脱剂，得到白色固体，即小分子化合物。
将得到的小分子化合物进行核磁鉴定，如图1所示，1H NMR(400MHz, CDCl3)δ8.59(d,J＝4.8Hz,1H)，8.28(d,J＝8.0Hz,1H)，7.90(d,J＝7.8Hz, 1H)，7.78(td,J＝7.8,1.7Hz,1H)，7.47-7.37(m,2H)，7.32-7.26(m,2H)，6.42 (br,1H)，5.55(br,1H)，2.65(s,3H)。
实验一、MTT测定药物对细胞生长影响
1.1实验对象：鼻咽癌细胞S18；乳腺癌细胞MDA-MB-231；非小细胞肺癌细胞A549；非小细胞肺癌细胞H1299；非小细胞肺癌细胞H1975；胃癌细胞MGC803。
1.2实验药物：小分子化合物。
1.3实验方法：铺板：收集对数期细胞，调整细胞悬液浓度，每孔加入 90ul，铺板使待测细胞密度为10000每孔。加药：5％CO2，37℃孵育，至细胞单层铺满孔底(96孔平底板)，加入浓度梯度的药物。5％CO2，37℃孵育72小时，倒置显微镜下观察。每孔加入20ul MTT溶液(5mg/ml，即0.5％MTT)，继续培养4h。终止培养，小心吸去孔内培养液。每孔加入150ul 二甲基亚砜，置摇床上低速振荡10min，使结晶物充分溶解。在酶联免疫检测仪OD490nm处测量各孔的吸光值，计算细胞相对存活率。本实验设不含细胞的培养基作为空白对照，每孔加入20ul MTT溶液作为实验对照组和含样品实验组。
1.4相对存活率＝(实验组OD-空白组OD)/(对照组OD-空白组OD) ×100％
结果表明：从图2可以看出，小分子化合物对鼻咽癌细胞S18的IC50 为26.12ug/ml，对乳腺癌细胞MDA-MB-231的IC50为25.12ug/ml，对非小细胞肺癌细胞A549的IC50为37.58ug/ml，对非小细胞肺癌细胞H1299 的IC50为64.2ug/ml，对非小细胞肺癌细胞H1975的IC50为76.28ug/ml，对胃癌细胞MGC803的IC50为20.17ug/ml。
实验二、Transwell侵袭实验测定药物对细胞侵袭能力的影响
2.1实验对象：鼻咽癌细胞S18；乳腺癌细胞MDA-MB-231；非小细胞肺癌A549；非小细胞肺癌H1299；非小细胞肺癌H1975；胃癌MGC803。
2.2实验药物：小分子化合物。
2.3实验方法：包被基底膜Matrigel(4℃操作)用4℃的无血清细胞培养基DMEM稀释Matrigel(10mg/ml to 250μg/ml)。使用时，取50μl Matrigel 加入1950μl的DMEM至EP管即可。取100μl稀释胶缓慢滴加到24-well transwell上室中，在培养箱中培养1小时。制备细胞悬液；消化细胞，终止消化后离心弃去培养液，用PBS洗1遍，无血清培养基重悬，调整细胞密度至合适浓度。接种细胞；取细胞悬液200μl均匀加入Transwell上室，加入2μl 10％BSA。立刻在24孔板下室一般加入800μl含10％FBS的培养基。常规培养24h。细胞染色；取出Transwell小室，弃去孔中培养液，用棉签擦去上室内的细胞，并放入干净的24孔板内。用无钙的1×PBS洗1 遍，甲醇固定30分钟，将小室放通风橱风干。0.1％结晶紫染色20min，用棉签轻轻擦掉上层未迁移细胞，用PBS洗1遍。结果统计，5X镜下观察， 10X显微镜下随机五个视野观察细胞，记数。
结果表明：从图3～8可以看出，小分子化合物可能通过影响鼻咽癌细胞S18、乳腺癌细胞MDA-MB-231、非小细胞肺癌细胞A549、非小细胞肺癌细胞H1299、非小细胞肺癌细胞H1975和胃癌细胞MGC803的侵袭能力来影响上述癌细胞的发生与发展。
上述实施例仅例示性说明本发明的原理及其功效，而非用于限制本发明。任何熟悉此技术的人士皆可在不违背本发明的精神及范畴下，对上述实施例进行修饰或改变。因此，举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变，仍应由本发明的权利要求所涵盖。
Claims (1)
1.一类小分子化合物在制备抗肿瘤转移药物中的应用，其特征在于，所述小分子化合物为
所述肿瘤为乳腺癌、肺癌、胃癌和鼻咽癌。
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