CN112047901B - 苯并噻唑杂萜类化合物及其衍生物以及制备方法与应用 - Google Patents
苯并噻唑杂萜类化合物及其衍生物以及制备方法与应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及药物化合物技术领域,具体涉及一种苯并噻唑杂萜类化合物及其衍生物以及制备方法与应用。
背景技术
肿瘤是当今严重威胁人类健康的疾病之一。核受体是一类配体依赖性的转录调节因子,分布于细胞中胞浆及细胞核内,在维持机体的稳态中发挥重要作用。视黄醇X受体(RXR)是核受体家族中重要的一份子,则被认为是最具有开发前景的核心成员,在调控肺癌、乳腺癌、肝癌和***癌等多种癌细胞的增殖和凋亡中发挥重要作用。RXRα包含一个N-末端区域、一个DNA结合域和一个配体结合域(LBD)。RXRα-LBD具有一个配体结合袋(LBP)用于小分子与配体的结合,它能够识别特定的激素和非激素配体。RXR配体能通过激活或拮抗的方式调节RXR相关信号通路,且都能在不同程度上起到对代谢性疾病或癌症的作用,因此RXRα配体的发现是研究热点。在先前报道的RXRα-LBD配体(如全反式维甲酸、9-顺式磺酸、靶向雷丁、CD3254、K8003、K8008)中有三个基本区域:疏水基、极性区和中心聚烯键连接体结构。
虽然目前已经报道了许多RXRα的天然配体,但它们的选择性较差,毒性较高。海洋微生物由于生存在特殊的海洋环境中能够产生结构新颖的次级代谢产物,且来源于海洋的这些次级代谢产物生物碱类、萜类、黄酮类化合物等可表现出强的抗肿瘤活性。因此,从天然产物中发现高效低毒的RXRα小分子调节剂是开发基于RXRα靶点的抗肿瘤药物的有效策略。
发明内容
本发明的目的在于提供一种苯并噻唑杂萜类化合物及其衍生物以及制备方法和引用,该苯并噻唑杂萜类化合物及其衍生物分离自青霉菌Penicillium allii-sativi的发酵产物,其具有显著的抗肿瘤活性,可用于抗癌药物的制备和研发。
为此,本发明的第一方面提供一种苯并噻唑杂萜类化合物及其衍生物,其为式I~III所示的化合物或其盐:
本发明的第二方面,提供上述苯并噻唑杂萜类化合物及其衍生物的制备方法,包括以下步骤:
S1、将青霉菌Penicillium allii-sativi进行发酵培养,得到发酵物;所述青霉菌Penicillium allii-sativi保藏于中国海洋微生物菌种保藏管理中心(Marine CultureCollection of China,MCCC),保藏编号为MCCC 3A00580;
S2、将步骤S1得到的发酵物进行萃取,所得萃取物经分离纯化,得到所述苯并噻唑杂萜类化合物及其衍生物。
优选的,步骤S2包括:
S21、将步骤S1得到的发酵物进行萃取发酵物用乙酸乙酯萃取,取有机萃取物进行层析,分别使用石油醚,二氯甲烷和甲醇进行洗脱;浓缩二氯甲烷层,得到粗提物;
S22、将步骤S21得到的粗提物用正相硅胶柱色谱进行分离,用石油醚-乙酸乙酯体系进行梯度洗脱,依次得到8个粗馏分:Fr.1~Fr.8;
S23、将步骤S22得到的粗馏分Fr.5先使用ODS柱色谱进行分离,使用水-甲醇体系进行梯度洗脱依次得到11段粗馏分:Fr.5.1~Fr.5.11;
S24、将步骤S23得到的粗馏分Fr.5.9用葡聚糖凝胶柱和半制备液相色谱柱分离后得到式I化合物;
S25、将步骤S22得到的粗馏分Fr.6先使用葡聚糖凝胶柱色谱进行分离,得到3段粗馏分:Fr.6.1~Fr.6.3;
S26、将步骤S25得到的粗馏分Fr.6.2用ODS柱色谱和和半制备液相色谱柱分离后得到式II化合物和式III化合物。
进一步的,步骤S22中所用正相硅胶柱色谱洗脱溶剂为石油醚-乙酸乙酯体系,比例为100:1,50:1,30:1,10:1,5:1,3:1,1:0。
进一步的,步骤S23中ODS柱所用流动相为甲醇-水,梯度洗脱(40%→100%,15×310mm,20ml/min)。
进一步的,步骤S24中葡聚糖凝胶柱所用流动相为甲醇,半制备液相色谱柱所用流动相为乙腈-水,梯度洗脱(ACN-H2O,60%→100%,10×250mm,5ml/min)。
进一步的,步骤S25中葡聚糖凝胶柱所用流动相为甲醇。
进一步的,步骤S26中ODS柱所用流动相为甲醇-水,梯度洗脱(40%→100%,15×310mm,20ml/min);半制备液相色谱柱所用流动相为乙腈-水,梯度洗脱(ACN-H2O,40%→100%,10×250mm,5ml/min)。
优选的,步骤S1中,所述青霉菌Penicillium allii-sativi的发酵培养条件包括:将菌丝体接到含有PDB的培养液中,经培养获得种子液;将所述种子液接种到发酵培养基中,于28℃静态培养30天;所述发酵培养基包括燕麦80g和盐度3%的海水120ml。
进一步,步骤S1中,所述菌丝体通过以下步骤制备得到:将青霉菌Penicilliumallii-sativi在PDA平板上于28℃培养3~4天,获得所述菌丝体。
本发明的第三方面,提供上述苯并噻唑杂萜类化合物及其衍生物化合物及其衍生物或其盐在制备以下产品中的应用:1)肿瘤细胞增殖抑制剂;2)预防和/或***疾病的药物。
优选的,所述肿瘤细胞包括但不限于***细胞、肝癌细胞乳腺癌细胞、***癌细胞。
优选的,所述肿瘤疾病包括包括但不限于***、肝癌、乳腺癌和***癌。
本发明的有益效果:
与现有技术相比,本发明具有以下优点:
本发明提供了三个新的化合物meroterpenthiazole A(式I),4-(5-hydroxy-7-methylbenzo[d]thiazol-4-yl)-2-methylbutanoic acid(式II),4-(5-hydroxy-4-methylbenzo[d]thiazol-7-yl)-2-methylbutanoic acid(式III),其分离自深海青霉菌Penicillium allii-sativi的发酵液,其中化合物meroterpenthiazole A是由倍半萜与苯并噻唑环组成的新骨架化合物,是一类结构新颖的含硫杂萜次生代谢产物,而在自然界中,含噻唑环的结构是非常罕见的。本发明首次发现了倍半萜与苯并噻唑环组成的新骨架化合物,这对于发现和研究新的RXRα靶点具有重要意义;本发明从发酵液中分离化合物I~III的方法,具有环保、步骤简单、产品纯度高等优点;本发明通过RXRα双报告基因实验、表面离子共振技术、分子对接技术以及细胞毒活性实验证明了该化合物I~III是通过与抗肿瘤靶点RXRα结合来抑制其转录活性来达到抗癌效果。因此,本发明提供的三个新化合物在制备抗癌药物方面具有良好的应用前景。
附图说明
通过阅读下文优选实施方式的详细描述,各种其他的优点和益处对于本领域普通技术人员将变得清楚明了。附图仅用于示出优选实施方式的目的,而并不认为是对本发明的限制。
图1为本发明的化合物I~III对RXRα的转录活性结果。
图2为本发明的化合物I与RXRα-LBD的结合结果。
实施例1.苯并噻唑杂萜类化合物的制备。
(1)将青霉菌Penicillium allii-sativi(保藏于中国海洋微生物菌种保藏管理中心,保藏编号MCCC 3A00580)在PDA平板上于25℃培养3天;然后将新鲜的菌丝体接到含有400ml PDB的培养液中;24h后,将10ml种子液接种到1L的三角烧瓶中(100瓶),每瓶中有80g燕麦和120ml盐度3%的海水,在28℃下静态培养30天;
(2)将步骤(1)得到的发酵物用乙酸乙酯萃取三次,减压蒸发掉有机溶剂,得到有机萃取物(200g);将这些萃取物过正相柱层析柱,分别使用石油醚,二氯甲烷和甲醇进行洗脱;浓缩二氯甲烷层,得到粗提物(63.0g);
(3)将步骤(2)得到的粗提物使用正相硅胶柱色谱进行分离,用石油醚-乙酸乙酯体系进行梯度洗脱,得到8个粗馏分(Fr.1~Fr.8);
(4)将步骤(3)中的粗馏分Fr.5(3.5g)先使用ODS柱色谱进行分离,使用水-甲醇体系进行梯度洗脱得到11段粗馏分(Fr.5.1-Fr.5.11)。Fr.5.9(89.1mg)使用葡聚糖凝胶柱(纯甲醇)和半制备液相色谱柱(乙腈-水,60%→100%)分离后得到式I化合物(6.2mg)。Fr.6(7.0g)使用葡聚糖凝胶色谱柱(纯甲醇),ODS色谱柱(甲醇-水,40%→100%)和半制备液相色谱柱(乙腈-水,40%→100%)分离后得到式II化合物(4.8mg)和式III化合物(3.7mg)。
(5)将上述步骤中得到的式I、式II、式III化合物分别用1D、2D NMR图谱以及高分辨质谱分析确定化合物的平面结构,然后利用ECD计算等确定其绝对构型,详述如下:
式I化合物为白色粉末。根据其在高分辨质谱中的主离子峰确定其分子式为C26H34N2O4S。1H、13C NMR数据(表1)以及DEPT和HMBC图谱显示26个碳信号,包括4个甲基,8个亚甲基,3个次甲基和11个季碳,经过详细的二维数据确定了化合物的平面结构,最后利用NOE图谱和ECD和13C NMR计算确定了式I化合物的相对及绝对构型,并命名为meroterpenthiazole A。
表1.式I~III化合物的1H和13C NMR数据
a DMSO;b CD3OD
式II化合物的分子式为C13H15NO3S,1H、13C NMR数据(表1)显示有13个碳,包括2个甲基,2个亚甲基,3个次甲基和6个季碳。这些信号与式1化合物中的部分数据相似。通过详细的1D、2D NMR解析,确定式II化合物为:4-(5-hydroxy-7-methylbenzo[d]isothiazol-4-yl)-2-methylbutanoic acid。
式III化合物的分子式为C13H15NO3S。其1H、13C NMR数据,除了C-4、C-7和C-12之外,其他与式II非常相似(表1)。通过详细的波谱解析,确定其结构为:4-(5-hydroxy-4-methylbenzo[d]thiazol-7-yl)-2-methylbutanoic acid。
实施例2.RXRα双报告基因活性检测:检测化合物是否会影响RXRα的转录活性,并初步探讨化合物是否可能存在与RXRα结合的作用。
本实施例采用的是萤火虫荧光素酶(Firefly luciferase,FL)报告基因和海肾荧光素酶(Rellina luciferase,RL)报告基因组成的双萤光素酶报告基因(Dual-luciferasereporter,DLR)检测***。RL报告基因作为内对照,使FL报告基因的测量结果正态化。在缺少内源性RXRα及其下游信号传导必要组成的细胞中,通过转染的方法引入受体RXRα以及含有RXRα应答元件的报告基因,从而简单模拟体内受体的转录活化过程。
本实施例设置以下3组:
阴性对照组:等量培养液,0.1%DMSO,含细胞,不加入式I~III化合物
阳性对照组:等量培养液,分别加入RXRα激动剂9-顺视黄酸,拮抗剂UVI3003;实验组:向细胞培养液分别加入式I~III化合物;
具体步骤包括:
(1)细胞的培养和供试品的配制
人胚肾细胞(293T)用含10%胎牛血清(fetal bovine serum,FBS)的DMEM培养基,在含5%CO2的37℃孵箱中培养,按细胞的生长规律定期传代,实验所用细胞均处于对数生长期。将待测样品、9-顺视黄酸(9-cis-RA)、UVI3003用DMSO配成储存液,临用前用含10%FBS的培养液稀释成所需的浓度。
(2)活性的测定
将人胚肾细胞(293T)以1×104/孔接种于96孔培养板,37℃培养24h;80-90%融合度的细胞换液,用脂质体转染目的质粒于细胞中;细胞转染后24h加药(12.5μM、25μM、50μM),药物持续作用12h;然后,细胞用PBS洗涤,加入40μL的细胞裂解液PLB(passive lysisbuffer),在摇床上中速振摇20min后,分出取20μl裂解液转移到96孔遮光板中,每孔加入50μL的荧光素酶检测试剂II(LARII)后立即测量萤火虫荧光素酶的活性,随后加入50μL的Stop&GloTM试剂,以淬灭萤火虫荧光素酶反应,同时激活海肾荧光素酶反应,并立即测量海肾荧光素酶的活性。
结果如图1,当与RXRα的激动剂9-cis-RA联合使用的情况下,化合物I能够抑制9-cis-RA对RXRα的转录作用,并表现出明显的浓度依赖性。
实施例3.Biacore实验:评价化合物I~III与RXRα-LBD蛋白有无直接结合。
先将纯化的核受体RXRα-LBD蛋白与Biacore的CM5芯片偶联。然后将待测化合物用PBS稀释配制成不同浓度的溶液后进样。当待测的样品流过芯片表面时,生物分子间的结合引起生物传感器表面质量的增加,导致折射率的变化,通过监测SPR的角度变化,可自动获得分析物的动力学结合和解离常数、亲和力及特异性等。BiacoreT200检测器能实时检测靶蛋白和待测样品之间的相互作用,以RU(response unites,RU)为单位表示结合强弱(芯片表面结合物质浓度改变1pg/mm2定义为1RU)。我们采用Biacore技术对化合物I~III进行筛选,并通过浓度梯度实验计算出小分子化合物与RXRa-LBD的结合常数KD。结果显示见图2,化合物I能够与RXRα蛋白结合,其结合模式为快速结合快速解离,其结合常数为12.3μM。
实施例4.化合物I~III的细胞毒活性检测。
本实施例选择四株肿瘤细胞:***细胞(Hela)、肝癌细胞(HepG2)、乳腺癌细胞(MDA-MB231)和***癌细胞(LNCap)。通过检测化合物样品对这些肿瘤细胞的抑制率,从而检测实施例1制备得到的化合物I~III的细胞毒性。
本实施例设置以下3组:
阴性对照组:等量培养液,0.1%DMSO,含细胞,不加入化合物I~III;
空白对照组:等量培养液,不含细胞,且不加入化合物I~III;
实验组:向细胞培养液分别加入化合物I~III;
具体步骤包括:
(1)细胞经常规消化后,于培养基中重悬并吹打成单细胞悬液,然后以每孔2000~5000个细胞接种到96孔板,每孔体积200μl;
(2)37℃,5%CO2的培养箱中培养24h,然后分别加入不同浓度的化合物处理细胞;
(3)继续培养48h后,每孔加10μl的5mg/ml MTT(3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-diphenytetrazoliumromide),37℃避光反应3h;小心吸弃上清液后,每孔加入150μl DMSO,振荡10min,使结晶物充分融解;
(4)酶标仪测定570nm光吸收值,计算抑制率,
结果化合物I~III对***细胞(Hela)、肝癌细胞(HepG2)、乳腺癌细胞(MDA-MB231)和***癌细胞(LNCap)均无明显的细胞毒性(IC50>50μM)。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到的变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应以所述权利要求的保护范围为准。
Claims (9)
2.如权利要求1所述的苯并噻唑杂萜类化合物及其衍生物的制备方法,其特征在于,包括以下步骤:
S1、将青霉菌Penicillium allii-sativi发酵培养,得到发酵物;所述青霉菌Penicillium allii-sativi保藏于中国海洋微生物菌种保藏管理中心,保藏编号为MCCC3A00580;
S2、将步骤S1得到的发酵物用乙酸乙酯进行萃取,所得萃取物经分离纯化,得到所述苯并噻唑杂萜类化合物及其衍生物。
3.根据权利要求2所述的制备方法,其特征在于,所述步骤S2包括:
S21、将步骤S1得到的发酵物进行萃取,发酵物用乙酸乙酯萃取,取有机萃取物进行层析,分别使用石油醚,二氯甲烷和甲醇进行洗脱;浓缩二氯甲烷层,得到粗提物;
S22、将步骤S21得到的粗提物用正相硅胶柱色谱进行分离,依次得到8个粗馏分:Fr.1~Fr.8;
S23、将步骤S22得到的粗馏分Fr.5先使用ODS柱色谱进行分离,依次得到11段粗馏分:Fr.5.1~Fr.5.11;
S24、将步骤S23得到的粗馏分Fr.5.9用葡聚糖凝胶柱和半制备液相色谱柱分离后得到式I化合物;
S25、将步骤S22得到的粗馏分Fr.6先使用葡聚糖凝胶柱色谱进行分离,得到3段粗馏分:Fr.6.1~Fr.6.3;
S26、将步骤S25得到的粗馏分Fr.6.2用ODS柱色谱和半制备液相色谱柱分离后得到式II和式III化合物。
4.根据权利要求2所述的制备方法,其特征在于,步骤S1中,所述青霉菌Penicilliumallii-sativi的发酵培养条件包括:将菌丝体接到含有PDB的培养液中,经培养获得种子液;将所述种子液接种到发酵培养基中,于28℃静态培养30天;所述发酵培养基包括燕麦80g和盐度3%的海水120ml。
5.根据权利要求4所述的制备方法,其特征在于,步骤S1中,所述菌丝体通过以下步骤制备得到:将青霉菌Penicillium allii-sativi在PDA平板上于28℃培养3~4天,获得所述菌丝体。
6.如权利要求1所述的苯并噻唑杂萜类化合物及其衍生物在制备肿瘤细胞抑制剂中的应用。
7.根据权利要求6所述的应用,其特征在于,所述肿瘤细胞为***细胞、肝癌细胞、乳腺癌细胞和***癌细胞。
8.如权利要求1所述的苯并噻唑杂萜类化合物及其衍生物在制备预防和/或***疾病的药物中的应用。
9.根据权利要求8所述的应用,其特征在于,所述肿瘤疾病为***、肝癌乳腺癌和***癌。
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