CN107629098A - 齐墩果酸型皂苷类化合物及其组合物 - Google Patents
齐墩果酸型皂苷类化合物及其组合物 Download PDFInfo
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- CN107629098A CN107629098A CN201710895130.XA CN201710895130A CN107629098A CN 107629098 A CN107629098 A CN 107629098A CN 201710895130 A CN201710895130 A CN 201710895130A CN 107629098 A CN107629098 A CN 107629098A
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- oleanolic acid
- acid type
- compound
- class compound
- type saponin
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- YBRJHZPWOMJYKQ-UHFFFAOYSA-N Oleanolic acid Natural products CC1(C)CC2C3=CCC4C5(C)CCC(O)C(C)(C)C5CCC4(C)C3(C)CCC2(C1)C(=O)O YBRJHZPWOMJYKQ-UHFFFAOYSA-N 0.000 title claims abstract description 45
- MIJYXULNPSFWEK-UHFFFAOYSA-N Oleanolinsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C MIJYXULNPSFWEK-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 229940100243 oleanolic acid Drugs 0.000 title claims abstract description 45
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 39
- MIJYXULNPSFWEK-GTOFXWBISA-N 3beta-hydroxyolean-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C MIJYXULNPSFWEK-GTOFXWBISA-N 0.000 title claims abstract description 35
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了齐墩果酸型皂苷类化合物其结构如下述式(I):其中,R1:‑H或者‑OH;R2:α‑OR3或者β‑OR3;R3:‑H或者单糖基中的1‑2个。其口服药用组合物,可应用于治疗炎症和肿瘤。可以作为前药使用,避免28‑羧基取代的皂苷作为药物使用时的胃肠道副作用;而且具有抗炎作用。
Description
技术领域
本发明具体涉及一种齐墩果酸型皂苷类化合物及其组合物。
背景技术
从传统中药和天然产物中寻找抗肿瘤、抗炎等药物是一种行之有效的方法。齐墩果酸及其苷类属于五环三萜类天然产物,广泛分布于女贞子、败酱、白头翁等植物药中,具有消炎、抗肿瘤、抗高血脂等多方面的药理作用,齐墩果酸已用于治疗急性化学性肝损伤、慢性肝硬化和肝纤维化。近年来,大量文献报道从常春藤、黄花败酱、白头翁等植物药中分离得到齐墩果酸型皂苷,该类成分具有较好的抗炎作用,并发现C-28位羧基游离的β-常春藤皂苷等化合物显示出较好的体内外抗肿瘤活性。后续深入研究发现,该类成分口服时具有强烈的胃肠道刺激性副作用,口服生物利用度低于5%,成为开发应用的瓶颈问题。
种类繁多的肠道菌群在人体肠道内构成一个微生态系统,参与食物中营养和功能成分的代谢。肠道菌群与宿主一同进化,直接参与和影响机体的营养吸收、生长发育、免疫调节等诸多健康与疾病进程,成为近年国际研究热点。本发明受此启发,根据前药设计策略和仿生原理,以β-常春藤皂苷和相关天然产物为先导化合物,设计对其C-3糖链结构、C-28位羧基分别进行糖基结构修饰,研究齐墩果酸型皂苷的抗肿瘤构效关系。对合成的化合物进行体外细胞毒性和溶血性测试,发现该类成分均不同程度保留了一定抗肿瘤活性,C-28位糖酯取代基同时可显著降低溶血性毒副作用。采用体外模拟消化道代谢过程分析,结果表明该类成分在人工胃液、肠液中不易代谢;特别地,研究中意外发现,C-28位糖基的种类对肠道菌群代谢产物有显著影响,只有葡萄糖基取代时才可代谢为相应C-28位羧基型皂苷。经进一步深入研究,从而完成了本发明。
发明内容
本发明目的是提供齐墩果酸型皂苷类化合物其组合物,根据前药设计策略和仿生原理,以β-常春藤皂苷和相关天然产物为先导化合物,设计对其C-3 糖链结构、C-28位羧基分别进行糖基结构修饰,解决其胃肠道刺激性副作用大、口服生物利用率低的问题。
本发明的一种技术方案是:一种齐墩果酸型皂苷类化合物,其结构如下述式(I):
其中,
R1:-H或者-OH;
R2:α-OR3或者β-OR3;
R3:-H或者单糖基中的1-2个。
进一步的,所述单糖基为葡萄糖、半乳糖、甘露糖、阿拉伯糖、木糖、鼠李糖、呋糖或芹糖基。
进一步的,所述R1为-H,R2为β-OR3。
进一步的,所述R1为-H,R2为α-OR3。
进一步的,所述R1为-OH,R2为β-OR3。
本发明的另一种技术方案是:一种口服药用组合物,其中含有治疗有效量的权利要求1-5中任意一项所述的齐墩果酸型皂苷类化合物和药学上可接受的载体。
进一步的,所述口服药用组合物在制备治疗炎症或者肿瘤的药物中的应用。
进一步的,所述炎症为结肠炎。
进一步的,所述药用组合物在肠道中代谢为28-羧基的相应化合物。
本发明优点是:
28-葡萄糖取代的齐墩果酸型双糖链皂苷一方面自身具有抗炎作用、无明显溶血性和胃肠道刺激性,另一方面还同时可以被肠道菌群代谢为28-齐墩果酸型皂苷,可以作为其前药使用,避免28-齐墩果酸型皂苷作为药物使用时的胃肠道副作用、相对口服生物利用度更高。
具体实施方式
该类成分可采用天然成分齐墩果酸(R1选自-H)或常春藤皂苷元(R1选自 -OH)为起始原料,与相应的糖基供体经化学方法合成,详见实施例1。同时也可从植物中分离纯化获得,例如常春藤、白头翁、黄花败酱、黑种草子、银莲花等。所述化合物的制备方法可从已公开文献中获得。
本发明同时对所述齐墩果酸衍生物及其组合物进行了抗炎、抗肿瘤、溶血性等活性筛选、肠道菌群代谢分析。研究结果:(1)二甲苯致小鼠急性耳肿胀试验结果表明,化合物灌药给药(100mg/kg)具有较强的抗炎作用;(2)体外抗肿瘤和溶血试验结果表明,化合物对人肝癌HepG-2等细胞株具有一定的抗肿瘤作用,但28-齐墩果酸型化合物同时也具有溶血作用,相应的28-糖酯溶血作用消失;(3)肠道菌群代谢分析实验结果表明,齐墩果酸皂苷的相应28-糖酯型化合物,具有不同的代谢途径,其中只有葡萄糖酯型的衍生物可以显著转化为相应齐墩果酸皂苷,从而可以在结肠部位经肠道菌群代谢为活性更好的原形齐墩果酸皂苷,发挥其抗肿瘤作用。结果表明,所述齐墩果酸衍生物组合物均具有较好的抗炎活性,可以根据使用需要应用于不同的功能食品和药品中。
为使本发明的上述目的、特征和优点能够更加明显易懂,下面实施例进一步说明本发明的技术方案。但是本发明不限于所列出的实施例,还应包括在本发明所要求的权利范围内其他任何公知的改变。
首先,此处所称的“一个实施例”或“实施例”是指可包含于本发明至少一个实现方式中的特定特征、结构或特性。在本说明书中不同地方出现的“在一个实施例中”并非均指同一个实施例,也不是单独的或选择性的与其他实施例互相排斥的实施例。
另外,本发明内容是通过大量创造性实验研究完成的,以下述具体实施例进行说明。
实施例1:齐墩果酸皂苷S1-S4的制备
参考本发明文献报道方法进行制备:Liming Wang,et al.Synthesis andcytotoxicity of oleanolic acid trisaccharide saponins.Carbohydrate Research,2017, 442:9-16.
分别将L-阿拉伯糖、L-鼠李糖(L-rhamnose,L-Rha)和D-葡萄糖(D-glucose, D-Glc)溶解在吡啶中,冰浴下滴加苯甲酰氯,然后升至室温,过夜反应即可获得全苯甲酰基保护的单糖。用33%氢溴酸(乙酸溶液)在室温下与全苯甲酰基糖反应,即可获得1-溴代糖基供体化合物(10a、10b、10c)。
(S1)3-O-α-L-吡喃鼠李糖基(1→2)-α-L-吡喃阿拉伯糖基齐墩果酸
将化合物3-O-[2″,3″,4″-三苯甲酰基-α-L-鼠李糖基(1→2)-3′,4′-二乙酰基]-α-L-阿拉伯糖基齐墩果酸(18)(200mg,0.181mmol)溶于CH2Cl2-MeOH (v/v,1:1,30mL)中,加入甲醇钠,室温反应4h,加入H+型阳离子交换树脂中和至中性,过滤,滤液旋干,经硅胶柱(氯仿-甲醇,6:1)纯化,得到白色粉末,化合物1(113mg,85%)。Rf=0.32(6:1,CHCl3-MeOH).[α]=+3.05(c0.96, CH3OH);ESI-MS(m/z):757.4[M+Na]+。
(S2)3-O-α-L-吡喃鼠李糖基(1→2)-α-L-吡喃阿拉伯糖基齐墩果酸-28-O-D- 吡喃葡萄糖苷
将化合物18(200mg,0.181mmol)和碳酸钾(100mg)溶于丙酮中(30mL),室温下搅拌30min,然后加入10c(140mg,0.213mmol),加热回流8h。旋干去除丙酮,加入二氯甲烷(30mL)复溶,用蒸馏水(20mL×3)萃取除盐,二氯甲烷层用无水Na2SO4干燥,抽滤,旋干二氯甲烷,加入CH2Cl2-MeOH(v/v, 1:1,30mL),加入甲醇钠(90mg),室温下反应4h。加入H+型阳离子交换树脂中和至中性,过滤,滤液旋干,经硅胶柱(氯仿-甲醇,3:1)纯化,得到白色粉末。进一步用C18反相硅胶柱纯化,收集50%-60%(甲醇-水,v/v)洗脱部分,旋干得到化合物4(120mg,74%)。Rf=0.33(氯仿-甲醇,3:1).[α]=-0.443 (c1.02,CH3OH);ESI-MS(m/z):919.5[M+Na]+;1HNMR(600MHz,CDCl3)δ5.34 (d,J8.2Hz,1H,H-1″′),5.22(t,J3.4Hz,1H,H-12),5.06(s,1H,H-1″),4.50(d,J 4.6Hz,1H,H-1′),3.84(dd,J3.2,1.6Hz,1H),3.82–3.77(m,2H),3.77(s,1H), 3.75–3.72(m,2H),3.69(dd,J6.5,3.3Hz,1H),3.67–3.62(m,2H),3.44(dd,J11.6,2.9Hz,1H),3.40–3.33(m,2H),3.30–3.25(m,3H),3.07(dd,J11.7,4.4Hz, 1H,H-3),2.82(dd,J13.8,4.0Hz,1H,H-18),1.18(d,J6.2Hz,3H,H-6″),1.12, 0.98,0.92,0.90,0.87,0.81,0.76(seach,3Heach,7×CH3).13CNMR(151MHz, CDCl3)δ177.82(C-28),144.64(C-13),123.57(C-12),104.59(C-1′),101.83(C-1″), 95.50(C-1″′),90.41(C-3),78.48,78.11,76.63,73.72,73.67,72.86,71.95,70.91, 70.00,68.19,63.54,62.21,56.86,47.81,47.03,42.73,42.40,40.52,40.06,39.73, 37.72,34.70,33.73,33.31,32.93,31.34,28.70,28.45,26.82,26.13,24.35,23.77, 19.18,17.79,17.53,16.87,15.87。
(S3)3-O-α-L-吡喃鼠李糖基(1→2)-α-L-吡喃阿拉伯糖基齐墩果酸-28-O-L- 吡喃阿拉伯糖苷
将化合物18(200mg,0.181mmol)和碳酸钾(100mg)溶于丙酮中(30mL),室温下搅拌30min,然后加入10a(110mg,0.210mmol),加热回流8h。旋干去除丙酮,加入二氯甲烷(30mL)复溶,用蒸馏水(20mL×3)萃取除盐,二氯甲烷层用无水Na2SO4干燥,抽滤,旋干二氯甲烷,加入CH2Cl2-MeOH(v/v,1:1, 30mL),加入甲醇钠(80mg),室温下反应4h。加入H+型阳离子交换树脂中和至中性,过滤,滤液旋干,经硅胶柱(氯仿-甲醇,4:1)纯化,得到白色粉末。进一步用C18反相硅胶柱纯化,收集50%-60%(甲醇-水,v/v)洗脱部分,旋干得到化合物2(80mg,51%)。Rf=0.40(氯仿-甲醇,3:1).[α]=+0.127(c1.26, CH3OH);ESI-MS(m/z):901.5[M+Cl]-;1HNMR(600MHz,CDCl3)δ5.40(d,J5.8 Hz,1H,H-1″′),5.26(t,J3.2Hz,1H,H-12),5.08(s,1H,H-1″),4.53(d,J4.6Hz, 1H,H-1′),3.89–3.84(m,3H),3.84–3.78(m,2H),3.78–3.74(m,3H),3.71(dd,J 6.5,3.3Hz,1H),3.69–3.62(m,3H),3.61–3.53(m,1H),3.46(dd,J11.6,2.8Hz, 1H),3.36(dd,J19.9,10.4Hz,1H),3.10(dd,J11.6,4.1Hz,1H,H-3),2.89(dd,J13.9,3.9Hz,1H,H-18),1.21(d,J6.2Hz,3H,H-6″),1.14,1.00,0.94,0.93, 0.89,0.83,0.77(seach,3Heach,7×CH3).13CNMR(151MHz,CDCl3)δ 177.81(C-28),144.70(C-13),123.66(C-12),104.60(C-1′),101.83(C-1″), 95.61(C-1″′),90.40(C-3),76.63,73.68,73.42,72.87,71.96,71.07,70.00,68.20, 66.12,63.55,56.85,56.80,47.94,46.99,42.70,42.36,40.51,40.06,39.72,37.71, 34.68,34.28,33.76,33.33,33.14,32.87,31.38,30.55,30.44,30.27,30.21,28.67, 28.45,26.82,26.18,24.35,23.97,23.81,23.75,23.64,23.53,19.17,17.79,17.54, 16.88,16.49,15.84,15.79,14.25。
(S4)3-O-α-L-吡喃鼠李糖基(1→2)-α-L-吡喃阿拉伯糖基齐墩果酸-28-O-L- 吡喃鼠李糖苷
将化合物18(200mg,0.181mmol)和碳酸钾(100mg)溶于丙酮中(30mL),室温下搅拌30min,然后加入10b(120mg,0.223mmol),加热回流8h。旋干去除丙酮,加入二氯甲烷(30mL)复溶,用蒸馏水(20mL×3)萃取除盐,二氯甲烷层用无水Na2SO4干燥,抽滤,旋干二氯甲烷,加入CH2Cl2-MeOH(v/v, 1:1,30mL),加入甲醇钠(80mg),室温下反应4h。加入H+型阳离子交换树脂中和至中性,过滤,滤液旋干,经硅胶柱(氯仿-甲醇,4:1)纯化,得到白色粉末。进一步用C18反相硅胶柱纯化,收集50%-60%(甲醇-水,v/v)洗脱部分,旋干得到化合物3(86mg,54%)。Rf=0.42(氯仿-甲醇,3:1);[α]=-0.093 (c0.90,CH3OH);ESI-MS(m/z):879.5[M+Cl]-;1HNMR(600MHz,CDCl3)δ5.40(d, J5.8Hz,1H,H-1″′),5.26(t,J3.1Hz,1H,H-12),5.08(s,1H,H-1″),4.53(d,J4.9 Hz,1H,H-1′),3.89–3.85(m,3H),3.84–3.78(m,3H),3.78–3.74(m,3H),3.71 (dd,J6.4,3.1Hz,1H),3.69–3.62(m,3H),3.55(d,J10.8Hz,1H),3.46(dd,J11.6,2.3Hz,1H),3.37(t,J9.5Hz,1H),3.10(dd,J11.7,4.3Hz,1H,H-3),2.89 (dd,J13.7,3.7Hz,1H,H-18),1.21(d,J6.2Hz,3H,H-6″),1.14,1.00,0.94, 0.93,0.89,0.86(d,J4.7Hz,3H,H-6″′),0.83,0.77(seach,3Heach,7×CH3).13C NMR(151MHz,CDCl3)δ176.60(C-28),143.47(C-13),122.43(C-12),103.37(C-1′), 100.60(C-1″),94.38(C-1″′),89.30(C-3),75.40,72.45,72.19,71.65,70.73,69.84, 68.78,67.00,64.89,55.69,55.61,46.72,45.76,41.48,41.13,39.28,38.83,38.48, 36.54,36.48,33.45,32.53,32.09,31.92,30.36,30.15,29.32,27.44,27.25,27.22, 25.59,25.07,24.94,23.12,22.89,22.57,22.41,17.94,16.75,16.56,16.31,15.65, 14.60,14.57。
实施例2:黄花败酱中单体化合物的分离
参考本发明文献报道方法进行制备:高亮,黄花败酱化学成分研究,苏州大学研究生论文,2011。
从黄花败酱中,可分离获得以下化合物P1~P9:3-O-β-D-吡喃木糖(1→3)-α-L-吡喃鼠李糖(1→2)-β-D-吡喃木糖齐墩果酸28-O-β-D-吡喃葡萄糖酯苷(P1);3-O-β-D-吡喃葡萄糖 (1→4)-β-D-吡喃木糖(1→3)-α-L-吡喃鼠李糖(1→2)-β-D-吡喃木糖齐墩果酸28-β-D-吡喃葡萄糖酯苷(P2);3-O-α-L-吡喃鼠李糖(1→2)-β-D-吡喃木糖齐墩果酸28-O-β-D-吡喃葡萄糖酯苷 (P3);3-O-β-D-吡喃木糖(1→3)-α-L-吡喃鼠李糖(1→2)-α-L-吡喃阿拉伯糖齐墩果酸 28-O-β-D-吡喃葡萄糖酯苷(P4);3-O-β-D-吡喃木糖(1→3)-α-L-吡喃鼠李糖(1→2)-β-D-吡喃木糖齐墩果酸28-O-β-D-吡喃葡萄糖基-(1→6)-β-D-吡喃葡萄糖酯苷(P5);3-O-β-D-吡喃葡萄糖 (1→4)-β-D-吡喃木糖(1→3)-α-L-吡喃鼠李糖(1→2)-β-D-吡喃木糖齐墩果酸28-O-β-D-吡喃葡萄糖基-(1→6)-β-D-吡喃葡萄糖酯苷(P6);3-O-β-D-吡喃葡萄糖(1→4)-β-D-吡喃木糖 (1→3)-α-L-吡喃鼠李糖(1→2)-α-L-吡喃阿拉伯糖齐墩果酸28-O-β-D-吡喃葡萄糖基 -(1→6)-β-D-吡喃葡萄糖酯苷(P7);3-O-α-L-吡喃鼠李糖(1→2)-α-L-吡喃阿拉伯糖常春藤皂苷元28-O-α-L-吡喃鼠李糖(1→4)-β-D-吡喃葡萄糖基-(1→6)-β-D-吡喃葡萄糖酯苷(P8);3-O-β-D- 吡喃木糖(1→3)-α-L-吡喃鼠李糖(1→2)-α-L-吡喃阿拉伯糖常春藤皂苷元28-O-α-L-吡喃鼠李糖(1→4)-β-D-吡喃葡萄糖基-(1→6)-β-D-吡喃葡萄糖酯苷(P9)。
实验例3:化合物的抗炎作用考察
取实施例2中败酱皂苷化合物进行测试。取20-25g小鼠(10只/组),随机分为P1~P9 组(100mg/kg)、齐墩果酸对照组(100mg/kg)和模型组五组,预灌药给药一周。最后一次灌药2小时后,用二甲苯25微升均匀涂于小鼠右耳,半小时后处死小鼠,用直径6mm打孔器,取小鼠的左右耳相同部位,用分析天平称重。取下的右耳减去左耳重量为肿胀度,计算对照组和给药组的均值与标准差,t检验比较组间差异显著性。按下式求出肿胀抑制率:
肿胀抑制率(%)=[1-给药组平均肿胀度/模型组平均肿胀度]×100%
结果:化合物P1~P9组(100mg/kg)对二甲苯所致小鼠耳廓急性炎症均有较强的抑制作用,肿胀抑制率在52%~75%范围,与齐墩果酸(61%)组间比较无明显差异。
实验例4:齐墩果酸皂苷化合物的体外抗肿瘤作用考察
采用MTT法考察实施例1-2中化合物(S1~S4;P1~P9)对A549人肺癌细胞、HePG2人肝癌细胞、HELA人宫颈癌细胞3种肿瘤细胞株和293T人胚胎肾细胞株的增殖抑制影响。
取对数生长期人肝癌HepG-2细胞株细胞,用胰酶消化后配制成浓度为1×105个/mL的细胞悬液,接种于96孔酶标板中,每孔100μl。24h后加含不同药物(终浓度25、12.5、6.25μmol/L)及相应溶媒对照的新鲜培养液,对照组以等体积溶媒替代样品的培养液,空白组加等体积的不含细胞的培养液,每孔50μl,每组设5个平行孔。在上述条件下培养24h,每孔加入5mg/mLMTT10μl,继续培养4h,吸除上清液,每孔加100μlDMSO溶解,混匀,于酶标仪上测定OD490值。实验重复3次,取平均值,计算抑制率。
抑制率(%)=[(1-样品组OD值/对照组OD值)]×100%
结果:(1)β-常春藤皂苷(S1)对3种癌细胞和正常细胞都具有很强的增殖抑制作用,其IC50为8-10μmol/L。(2)糖酯类衍生物化合物(S2~S4;P1~P9) 保留有一定程度的抗肿瘤活性,25μmol/L的抑瘤率约为30~50%;其中28-葡萄糖基酯衍生物(S2)对A549的抗肿瘤活性较高,25μmol/L时抑瘤率约为65%。
实施例5:齐墩果酸皂苷的体外溶血性考察
采用2015版中国药典方法考察实施例1-2中化合物(S1~S4;P1~P9)溶血性。精密称取测试化合物2.0mg,加20μLDMSO溶解,加PBS配成1mg/mL的储备液,用0.9%NaCl溶液依次稀释成不同浓度的溶液(25、12.5、6.25、3.12μg·mL-1),待用。每个样品分别取6只洁净的EP管,1至4号分别加入500μL不同浓度的溶液,5号加入500μL0.9%NaCl溶液作阴性对照组,6号加入500μL蒸馏水作阳性对照组;向6只管中加入500μL处理好的4%兔血红细胞液,轻轻混匀, 37±0.5℃水浴3h后取出,5000r·min-1离心5min,吸取上清,用酶标仪测其OD570值,重复三次,计算溶血率。
[溶血率=(实验组-阴性对照组)/(阳性对照组-阴性对照组)×100%]。
结果:(1)β-常春藤皂苷(S1)具有很强的溶血性,浓度为3.12μg·mL-1时,就可以让红细胞100%溶血。(2)糖酯类衍生物化合物(S2~S4;P1~P9)基本无溶血性,25μg/mL时溶血率均低于5%。
实施例6:齐墩果酸皂苷的肠道菌群代谢分析
采用体外模拟消化道代谢的研究方法,考察实施例1-2中化合物(S1~S4;P1~P9)在人工胃液、人工肠液、大鼠离体肠道菌群人工肠液中的代谢情况。
(1)人工胃肠液代谢分析:人工胃液和人工肠液均按照2015版药典附录方法配置,37 ±0.5℃温孵备用。
分别精密称取5mg测试化合物,加入500μLDMSO溶解,再加入0.9%生理盐水定容至5ml,备用。吸取样品储备液100μL,与3.9mL预温孵的人工胃液、人工肠液涡旋混匀,于 37±0.5℃恒温振荡水槽中温孵。依次分别于反应0、0.5、1、2、3、4、8、12、24h取样,每次取样500μL,每样分别加入500μL正丁醇,涡旋混匀,离心(5000r·min-1,3min)使其分层,取上层进行硅胶薄层检测,经10%硫酸乙醇喷雾后110℃加热显色观察。
结果:各化合物(S1~S4;P1~P9)在人工胃液和人工肠液中很稳定,未发生明显代谢。
(2)体外肠道菌群代谢分析:取正常清洁级SD雄性大鼠的混合新鲜粪便,加入4倍生理盐水捣碎搅匀制成匀浆,500r·min-1离心10min,取上清液,即为肠道菌群液。
吸取800μL新配置的肠道菌群液和200μL(1)中样品储备液于EP管中,涡旋混匀。加入500μL液体石蜡封住液面,使其形成厌氧环境,37±0.5℃温孵。以空白的肠道菌群液做空白对照。每个样品设置9个实验管,分别依次在0、0.5、1、2、4、6、8、12、24h取出,小心吸弃液体石蜡,迅速加入500μL正丁醇,涡旋混匀,离心(5000r·min-1,5min)使其分层,取上层进行硅胶薄层检测,经10%硫酸乙醇喷雾后110℃加热显色观察。
结果:主要实验结果如下。
(1)β-常春藤皂苷(S1):硅胶薄层检测,二氯甲烷-甲醇-三氟乙酸(9:1:0.1)展开时Rf约为0.5。S1在孵育24h均以原形存在,基本不发生代谢。此外未检测到代谢产物齐墩果酸。
(2)化合物S2~S4:硅胶薄层检测,二氯甲烷-甲醇-三氟乙酸(9:1:0.1)展开时Rf依次约为0.1、0.2、0.0。S2在孵育0.5h时即有S1代谢产物,2h后基本完全代谢为 S1。S3和S4在孵育2h内均主要以原形存在,24h后基本完全代谢,代谢产物未知,此外未检测到代谢物齐墩果酸和S1。
(3)化合物P1~P9:硅胶薄层检测,二氯甲烷-甲醇-三氟乙酸(9:1:0.1)展开时Rf约为0.0~0.2。化合物P1~P9在孵育1h时即有S1或相似Rf的代谢产物,4h后基本代谢完全。
本实验首次发现,β-常春藤皂苷在肠道菌群中基本不发生代谢;其28-糖酯衍生物具有不同的代谢途径,其中只有葡萄糖酯型的衍生物S2可以显著转化为相应28-齐墩果酸皂苷;进一步测试发现,28-葡萄糖酯衍生物P1~P9也可发生类似代谢,表明该葡萄糖基是代谢必需基团,该葡萄糖基6-寡糖基取代的衍生物也可被肠道菌群识别和代谢。因此,该类衍生物可以经结肠部位的肠道菌群代谢为活性更好的原形3-齐墩果酸型皂苷。
综上所述,本发明公开了齐墩果酸型皂苷类化合物及其组合物解决刺激性副作用大、口服生物利用率低的问题。
应说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,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精神和范围,其均应涵盖在本发明的权利要求范围当中。
Claims (9)
1.齐墩果酸型皂苷类化合物,其结构如下述式(I):
其中,
R1:-H或者-OH;
R2:α-OR3或者β-OR3;
R3:-H或者单糖基中的1-2个。
2.根据权利要求1所述的齐墩果酸型皂苷类化合物,其特征在于:所述单糖基为葡萄糖、半乳糖、甘露糖、阿拉伯糖、木糖、鼠李糖、呋糖或芹糖基。
3.根据权利要求1所述的齐墩果酸型皂苷类化合物,其特征在于:所述R1为-H,R2为β-OR3。
4.根据权利要求1所述的齐墩果酸型皂苷类化合物,其特征在于:所述R1为-H,R2为α-OR3。
5.根据权利要求1所述的齐墩果酸型皂苷类化合物,其特征在于:所述R1为-OH,R2为β-OR3。
6.一种口服药用组合物,其中含有治疗有效量的权利要求1-5中任意一项所述的齐墩果酸型皂苷类化合物和药学上可接受的载体。
7.根据权利要求6所述的口服药用组合物,在制备治疗炎症或者肿瘤的药物中的应用。
8.根据权利要求7所述的口服药用组合物,其特征在于:所述炎症为结肠炎。
9.根据权利要求6所述的口服药用组合物,其特征在于:所述药用组合物在肠道中代谢为28-羧基的相应化合物。
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