CN117285436A - 一种选择性txnrd1的抑制剂及其应用 - Google Patents
一种选择性txnrd1的抑制剂及其应用 Download PDFInfo
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Abstract
本发明属于医药技术领域,具体涉及靶向TXNRD1的丙炔酰胺衍生物及其在抗肿瘤方面的应用,本发明公开了一种选择性靶向TXNRD1的抑制剂,即丙炔酰胺类衍生物小分子化合物,其结构如式(I)所示。该分子通过靶向TXNRD1,从而发挥抗肿瘤作用,在分子水平、细胞水平和小鼠模型中均表现出明显的抗肿瘤效果。
Description
技术领域
本发明属于医药技术领域,具体涉及靶向TXNRD1的丙炔酰胺衍生物及其在抗肿瘤方面的应用。
背景技术
目前,治疗癌症的药物有近百种,各种创新疗法也取得突破性进展,而事实上化疗仍然是当下非常重要的***性抗癌方法之一,目前临床上应用的抗肿瘤药物远不能满足治疗的要求,仍然缺乏有效***的药物。因此,进一步开发新型的抗肿瘤药物具有重要意义。
硫氧还蛋白***(TXN system)是细胞内氧化还原稳态以及信号转导的重要调控***,硫氧还蛋白还原酶(TXNRD)将生理底物硫氧还蛋白(TXN)还原。随后TXN还原其下游的分子靶标,在细胞的生长增殖和分化发育中发挥着重要的作用。研究表明,TXNRD在肿瘤中高表达,是癌症治疗中的潜在靶标,大量的药物通过抑制TXNRD而展现出抗肿瘤活性。
目前为止,还没有正式获批上市的TXNRD抑制剂药物分子,大多处于临床前研究阶段,主要有天然产物和人工合成的药物两大类,例如小白菊内酯、土木香内酯、姜黄素、金诺分和顺铂等。进入临床研究的选择性靶向TXNRD的抑制剂相对较少,因此,开发新的靶向TXNRD的小分子抑制剂,揭示抑制剂与TXNRD的相互作用机制,具有重要的科学研究意义和临床医学应用价值。
发明内容
为克服上述现有技术的不足,本发明的目的是提供一种选择性TXNRD1的抑制剂,所述抑制剂为丙炔酰胺衍生物类小分子化合物,本发明经研究发现丙炔酰胺衍生物类小分子化合物具有良好的抗肿瘤活性,在制备抗肿瘤药物中具有广泛的用途。
为实现上述目的,本发明所采用的技术方案为:
一种选择性TXNRD1的抑制剂,所述抑制剂为丙炔酰胺衍生物类小分子化合物(其分子式为C26H22BrFN2O4,分子量为:525.37),所述抑制剂的结构如式(I)所示:
本发明还提供了所述的选择性TXNRD1的抑制剂在制备靶向TXNRD1的药物中的应用。
本发明还提供了上述的选择性TXNRD1抑制剂在制备抗肿瘤药物中的应用。
本发明还提供了,特定结构的丙炔酰胺衍生物类小分子化合物在制备抗肿瘤药物中的用途。
优选地,所述肿瘤包括但不限于乳腺癌。
本发明还提供了上述的选择性TXNRD1抑制剂在制备抑制肿瘤细胞生长的药物中的应用。
优选地,所述肿瘤细胞包括但不限于乳腺癌细胞。
本发明还提供了一种选择性靶向TXNRD1的药物或一种抗肿瘤药物或一种抑制肿瘤细胞生长的药物,所述药物以所述的选择性TXNRD1抑制剂作为主要活性成分。
优选地,在上述应用及药物方案中,所述选择性TXNRD1抑制剂还包括丙炔酰胺衍生物类小分子化合物在药学上可接受的载体和/或赋形剂混合制备成组合物,并制备成临床上可接受的剂型。
优选地,所述赋形剂是指可用于药学领域的稀释剂、黏合剂、润滑剂、崩解剂、助溶剂、稳定剂以及其他一些药用基质。
优选地,所述载体是药物领域中可接受的功能性药用辅料,包括表面活性剂、助悬剂、乳化剂以及一些新型药用高分子材料,如环糊精、壳聚糖、聚乳酸(PLA)、聚乙醇酸聚乳酸共聚物(PLGA)、透明质酸等。
优选地,所述剂型是指临床上常用的注射剂、片剂、胶囊剂等。药物制剂可以经口服或胃肠外方式(例如静脉、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下是不稳定的,可将其制备成肠衣片剂。
与现有技术相比,本发明的有益效果是:
本发明中,丙炔酰胺衍生物类小分子化合物可特异性靶向TXNRD1,从而实现对肿瘤细胞的杀伤。在分子水平、细胞水平和癌症小鼠模型中均表现出强效的抗肿瘤作用,且抗肿瘤活性优于其他类TXNRD1抑制剂,有望制备成抗肿瘤药物,丙炔酰胺衍生物类小分子化合物对人乳腺癌细胞(MDA-MB-231)具有很好的抑制作用,其IC50值可低至4.72nM,可制备成抗乳腺癌药物。
附图说明
图1为丙炔酰胺衍生物类小分子化合物的制备化学式;
图2为XF-5079-D对TXNRD1在分子层面和细胞层面的测试结果,A为化合物对重组TXNRD1纯酶的抑制IC50曲线,B为化合物对细胞TXNRD的抑制IC50曲线,C为化合物在体外试验中对各类细胞的抗增殖效果;
图3为在小鼠皮下乳腺癌细胞移植瘤模型中给药期间的肿瘤变化情况,A为给药27天内肿瘤体积变化情况,B为给药27天后剥离的乳腺癌皮下肿瘤的质量图,C为给药27天后剥离的乳腺癌皮下肿瘤外观图,D为化合物和阳性对照紫杉醇的肿瘤抑制率;
图4为抑制剂的分子结构式。
具体实施方式
下面对本发明的具体实施方式作进一步说明。在此需要说明的是,对于这些实施方式的说明用于帮助理解本发明,但并不构成对本发明的限定。此外,下面所描述的本发明各个实施方式中所涉及的技术特征只要彼此之间未构成冲突就可以相互组合。
下述实施例中的实验方法,如无特殊说明,均为常规方法,下述实施例中所用的试验材料,如无特殊说明,均为可通过常规的商业途径购买得到的。
实施例1
本实施例提供一种丙炔酰胺衍生物类小分子化合物(XF-5079-D)的制备方法。
研究发现,本发明的丙炔酰胺衍生物类小分子化合物可特异性靶向TXNRD1,丙炔酰胺衍生物类小分子化合物的制备方法按图1所示的反应式进行:
根据图1反应式,将式1所示化合物(亚胺,133mg,0.48mmol),式2所示化合物(丙炔酰胺,27mg,0.40mmol),辛酸铑(Rh2(oct)4,3mg,0.004mmol),磷酸(联萘酚磷酸酯,3.5mg,0.01mmol),分子筛(50mg)加入到25mL单口瓶中,氮气置换处理,再加入无水二氯甲烷溶剂(DCM,8mL),制成混合溶液a,并降温至0℃;将式3(重氮化合物,123mg,0.60mmol)溶于无水二氯甲烷溶剂(DCM,8mL)中,制成溶液b,将混合溶b液用蠕动泵缓慢注入到溶液a中,约2小时注入完毕,滴毕后,0℃条件下搅拌8小时。TLC检测重氮原料消耗完毕,过滤除去分子筛,滤液减压浓缩,粗品经柱层析分离(PE:EA=15:1),得白色固体,石油醚和二氯甲烷重结晶,得白色晶体式(I)(XF-5079-D,160mg,76%)。产物的谱图信息如下:
1H NMR(500MHz,CDCl3)δ7.5–7.4(m,2H),7.2–7.1(m,2H),7.1–6.9(m,4H),6.9–6.8(m,2H),6.4–6.3(m,1H),6.3–6.2(m,1H),6.2–6.1(m,1H),5.7(d,J=6.8Hz,1H),5.4(d,J=6.8Hz,1H),3.9(s,3H),3.8(s,3H),2.8(s,1H).13C NMR(125MHz,CDCl3)δ170.59,164.88,162.94,159.62,151.17,147.69,147.61,136.70,131.67,130.42,130.34,129.64,129.08,127.13,122.47,113.68,109.27,109.25,104.74,104.57,100.46,100.25,73.87,69.54,59.06,55.29,53.79.19F NMR(471MHz,CDCl3)δ-112.47.
实施例2
如图2所示,本实施例提供体外酶学丙炔酰胺衍生物(XF-5079-D)对TXNRD1酶活力的测定。
(1)DTNB还原法测定重组TXNRD1酶活力
1)化合物、酶及缓冲液配置
①制备含有EDTA(0.4mM)的磷酸盐PB缓冲液(PH 7.4)。
②重组纯酶Thioredoxin reductase 1(rat,recombinant,购自Cayman公司,ItemNo.30586)用配得的PB缓冲液稀释200倍。
③用所配PB缓冲液配置1mM NADPH溶液和15mM的DTNB溶液,化合物XF-5079-D使用DMSO梯度稀释为目标浓度60X的母液。
④使用96孔板100uL标准反应体系测定酶的剩余活力:每孔依次加入56uL PB缓冲液,3uL纯酶、1uL化合物XF-5079-D,在37℃下孵育30分钟。
2)吸光度的测定
孵育结束后,每孔迅速加入20uL的NADPH和DTNB溶液,通过动力学检测跟踪412nm下TNB-10min内的生成量,用以计算酶的活力。
3)实验结果
以动力学检测1min所得数据进行处理,化合物对重组TXNRD1酶活力的半数抑制浓度如表1所示
表1重组TXNRD1酶活力的半数抑制浓度
化合物 | 重组TXNRD1酶活力的半数抑制浓度 |
XF-5079-D | 0.86±0.36nM |
(2)细胞中TXNRD酶活力的测定
1)细胞培养
本实验中所用的MDA-MB-231(购自ATCC)细胞培养于含有10%胎牛血清与1%双抗(青霉素与链霉素)的DMEM培养基中,置于37℃。5%CO2的细胞培养箱中进行培养。
2)DTNB还原法测定细胞TXNRD酶活力
①本实验所用试剂为硫氧还蛋白还原酶活性检测试剂盒(Solarbio公司,BC1115)。不同浓度梯度的化合物处理六孔板中7x105个已贴壁的细胞2小时,孵育结束后按照试剂盒步骤依次处理样本与测定。
②利用BCA法测定蛋白浓度,本实验所用试剂为BCA蛋白浓度测定试剂盒(Beyotime公司P0010),按照试剂盒步骤测定酶活实验中所得细胞裂解上清液中蛋白浓度。
3)实验结果
通过动力学检测跟踪412nm下TNB-10min内的生成量,用以反应酶的活力。所得细胞TXNRD活性用BCA法所测得的蛋白浓度做归一化处理。以动力学检测3min所得数据进行处理,化合物对细胞TXNRD酶活力的半数抑制浓度如表2所示:
表2TXNRD酶活力的半数抑制浓度
化合物 | TXNRD酶活力的半数抑制浓度 |
XF-5079-D | 55.87±29.51nM |
实施例3
如图2所示,本实施例提供丙炔酰胺衍生物(XF-5079-D)在体外模型对肿瘤细胞生长抑制作用的测定。
(1)CCK-8法测定细胞活力
1)细胞培养:
本实验中所用的MDA-MB-231、LX-2(购自ATCC)细胞培养于含有10%胎牛血清与1%双抗(青霉素与链霉素)的DMEM培养基中,SKOV3、Caki-1、Kyse-520(购自ATCC)细胞培养于含有10%胎牛血清与1%双抗(青霉素与链霉素)的RPIM-1640培养基中上述细胞均置于37℃。5%的细胞培养箱中进行培养。
2)化合物活性测试
①在96孔板中接种细胞悬液200uL(5000个/孔),将96孔板置于37℃。5%的细胞培养箱中进行培养24h。化合物使用DMSO溶解,将不同浓度的的化合物加入培养板1uL,继续孵育48h。
②弃去培养基,向其加入10%CCK-8的新鲜培养基,37℃、5%CO2孵育2小时后,测定450nm下的吸光度。
3)实验结果
如表3所示,化合物XF-5079-D在多种细胞系中显示出纳摩尔范围的IC50,并具有一定的细胞系差异,在三阴乳腺癌细胞MDA-MB-231中活性最好,其在对正常人肝星型细胞系LX2的选择性为300倍。
表3化合物XF-5079-D在多种细胞系中的IC50
实施例4
如图3所示,本实施例提供丙炔酰胺衍生物(XF-5079-D)在体内模型对肿瘤生长的抑制作用研究。
(1)对小鼠皮下乳腺癌4T1细胞移植瘤模型的影响
1)肿瘤小鼠模型建造及给药方案
①取对数生长期的小鼠乳腺癌细胞(4T1乳腺癌细胞),消化后计数,将预冷PBS与Mat rigel按1:1的比例混合,重悬细胞,得到浓度为5x106个/ml的细胞悬液,置于冰上。
②在4-5周龄的Balb/C小鼠腹背两侧的皮下部位各注射100uL细胞悬液,待皮下肿瘤大小为50mm时,随机分为四组,组别及给药设置如下;
空白对照组;
给药组:XF-5079-D 5mg/Kg组;XF-5079-D 10mg/Kg组;
阳性对照组:Taxol 15mg/Kg组。
给药:对照组隔天安慰剂(即溶药所用溶剂:15%蓖麻油+85%无菌PBS)腹腔注射100uL;其余各给药组隔天腹腔注射不同剂量的药物溶液100uL。
③连续给药27天内,隔天测量小鼠体重和肿瘤大小,绘制小鼠体重生长曲线;
④给药27后,处死小鼠进行解剖,剥离皮下肿瘤,称重。
2)实验结果
实验结果如表4所示,表为在小鼠皮下乳腺癌细胞移植瘤模型中给药后的抑瘤率,10mg/kg化合物XF-5079-D与15mg/kg紫杉醇活性相当,均能够抑制小鼠的肿瘤的生长。
表4小鼠皮下乳腺癌细胞移植瘤模型中给药后的抑瘤率
分组 | 抑瘤率TGI(%) |
XF-5079-D 5mg/Kg | 27.7% |
XF-5079-D 10mg/Kg | 66.3% |
Taxol 15mg/Kg | 65.5% |
通过Balb/c小鼠皮下细胞移植肿瘤模型实验发现,丙炔酰胺衍生物类小分子化合物能够有效抑制乳腺癌细胞的生长。
以上对本发明的实施方式作了详细说明,但本发明不限于所描述的实施方式。对于本领域的技术人员而言,在不脱离本发明原理和精神的情况下,对这些实施方式进行多种变化、修改、替换和变型,仍落入本发明的保护范围内。
Claims (10)
1.一种选择性靶向TXNRD1的抑制剂,其特征在于,所述抑制剂为丙炔酰胺类衍生物小分子化合物,所述抑制剂的结构如式(I)所示:
2.权利要求1所述的选择性TXNRD1的抑制剂在制备靶向TXNRD1的药物中的应用。
3.权利要求1所述的选择性TXNRD1的抑制剂在制备抗肿瘤药物中的应用。
4.根据权利要求3所述的抑制剂在制备抗肿瘤药物中的应用,其特征在于,所述肿瘤包括但不限于乳腺癌。
5.权利要求1所述的选择性TXNRD1的抑制剂在制备抑制肿瘤细胞生长的药物中的应用。
6.根据权利要求5所述的选择性TXNRD1的抑制剂在制备抑制肿瘤细胞生长的药物中的应用,其特征在于,所述肿瘤细胞包括但不限于乳腺癌细胞。
7.包含权利要求1所述的选择性靶向TXNRD1的药物,其特征在于,所述的选择性TXNRD1的抑制剂作为主要活性成分。
8.根据权利要求7所述的选择性靶向TXNRD1的药物,其特征在于,所述选择性TXNRD1抑制剂还包括丙炔酰胺衍生物类小分子化合物在药学上可接受的载体或赋形剂混合制备成组合物,并制备成临床上可接受的剂型。
9.根据权利要求8所述的选择性靶向TXNRD1的药物,其特征在于,所述载体是药物领域中可接受的功能性药用辅料,包括表面活性剂、助悬剂、乳化剂以及一些药用高分子材料。
10.根据权利要求8所述的选择性靶向TXNRD1的药物,其特征在于,所述赋形剂是指用于药学领域的稀释剂、黏合剂、润滑剂、崩解剂、助溶剂、稳定剂以及其他一些药用基质。
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