CN111559977B - 一类小分子化合物及其在制备抗肿瘤转移药物中应用 - Google Patents
一类小分子化合物及其在制备抗肿瘤转移药物中应用 Download PDFInfo
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- CN111559977B CN111559977B CN202010501351.6A CN202010501351A CN111559977B CN 111559977 B CN111559977 B CN 111559977B CN 202010501351 A CN202010501351 A CN 202010501351A CN 111559977 B CN111559977 B CN 111559977B
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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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及其在制备抗肿瘤转移药物中应用。本发明通过对氨基苯酚和叔丁基二甲基氯硅烷为起始原料制备得到中间体1，中间体1与烟酰氯盐酸盐反应得到中间体2，中间体2与四丁基氟化铵三水合物反应得到中间体3，中间体3与邻氯苄醇反应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及其在制备抗肿瘤转移药物中应用。
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及其在制备抗肿瘤转移药物中应用。
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，所述小分子化合物的通式为(Ⅰ)的化合物，
其中，所述R1选自氟、溴和碘中的任意一种，可位于苯环的邻、间、对位，可以是单取代或多取代；
所述R2选自氢原子或任意取代基，可位于吡啶的邻、间、对位，可以是单取代或多取代；
所述R3、R4、R5、R6分别选自氢原子或任意取代基。
进一步地，所述小分子化合物包括
本发明提供小分子化合物的制备方法，包括以下步骤：
S1)中间体1的合成：在室温和氮气保护条件下，将对氨基苯酚溶于无水四氢呋喃，加入无水三乙胺并搅拌；另取叔丁基二甲基氯硅烷溶于无水四氢呋喃，然后滴加到反应体系；滴毕，反应10～15h，直到对氨基苯酚消失；反应完成后，分离纯化，得到中间体1；
S2)中间体2的合成：将步骤S1的中间体1溶于无水四氢呋喃，加入无水三乙胺，搅拌并降温至0℃；另取烟酰氯盐酸盐溶于无水四氢呋喃，然后滴加到反应体系；滴毕，保温反应25～35min，移至室温继续反应，直到反应完全；反应完成后，分离纯化，得到中间体2；
S3)中间体3的合成：室温下，将步骤S2的中间体2加入到无水四氢呋喃并搅拌，另取四丁基氟化铵三水合物分批加入到反应体系；反应3～5h，直到中间体2和四丁基氟化铵三水合物消失；反应完成后，分离纯化，得到中间体3；
S4)小分子化合物的合成：在室温和氮气保护条件下，依次将步骤S3 的中间体3、邻氯苄醇、三苯基膦加入到无水四氢呋喃，搅拌并降温至0℃；另取偶氮二甲酸二异丙酯缓慢滴入反应体系；滴毕，保温1小时，移至室温继续反应，直到原料不再减少；反应完成后，分离纯化，得到小分子化合物。
进一步地，所述步骤S1、步骤S2、步骤S3或步骤S4的分离纯化步骤为：加水，用乙酸乙酯萃取，无水硫酸镁干燥有机相，浓缩至干，再用硅胶柱层析分离纯化，即可。
进一步地，所述小分子化合物还包括以下化合物
本发明提供小分子化合物在制备抗肿瘤转移药物中的应用。
进一步地，所述肿瘤包括乳腺癌、肺癌、胃癌、鼻咽癌、胰腺癌和膀胱癌。
进一步地，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SBC3 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。
一种小分子类化合物制剂，包含小分子类化合物及药学上可用的辅料。
进一步地，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。
进一步地，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。
进一步地，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。
进一步地，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。
进一步地，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。
进一步地，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。
进一步地，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。
进一步地，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。
进一步地，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。
进一步地，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。
进一步地，黏结剂包括但不限于：蒸馏水、乙醇。
进一步地，润滑剂包括但不限于：硬脂酸镁、硬脂酸。
进一步地，分散剂包括但不限于：水溶性分散剂和油性分散剂。
进一步地，助流剂包括但不限于：二氧化硅或滑石粉。
进一步地，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。
进一步地，所述剂型为口服剂。
进一步地，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。
进一步地，所述剂型为注射剂。
进一步地，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。
与现有技术相比，本发明具有以下有益效果：
(1)本发明通过对氨基苯酚和叔丁基二甲基氯硅烷为起始原料制备得到中间体1，中间体1与烟酰氯盐酸盐反应得到中间体2，中间体2与四丁基氟化铵三水合物反应得到中间体3，中间体3与邻氯苄醇反应得到了小分子化合物，产率为60％。
(2)本发明的小分子化合物对乳腺癌细胞MDA-MB-231的IC50为 41.18μg/mL，对肺癌细胞H1299的IC50为32.3μg/mL，对胃癌MGC803的 IC50为21.94μg/mL，对鼻咽癌细胞S18的IC50为26.92μg/mL。同时，经过实验过发现小分子化合物能够显著抑制乳腺癌细胞MDA-MB-231、肺癌细胞H1299、胃癌MGC803和鼻咽癌细胞S18为代表的肿瘤细胞的迁移与侵袭，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。
附图说明
图1为本发明小分子化合物的质谱图。
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乳腺癌细胞MDA-MB-231划痕实验测定。
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H1299体外侵袭的抑制影响。
图6为本发明小分子化合物对胃癌MGC803体外侵袭的抑制影响。
图7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，C09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
化学反应路线为：
具体为：
S1)中间体1的合成：在室温和氮气保护条件下，将对氨基苯酚(1.0g, 1.0eq)溶于20mL无水四氢呋喃，加入无水三乙胺(1.9g,2.0eq)并搅拌；另取叔丁基二甲基氯硅烷(1.6g,1.2eq)溶于10mL无水四氢呋喃，然后滴加到反应体系；滴毕，反应12h，直到对氨基苯酚消失；反应完成后，加水，用乙酸乙酯萃取3次，无水硫酸镁干燥有机相，浓缩至干，再用硅胶柱层析分离纯化，得到中间体1(1.7g,Yield＝81％)；
S2)中间体2的合成：将步骤S1的中间体1(1.7g,1.0eq)溶于20mL 无水四氢呋喃，加入无水三乙胺(2.3g,3.0eq)，搅拌并降温至0℃；另取烟酰氯盐酸盐(1.3g,1.0eq)溶于10mL无水四氢呋喃，然后滴加到反应体系；滴毕，保温反应30min，移至室温继续反应，直到反应完全；反应完成后，加水，用乙酸乙酯萃取3次，无水硫酸镁干燥有机相，浓缩至干，再用硅胶柱层析分离纯化，得到中间体2(1.0g,Yield＝70％)；
S3)中间体3的合成：室温下，将步骤S2的中间体2(1.0g,1.0eq)加入到15mL无水四氢呋喃并搅拌，另取四丁基氟化铵三水合物(1.9g,2.0eq) 分批加入到反应体系；反应4h，直到中间体2和四丁基氟化铵三水合物消失；反应完成后，加水，用乙酸乙酯萃取3次，无水硫酸镁干燥有机相，浓缩至干，再用硅胶柱层析分离纯化，得到中间体3(0.6g,Yield＝90％)；
S4)小分子化合物的合成：在室温和氮气保护条件下，依次将步骤S3 的中间体3(0.6g,1.0eq)、邻氯苄醇(0.4g,1.1eq)、三苯基膦(1.1g,1.5eq) 加入到20mL无水四氢呋喃，搅拌并降温至0℃；另取偶氮二甲酸二异丙酯 (0.85g,1.5eq)缓慢滴入反应体系；滴毕，保温1小时，移至室温继续反，直到原料不再减少；反应完成后，加水，用乙酸乙酯萃取3次，无水硫酸镁干燥有机相，浓缩至干，再用硅胶柱层析分离纯化，得到小分子化合物 (0.58g,Yield＝60％)，质谱图为图1。
实验一、MTT测定药物对细胞生长影响
1.1实验对象：乳腺癌细胞MDA-MB-231；肺癌细胞H1299；胃癌 MGC803，鼻咽癌细胞S18。
1.2实验药物：小分子化合物，即化合物C09。
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，化合物C09对乳腺癌细胞MDA-MB-231、肺癌细胞H1299、胃癌MGC803和鼻咽癌细胞S18增长的影响，而化合物 C09对乳腺癌细胞MDA-MB-231、肺癌细胞H1299、胃癌MGC803和鼻咽癌细胞S18的IC50分别为41.18μg/ml，32.3μg/ml，21.94μg/ml和26.92 μg/ml。
实验二、细胞划痕实验测定药物对细胞迁移能力的影响
2.1实验对象：乳腺癌细胞MDA-MB-231。
2.2实验药物：小分子化合物，即化合物C09。
2.3实验方法：用marker笔细头在6孔板背后，用直尺比着，均匀得划线，大约每隔0.5-1cm一道，横穿过孔,我们一般划三道线，依次命名为 a、b、c线。b线横穿正中央，其他两条等间距划在两侧。六孔板种板，每孔2ml,不同细胞种板浓度不同，如S18，每孔加入5×105个细胞，各设置2个复孔，培养约24h。细胞数量以过夜贴壁能铺满70％-80％以上为宜，适当调整。打开孔板盖子，吸掉旧培养基，直尺垂直b线架在孔板上，用 200ul枪头紧贴直尺均匀移动制造细胞划痕线，同样，在线两侧等间距划两条平行线，分别命名为线1和线2。用无菌1×PBS冲洗细胞3次，去除划下的细胞后，再加入血清培养基，放入37℃5％CO2培养箱。按0，24小时取样拍照。
结果表明：从图3可以看出，当作用24h后，化合物C09乳腺癌细胞 MDA-MB-231抑制作用表现显著。
实验三、Transwell侵袭实验测定药物对细胞侵袭能力的影响
3.1实验对象：乳腺癌细胞MDA-MB-231；肺癌细胞H1299；胃癌 MGC803，鼻咽癌细胞S18。
3.2实验药物：小分子化合物，即化合物C09。
3.3实验方法：包被基底膜(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4～图7可以看出，化合物C09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H1299、胃癌MGC803 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 (2)
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
所述小分子化合物的制备方法，包括以下步骤：
S1)中间体1的合成：在室温和氮气保护条件下，将对氨基苯酚溶于无水四氢呋喃，加入无水三乙胺并搅拌；另取叔丁基二甲基氯硅烷溶于无水四氢呋喃，然后滴加到反应体系；滴毕，反应10～15h，直到对氨基苯酚消失；反应完成后，分离纯化，得到中间体1；
S2)中间体2的合成：将步骤S1的中间体1溶于无水四氢呋喃，加入无水三乙胺，搅拌并降温至0℃；另取烟酰氯盐酸盐溶于无水四氢呋喃，然后滴加到反应体系；滴毕，保温反应25～35min，移至室温继续反应，直到反应完全；反应完成后，分离纯化，得到中间体2；
S3)中间体3的合成：室温下，将步骤S2的中间体2加入到无水四氢呋喃并搅拌，另取四丁基氟化铵三水合物分批加入到反应体系；反应3～5h，直到中间体2和四丁基氟化铵三水合物消失；反应完成后，分离纯化，得到中间体3；
S4)小分子化合物的合成：在室温和氮气保护条件下，依次将步骤S3的中间体3、邻氯苄醇、三苯基膦加入到无水四氢呋喃，搅拌并降温至0℃；另取偶氮二甲酸二异丙酯缓慢滴入反应体系；滴毕，保温1小时，移至室温继续反应，直到原料不再减少；反应完成后，分离纯化，得到小分子化合物；
所述肿瘤为胃癌和鼻咽癌。
2.根据权利要求1所述应用，其特征在于，所述步骤S1、步骤S2、步骤S3或步骤S4的分离纯化步骤为：加水，用乙酸乙酯萃取，无水硫酸镁干燥有机相，浓缩至干，再用硅胶柱层析分离纯化，即可。
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