CN108383892A - 一种薯蓣皂苷元季铵盐类衍生物及其制备方法及应用 - Google Patents
一种薯蓣皂苷元季铵盐类衍生物及其制备方法及应用 Download PDFInfo
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Abstract
本发明属于医药学技术领域,公开了一种薯蓣皂苷元季铵盐类衍生物及其制备方法及应用,经相应的化学反应制备了一系列季铵盐类衍生物,以及衍生物在抗肿瘤方面的应用。本发明经药理实验表明:所有合成的薯蓣皂苷元季铵盐衍生物对A549、H1975、HCT‑116、Aspc‑1细胞具有明显的抑制作用,抗肿瘤活性均优于薯蓣皂苷元,大部分衍生物对Ramos、A431细胞抗肿瘤活性优于薯蓣皂苷元,部分衍生物对HBE、LO‑2细胞呈低毒性;本发明属于四川省科技厅应用基础项目No.2016JY0212,西南民族大学中央高校基本科研业务费专项资金No.2018NQN31。
Description
技术领域
本发明属于医药学技术领域,尤其涉及一种薯蓣皂苷元季铵盐类衍生物及其制备方法及应用。
背景技术
目前,业内常用的现有技术是这样的:
癌症是威胁人类生命和健康的重大疾病,已成为人类死亡的重要因素之一。随着环境与生活方式的变化,我国癌症发病率、死亡率持续上升。因此,探索新型的抗肿瘤药已成为新药研发的重要方向之一。
天然的活性抗肿瘤药物具有疗效显著、毒副作用小等优点。薯蓣皂苷元在自然界中资源丰富,具有抗肿瘤、降血脂、抗血栓、抗炎等多种药理活性。国内外大量研究工作表明,薯蓣皂苷元及其某些衍生物具有明显抗肿瘤作用。以薯蓣皂苷元为先导物进行结构修饰,为寻找更好的抗肿瘤药物提供了一条途径,已受到国内外科学工作者的重视,是一项颇具价值和前景的研究工作。
近年来,科研工作者对薯蓣皂苷元的结构修饰和改造主要集中在A环与F环上,部分已报道薯蓣皂苷元衍生物具有显著地抗肿瘤活性,但并未完全解决薯蓣皂苷元存在的缺陷,还需从中探索出更优的药物结构。因此,对薯蓣皂苷元进行合理的结构修饰,设计合成新型衍生物,筛选出更加有效的化学结构,仍然具有一定的挑战性。
综上所述,现有技术存在的问题是:
薯蓣皂苷元及其衍生物作为潜在的抗肿瘤活性物质,同时也具有毒性大,疏水性强,生物利用度低等缺陷,这在很大程度上限制了其适用范围。
解决上述技术问题的难度和意义:
本发明以改善薯蓣皂苷元的水溶性,增加其抗肿瘤活性为目的,设计并合成了新型的薯蓣皂苷元季铵盐类衍生物,且所有目标衍生物国内外均未报道。为了合成薯蓣皂苷元季铵盐类衍生物,需要在甾体环上引入氨基。
本发明设计将薯蓣皂苷元C3-位羟基通过三步反应转化为氨基,以此为中间体分别与不同的卤代烃发生取代反应,得到相对应的一系列季铵盐类衍生物。
发明内容
针对现有技术存在的问题,本发明提供了一种薯蓣皂苷元季铵盐类衍生物及其制备方及应用。薯蓣皂苷元具有的抗肿瘤作用。大量研究表明,薯蓣皂苷元具有广谱的抗肿瘤活性,对于HeLa,K562,HEL,HEP-2等多种肿瘤细胞,它能有效通过抑制细胞增殖并诱导细胞凋亡的方式来发挥作用。但是,薯蓣皂苷元及其衍生物作为潜在的抗肿瘤活性物质,同时也具有水溶性差、生物利用度较低、细胞毒性大、适用范围相对较窄等缺点,因此需要更进一步地进行结构修饰和药理研究来提高其生物利用度及应用范围。
本发明是这样实现的,一种薯蓣皂苷元季铵盐类衍生物的合成方法:首先以薯蓣皂苷元为先导物,与甲磺酰氯反应,使C3-位羟基磺酰化得到化合物1,然后与叠氮化钠发生亲核取代反应得到化合物2,再用三苯基膦将C3-位叠氮基还原为氨基,得到化合物3。通过三步反应得到的化合物3作为薯蓣皂苷元C3-位衍生物的共同中间体,分别与不同的卤代烃发生取代反应,得到相对应的一系列季铵盐类衍生物。分子结构通式为:
其中R1、R2、R3为烃基或取代烃基;
X=F、Cl、Br、I。
本发明的另一目的在于提供一种薯蓣皂苷元季铵盐类衍生物的制备方法包括:
将薯蓣皂苷元C-3位氨基衍生物(1g,1eq)溶于乙腈(5~100mL)或乙腈和二氯甲烷(v/v=1:1)的混合溶剂(5~100mL),加入碳酸钾5~10eq,卤代烃10~30eq,加热回流5~50h;
将反应液过滤,滤液减压浓缩;
经柱色谱分离得中间体(1g,1eq)溶于二氯甲烷和乙腈(v/v=1:1)的混合溶剂(5~100mL)中,加入碘甲烷30eq,加热回流5~50h将反应液减压浓缩;
重结晶或柱层析得薯蓣皂苷元季铵盐类衍生物化合物。
进一步,所述薯蓣皂苷元季铵盐类衍生物的制备方法的反应式为:
本发明的另一目的在于提供一种利用所述薯蓣皂苷元季铵盐类衍生物制备的抗肿瘤药物
本发明的另一目的在于提供一种利用所述薯蓣皂苷元季铵盐类衍生物制备的对A549肺癌细胞抑制的药物。
本发明的另一目的在于提供一种利用所述薯蓣皂苷元季铵盐类衍生物制备的对A431皮肤鳞癌细胞抑制的药物。
本发明的另一目的在于提供一种利用所述薯蓣皂苷元季铵盐类衍生物制备的对H1975肺腺癌细胞抑制的药物。
本发明的另一目的在于提供一种利用所述薯蓣皂苷元季铵盐类衍生物制备的HCT-116结直肠腺癌细胞抑制的药物。
本发明的另一目的在于提供一种利用所述薯蓣皂苷元季铵盐类衍生物制备的对spc-1转移胰腺癌细胞抑制的药物。
本发明的另一目的在于提供一种利用所述薯蓣皂苷元季铵盐类衍生物制备的对Ramos B淋巴瘤细胞抑制的药物。
综上所述,本发明的优点及积极效果为:
本发明改善了薯蓣皂苷元的水溶性,以抗肿瘤活性、降低毒副作用为目的,设计了薯蓣皂苷元季铵盐类衍生物,筛选出了具有较高抗肿瘤活性的甾体化合物。
所有合成新型衍生物结构都经1H NMR,13C NMR,HRMS(ESI)确证。同时考察了目标衍生物的水溶性,以及对A549(人肺癌细胞)、H1975(人肺腺癌细胞)、A431(人皮肤鳞癌细胞)、HCT-116(人结直肠腺癌细胞)、Aspc-1(人转移胰腺癌细胞)、Ramos(人B淋巴瘤细胞)的抗肿瘤活性和HBE(人支气管上皮样细胞)、LO-2(正常肝细胞)的细胞毒性。
本发明经水溶性实验测定表明:所有合成的薯蓣皂苷元季铵盐衍生物的水溶性均不同程度优于先导物薯蓣皂苷元。
本发明经药理实验表明:所有合成的薯蓣皂苷元季铵盐衍生物对A549、H1975、HCT-116、Aspc-1细胞具有明显的抑制作用,抗肿瘤活性均优于薯蓣皂苷元,大部分衍生物对Ramos、A431细胞抗肿瘤活性优于薯蓣皂苷元,部分衍生物对HBE、LO-2细胞呈低毒性。
本发明属于四川省科技厅应用基础项目No.2016JY0212。
附图说明
图1是本发明实施例提供的薯蓣皂苷元季铵盐类衍生物的制备方法流程图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
现有技术中,没有改善薯蓣皂苷元的水溶性,在抗肿瘤活性、降低毒副作用上效果差。
本发明实施例提供的薯蓣皂苷元季铵盐类衍生物用下列通式(Ⅰ)表示:
其中R1、R2、R3为烃基或取代烃基;
X=F、Cl、Br、I;
本发明实施例提供的薯蓣皂苷元季铵盐类衍生物的制备方法,化学反应式为:
如图1所示,本发明实施例提供的薯蓣皂苷元季铵盐类衍生物的制备方法,具体包括:
S101:将薯蓣皂苷元C-3位氨基衍生物(1eq)溶于乙腈(或乙腈和二氯甲烷的混合溶剂),加入碳酸钾(5-10eq),卤代烃(10-30eq),加热回流5-50h。
S102:将反应液过滤,滤液减压浓缩。
S103:经柱色谱分离得中间体(1eq)溶于二氯甲烷和乙腈的混合溶剂中,加入碘甲烷(30eq),加热回流5-50h将反应液减压浓缩。
S104:重结晶或柱层析得通式(Ⅰ)化合物。
下面结合具体分析对本发明作进一步描述。
1)本发明所有合成的新化合物结构都经1H NMR,13C NMR,IR,HRMS(ESI)确证,用红外、熔点、旋光度表征。所合成的季铵盐类衍生物对A549(人肺癌细胞)、A431(人皮肤鳞癌细胞)、H1975(人肺腺癌细胞)、HCT-116(人结直肠腺癌细胞)、Aspc-1(人转移胰腺癌细胞)、Ramos(人B淋巴瘤细胞)、HBE(人支气管上皮样细胞)、LO-2(正常肝细胞)。细胞进行了相应的生物活性实验。
2)实验所用试剂除特别说明外,都为分析纯试剂,且未经纯化直接使用。1H NMR和13C NMR用Agilent DD2400-MR(400MHz)核磁共振波谱仪测定,TMS作为内标,CDCl3作为溶剂;IR用FTS 3000傅里叶变换红外光谱仪(美国Digilab公司)测定,KBr压片;HRMS用LCQAdvantage Max质谱仪测定;旋光用SGW-1(上海仪电物理光学仪器有限公司)旋光仪测定;熔点用SGW X-4显微熔点测试仪(上海精密科学仪器有限公司),温度未经校准。
3)细胞培养:
收集A549、A431、H1975、HCT-116、Aspc-1、Ramos、HBE、LO-2的对数生长期细胞,调整细胞悬液浓度,以每孔7×103个细胞,每孔体积100μL接种到96孔板,每孔设4个复孔(边缘孔用无菌PBS填充)。细胞贴壁后,0%FBS RPMI-1640饥饿8h,对照组用10%FBS RPMI-1640培养。37℃,5%CO2培养箱中继续培养48h。
4)MTT检测:
在八组细胞分别于培养48h后,加入100μL MTT溶液(5mg·mL-1),4h后终止培养,每孔加入100μL三联液,于摇床上低速振荡10min,使结晶充分溶解。在酶联免疫检测仪上测定各孔光度值(OD值),选择570nm波长,以无细胞的即RPMl-1640培养液空白孔调零,测各孔的吸光度值。实验重复三次,记录结果:细胞生长抑制率=(对照组吸光度值-实验组吸光度值)/对照组吸光度值×100%。在GraphPad Prism作图软件中针对抑制剂浓度做图,以便由log[抑制剂]相对于反应,可变斜率模型估算出IC50值。
5)水溶性检测:
分别将化合物5a-5k以甲醇作溶剂,配成不同浓度的溶液,在199nm波长下测紫外吸收值,作出相应的标准曲线。再分别取5mg化合物5a-5k溶于5mL水中,超声10min,水溶液中有不溶物,将此混悬液通过滤膜,取1mL滤液,用水稀释至6mL,在199nm波长下测得的紫外吸收值,分别代入相对应的标准曲线中得到相对的浓度值。
下面结合具体实施例对本发明作进一步描述。
本发明实施例提供的薯蓣皂苷元季铵盐类衍生物的制备方法,通式(Ⅰ)化合物的制备路线:
1.化合物1的合成
氮气保护下,将薯蓣皂苷元(3.00g,7.24mmol)溶于二氯甲烷(30mL),加入三乙胺(5.0mL,36.2mmol),在冰浴下滴加甲磺酰氯(2.2mL,28.9mmol),室温搅拌至TLC检测反应完全。反应液用饱和碳酸氢钠洗涤,无水硫酸钠干燥,减压浓缩,得淡黄色固体1(3.32g,93%)。1H NMR(400MHz,CDCl3)δ5.41(d,J=4.1Hz,1H,H-6),4.50(tt,J=10.8,5.2Hz,1H,H-3),4.39(q,J=7.3Hz,1H,H-16),3.46(d,J=7.0Hz,1H,H-26α),3.36(t,J=10.9Hz,1H,H-26β),2.99(s,3H,CH3S),2.61-2.39(m,2H).13C NMR(100MHz,CDCl3)δ138.81,123.65,109.40,82.02,80.87,66.96,62.18,56.48,49.95,41.72,40.37,39.77,39.25,38.89,36.98,36.64,32.13,31.93,31.50,31.45,30.40,29.07,28.91,20.93,19.34,17.26,16.39,14.64.HR-ESI-MS m/z calcd for C28H44O5S[M+H]+493.2987,found 493.2999.
2.化合物2的合成
取化合物1(3.00g,6.09mmol)溶于DMF(20mL),于80℃下加入NaN3(0.79g,12.2mmol),在90℃反应12h,TLC检测反应完全。反应液用乙酸乙酯稀释,依次用饱和氯化钠溶液、水、饱和碳酸氢钠溶液洗涤,无水硫酸钠干燥,减压浓缩。经柱色谱(石油醚:乙酸乙酯=150:1)分离得到白色固体2(1.37g,51%)。1H NMR(400MHz,CDCl3)δ5.39(d,J=4.7Hz,1H,H-6),4.40(q,J=7.5Hz,1H,H-16),3.87(s,1H,H-3),3.46(dd,J=10.2,3.4Hz,1H,H-26α),3.36(t,J=10.9Hz,1H,H-26β),2.51(d,J=14.9Hz,1H),2.19(d,J=15.0Hz,1H).13C NMR(100MHz,CDCl3)δ138.25,123.02,109.40,80.94,66.97,62.20,58.30,56.60,49.96,41.75,40.37,39.87,37.35,36.18,33.73,32.10,31.95,31.53,31.45,30.45,28.96,26.23,20.65,19.16,17.29,16.43,14.67.HR-ESI-MS m/z calcd for C27H41N3O2[M+H]+440.3277,found 440.3278.
3.化合物3的合成
将化合物2(2.50g,5.69mmol)溶于四氢呋喃(20mL),加入水(2mL),PPh3(2.98g,11.4mmol),60℃下搅拌,TLC检测反应完全,减压回收溶剂。经柱色谱(二氯甲烷:甲醇=50:1)分离得到白色固体3(1.41g,60%)。1H NMR(400MHz,CDCl3)δ5.37(d,J=5.0Hz,1H,H-6),4.41(q,J=7.5Hz,1H,H-16),3.47(dd,J=10.2,3.4Hz,1H,H-26α),3.37(t,J=10.9Hz,1H,H-26β),3.20(s,1H,H-3),2.58(d,J=13.9Hz,1H).13C NMR(100MHz,CDCl3)δ138.92,123.36,109.42,80.97,66.97,62.23,56.65,50.46,47.07,41.75,40.38,39.92,39.87,37.69,33.16,32.27,31.97,31.53,30.44,29.84,29.35,28.95,20.71,19.01,17.28,16.42,14.68.HR-ESI-MS m/z calcd for C27H43NO2[M+H]+414.3372,found 414.3366.
4.化合物5a的合成
将化合物3(0.20g,0.48mmol,1eq)溶于二氯甲烷(10mL)和乙腈(10mL)的混合溶剂中,加入碳酸钾(0.33g,2.42mmol,5eq),碘甲烷(0.3mL,4.83mmol,10eq),60℃下反应至TLC检测反应完全。将反应液过滤,滤液减压浓缩。经柱色谱(二氯甲烷:甲醇=50:1)分离得到浅黄色固体5a(0.24g,84%)。mp265-266℃.–59.5(c 0.002,CHCl3).IR(KBr)νmax3547,3487,2963,1467,1059,807cm-1.1H NMR(400MHz,acetone-d6)δ5.73(s,1H,H-6),4.36(q,J=7.8Hz,1H,H-16),4.04(s,1H,H-3),3.41(d,J=9.5Hz,1H,H-26α),3.34(s,9H,N+-CH3),3.29(t,J=11Hz,1H,H-26β).13C NMR(100MHz,CD3OD)δ139.43,126.34,110.58,82.20,73.01,67.86,63.71,57.88,52.22,52.19,52.16,47.90,42.88,41.60,40.86,37.93,32.75,32.70,32.62,32.58,32.42,31.43,30.65,29.88,22.09,17.50,16.89,14.89.HR-ESI-MS m/z calcd for C30H50O2N+[M–I]+493.2987,found 493.2999.
5.化合物4b的合成
将化合物3(0.45g,1.09mmol,1eq)溶于二氯甲烷(20mL)和乙腈(20mL)的混合溶剂中,加入碳酸钾(1.51g,10.9mmol,10eq),烯丙基溴(0.9mL,10.9mmol,10eq),40℃下搅拌至TLC检测反应完全。将反应液过滤,滤液减压浓缩。经柱色谱(石油醚:乙酸乙酯=50:1)分离得到黄色固体4b(0.050g,93%)。mp 267-269℃.–84.0(c 0.001,CHCl3).IR(KBr)νmax3457,2939,2865,1463,1267,1058,914,805cm-1.1H NMR(400MHz,CDCl3)δ5.86(d,J=6.8Hz,2H,-CH=CH2in allyl moiety),5.25(s,1H,H-6),5.12(d,J=16.1Hz,4H,-CH=CH 2in allyl moiety),4.40(q,J=7.4Hz,1H,H-16),3.47(d,J=8.4Hz,1H,H-26α),3.37(t,J=10.9Hz,1H,H-26β),3.20(s,4H,N-CH2-),2.77(s,1H,H-3),2.29(q,J=14.5Hz,1H).13C NMR(100MHz,CDCl3)δ136.16,120.63,116.71,109.40,81.04,66.98,62.23,56.73,55.18,52.33,49.53,41.75,40.45,40.00,37.33,35.53,33.59,32.08,31.96,31.54,30.46,29.85,29.52,28.96,25.06,22.84,20.75,20.27,17.29,16.47,14.68,14.27,1.16.HR-ESI-MS m/z calcd for C33H51NO2[M+H]+494.3998,found 494.3999.
6.化合物4c的合成
将化合物3(0.40g,0.97mmol,1eq)溶于二氯甲烷(15mL)和乙腈(15mL)的混合溶剂中,加入碳酸钾(1.34g,9.70mmol,10eq),碘化钾(1.48g,2.89mmol,3eq),炔丙基氯(2.1mL,29.3mmol,30eq),60℃下反应至TLC检测反应完全。将反应液过滤,滤液减压浓缩。经柱色谱(二氯甲烷:丙酮=60:1)分离得到黄色固体4c(0.38g,80%)。mp 160-163℃.–99.0(c0.002,CHCl3).IR(KBr)νmax3453,3316,2953,1459,1382,1061,986,903,807,638cm-1.1HNMR(400MHz,CDCl3)δ5.25(s,1H,H-6),4.39(q,J=7.3Hz,1H,H-16),3.60-3.27(m,6H,N-CH2-and H-26),2.71(s,1H,H-3),2.37(d,J=15.3Hz,1H).13C NMR(100MHz,CDCl3)δ140.61,120.78,109.38,80.98,79.79,72.74,66.95,62.19,56.66,55.17,49.57,41.73,40.39,39.95,39.70,37.31,35.50,33.64,32.07,32.00,31.50,31.45,30.44,29.84,28.94,25.21,22.83,20.65,19.90,17.28,16.43,14.66,1.15.HR-ESI-MS m/z calcd forC33H47NO2[M+H]+490.3685,found490.3685.
7.化合物4d的合成
将化合物3(0.30g,0.73mmol,1eq)溶于二氯甲烷(20mL)和乙腈(20mL)的混合溶剂中,加入碳酸钾(1.00g,7.24mmol,10eq),溴甲基环丙烷(1.4mL,15.2mmol,20eq),60℃下搅拌至TLC检测反应完全。将反应液过滤,滤液减压浓缩。经柱色谱(二氯甲烷:甲醇=80:1)分离得到白色固体4d(0.35g,92%)。mp 169-172℃.–81.0(c 0.002,CHCl3).IR(KBr)νmax3447,2956,2858,1462,1379,1177,1058,983,903cm-1.1H NMR(400MHz,CDCl3)δ5.20(s,1H,H-6),4.40(q,J=15.0,7.5Hz,1H,H-16),3.47(d,J=8.2Hz,1H,H-26α),3.38(t,J=10.9Hz,1H,H-26β),2.95(s,1H,H-3),2.54(ddd,J=40.1,13.7,6.2Hz,3H),2.34(s,1H),2.23(d,J=14.5Hz,1H).13C NMR(100MHz,CDCl3)δ109.23,80.86,77.2,66.80,62.05,56.56,55.18,54.04,48.95,41.57,40.29,39.81,37.13,33.51,31.88,31.77,31.39,31.36,30.28,29.68,28.78,20.63,20.44,17.12,16.32,14.51,7.82,4.21,0.97.HR-ESI-MS m/z calcd for C35H55NO2[M+H]+522.4311,found 522.4316.
8.化合物4e的合成
将化合物3(0.30g,0.73mmol,1eq)溶于二氯甲烷(25mL)和乙腈(25mL)的混合溶剂中,加入碳酸钾(2.01g,14.5mmol,20eq),1,4-二溴丁烷(0.9mL,7.33mmol,10eq),60℃下搅拌至TLC检测反应完全。将反应液过滤,滤液减压浓缩。经柱色谱(二氯甲烷:甲醇=70:1)分离得到白色固体4e(0.23g,80%)。mp 189-191℃.–93.6(c 0.002,CHCl3).IR(KBr)νmax3444,2968,2789,1462,1382,1052,980,903cm-1.1H NMR(400MHz,CDCl3)δ5.30(s,1H,H-6),4.38(q,J=7.5Hz,1H,H-16),3.45(d,J=8.2Hz,1H,H-26α),3.35(t,J=10.9Hz,1H,H-26β),2.65(s,br.,4H),2.43(d,J=12.7Hz,1H),2.19(d,J=14.8Hz,1H).13C NMR(100MHz,CDCl3)δ109.20,80.84,77.21,66.77,62.87,61.99,56.22,52.21,48.83,41.56,40.21,39.65,37.18,33.27,31.84,31.78,31.37,31.34,30.26,28.78,23.67,20.50,19.64,17.11,16.25,14.50,0.98.HR-ESI-MS m/z calcd for C31H49NO2[M+H]+468.3841,found468.3844.
9.化合物4f的合成
将化合物3(0.20g,0.48mmol,1eq)溶于乙腈(25mL),加入碳酸钾(0.67g,4.85mmol,10eq),正溴丁烷(1.0mL,9.71mmol,20eq),80℃下搅拌至TLC检测反应完全。将反应液过滤,滤液减压浓缩。经柱色谱(二氯甲烷:乙醇=50:1)分离得到黄色油状物4f(0.23g,92%)。–54.7(c 0.003,CHCl3).IR(KBr)νmax3456,2944,2881,1462,1388,1052,986,903cm-1.1H NMR(400MHz,CDCl3)δ5.41(s,1H,H-6),4.40(q,J=7.3Hz,1H,H-16),3.47(d,J=8.5Hz,1H,H-26α),3.36(t,J=10.9Hz,1H,H-26β),3.17(s,1H,H-3),2.83(d,J=38.3Hz,3H),2.55(s,1H),2.39(d,J=15.4Hz,1H).13C NMR(100MHz,CDCl3)δ109.40,80.98,77.36,66.97,62.17,56.48,50.53,48.37,41.75,40.45,39.78,37.23,33.11,31.98,31.92,31.54,31.51,30.44,29.84,28.96,26.84,20.83,20.70,20.64,17.28,16.48,14.67,13.95,1.16.HR-ESI-MS m/z calcd for C35H59NO2[M+H]+526.4624,found526.4623.
10.化合物4g的合成
将化合物3(0.30g,0.73mmol,1eq)溶于乙腈(30mL),加入碳酸钾(1.00g,7.24mmol,10eq),2-溴乙基甲基醚(2.1mL,21.9mmol,30eq),80℃下搅拌至TLC检测反应完全。将反应液过滤,滤液减压浓缩。经柱色谱(二氯甲烷:丙酮=25:1)分离得到黄色油状物4g(0.28g,73%)。–44.3(c 0.002,CHCl3).IR(KBr)νmax 3461,2938,1459,1385,1260,1177,1117,1058,903cm-1.1H NMR(400MHz,CDCl3)δ5.30(s,1H,H-6),4.40(q,J=7.4Hz,1H,H-16),3.62-3.20(m,8H,-OCH3and H-26),2.82(s,4H),2.33(d,J=59.4Hz,3H).13C NMR(100MHz,CDCl3)δ109.43,81.01,77.37,66.98,62.18,59.02,56.70,50.69,49.09,41.73,40.45,39.94,37.25,33.25,32.03,31.92,31.50,30.44,29.85,29.80,28.93,22.85,20.78,20.51,17.29,16.49,14.67,1.17.HR-ESI-MS m/z calcd for C33H55NO4[M+H]+530.4209,found 530.4208.
11.化合物4h的合成
将化合物3(0.30g,0.73mmol,1eq)溶于乙腈(40mL),加入碳酸钾(1.00g,7.24mmol,10eq),碘化钾(0.36g,2.17mmol,3eq),2-氯乙醇(1.5mL,21.9mmol,30eq),80℃下搅拌至TLC检测反应完全。将反应液过滤,滤液减压浓缩。经柱色谱(乙酸乙酯:甲醇=60:1)分离得到白色固体4h(0.28g,76%)。mp229-231℃.–42.4(c 0.009,CHCl3).IR(KBr)νmax 3429,2971,1465,1385,1266,1061,805cm-1.1H NMR(400MHz,CDCl3)δ5.62(s,1H,H-6),4.40(q,J=7.5Hz,1H,H-16),4.05(s,4H,-CH 2-OH),3.85(s,1H,H-3),3.29-3.70(m,6H,N-CH2-and H-26),2.79(d,J=13.9Hz,1H),2.52(d,J=16.2Hz,1H).13C NMR(100MHz,CDCl3)δ135.99,127.06,109.40,80.89,66.98,62.11,60.93,56.28,55.55,53.93,48.16,41.73,40.42,39.63,37.20,32.66,32.47,31.94,31.87,31.51,31.38,30.41,29.82,28.92,22.52,20.82,20.44,17.27,16.45,14.67,1.14.HR-ESI-MS m/z calcd for C31H51NO4[M+H]+502.3896,found 502.3894.
12.化合物4i的合成
将邻苯二甲酰亚胺(3.20g,0.05mmol)溶于丙酮(40mL),加入碳酸钾(10.4g,0.15mmol),1,4-二溴丁烷(9.1mL,0.15mmol),50℃反应12h,TLC检测反应完全。反应液减压浓缩,加入水(50mL),用二氯甲烷萃取(3×25mL),合并有机层,无水硫酸钠干燥,减压浓缩。经柱色谱(石油醚:乙酸乙酯=3:1),得N-(4-溴丁基)邻苯二甲酰亚胺(6.10g,86%)。1HNMR(400MHz,CDCl3)δ7.86-7.77(m,2H),7.75-7.64(m,2H),3.70(t,J=6.7Hz,2H),3.42(t,J=6.4Hz,2H),1.95-1.77(m,4H).
制备方法同4f,卤代烃为上述N-(4-溴丁基)邻苯二甲酰亚胺,经柱色谱(二氯甲烷:丙酮=20:1)分离得到黄色固体4i,产率63%。mp 124-126℃.–32.8(c 0.006,CHCl3).IR(KBr)νmax 3453,2953,1715,1403,1052,724cm-1.1H NMR(400MHz,CDCl3)δ7.83(dd,J=5.3,3.1Hz,4H,H-Ar),7.70(dd,J=5.3,3.0Hz,4H,H-Ar),5.16(s,1H,H-6),4.33(q,J=7.5Hz,1H,H-16),3.66(t,J=7.3Hz,4H),3.48(d,J=10.2Hz,1H,H-26α),3.38(t,J=10.9Hz,1H,H-26β),2.65(s,1H,H-3),2.51(t,J=7.0Hz,3H),2.29(d,J=14.3Hz,1H),2.13(d,J=14.9Hz,1H).13C NMR(100MHz,CDCl3)δ168.41,134.25,132.06,123.51,109.25,80.85,66.84,62.00,56.13,47.86,41.63,40.31,39.66,37.01,33.20,32.59,32.02,31.77,31.44,31.19,30.31,29.71,29.29,28.84,26.73,20.98,20.79,17.17,16.41,14.58,14.15,10.06,1.04.HR-ESI-MS m/z calcd for C51H65N3O6[M+H]+816.4951,found816.4952.
13.化合物4j的合成
制备方法同4g,卤代烃为肉桂基氯。经柱色谱(二氯甲烷:甲醇=90:1)分离得到黄色固体4j,产率73%。mp 175-177℃.–32.0(c 0.003,CHCl3).IR(KBr)νmax 3441,2959,1664,1456,1382,1058,977,906,751,698cm-1.1H NMR(400MHz,CDCl3)δ7.48-7.16(m,10H,H-Ar),6.52(d,J=15.3Hz,2H,-CH=CH-),6.36(s,2H,-CH=CH-),5.35(s,1H,H-6),4.42(q,J=7.2Hz,1H,H-16),3.76-3.21(m,6H,N-CH2-and H-26).13C NMR(100MHz,CDCl3)δ128.69,127.62,126.47,114.08,109.41,81.02,77.36,66.97,62.20,56.68,52.21,49.30,41.75,40.45,39.95,37.34,33.52,32.06,31.94,31.53,30.44,29.84,28.95,20.78,20.33,17.28,16.48,14.67,14.27,1.16.HR-ESI-MS m/z calcd for C45H59NO2[M+H]+646.4624,found 646.4622.
14.化合物4k的合成
制备方法同4c,卤代烃为2-氯乙腈。经柱色谱(石油醚:乙酸乙酯=20:1)分离得到黄色固体4k,产率68%。mp 212-214℃.–114(c 0.001,CHCl3).IR(KBr)νmax 3423,2953,1465,1379,1054,983,897cm-1.1H NMR(400MHz,CDCl3)δ5.31(s,1H,H-6),4.40(q,J=7.5Hz,1H,H-16),3.57(s,2H,N-CH2-CN),3.46(d,J=10.7Hz,1H,H-26α),3.37(t,J=10.9Hz,1H,H-26β),3.09(s,1H,H-3),2.55(d,J=14.3Hz,1H).13C NMR(100MHz,CDCl3)δ139.31,122.60,110.36,109.51,81.02,67.07,62.28,56.75,52.50,50.34,41.83,40.47,39.99,37.65,37.09,34.96,33.45,32.17,32.02,31.60,31.57,30.53,29.03,25.78,20.77,19.33,17.37,16.51,14.76.HR-ESI-MS m/z calcd for C29H44N2O2[M+H]+453.3481,found 453.3480.
15.化合物5b的合成
将化合物4b(0.25g 0.51mmol,1eq)溶于二氯甲烷(10mL)和乙腈(10mL)的混合溶剂中,加入碘甲烷(1.0mL,15.2mmol,30eq),60℃下搅拌至TLC检测反应完全,将反应液减压浓缩。经柱色谱(二氯甲烷:甲醇=50:1)分离得到黄色固体5b(0.20g,61%)。mp 209-210℃.–50.7(c 0.003,CHCl3).IR(KBr)νmax 3447,2968,1461,1056,984,903cm-1.1H NMR(400MHz,CDCl3)δ6.17-6.00(m,2H,-CH=CH2in allyl moiety),5.85(s,1H,H-6),5.83-5.73(m,2H,-CH=CHH in allyl moiety),5.69(d,J=10.0Hz,2H,-CH=CHH in allylmoiety),4.37(q,J=7.3Hz,1H,H-16),4.19(dd,J=13.3,7.1Hz,1H,N+-CHH-),4.12(d,J=7.0Hz,2H,N+-CHH-),4.00(dd,J=13.3,7.3Hz,1H,N+-CHH-),3.89(s,1H,H-3),3.43(d,J=8.0Hz,1H,H-26α),3.33(t,J=10.9Hz,1H,H-26β),3.09(s,3H,N+-CH3),2.78(d,J=16.3Hz,2H).13C NMR(100MHz,CDCl3)δ137.80,129.47,129.27,125.82,124.78,124.70,109.31,80.78,77.37,68.46,66.87,62.51,62.02,56.59,46.38,46.18,41.60,40.47,39.68,36.87,32.01,31.71,31.55,31.39,31.35,30.30,29.45,28.81,22.01,21.26,21.06,17.19,16.48,14.58.HR-ESI-MS m/z calcd for C34H54O2N+[M–I]+508.4149,found508.4154.
16.化合物5c的合成
制备方法同5b,经柱色谱(二氯甲烷:甲醇=70:1)分离得到黄色固体5c,产率65%。mp 190-192℃.–55.3(c 0.003,CHCl3).IR(KBr)νmax 3473,3241,2961,2915,2135,1463,1056,985,902cm-1.1H NMR(400MHz,CDCl3)δ5.82(s,1H,H-6),4.81-4.47(m,4H,N+-CH2-),4.35(s,1H,H-16),4.19(s,1H,H-3),3.55-3.19(m,5H,N+-CH3and H-26),3.00(d,J=1.7Hz,2H,CH in propargyl moiety),2.89(d,J=16.6Hz,1H),2.78(s,1H).13C NMR(100MHz,CDCl3)δ137.08,126.08,109.21,82.46,82.42,80.69,77.37,70.97,70.02,66.77,61.92,56.43,52.18,52.09,46.57,46.33,41.51,40.36,39.54,36.77,31.88,31.64,31.49,31.30,31.25,30.21,30.07,29.44,28.72,21.79,20.94,17.12,16.39,14.51.HR-ESI-MS m/z calcd for C34H50O2N+[M–I]+504.3836,found 504.3833.
17.化合物5d的合成
制备方法同5b,经柱色谱(二氯甲烷:甲醇=70:1)分离得到白色固体5d,产率96%。mp 229-230℃.–47.7(c 0.003,CHCl3).IR(KBr)νmax 3450,2965,1464,1058,985,903cm-1.1H NMR(400MHz,CDCl3)δ5.63(s,1H,H-6),4.38(q,J=7.2Hz,1H,H-16),4.22(d,J=5.6Hz,1H,H-3),3.58-3.38(m,5H,N+-CH2-and H-26α),3.33(t,J=11.0Hz,1H,H-26β),3.20(s,3H,N+-CH3),2.75(s,1H),2.59(d,J=16.5Hz,1H).13C NMR(100MHz,CDCl3)δ138.14,125.52,109.35,80.80,77.36,67.89,66.91,64.83,64.33,62.05,56.62,46.77,46.58,41.63,40.49,39.71,36.91,32.18,31.73,31.61,31.41,31.36,30.32,29.89,28.83,22.05,21.28,21.06,17.21,16.50,14.59,5.57,5.51,5.26,5.20,5.03.HR-ESI-MSm/z calcd for C36H58O2N+[M–I]+536.4462,found 536.4464.
18.化合物5e的合成
制备方法同5b,经柱色谱(二氯甲烷:甲醇=70:1)分离得到白色固体5e,产率65%。mp 272-273℃.–51.3(c 0.003,CHCl3).IR(KBr)νmax 3461,2965,1462,1060,986,903cm-1.1H NMR(400MHz,CDCl3)δ5.57(s,1H,H-6),4.34(d,J=6.3Hz,1H,H-16),4.09(s,1H,H-3),3.72(d,J=33.6Hz,4H,N+-CH2-),3.39(s,1H,H-26α),3.29(t,J=10.8Hz,1H,H-26β),3.00(s,3H,N+-CH3),2.81(s,1H),2.43(d,J=16.7Hz,1H),2.25(s,4H).13C NMR(100MHz,CDCl3)δ137.93,125.09,109.21,80.66,77.37,70.17,66.77,64.58,64.23,61.90,56.44,47.01,46.22,41.49,40.30,39.55,36.81,32.10,31.60,31.53,31.27,31.20,30.19,28.70,22.32,21.71,21.50,21.34,20.82,17.10,16.35,14.48.HR-ESI-MSm/z calcd for C32H52O2N+[M–I]+482.3993,found 482.3997.
19.化合物5f的合成
制备方法同5b,重结晶(石油醚:乙醇=5:1)得白色固体5f(0.13g,41%)。mp 211-212℃.–47.0(c 0.002,CHCl3).IR(KBr)νmax 3464,2970,2884,1464,1387,1058,987,904cm-1.1H NMR(400MHz,CDCl3)δ5.68(s,1H,H-6),4.38(q,J=7.3Hz,1H,H-16),3.97(d,J=6.6Hz,1H,H-3),3.33(m,6H,N+-CH2-and H-26),3.12(s,3H,N+-CH3),2.86-2.73(m,1H),2.59(d,J=16.7Hz,1H).13C NMR(100MHz,CDCl3)δ138.12,125.63,109.35,80.81,77.36,68.59,66.91,62.06,60.11,59.89,56.66,46.96,46.49,41.64,40.50,39.72,36.98,31.99,31.73,31.63,31.42,31.36,30.33,29.59,28.84,24.74,24.66,21.99,21.09,20.01,19.98,17.21,16.50,14.59,13.83,13.79.HR-ESI-MS m/z calcd for C36H62O2N+[M–I]+540.4775,found 540.4774.
20.化合物5g的合成
制备方法同5b,经柱色谱(二氯甲烷:乙醇=80:1)分离得到黄色固体5g,产率75%。mp 215-216℃.–44.0(c 0.002,CHCl3).IR(KBr)νmax 3453,2966,1466,1388,1124,1059,984,903cm-1.1H NMR(400MHz,CDCl3)δ5.68(s,1H,H-6),4.38(q,J=7.2Hz,1H,H-16),4.11(d,J=6.1Hz,1H,H-3),3.99-3.62(m,8H,N+-CH2-CH2-),3.44(d,J=10.1Hz,1H,H-26α),3.41-3.29(m,7H,-O-CH3and H-26β),3.22(s,3H,N+-CH3),2.85-2.70(m,1H),2.60(d,J=16.6Hz,1H).13C NMR(100MHz,CDCl3)δ138.25,125.67,109.35,80.84,77.37,70.54,66.92,66.47,66.43,62.10,60.85,60.37,59.39,56.67,47.82,46.44,41.67,40.53,39.75,36.89,32.00,31.75,31.56,31.44,31.41,30.35,30.02,29.76,28.86,22.13,21.29,17.21,16.50,14.58.HR-ESI-MS m/z calcd for C34H58O2N+[M–I]+544.4360,found544.4360.
21.化合物5h的合成
制备方法同5b,重结晶(石油醚:乙醇=3:1)得到白色固体5h,产率55%。mp 248-249℃.–46.5(c 0.002,CHCl3).IR(KBr)νmax 3378,2967,1464,1384,1059,985,903cm-1.1H NMR(400MHz,CDCl3)δ5.65(s,1H,H-6),4.40(q,J=7.2Hz,1H,H-16),4.14(s,5H,-CH 2-OH and H-3),3.74(s,4H,N+-CH2-),3.46(d,J=7.5Hz,1H,H-26α),3.36(t,J=10.8Hz,1H,H-26β),3.22(s,3H,N+-CH3),2.74(d,J=31.6Hz,1H),2.53(d,J=16.0Hz,1H).13C NMR(100MHz,CDCl3)δ138.26,125.76,109.40,80.90,77.36,69.83,66.99,62.39,62.14,61.71,56.67,56.12,48.26,46.43,41.72,40.58,39.80,37.00,32.03,31.83,31.66,31.48,30.41,30.07,29.83,28.93,22.19,21.19,17.28,16.58,14.67,1.14.HR-ESI-MS m/z calcd for C32H54O4N+[M–I]+516.4047,found 516.4053.
22.化合物5i的合成
制备方法同5b,经柱色谱(二氯甲烷:乙醇=50:1)分离得到黄色固体5i,产率64%。mp 189-190℃.–27.0(c 0.002,CHCl3).IR(KBr)νmax 3436,2966,1718,1405,1055,722cm-1.1H NMR(400MHz,CDCl3)δ7.77(dd,J=5.3,3.1Hz,4H,H-Ar),7.68(dd,J=5.3,2.9Hz,4H,H-Ar),5.75(s,1H,H-6),4.36(dd,J=14.9,7.3Hz,1H,H-16),3.96(d,J=5.3Hz,1H,H-3),3.77-3.48(m,8H,N+-CH 2-CH2-CH2-CH 2-),3.43(d,J=7.3Hz,1H,H-26α),3.33(t,J=10.9Hz,1H,H-26β),3.15(s,3H,N+-CH3),2.80(d,J=19.3Hz,1H),2.67(d,J=16.5Hz,1H).13C NMR(100MHz,CDCl3)δ168.53,138.25,134.24,131.91,125.58,123.41,109.32,80.82,77.36,68.98,66.88,62.06,59.39,59.17,56.59,46.89,46.34,41.63,40.48,39.70,36.94,36.47,31.96,31.72,31.63,31.42,31.36,30.32,29.73,29.40,28.83,25.84,21.99,21.08,21.00,19.83,19.65,17.19,16.48,14.58.HR-ESI-MS m/zcalcd for C52H68O6N3 +[M–I]+830.5103,found 830.5104.
23.化合物5j的合成
制备方法同5b,重结晶(石油醚:乙醇=4:1)得到浅紫色固体5j,产率69%。mp208-209℃.–17.0(c 0.002,CHCl3).IR(KBr)νmax 3434,2964,1659,1461,1058,986,902,751,695cm-1.1H NMR(400MHz,CDCl3)δ7.51(s,4H,H-Ar),7.28(s,6H,H-Ar),7.11(dd,J=22.0,15.7Hz,2H,=CH-Ph),6.42(s,2H,-CH=CH-Ph),5.84(s,1H,H-6),4.41(dd,J=17.7,8.2Hz,4H,N+-CH2-),4.26(s,1H,H-16),3.94(s,1H,H-3),3.47(d,J=8.3Hz,1H,H-26α),3.36(t,J=10.9Hz,1H,H-26β),3.13(s,3H,N+-CH3),2.89(d,J=16.3Hz,1H),2.76(s,1H).13C NMR(100MHz,CDCl3)δ143.04,142.90,137.92,134.87,134.82,129.46,129.43,128.90,128.87,127.64,127.61,125.90,114.90,114.85,109.37,80.87,77.36,68.43,66.95,62.79,62.12,56.69,46.44,46.04,41.68,40.52,39.76,36.93,32.15,31.77,31.63,31.47,31.37,30.38,29.64,28.89,21.99,21.57,21.10,17.25,16.52,14.63.HR-ESI-MS m/z calcd for C46H62O2N+[M–I]+660.4775,found 660.4772.
24.化合物5k的合成
将化合物4k(0.20g,0.44mmol,1eq)溶于乙腈(20mL),加入碳酸钾(0.61g,4.42mmol,10eq),碘甲烷(0.8mL,13.2mmol,30eq),80℃下搅拌至TLC检测反应完全。将反应液过滤,滤液减压浓缩。经柱色谱(二氯甲烷:乙醇=80:1)分离得到白色固体5k(0.23g,85%)。mp 203-204℃.–49.2(c 0.002,CHCl3).IR(KBr)νmax 3459,2966,1465,1385,1062,984,903cm-1.1H NMR(400MHz,DMSO-d6)δ5.62(s,1H,H-6),4.85(s,2H,-CH2-CN),4.29(d,J=6.5Hz,1H,H-16),3.84(s,1H,H-3),3.41(d,J=10.7Hz,1H,H-26α),3.35(s,1H,H-26β),3.21(d,J=10.8Hz,1H),3.15(d,J=10.5Hz,6H,N+-CH3),2.66(s,2H).13C NMR(100MHz,DMSO-d6)δ137.80,124.54,112.27,108.42,80.22,71.46,65.90,61.74,56.06,50.20,49.67,49.50,45.56,41.07,39.23,36.22,31.28,30.97,30.88,30.80,29.79,28.46,28.17,21.33,20.54,20.36,17.08,16.14,14.64.HR-ESI-MS m/z calcd for C31H49O2N2 +[M–I]+481.3789,found 481.3790.
薯蓣皂苷元季铵盐衍生物水溶性测试结果如下表所示:
薯蓣皂苷元季铵盐衍生物体外抗肿瘤活性测试结果如下表所示:
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种薯蓣皂苷元季铵盐类衍生物,其特征在于,所述薯蓣皂苷元季铵盐类衍生物的分子结构为:
其中R1、R2、R3为烃基或取代烃基;
X=F、Cl、Br、I。
2.一种如权利要求1所述薯蓣皂苷元季铵盐类衍生物的制备方法,其特征在于,所述薯蓣皂苷元季铵盐类衍生物的制备方法包括:
将薯蓣皂苷元C-3位氨基衍生物溶于乙腈或乙腈和二氯甲烷的混合溶剂,加入碳酸钾,卤代烃,加热回流5~50h;其中,乙腈和二氯甲烷v/v=1:1;
将反应液过滤,滤液减压浓缩;
经柱色谱分离得中间体溶于二氯甲烷和乙腈的混合溶剂中,加入碘甲烷30eq,加热回流5~50h将反应液减压浓缩;其中,二氯甲烷和乙腈v/v=1:1;
重结晶或柱层析得薯蓣皂苷元季铵盐类衍生物化合物。
3.如权利要求2所述薯蓣皂苷元季铵盐类衍生物的制备方法,其特征在于,所述薯蓣皂苷元季铵盐类衍生物的制备方法的反应式为:
4.一种利用权利要求1所述薯蓣皂苷元季铵盐类衍生物制备的抗肿瘤药物。
5.一种利用权利要求1所述薯蓣皂苷元季铵盐类衍生物制备的对A549肺癌细胞抑制的药物。
6.一种利用权利要求1所述薯蓣皂苷元季铵盐类衍生物制备的对A431皮肤鳞癌细胞抑制的药物。
7.一种利用权利要求1所述薯蓣皂苷元季铵盐类衍生物制备的对H1975肺腺癌细胞抑制的药物。
8.一种利用权利要求1所述薯蓣皂苷元季铵盐类衍生物制备的HCT-116结直肠腺癌细胞抑制的药物。
9.一种利用权利要求1所述薯蓣皂苷元季铵盐类衍生物制备的对spc-1转移胰腺癌细胞抑制的药物。
10.一种利用权利要求1所述薯蓣皂苷元季铵盐类衍生物制备的对Ramos B淋巴瘤细胞抑制的药物。
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CN110452283A (zh) * | 2019-04-24 | 2019-11-15 | 西南民族大学 | 一种抗肿瘤季铵盐类衍生物及其制备方法及应用 |
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CN111362998A (zh) * | 2020-04-23 | 2020-07-03 | 烟台大学 | 氮杂20(r)-人参二醇衍生物及其抗肿瘤应用 |
CN111362998B (zh) * | 2020-04-23 | 2022-11-25 | 烟台大学 | 氮杂20(r)-人参二醇衍生物及其抗肿瘤应用 |
WO2024136117A1 (ko) * | 2022-12-23 | 2024-06-27 | 한국과학기술연구원 | 디오스게닌 유도체를 포함하는 신경염증질환의 예방 또는 치료용 조성물 |
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