CN101792449B - 阿吗碱类衍生物及制备和用途 - Google Patents
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Abstract
本发明提供了一种阿吗碱类衍生物及其可药用的盐,通过将取代异胡豆苷在β-糖苷酶的作用下脱去一分子葡萄糖,然后经过量的硼氢化钠还原制备得到。本发明提供的化合物,体外对人肺癌细胞和人慢性髓原细胞白血病细胞的细胞毒活性试验表明,此类阿吗碱类衍生物对肿瘤细胞生长具有抑制作用,可在制备防治肺癌和慢性髓原细胞白血病药物中应用。具有以下结构通式。
Description
发明领域
本发明属酶化学、药物化学和药理学领域,涉及一种阿吗碱类衍生物及制备方法,以及该类化合物在制备抗肿瘤药物中的用途。
发明背景
萜类吲哚生物碱是天然产物中的一大类,它具有非常广泛的药理活性,如具有抗癌活性的长春花碱、长春新碱和喜树碱等,研究发现,大多数的萜类吲哚生物碱都是从异胡豆苷经不同的次生代谢转化而来的,而异胡豆苷合成酶(STR)是异胡豆苷合成中的关键酶。在了解生源途径的基础上,研究人员对其生源合成途径中的关键酶异胡豆苷合成酶进行了深入的研究,对其三维结构、催化功能等方面有了进一步的认识(Joachim Stockigt,Santosh Panjikar,Structural biology in plant natural product biosynthesis-architecture of enzymesfrom mono-terpenoid indole and tropane alkaloid biosynthesis.Natural ProductReports,2007,24,1382-1400)。然而基于该酶催化活性功能基础上的新活性生物碱化合物的合成却鲜有报道。由于萜类吲哚生物碱具有良好的药理活性,发明人在上述研究基础上已经有对异胡豆苷合成酶结构进行一定的改造经验,从而使其能催化合成一系列的取代异胡豆苷(Elke A.Loris,Santosh Panjikar,Martin Ruppert,Leif Barleben,Matthias Unger,Helmut Schubel,Joachim Stockigt,Structure-Based Engineering of Strictosidine Synthase:Auxiliary for AlkaloidLibraries.Chemistry & Biology,14,1-6.)。因此,本发明着重从通过获得的取代异胡豆苷衍生物通过一定的化学方法将其转化为新的阿吗碱类衍生物,丰富了生物碱的多样性,同时体外的细胞毒活性实验表明,该发明为发现抗肿瘤生物碱药物提供了一种机遇。
发明内容
本发明的目的是提供一种阿吗碱类衍生物及其可药用的盐,具有以下结构通式:
其中:
W,X,Y,Z相同或不同,选用碳、氮;
R1,R2,R3,R4相同或不同,选用氢、硝基、卤素、羟基、胺基、酰基、含1~8个碳的饱和或不饱和烃基或烷氧基或含1~8个碳的烷胺基或酰基;
当W,X,Y,Z都为碳时,若R2,R3,R4都为氢时,R1不能为甲氧基;若R1,R3,R4都为氢时,R2不能为甲基、氯、氟、甲氧基、胺基、羟基、硝基或甲酰基;若R1,R2,R4都为氢时,R3不能为羟基或甲氧基;若R1,R2,R3都为氢时,R4不能为甲基;若R1,R4都为氢时,R2,R3不能同时为甲氧基。
优选的式(I)化合物是:
I-1:(3α,15α,19α)-12-氮杂-16,17-双脱氢-19-甲基-氧代育亨宾烷-16-甲酸甲酯,
I-2:(3α,15α,19α)-12-甲氧基-16,17-双脱氢-19-甲基-氧代育亨宾烷-16-甲酸甲酯,
I-3:(3α,15α,19α)-11-氯-16,17-双脱氢-19-甲基-氧代育亨宾烷-16-甲酸甲酯。
本发明的另一个目的是提供一种由取代异胡豆苷类化合物制备式(I)化合物的方法:将取代异胡豆苷在酶(β-糖苷酶)的作用下脱去一分子葡萄糖,然后经过量的硼氢化钠还原制备得到式(I)化合物,反应式为:
本发明的再一个目的是提供阿吗碱类衍生物及其可要用的盐在制备防治肺癌和慢性髓原细胞白血病药物中的应用。
本发明式(I)化合物具有重要的生物活性,体外对人肺癌细胞(A549),人慢性髓原细胞白血病细胞(K562)肿瘤细胞的细胞毒活性试验表明此类新阿吗碱类衍生物对肿瘤细胞生长具有抑制作用,可在制备防治肺癌和慢性髓原细胞白血病药物中应用。
本发明的有益之处是:着重对阿吗碱类衍生物进行探索,提供了基于异胡豆苷合成酶催化的快速一步法合成具有多个手性中心多环结构的吲哚类生物碱的方法;提供的新阿吗碱类衍生物具有重要的生物活性,体外对多株肿瘤细胞有抑制作用,可制备成新的防治肺癌和慢性髓原细胞白血病的药物。
具体实施方式
下面通过具体的实施例进一步说明本发明。下述实施例给出了代表性化合物的合成及相关结构鉴定数据。必须说明,下述实施例是用于说明本发明而不是对本发明的限制。根据本发明的实质对本发明进行的简单改进都属于本发明要求保护的范围。
实施例1:(3α,15α,19α)-12-氮杂-16,17-双脱氢-19-甲基-氧代育亨宾烷-16-甲酸甲酯(化合物I-1)的制备
本例涉及到一类如式(I)所示的具有细胞毒活性的新阿吗碱类衍生物的一般合成方法。具体涉及(3α,15α,19α)-12-氮杂-16,17-双脱氢-19-甲基-氧代育亨宾烷-16-甲酸甲酯的合成。将12-氮杂异胡豆苷(20毫克,0.0376毫摩尔)溶于醋酸缓冲液(pH 5.0,2.0毫升),再将β-糖苷酶(10毫克)加入反应液中,在氮气保护下于37℃搅拌24小时,而后反应液冷冻干燥,冻干产物加入适量甲醇溶解后离心,取上清液加入到反应瓶中,在氮气保护下加入冰醋酸(32.0毫升)和过量的硼氢化钠(21.0毫克),室温反应过夜,减压蒸馏除去溶剂并用水(5.0毫升)溶解,然后用乙酸乙酯萃取三次(3×10.0毫升),合并后的有机相分别用水和饱和食盐水洗涤后浓缩除去溶剂,所得粗品用制备液相分离得到(3α,15α,19α)-12-氮杂-16,17-双脱氢-19-甲基-氧代育亨宾烷-16-甲酸甲酯(化合物I-1)。
下面用统一方式表述合成得到的化合物的物理及化学数据。包括比移值(Rf)及其展开溶剂、核磁共振氢谱(1H NMR,数据于500MHz核磁共振仪得到)、核磁共振碳谱(13C NMR,数据于125MHz核磁共振仪得到)、电喷雾质谱(ESI-MS);1H NMR和13C NMR所使用的试剂一般为氘代氯仿(CDCl3);NMR谱图峰形表示为:单峰(s)、双峰(d)、宽单峰(brs)、双双峰(dd)、三重峰(t)、四重峰(q);耦合常数(J)的单位用赫兹(Hz)表示;化学位移值(δ)单位用ppm表示。
化合物I-1:淡黄色固体;收率49.7%;Rf(氯仿/甲醇18∶1)0.36;ESI-MS m/z[M+H]+354;1H NMR(500MHz,CDCl3):δ9.92(1H,s,NH),8.28(1H,d,J=5.0Hz,H-9),7.60(1H,d,J=8.0Hz,H-11),7.56(1H,s,H-17),7.04(1H,dd,J=8.0,5.0Hz,H-10),4.52(1H,m,H-19),3.76(3H,s,COOCH3-16),3.43(1H,dd,J=11.5,2.0Hz,H-3),3.12(1H,dd,J=12.5,1.5Hz,H-21b),2.98(1H,m,H-5a),2.92(1H,m,H-6b),2.83(1H,dt,J=12.0,4.5Hz,H-6a),2.76(1H,dd,J=12.5,3.5Hz,H-21a),2.68(1H,m,H-5b),2.61(1H,m,H-15),2.58(1H,m,H-20),1.59(2H,m,H-14),1.41(3H,d,J=6.5Hz,CH3-19);13C-NMR(125MHz,CDCl3):168.0(COOCH3-16),155.8(C-17),149.2(C-13),142.3(C-2),135.5(C-11),126.2(C-8),120.1(C-10),115.7(C-9),109.7(C-16),106.6(C-7),72.5(C-19),59.9(C-3),56.6(C-21),53.5(C-5),51.3(COOCH3-16),38.6(C-20),34.3(C-14),31.5(C-15),21.8(C-6),18.7(CH3-19)。
实施例2:化合物I-2和I-3的制备
根据实施例1的方法,以相应的12-甲氧基异胡豆苷和11-氯代异胡豆苷为原料,经β-糖苷酶脱糖和硼氢化钠还原制备得到化合物I-2和I-3。
化合物I-2:淡黄色固体;收率51.3%;Rf(氯仿/甲醇15∶1)0.35;ESI-MS m/z[M+H]+431;1H NMR(500MHz,CDCl3):δ7.81(1H,s,NH),7.56(1H,s,H-17),7.46(1H,d,J=8.0Hz,H-9),7.17(1H,d,J=7.5Hz,H-11),7.08(1H,dd,J=7.5,8.0Hz,H-10),4.50(1H,m,J=6.5Hz,H-19),3.84(3H,s,CH3O-12),3.75(3H,s,COOCH3-16),3.60(1H,dd,J=11.5,1.5Hz,H-3),3.11(1H,dd,J=12.5,1.5Hz,H-21b),2.96(1H,m,H-5a),2.92(1H,m,H-6b),2.68-2.78(3H,m,H-6a,21a,5b),2.47-2.59(2H,m,H-15,20),1.53(2H,m,H-14),1.41(3H,d,J=6.5Hz,CH3-19)。
化合物I-3:淡黄色固体;收率54.8%;Rf(氯仿/甲醇15∶1)0.38;ESI-MS m/z[M+H]+371;1H NMR(500MHz,CDCl3):δ8.25(1H,s,NH),7.73(1H,s,H-12),7.56(1H,s,H-17),7.43(1H,d,J=7.5Hz,H-9),7.07(1H,d,J=7.5Hz,H-10),4.48(1H,m,J=6.5Hz,H-19),3.76(3H,s,COOCH3-16),3.58(1H,dd,J=11.5,1.5Hz,H-3),3.10(1H,dd,J=12.5,1.5Hz,H-21b),2.95(1H,m,H-5a),2.90(1H,m,H-6b),2.66-2.76(3H,m,H-6a,21a,5b),2.49-2.58(2H,m,H-15,20),1.55(2H,m,H-14),1.39(3H,d,J=6.5Hz,CH3-19)。
为了更好地理解本发明的实质,下面通过药理实施例进一步说明本发明。药理实施例给出了代表性化合物的部分活性数据。必须说明,下述药理实施例是用于说明本发明而不是对本发明的限制,根据本发明的实质对本发明进行的简单改进都属于本发明要求保护的范围。
实施例3:化合物I-1对A549细胞的细胞毒活性
A549(人肺癌)细胞用RPMI 1640培养基培养,培养基中含10%的胎牛血清,100U/毫升青霉素和100U/毫升的链霉素。细胞以每孔5×103的浓度加入到96孔板中,在37℃含5%CO2潮湿空气的培养箱中培养24小时。
细胞存活率的测定用改良MTT法。细胞经过24小时的孵育后,分别将新配的化合物I-1的二甲亚砜溶液以浓度梯度加入到各孔中,使孔中化合物最终浓度分别为100微克/毫升,33.3微克/毫升,11.1微克/毫升和3.7微克/毫升。72小时后,加入10微升MTT(5毫克/毫升)的磷酸盐缓冲液,再继续在37℃培养4小时后,离心5分钟除去未转化的MTT,每孔中加入200微升二甲亚砜,以溶解还原的MTT晶体甲臜(formazan),所形成的formazan用酶标仪在570nm波长下比色,细胞存活率由样品相对于对照品的比值计算。
其中化合物I-1对A549细胞半抑制浓度IC50由剂量效应曲线得到。化合物I-1的IC50为16.6μM。
本试验以抗肿瘤一线用药喜树碱(CPT)作为阳性对照,CPT对人肺癌A549细胞的半抑制浓度IC50为0.11μM。
本试验表明此类新阿吗碱类衍生物对人肺癌A549细胞具有较强的细胞毒性,有可能发展成为新的具有抗肺癌作用的药物。
实施例4:化合物I-2对人慢性髓原细胞白血病细胞(K562)的细胞毒活性
人慢性髓原细胞白血病细胞(K562)用RPMI 1640培养基培养,培养基中含10%小牛血清,100U/毫升青霉素和100U/毫升链霉素。细胞以每孔1×104个密度接种到96孔板中,在37℃,5%CO2潮湿空气的培养箱中培养24小时。
细胞存活率的测定方法用改良MTT法。细胞经24小时的孵育后,分别将新配的化合物I-2的二甲亚砜溶液以浓度梯度加入到各孔中,使孔中化合物的最终浓度分别为100微克/毫升、50微克/毫升、25微克/毫升、5微克/毫升。72小时后,加入10微升MTT(5毫克/毫升)的生理盐水溶液,再继续在37℃,5%CO2潮湿空气的培养箱中培养3小时,每孔中加入150毫升二甲亚砜,振荡溶解生成的MTT晶体甲臜(formazan),所形成的甲臜用酶标仪在570nm波长下比色,细胞存活率由样品OD值对于对照OD值的比值计算。其中化合物I-2对K562细胞的半数抑制浓度(IC50)由剂量效应曲线得到。
细胞存活率的测定用改良MTT法,具体方法同实施例4。
对人慢性髓原细胞白血病K562细胞半抑制浓度IC50由剂量效应曲线得到。化合物I-2的IC50为:58.3μM。
本试验以抗肿瘤一线用药喜树碱(CPT)作为阳性对照,CPT对人慢性髓原细胞白血病细胞的半抑制浓度IC50为0.6μM。
本实验表明此类新阿吗碱类衍生物对人慢性髓原细胞白血病癌细胞K562细胞具有细胞毒性,有可能发展成为新的具有抗慢性髓原细胞白血病作用的药物。
Claims (2)
1.一种化合物及其可药用的盐,其特征在于,所述化合物是:
I-2:(3α,15α,19α)-12-甲氧基-16,17-双脱氢-19-甲基-氧代育亨宾烷-16-甲酸甲酯。
2.根据权利要求1所述的化合物及其可药用的盐在制备防治慢性髓原细胞白血病药物中的应用。
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