CN109260201B - 一种吡啶类化合物在制备抗肿瘤药物中的用途 - Google Patents
一种吡啶类化合物在制备抗肿瘤药物中的用途 Download PDFInfo
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- CN109260201B CN109260201B CN201811075013.XA CN201811075013A CN109260201B CN 109260201 B CN109260201 B CN 109260201B CN 201811075013 A CN201811075013 A CN 201811075013A CN 109260201 B CN109260201 B CN 109260201B
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- pharmaceutically acceptable
- acceptable salt
- tetrahydropyridine
- phenyl
- methyl
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- PLRACCBDVIHHLZ-UHFFFAOYSA-N 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Chemical compound C1N(C)CCC(C=2C=CC=CC=2)=C1 PLRACCBDVIHHLZ-UHFFFAOYSA-N 0.000 claims abstract description 20
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Abstract
本发明涉及一种吡啶类化合物在制备抗肿瘤药物中的用途，属于医药技术领域。本发明公开了一种吡啶类化合物、其药学上可接受的盐或其溶剂化物在制备抗肿瘤药物中的用途，本发明的1‑甲基‑4‑苯基‑1,2,3,6‑四氢吡啶具有抑制RAS mRNA表达的作用，24mM的1‑甲基‑4‑苯基‑1,2,3,6‑四氢吡啶能够使RAS mRNA的拷贝数减少3.5倍，同时对果蝇肿瘤模型具有显著地抑癌作用，利用1‑甲基‑4‑苯基‑1,2,3,6‑四氢吡啶对肿瘤进行干预和治疗将成为极具潜力的临床抗肿瘤产品。
Description
技术领域
本发明涉及一种吡啶类化合物在制备抗肿瘤药物中的用途，属于医药技术领域。
背景技术
癌症是一种死亡率极高的恶性疾病，治疗难度高，给患者和家庭带来沉重的负担。近年来，我国癌症发生率明显增加，使癌症防治面临着严峻的形势。我国癌症发生率呈逐渐上升趋势，受到社会各界人士的广泛关注。据相关研究报道显示，在20世纪70年代，我国癌症由10.13％增加至22.32％，死亡增加率为82.11％。癌症是排在城市死亡率的第一位，在农村排列为第二位。尤其是现今老龄化日益加重，吸烟、饮食结构变化、微生物感染、肥胖、活动减少、作息不良等因素是导致癌症发生的主要原因，尤其是我国超重率及肥胖率明显超过50％。目前排在我国癌症前十位的是：肺癌、胃癌、结直肠癌、肝癌、食管癌、女性乳腺癌、胰腺癌、淋巴癌、膀胱癌与甲状腺癌。肺癌是城市男性常见癌症，乳腺癌是城市女性常见癌症；胃癌是农村男女发病首位，肺癌死亡率占据最高位。
RAS基因家族包含3种功能性基因，即H-RAS、N-RAS、K-RAS，3种基因内部的核甘酸序列相差较大，但均含有1个5'非编码外显子和4个编码外显子，编码的产物相对分子质量为21000的G蛋白单体，称为p21蛋白(RAS蛋白)。RAS蛋白主要调节细胞的分化增殖，被称为细胞信号网络传递中的“分子开关”：当正常时能控制调控细胞生长的路径；发生异常时，则导致细胞持续生长，并阻止细胞自我毁灭。RAS基因是原癌基因，其被激活后就成为了具有致癌活性的癌基因。它参与细胞内的信号传递，当K-RAS基因突变时，该基因永久活化，不能产生正常的RAS蛋白，使细胞内信号传导紊乱，细胞增殖失控而癌变。其激活方式主要有3种，即基因的点突变、基因大量表达以及基因的插入及转位。其中最常见的就是点突变，约30％的人类恶性肿瘤存在RAS基因的点突变。若RAS蛋白持续处于活化状态，可与下游的效应蛋白结合，将信号传递到下游信号元件，引起细胞的异常增殖，导致肿瘤的发生。
最常见是K-RAS的点突变，其次是N-RAS、H-RAS；常见的突变位点是12、13、61密码子，其中又以第12位密码子突变最常见。在不同类型肿瘤中存在不同的RAS基因突变，胰腺癌、结直肠癌、子宫内膜癌、胆管癌和肺癌中普遍存在K-RAS基因突变，黑色素瘤和髓系恶性肿瘤常为N-RAS基因突变所致，而肝癌、甲状腺癌和膀胱癌常见H-RAS基因突变。RAS基因是一类在生物进化过程中较为保守的原癌基因，在多种细胞生命活动中起到包括细胞的增殖分化和细胞骨架的构建等重要作用。人们对RAS基因蛋白及其信号转导通路进行了深入的研究，发现RAS与肿瘤的发生、发展具有密切相关性。因此，RAS蛋白已成为公认的筛选抗相关恶性肿瘤药物的靶标。这意味着开发RAS抑制剂可以选择性地针对于肿瘤细胞。
癌症药物的开发长期以来一直是研发的热点，化学类药物和生物类药物争相角逐，但是新的有效的恶性肿瘤治疗药物依然需求迫切。
发明内容
本发明的目的在于克服上述现有技术的不足之处而提供一种吡啶类化合物在制备抗肿瘤药物中的用途，本发明化合物具有抑制RAS mRNA表达的作用，同时对果蝇肿瘤模型具有显著地抑癌作用，本发明化合物可以用于抗癌药物进行研究。
为实现上述目的，本发明采取的技术方案为：一种吡啶类化合物、其药学上可接受的盐或其溶剂化物在制备抗肿瘤药物中的用途，所述吡啶类化合物为式I化合物，其化学名称为：1-甲基-4-苯基-1,2,3,6-四氢吡啶
本发明对该化合物对RAS基因的扩增抑制作用和对果蝇肿瘤模型的治疗效果进行评价，发现本发明化合物能很好的抑制RAS mRNA的表达，24mM的1-甲基-4-苯基-1,2,3,6-四氢吡啶能够使RAS mRNA的拷贝数减少3.5倍，并且对果蝇肿瘤具有很好的抗肿瘤活性。因此利用1-甲基-4-苯基-1,2,3,6-四氢吡啶对肿瘤进行干预和治疗将成为极具潜力的临床抗肿瘤产品。
作为本发明所述用途的优选实施方式，所述药学上可接受的盐为1-甲基-4-苯基-1,2,3,6-四氢吡啶与无机酸或有机酸中的一种或两种以上形成的药学上可接受的无机酸盐或有机酸盐。
作为本发明所述用途的优选实施方式，所述无机酸盐为盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、高氯酸盐中的至少一种。
作为本发明所述用途的优选实施方式，所述有机酸盐为乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐中的至少一种。
作为本发明所述用途的优选实施方式，所述药学上可接受的盐为己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐中的至少一种。
作为本发明所述用途的优选实施方式，所述药学上可接受的盐为碱金属盐、碱土金属盐、铵盐、季铵盐中的至少一种。所述碱金属或碱土金属包括钠、锂、钾、钙、镁等。所述铵盐包括和抗平衡离子形成的胺阳离子，如卤化物、氢氧化物、羧化物、硫酸化物、磷酸化物、硝酸化物、C1-8磺酸化物、芳香磺酸化物等。
作为本发明所述用途的优选实施方式，所述溶剂化物为1-甲基-4-苯基-1,2,3,6-四氢吡啶与一个或多个溶剂分子所形成的缔合物。
作为本发明所述用途的优选实施方式，所述溶剂为水、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸、氨基乙醇中的至少一种。
第二方面，本发明提供了一种药物组合物，包含1-甲基-4-苯基-1,2,3,6-四氢吡啶、其药学上可接受的盐或其溶剂化物，以及药学上可接受的载体。所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。本发明药物可以制成注射液、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂等多种形式。上述各种剂型的药物均可以按照药学领域的常规方法制备。
第三方面，本发明提供了上述药物组合物在制备抗肿瘤药物中的用途。
与现有技术相比，本发明的有益效果为：本发明化合物具有抑制RAS mRNA表达的作用，24mM的1-甲基-4-苯基-1,2,3,6-四氢吡啶能够使RAS mRNA的拷贝数减少3.5倍，并且本发明化合物对果蝇肿瘤模型具有显著地抑癌作用。因此，利用1-甲基-4-苯基-1,2,3,6-四氢吡啶对肿瘤进行干预和治疗将成为极具潜力的临床抗肿瘤产品。
附图说明
图1为本发明化合物对RAS mRNA表达抑制作用的统计图。
图2为本发明化合物对果蝇荧光蛋白表达的成像图及表达量的统计图。
具体实施方式
为更好地说明本发明的目的、技术方案和优点，下面将结合附图和具体实施例对本发明作进一步说明。
下述实施例中，若未特别指明，所用的技术手段为本领域技术人员所熟知的常规手段，本申请中的试剂和材料均可从市场上或其它公共渠道获得。
实施例1本发明化合物对RAS mRNA的抑制作用试验
1-甲基-4-苯基-1,2,3,6-四氢吡啶的分子量为173.25g/mol，精密称取1.7325g该化合物溶于10mL DMSO溶液中配成1M母液待用。
普通培养基制备：取50mL H2O，加入琼脂0.53g、酵母粉1.6g，加热沸腾，再加入NaKT0.43g、无水CaCl20.033g、蔗糖1.58g、葡萄糖3.17g、玉米粉3.88g(冷水调匀，否则易结块)，沸腾后停止加热，分装入内径25mm培养管中，每管约5-8mL，高温消毒(30min，116℃)，取出后冷却至50℃左右，加入1-2滴氨苄西林贮存液，4℃保存，使用前加入少量活性干酵母。氨苄西林贮液的配制：0.0623g氨苄西林，加入8.2mL 95％乙醇和7.4mLdH2O，超声匀质后-20℃保存。
加药培养基制备：在普通培养基中加入适量母液，配制成含24mM的1-甲基-4-苯基-1,2,3,6-四氢吡啶的加药培养基。
本发明使用RT-PCR法测量RAS mRNA的含量，按照总RNA提取试剂盒(天根生化科技有限公司，北京)操作指南提取果蝇中K-RAS的总RNA，逆转录(RNA preppureTissueKit、Quantc DNA、Quantone step qRT-PCR均购自Thermo公司，美国)为cDNA后扩增并分析。采用GAPDH为内参照、K-RAS mRNA引物序列由上海生物工程有限公司设计合成。K-RAS上、下游引物分别为：5c-TGTCATCTTGCCCTCCTACC-3c(20bp)、5c-TCAAAGCATCAGCCACCAC-3c(19bp)；GAPDH上、下游引物分别为：5c-CCACGGCTGCTTCCAGCTCC-3c(20bp)、5c-GGACTCCATGCCCAGGAAGGAA-3c(20bp)。反应条件为25μL反应体系：94℃预变性3min，94℃变性30s，52℃退火30s，72℃延伸1min，35个循环，最后72℃延伸5min，最后至4℃终止。K-RAS引物对应的PCR扩增产物分别为242bp，GAPDH引物对应的PCR扩增产物为295bp。扩增后附加熔解曲线程序，利用2-ΔΔCt法确定果蝇中K-RAS的相对表达量。
普通培养基和含24mM 1-甲基-4-苯基-1,2,3,6-四氢吡啶的加药培养基培养5天后，从用作试验的培养管中各取虫蛹40只，PBS(磷酸缓冲盐溶液)洗2次，转移入冰盒内冷冻2h后，按上法操作测定RAS mRNA的相对含量，测试结果如图1所示。
由图1可知，本发明化合物具有RAS蛋白抑制作用，其中24mM的1-甲基-4-苯基-1,2,3,6-四氢吡啶能够减少3.5倍RAS mRNA的表达量。
实施例2本发明化合物对果蝇肿瘤模型中肿瘤的抑制作用试验
黑腹果蝇(Drosophila melanogaster)为含GFP标记的FLP/FRT重组体系的种系(L185+L186)。普通培养基和加药培养基的制备同实施例1。普通培养基和加药培养基培养5天后，从用作试验的培养管中各取虫蛹80只，PBS(磷酸缓冲盐溶液)洗2次，取出整齐排列于载玻片上，转移入冰盒内冷冻2h，IVIS Lumina X5活体成像仪下观察取像(激发光波长450-490nm，下同)，统计绿色荧光蛋白表达的情况，结果如图2所示。
由图2可知，本发明化合物对L185+L186果蝇肿瘤模型具有较好的体外抑制活性，没有使用1-甲基-4-苯基-1,2,3,6-四氢吡啶时，果蝇模型的荧光绝对值为2.37×109μW/cm2，在口服给予果蝇肿瘤模型24mM的1-甲基-4-苯基-1,2,3,6-四氢吡啶后，果蝇的荧光绝对值为3.5×108μW/cm2，说明本发明化合物可以用于抗癌药物进行研究。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。
Claims (7)
1.一种吡啶类化合物或其药学上可接受的盐作为唯一活性成分在制备抗肿瘤药物中的用途，其特征在于，所述吡啶类化合物为式I化合物，其化学名称为：1-甲基-4-苯基-1,2,3,6-四氢吡啶
2.如权利要求1所述的用途，其特征在于，所述药学上可接受的盐为1-甲基-4-苯基-1,2,3,6-四氢吡啶与无机酸或有机酸中的一种或两种以上形成的药学上可接受的无机酸盐或有机酸盐。
3.如权利要求2所述的用途，其特征在于，所述无机酸盐为盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、高氯酸盐中的至少一种。
4.如权利要求2所述的用途，其特征在于，所述有机酸盐为乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐中的至少一种。
5.如权利要求1所述的用途，其特征在于，所述药学上可接受的盐为己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、苹果酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐中的至少一种。
6.如权利要求1所述的用途，其特征在于，所述药学上可接受的盐为碱金属盐、碱土金属盐、铵盐、季铵盐中的至少一种。
7.药物组合物在制备抗肿瘤药物中的用途，其特征在于，所述药物组合物包含作为唯一活性成分的1-甲基-4-苯基-1,2,3,6-四氢吡啶或其药学上可接受的盐，以及药学上可接受的载体。
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