CN111662351B - 新奥克梯隆型皂苷元衍生物及制备抗耐药菌药物应用 - Google Patents
新奥克梯隆型皂苷元衍生物及制备抗耐药菌药物应用 Download PDFInfo
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Abstract
本发明公开了新奥克梯隆型皂苷元衍生物及制备抗耐药菌药物应用。所述奥克梯隆型人参皂苷元衍生物的制备方法如下:a.20(S)‑原人参二醇为原料,乙酸酐保护C‑3位、C‑12位羟基;b.间氯过氧苯甲酸氧化使C‑24位成四氢呋喃环;c.氢氧化钠脱去C‑3、C‑12位保护基;d.在DMAP、EDCI的催化下,与不同的Boc‑氨基酸、Fmoc‑Boc‑氨基酸发生反应;e.在三氟乙酸的催化下,脱去Boc保护基,得到粗产物,柱层析法提纯得到目标化合物;f.在DIEA催化下、氨基与丹酰氯的反应;g.在哌啶催化下,脱去Fmoc保护,得到粗产物,柱层析法提纯得到目标化合物。本发明所述的奥克梯隆型人参皂苷元衍生物具有较好的抗菌作用,相比于奥克梯隆型人参皂苷元母核对耐甲氧西林金黄色葡萄球菌的抑制作用得到显著增强。
Description
技术领域
本发明涉及有机合成和药物化学领域,具体涉及一类结构新颖的奥克梯隆型人参皂苷元衍生物。本发明公开了这些奥克梯隆型人参皂苷元衍生物的制备方法,含有它们的药物组合物及其抗细菌感染疾病用途。
背景技术
天然产物是药物研发中先导化合物的重要来源,具有结构类型丰富,毒副作用小等特点,所以从天然产物中寻找具有抗菌作用的成分成为科研工作者研究的热点方向。奥克梯隆型人参皂苷(ocotillol-type)是一类侧链上含有四氢呋喃环的达玛烷型四环三萜皂苷,主要存在于人参属植物中,具有抗肿瘤等多种药理作用。
抗菌药物的发现与研究对治疗由细菌引发的感染性疾病发挥了重要作用。但是,对抗菌药物的滥用,促使细菌出现耐药性。金黄色葡萄球菌是医院和社区获得性感染最常见的病原菌之一。近年来,由于临床上抗生素的大量使用,导致耐药性金黄色葡萄球菌菌株如耐甲氧西林金黄色葡萄球菌(MRSA)的产生。MRSA通常被称作超级细菌,其引起的感染有很高的发病率和死亡率,临床治疗具有较高的难度。因此新型高效抗耐药菌药物(耐甲氧西林金黄色葡萄球菌(MRSA))的研发对于抵抗日益严重的细菌感染具有重要意义。
发明内容
本发明提供了一类新奥克梯隆型皂苷元衍生物,其具有较好的耐药菌抗菌活性,本发明同时提供了该类衍生物的制备方法和用途。
本发明要解决的技术问题是寻找新结构类型具有优良抗菌活性的化合物,进一步提供上述化合物制备耐甲氧西林金黄色葡萄球菌抗菌药物的应用。
为解决上述技术问题,本发明提供如下技术方案:
通式(I)所示奥克梯隆型人参皂苷元衍生物及其医学上可接受的盐,
其中,
R3代表(C1-C8)直链或支链烷基;
R4代表(C1-C3)、(C5-C8)直链或支链烷基。
优选,所述化合物及其医学上可接受的盐,其中,
R3代表(C1-C8)直链或支链烷基;
R4代表(C1-C3)、(C5-C8)直链或支链烷基。
优选,本发明的部分化合物为:
(20S,24R)-环氧-3β-氧基-[2-(N’-Fmoc)-5-氨基丁酰]-达玛烷-12β,25-二醇;
(20S,24S)-环氧-3β-氧基-[2-(N’-Fmoc)-5-氨基丁酰]-达玛烷-12β,25-二醇;
(20S,24R)-环氧-3β-氧基-[2-(N’-Fmoc)-6-氨基戊酰]-达玛烷-12β,25-二醇;
(20S,24S)-环氧-3β-氧基-[2-(N’-Fmoc)-6-氨基戊酰]-达玛烷-12β,25-二醇;
(20S,24R)-环氧-3β-氧基-[2-氨基-5-(5-二甲氨基-1-萘磺酰胺)丁酰]-达玛烷-12β,25-二醇;
(20S,24S)-环氧-3β-氧基-[2-氨基-5-(5-二甲氨基-1-萘磺酰胺)丁酰]-达玛烷-12β,25-二醇;
(20S,24R)-环氧-3β-氧基-[2-氨基-6-(5-二甲氨基-1-萘磺酰胺)戊酰]-达玛烷-12β,25-二醇;
(20S,24S)-环氧-3β-氧基-[2-氨基-6-(5-二甲氨基-1-萘磺酰胺)戊酰]-达玛烷-12β,25-二醇;
(20S,24R)-环氧-3β-氧基-[2-(5-二甲氨基-1-萘磺酰胺)-6-氨基己酰]-达玛烷-12β,25-二醇;
(20S,24S)-环氧-3β-氧基-[2-(5-二甲氨基-1-萘磺酰胺)-6-氨基己酰]-达玛烷-12β,25-二醇。
本发明所述奥克梯隆型人参皂苷元衍生物的制备方法如下:
a.以20(S)-原人参二醇为原料,乙酸酐保护C-3位、C-12位羟基;
b.间氯过氧苯甲酸氧化使C-24位成四氢呋喃环;
c.氢氧化钠脱去C-3、C-12位保护基;
d.在DMAP、EDCI的催化下,与不同的Boc-氨基酸、Fmoc-Boc-氨基酸发生反应;
e.在三氟乙酸的催化下,脱去Boc保护基,得到粗产物,柱层析法提纯得到目标化合物;
f.在DIEA催化下、氨基与丹酰氯的反应;
g.在哌啶催化下,脱去Fmoc保护,得到粗产物,柱层析法提纯得到目标化合物。
本发明包括一种用于制备治疗哺乳动物,优选制备治疗人类疾病或病症的药物,其包括治疗败血症、肺炎、脑膜炎、心内膜炎、骨与关节感染、烧伤感染、外科以及创伤感染、皮肤感染等疾病或病症,如通式(I)所示的化合物或其盐和可药用载体。
所述通式(I)所示奥克梯隆型人参皂苷元衍生物及其医学上可接受的盐制备抗菌药物的应用。
优选,所述通式(I)所示奥克梯隆型人参皂苷元衍生物及其医学上可接受的盐制备耐甲氧西林金黄色葡萄球菌抗菌药物的应用。
耐药性金黄色葡萄球菌菌株如耐甲氧西林金黄色葡萄球菌(MRSA)对β-内酰胺类抗生素均具有耐药性,并对多数氨基糖苷类、氟喹诺酮类、大环内酯类等抗菌药物耐药,甚至一些地区已经出现了对万古霉素耐药的MRSA菌株。但是,本发明的抗菌活性结果表明,本发明经过结构修饰与改造后得到的奥克梯隆型人参皂苷元衍生物,其对耐甲氧西林金黄色葡萄球菌的抑制作用得到显著增强。本发明所述的奥克梯隆型人参皂苷元衍生物具有较好的抗菌作用,相比于奥克梯隆型人参皂苷元母核,本发明所示实施例1-10对耐甲氧西林金黄色葡萄球菌表现出较好的活性,MIC值主要分布在1-16μg/mL范围内,证明可以用于制备抗细菌感染类药物。因此,本发明公开的衍生物为具有耐甲氧西林金黄色葡萄球菌抗菌活性的新型奥克梯隆型人参皂苷元衍生物。
因此,本发明提供了一类奥克梯隆型人参皂苷元衍生物,其具有较好的耐药菌抗菌活性,本发明同时提供了该类衍生物的制备方法。本发明所述的奥克梯隆型人参皂苷元衍生物相比于奥克梯隆型人参皂苷元母核对耐甲氧西林金黄色葡萄球菌表现出较好的抗菌活性,MIC值1-16μg/mL范围内。本发明提供一种制备耐甲氧西林金黄色葡萄球菌感染疾病或病症的药物的应用。
具体实施方式
下面通过实施例进一步详细描述本发明,但本发明不仅仅局限于以下实施例。
实施例1
(20S,24R)-环氧-3β-氧基-[2-(N’-Fmoc)-5-氨基丁酰]-达玛烷-12β,25-二醇
将20(S)-原人参二醇(500.0mg,1.1mmol)溶于氯仿(3.0mL)中,加入DMAP(20.0mg,0.2mmol)搅拌,后缓慢滴加乙酸酐(0.4mL,4.4mmol),室温搅拌1h。乙酸乙酯(20.0mL)稀释,10%盐酸洗至酸性,水洗,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析(石油醚:乙酸乙酯=10:1),得白色固体20(S)-3,12-二乙酰基原人参二醇(500.0mg,85%)。
将20(S)-3,12-二乙酰基原人参二醇(210.0mg,0.4mmol)溶于无水二氯甲烷(6.0mL)中,冰盐浴预冷下缓慢滴加间氯过氧苯甲酸(190.0mg,0.2mmol,75%)的二氯甲烷(5.0mL)溶液,0.5h后升至室温搅拌反应2h。加入异丙醇(1.0mL),继续搅拌1h,加入饱和碳酸氢钠溶液搅拌1h后分液萃取,有机相依次用饱和硫代硫酸钠溶液、水、饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析(石油醚:乙酸乙酯=8:1),得白色固体20(S)-20,24-环氧-3,12-二乙酰基原人参二醇(146.0mg,70.0%)。
将20(S)-20,24-环氧-3,12-二乙酰基原人参二醇(130.0mg,0.2mmol)溶于甲醇(8.0mL)中,加入氢氧化钾(85.0mg,1.5mmol),135℃搅拌反应2h。反应液冷至室温后,加入适量的水,大量白色固体析出,抽滤,干燥,柱层析(石油醚:乙酸乙酯=2:1-1:1),得化合物OR{(20S,24R)-环氧达玛烷-3,12,25-三醇,66.0mg}和OS{(20S,24S)-环氧达玛烷-3,12,25-三醇,50.0mg}。
将OR(80.0mg,0.2mmol)溶解于无水二氯甲烷(5.0mL)中,加入4-二甲氨基吡啶(56.0mg,0.5mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(96.0mg,0.5mmol)和(R)-4-(Boc-氨基)-2-(Fmoc-氨基)丁酸(110.0mg,0.3mmol),室温下反应3h。反应液用二氯甲烷稀释,5%盐酸洗,去离子水洗,饱和氯化钠洗,无水硫酸钠干燥,浓缩。将干燥后的中间体溶于无水二氯甲烷中,加入过量三氟乙酸,室温反应1h。反应液减压蒸馏后硅胶柱层析(氯仿:甲醇=80:1-50:1),得到白色固体(0.1g,77.4%)。1H-NMR(CDCl3,400MHz)δ(ppm):8.27(s,2H,-NH2),7.70(d,J=7.6Hz,2H,Ar-H×2),7.55(d,J=6.6Hz,2H,Ar-H×2),7.34(t,J=7.4Hz,2H,Ar-H×2),7.26(t,J=7.5Hz,2H,Ar-H×2),6.20(d,J=7.4Hz,1H,-NH-),4.47(d,J=7.3Hz,1H,-OCH-),4.32(d,J=6.5Hz,3H,-OCH2-,-NCH-),4.14(t,J=6.8Hz,1H,-CH-),3.81(t,J=7.6Hz,1H,-OCH-),3.60–3.47(m,1H,-OCH-),3.04(d,J=43.0Hz,2H,-NCH2-),2.23(d,J=55.9Hz,2H,-CH2-),1.26(s,3H,-CH3),1.24(s,3H,-CH3),1.22(s,3H,-CH3),1.09(s,3H,-CH3),0.94(s,3H,-CH3),0.86(s,3H,-CH3),0.82(s,3H,-CH3),0.79(s,3H,-CH3).
实施例2
(20S,24S)-环氧-3β-氧基-[2-(N’-Fmoc)-5-氨基丁酰]-达玛烷-12β,25-二醇将OS(80.0mg,0.2mmol)溶解于无水二氯甲烷(5.0mL)中,加入4-二甲氨基吡啶(56.0mg,0.5mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(96.0mg,0.5mmol)和(R)-4-(Boc-氨基)-2-(Fmoc-氨基)丁酸(110.0g,0.3mmol),室温下反应3h。反应液用二氯甲烷稀释,5%盐酸洗,去离子水洗,饱和氯化钠洗,无水硫酸钠干燥,浓缩。将干燥后的中间体溶于无水二氯甲烷中,加入过量三氟乙酸,室温反应1h。反应液减压蒸馏后硅胶柱层析(氯仿:甲醇=80:1-50:1),得到白色固体(94.3mg,70.1%)。1H-NMR(CDCl3,400MHz)δ(ppm):8.24(s,2H,-NH2),7.69(d,J=7.5Hz,2H,Ar-H×2),7.54(d,J=5.6Hz,2H,Ar-H×2),7.34(t,J=7.4Hz,2H,Ar-H×2),7.25(t,J=7.4Hz,3H,Ar-H×2),6.13(d,J=7.5Hz,1H,-NH-),4.55–4.43(m,1H,-OCH-),4.40–4.26(m,3H,-OCH2-,-NCH-),4.13(t,J=6.9Hz,1H,-CH-),3.92–3.79(m,1H,-OCH-),3.50(s,1H,-OCH-),3.02(d,J=55.7Hz,2H,-NCH2-),2.26(d,J=41.9Hz,2H,-CH2-),1.24(s,3H,-CH3),1.23(s,3H,-CH3),1.18(s,3H,-CH3),1.10(s,3H,-CH3),0.96(s,3H,-CH3),0.85(s,3H,-CH3),0.84(s,3H,-CH3),0.79(s,3H,-CH3).
实施例3
(20S,24R)-环氧-3β-氧基-[2-(N’-Fmoc)-6-氨基戊酰]-达玛烷-12β,25-二醇
参照(20S,24R)-环氧-3β-氧基-[2-(N’-Fmoc)-5-氨基丁酰]-达玛烷-12β,25-二醇的合成方法,OR与N-Fmoc-N'-Boc-L-鸟氨酸反应,脱去Boc保护基后得到白色固体(95.1mg,69.9%)。1H-NMR(CDCl3,400MHz)δ(ppm):8.01(s,2H,-NH2),7.69(d,J=7.5Hz,2H,Ar-H×2),7.54(t,J=7.0Hz,2H,Ar-H×2),7.32(t,J=7.5Hz,2H,Ar-H×2),7.24(d,J=5.7Hz,2H,Ar-H×2),5.84(d,J=8.0Hz,1H,-NH-),4.50–4.38(m,1H,-OCH-),4.27(d,J=6.8Hz,3H,-OCH2-,-NCH-),4.12(t,J=7.0Hz,1H,-CH-),3.86–3.77(m,1H,-OCH-),3.48(dd,J=10.2,4.1Hz,1H,-OCH-),2.95(s,2H,-NCH2-),1.25(s,3H,-CH3),1.24(s,6H,-CH3×2),1.08(s,3H,-CH3),0.93(s,3H,-CH3),0.83(s,3H,-CH3),0.79(s,3H,-CH3),0.75(s,3H,-CH3).
实施例4
(20S,24S)-环氧-3β-氧基-[2-(N’-Fmoc)-6-氨基戊酰]-达玛烷-12β,25-二醇
参照(20S,24S)-环氧-3β-氧基-[2-(N’-Fmoc)-5-氨基丁酰]-达玛烷-12β,25-二醇的合成方法,OS与N-Fmoc-N'-Boc-L-鸟氨酸反应,脱去Boc保护基后得到白色固体(92.0mg,67.8%)。1H-NMR(CDCl3,400MHz)δ(ppm):8.07(s,2H,-NH2),7.69(d,J=7.5Hz,2H,Ar-H×2),7.55(t,J=6.3Hz,2H,Ar-H×2),7.33(t,J=7.5Hz,2H,Ar-H×2),7.24(t,J=7.4Hz,2H,Ar-H×2),5.83(d,J=8.0Hz,1H,-NH-),4.47(t,J=8.7Hz,1H,-OCH-),4.28(d,J=6.6Hz,3H,-OCH2-,-NCH-),4.13(t,J=7.1Hz,1H,-CH-),3.90–3.81(m,1H,-OCH-),3.54–3.44(m,1H,-OCH-),2.97(s,2H,-NCH2-),1.24(s,3H,-CH3),1.19(s,3H,-CH3),1.09(s,3H,-CH3),0.96(s,3H,-CH3),0.85(s,3H,-CH3),0.84(s,3H,-CH3),0.77(s,3H,-CH3),0.76(s,3H,-CH3).
实施例5
(20S,24R)-环氧-3β-氧基-[2-氨基-(5-二甲氨基-1-萘磺酰胺)丁酰]-达玛烷-12β,25-二醇
将实施例1得到的目标化合物(20S,24R)-环氧-3β-氧基-[2-(N’-Fmoc)-5-氨基丁酰]-达玛烷-12β,25-二醇(60.0mg,0.1mmol)溶解于无水二氯甲烷(5.0mL)中,加入N,N-二异丙基乙胺(36.0mg,0.3mmol)、丹酰氯(24.0mg,0.1mmol),室温下反应4h。反应液用二氯甲烷稀释,5%盐酸洗,去离子水洗,饱和氯化钠洗,无水硫酸钠干燥,浓缩,得到中间体。将干燥后的中间体溶于无水二氯甲烷中,加入过量哌啶,室温反应2h。反应液减压蒸馏后硅胶柱层析(氯仿:甲醇=100:1-50:1),得到淡绿色固体Ⅴ-5(44.0mg,72.2%)。1H-NMR(CDCl3,400MHz)δ(ppm):8.50(dt,J=8.5,1.0Hz,1H,Ar-H),8.27(d,J=8.7Hz,1H,Ar-H),8.22(dd,J=7.3,1.3Hz,1H,Ar-H),7.51(ddd,J=14.7,8.6,7.4Hz,2H,Ar-H×2),7.16(dd,J=7.6,0.7Hz,1H,Ar-H),5.60(s,1H,-OH),4.36(dd,J=10.6,5.9Hz,1H,-OCH-),3.82(dd,J=8.8,6.5Hz,1H,-OCH-),3.49–3.42(m,1H,-OCH-),3.30(dd,J=9.6,3.5Hz,1H,-NH2CH-),3.14(dd,J=11.7,7.4Hz,1H,-NCH2-),3.01–2.91(m,1H,-NCH2-),2.87(s,6H,-CH3×2),1.25(s,3H,-CH3),1.24(s,3H,-CH3),1.07(s,3H,-CH3),0.94(s,3H,-CH3),0.86(s,3H,-CH3),0.81(s,3H,-CH3),0.73(s,3H,-CH3),0.72(s,3H,-CH3).
实施例6
(20S,24S)-环氧-3β-氧基-[2-氨基-(5-二甲氨基-1-萘磺酰胺)丁酰]-达玛烷-12β,25-二醇参照实施例5的合成方法,将实施例2得到的目标化合物(20S,24S)-环氧-3β-氧基-[2-(N’-Fmoc)-5-氨基丁酰]-达玛烷-12β,25-二醇与丹酰氯反应,后脱去Fmoc保护基,得到淡绿色固体Ⅴ-6(42.1mg,69.6%)。1H-NMR(CDCl3,400MHz)δ(ppm):8.51(d,J=8.4Hz,1H,Ar-H),8.27(d,J=8.6Hz,1H,Ar-H),8.22(d,J=7.3Hz,1H,Ar-H),7.56(s,1H,Ar-H),7.52–7.47(m,1H,Ar-H),7.17(d,J=7.5Hz,1H,Ar-H),5.75(s,1H,-OH),4.38(dd,J=10.8,5.8Hz,1H,-OCH-),3.85(dd,J=10.9,5.3Hz,1H,-OCH-),3.50(td,J=9.8,4.7Hz,1H,-OCH-),3.30(dd,J=9.7,3.5Hz,1H,-NH2CH-),3.20–3.12(m,1H,-NCH2-),2.97(dd,J=8.9,4.2Hz,1H,-NCH2-),2.87(s,6H,-CH3×2),1.26(s,3H,-CH3),1.23(s,3H,-CH3),1.08(s,3H,-CH3),0.98(s,3H,-CH3),0.88(s,3H,-CH3),0.86(s,3H,-CH3),0.75(s,3H,-CH3),0.74(s,3H,-CH3).
实施例7
(20S,24R)-环氧-3β-氧基-[2-氨基-(5-二甲氨基-1-萘磺酰胺)戊酰]-达玛烷-12β,25-二醇
参照实施例5的合成方法,将实施例3得到的目标化合物(20S,24R)-环氧-3β-氧基-[2-(N’-Fmoc)-6-氨基鸟氨酰]-达玛烷-12β,25-二醇与丹酰氯反应,后脱去Fmoc保护基,得到淡绿色固体Ⅴ-7(40.0mg,65.1%)。1H-NMR(CDCl3,400MHz)δ(ppm):8.50(d,J=8.5Hz,1H,Ar-H),8.29(d,J=8.7Hz,1H,Ar-H),8.21(dd,J=7.3,1.3Hz,1H,Ar-H),7.55–7.50(m,1H,Ar-H),7.51–7.46(m,1H,Ar-H),7.15(d,J=7.5Hz,1H,Ar-H),5.57(s,1H.-OH),4.47–4.39(m,1H,-OCH-),3.82(dd,J=8.8,6.6Hz,1H,-OCH-),3.49(td,J=10.5,4.6Hz,1H,-OCH-),3.21(dd,J=8.6,4.1Hz,1H,-NH2CH-),2.99–2.91(m,1H,-NCH2-),2.86(s,6H,-CH3×2),2.81(ddd,J=12.7,7.5,5.4Hz,1H,-NCH2-),1.25(s,3H,-CH3),1.24(s,3H,-CH3),1.07(s,3H,-CH3),0.96(s,3H,-CH3),0.87(s,3H,-CH3),0.84(s,3H,-CH3),0.77(s,3H,-CH3),0.74(s,3H,-CH3).
实施例8
(20S,24S)-环氧-3β-氧基-[2-氨基-(5-二甲氨基-1-萘磺酰胺)戊酰]-达玛烷-12β,25-二醇参照实施例5的合成方法,将实施例4得到的目标化合物(20S,24S)-环氧-3β-氧基-[2-(N’-Fmoc)-6-氨基鸟氨酰]-达玛烷-12β,25-二醇与丹酰氯反应,后脱去Fmoc保护基,得到淡绿色固体Ⅴ-8(39.1mg,63.4%)。1H-NMR(CDCl3,400MHz)δ(ppm):8.51(d,J=10.6Hz,1H,Ar-H),8.29(d,J=8.7Hz,1H,Ar-H),8.24–8.19(m,1H,Ar-H),7.58–7.52(m,1H,Ar-H),7.53–7.47(m,1H,Ar-H),7.16(d,J=8.3Hz,1H,Ar-H),5.75(s,1H,-OH),4.44(dd,J=9.3,7.2Hz,1H,-OCH-),3.86(dd,J=10.8,5.4Hz,1H,-OCH-),3.51(td,J=10.3,4.8Hz,1H,-OCH-),3.23(dd,J=8.7,4.1Hz,1H,-NH2CH-),3.01–2.91(m,1H,-NCH2-),2.87(s,6H,-CH3×2),2.80(ddd,J=12.7,7.6,5.3Hz,1H,-NCH2-),1.26(s,3H,-CH3),1.23(s,3H,-CH3),1.08(s,3H,-CH3),0.99(s,3H,-CH3),0.89(s,3H,-CH3),0.88(s,3H,-CH3),0.79(s,3H,-CH3),0.75(s,3H,-CH3).
实施例9
(20S,24R)-环氧-3β-氧基-[2-(5-二甲氨基-1-萘磺酰胺)-6-氨基己酰]-达玛烷-12β,25-二醇
参照实施例1,将OR(80.0mg,0.2mmol)溶解于无水二氯甲烷(5.0mL)中,加入4-二甲氨基吡啶(56.0mg,0.5mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(96.1mg,0.5mmol)和N-Boc-N'-Fmoc-L-赖氨酸(116.0mg,0.3mmol),室温下反应3h。反应液用二氯甲烷稀释,5%盐酸洗,去离子水洗,饱和氯化钠洗,无水硫酸钠干燥,浓缩得黄色中间体X1。将干燥后的中间体X1溶于无水二氯甲烷中,加入过量三氟乙酸(1.0ml,13.4mmol),室温反应1h,反应液减压蒸馏干燥得黄色中间体X2。将干燥后的中间体X2溶于无水二氯甲烷(5.0ml)中加入N,N-二异丙基乙胺(36.0mg,0.3mmol)、丹酰氯(24.2mg,0.1mmol),室温下反应4h,后脱去Fmoc保护基,经硅胶柱层析,得到淡绿色固体Ⅴ-9(80.1mg,57.4%)。1H-NMR(CDCl3,400MHz)δ(ppm):8.51(d,J=8.5Hz,1H,Ar-H),8.29(d,J=8.7Hz,1H,Ar-H),8.21(d,J=7.3Hz,1H,Ar-H),7.60–7.52(m,1H,Ar-H),7.52–7.44(m,1H,Ar-H),7.16(d,J=6.8Hz,1H,Ar-H),4.15(dd,J=11.8,4.5Hz,1H,-OCH-),3.86–3.78(m,2H,-OCH-,COCH-),3.53–3.41(m,1H,-OCH-),2.85(s,6H,-CH3×2),1.26(s,3H,-CH3),1.24(s,3H,-CH3),1.08(s,3H,-CH3),0.93(s,3H,-CH3),0.83(s,3H,-CH3),0.77(s,3H,-CH3),0.67(s,3H,-CH3),0.66(s,3H,-CH3).
实施例10
(20S,24S)-环氧-3β-氧基-[2-(5-二甲氨基-1-萘磺酰胺)-6-氨基己酰]-达玛烷-12β,25-二醇
将OS(80.0mg,0.2mmol)溶解于无水二氯甲烷(5.0mL)中,加入4-二甲氨基吡啶(56.0mg,0.5mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(96.0mg,0.5mmol)和N-Boc-N'-Fmoc-L-赖氨酸(116.2mg,0.3mmol),室温下反应3h。反应液用二氯甲烷稀释,5%盐酸洗,去离子水洗,饱和氯化钠洗,无水硫酸钠干燥,浓缩得白色中间体X3。将干燥后的中间体X3溶于无水二氯甲烷中,加入过量三氟乙酸(1.0ml,13.4mmol),室温反应1h,反应液减压蒸馏干燥得白色中间体X4。将干燥后的中间体X4溶于无水二氯甲烷(5.0ml)中加入N,N-二异丙基乙胺(36.1mg,0.3mmol)、丹酰氯(24.0mg,0.1mmol)反应,后脱去Fmoc保护基,经硅胶柱层析,得到淡绿色固体Ⅴ-10(80.1mg,57.4%)
1H-NMR(CDCl3,400MHz)δ(ppm):8.48(d,J=8.5Hz,1H,Ar-H),8.32(d,J=8.7Hz,1H,Ar-H),8.20(dd,J=7.3,1.1Hz,1H,Ar-H),7.58–7.52(m,1H,Ar-H),7.45(dd,J=8.5,7.4Hz,1H,Ar-H),7.14(d,J=7.5Hz,1H,Ar-H),5.72(s,1H,-OH),4.11(dd,J=11.8,4.4Hz,1H,-OCH-),3.90–3.77(m,2H,-OCH-,COCH-),3.46(td,J=10.1,4.5Hz,1H,-OCH-),2.83(s,6H,-CH3×2),1.24(s,3H,-CH3),1.21(s,3H,-CH3),1.08(s,3H,-CH3),0.94(s,3H,-CH3),0.83(s,3H,-CH3),0.77(s,3H,-CH3),0.62(s,3H,-CH3),0.61(s,3H,-CH3).
药理试验证明,本发明的奥克梯隆型人参皂苷元衍生物具有较好的抗菌作用,可以用于制备抗感染类药物。
下面是本发明部分化合物的药理实验结果。
1仪器和设备:
隔水式恒温培养箱:型号GNP-9080,上海精宏实验设备有限公司
酶标仪:型号800TS,序列号17101018,BioTekInstruments,Inc
电子天平:型号PL203,MettlerToledoGroup
电子天平:型号DT1000,常熟市衡器厂
立式压力蒸汽灭菌器:型号LDZX-75KBS,上海申安医疗器械厂
2细胞株与试剂:
二甲基亚砜(DMSO)
氯化钠注射液
MH肉汤(MHB)
MH(A)培养基
选用细菌:耐甲氧西林金黄色葡萄球菌MRSA18-19、MRSA18-20、ATCC29213。
MH(A)培养基划线,35-37℃孵育24h后,挑取单菌落,麦氏比浊法调至0.5麦氏单位左右(约108CFU/ml),再将此菌悬液用MHB培养基进行100倍稀释,使菌悬液最终浓度约为106CFU/ml。
3实验方法:
采取美国国家临床实验室标准化委员会(ClinicalandLaboratoryStandardsInstituteCLSI)推荐的微量肉汤二倍稀释法。
设定实验药物浓度按二倍稀释在128-0.008μg/ml范围内,根据实际情况再适当调整。
将定量的受试药物用DMSO助溶,MHB培养基稀释,得到浓度为256μg/ml的受试药物溶液。分别取200μl各个受试药物溶液加入96孔板首孔。其余每孔加入100μlMHB培养基,依次对倍稀释至0.08μg/ml,尾孔吸出100μl液体弃去。得到药物浓度依次为128、64、32、16、8、4、2、1、0.5、0.25、0.125、0.06、0.03、0.015、0.008μg/ml的孔板。再每孔加入100μl稀释后的对应菌液,混匀,是菌液最终浓度为5×105CFU/ml。另设置受试药物对照组,菌对照组(100μl菌液+100μlMHB培养基),溶媒菌对照组(100μl菌液+含1%DMSOMHB培养液100μl)、溶媒培养基空白对照组(含1%DMSOMHB培养液200μl)。将孔板置培养箱中35-37℃培养20小时后,用酶标仪测定各孔A600值,判断各孔是否有菌生长,确定其MIC值。
4实验结果:
本实验选用耐甲氧西林金黄色葡萄球菌(MRSA)18-19、18-20为2018年成都地区收集的临床分离致病菌。MRSA18-19、MRSA18-20经VITEK-60自动微生物鉴定仪鉴定再经实验室常规方法鉴定。ATCC29213为外购具有鉴定证书的指控菌株。
活性测定结果见表1。
表1.奥克梯隆型人参皂苷元衍生物的体外抗菌活性
抗菌活性结果显示奥克梯隆型人参皂苷元衍生物的24(R)-构型ocotillol型人参皂苷元OR对耐甲氧西林金黄色葡萄球菌MRSA18-19、MRSA18-20、ATCC29213的抑制率均大于128μg/mL。实施例1、3、5、7、9为以OR为母核得到的衍生物,它们的MIC值在2-64μg/mL范围内。其中,实施例3对MRSA18-20的抑制活性最强,MIC=2μg/mL,明显强于母核OR。24(S)-构型ocotillol型人参皂苷元OS对耐甲氧西林金黄色葡萄球菌MRSA18-19、MRSA18-20、ATCC29213的抑制率均为64μg/mL。在以OS为母核得到的实施例中,实施例2对MRSA18-19、MRSA18-20、ATCC29213的抑制率均为1μg/mL,对耐药菌的抑制作用明显强于母核。
当前,耐药性金黄色葡萄球菌菌株如耐甲氧西林金黄色葡萄球菌(MRSA)对β-内酰胺类抗生素均具有耐药性,并对多数氨基糖苷类、氟喹诺酮类、大环内酯类等抗菌药物耐药。而且,MRSA耐药性发展迅速,与实验室常用质控菌株相比,临床分离致病菌往往具有更强的耐药性。但是,本发明的抗菌活性结果表明,经过结构修饰与改造后得到的奥克梯隆型人参皂苷元衍生物对耐甲氧西林金黄色葡萄球菌的抑制作用得到显著增强。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种等同变换,这些等同变换均属于本发明的保护范围。另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合。为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。此外,本发明的各种不同的实施方式之间也可以进行任意组合,只要其不违背本发明的思想,其同样应当视为本发明所公开的内容。
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CN108992453A (zh) * | 2018-09-12 | 2018-12-14 | 烟台大学 | 一类ocotillol型皂苷元衍生物的肿瘤耐药逆转的新用途 |
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CN106967143A (zh) * | 2017-05-01 | 2017-07-21 | 烟台大学 | 结构新颖的pyxinol衍生物及其制备方法和用途 |
CN108992453A (zh) * | 2018-09-12 | 2018-12-14 | 烟台大学 | 一类ocotillol型皂苷元衍生物的肿瘤耐药逆转的新用途 |
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"Design, synthesis, nitric oxide release and antibacterial evaluation of novel nitrated ocotillol-type derivatives";Yi Bi et al.;《European Journal of Medicinal Chemistry》;20150617;摘要,75-76页 * |
"Synthesis and biological evaluation of novel ocotillol-type triterpenoid derivatives as antibacterial agents";Zhiwen Zhou et al.;《European Journal of Medicinal Chemistry》;20131031;摘要,图表1 * |
Yi Bi et al.."Design, synthesis, nitric oxide release and antibacterial evaluation of novel nitrated ocotillol-type derivatives".《European Journal of Medicinal Chemistry》.2015, * |
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