CN1133653C - 灵芝α-(1→3)-D-葡聚糖硫酸酯衍生物及其用途和制备方法 - Google Patents
灵芝α-(1→3)-D-葡聚糖硫酸酯衍生物及其用途和制备方法 Download PDFInfo
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Abstract
本发明公开了具有抗肿瘤活性的灵芝α-(1→3)-D-葡聚糖硫酸酯化衍生物及其用途和制备方法。该方法用碱水溶液首次从灵芝子实体中提取出水不溶性线型α-(1→3)-D-葡聚糖,将其溶解在0.25M LiCl/DMSO中,加入磺化试剂,在室温下反应4-6小时得到水溶性的多糖的硫酸酯衍生物。这种衍生物对植入小鼠体内的爱氏腹水瘤(EAC)的生长具有明显的抑制作用,并且无毒副作用。
Description
本发明涉及一种α-(1→3)-D-葡聚糖的衍生物及其用途和制备方法,这种衍生物具有明显的抗肿瘤活性。它属于高分子化学领域,也属于分子生物学领域。
80年代以来的研究表明,灵芝水不溶性多糖是灵芝多糖的主要成分。Sone等人(Agric.Biol.Chem.49,2641,1985)的研究认为灵芝水不溶性多糖是灵芝子实体β-(1→3)-D-葡聚糖,但不具有抗肿瘤活性且不能被β-(1→3)-D-葡聚糖水解酶水解。通过化学修饰改变多糖生物活性的报道主要有Smith降解(药学学报21,944,1986),高碘酸氧化后硼氢化还原(Carbohydr.Res.115,273,1983),羧甲基化(Eur.J.Cancer 15,2110,1978)和硫酸酯化(Antimicrob.Agents Chemother.85,6132,1985;Biochem.Pharmcol.37,2887,1988;J.Immunopharmcol.12,225,1990)等,由此提高多糖在抗肿瘤、抗爱滋病毒及抗凝血等方面生物活性。
本发明的目的是提供一种α-(1→3)-D-葡聚糖硫酸酯化衍生物及其用途和制备方法,该方法将充分利用灵芝子实体中含量最多(含量占3%)而又无生物活性的水不溶性α-(1→3)-D-葡聚糖,通过硫酸酯化后变为水溶性衍生物,使其具有明显抗肿瘤活性和免疫功能的多糖,可用作保健品,并可望开发成天然药物,是一种科技含量高的产物。
为实现上述目的,本发明所采用的技术方案如下:
一种α-(1→3)-D-葡聚糖硫酸酯化衍生物,它是以灵芝子实体中水不溶性的线型α-(1→3)-D-葡聚糖为原料,将其溶解在0.25M LiCl/DMSO中,加入由氯磺酸和吡啶制成的磺化试剂,反应4-6小时,经丙酮沉淀、洗涤和真空干燥后得到硫酸酯化衍生物。
这种硫酸酯化衍生物对植入小鼠(昆明种小白鼠)体内的爱氏腹水肿瘤(EAC)具有明显的抑制作用(动物实验结果见附表1),且无毒副作用,因此,本发明的α-(1→3)-D-葡聚糖硫酸酯化衍生物可用于制备抗肿瘤药物和提高人体免疫机能的保健品。
一种制备α-(1→3)-D-葡聚糖硫酸酯化衍生物的方法:以从灵芝子实体中分离出的不溶性α-(1→3)-D-葡聚糖为原料,将溶解在0.25M LiCl/DMSO中,加入磺化试剂,反应4-6小时,得产物。经丙酮沉淀、洗涤和真空干燥后得到硫酸酯化衍生物。
磺化试剂的制备方法为:在冰浴条件下,将4.9mL氯磺酸缓慢地滴加到24mL吡啶中,制成磺化试剂。
从灵芝子实体中分离出的水不溶性线型α-(1→3)-D-葡聚糖分子量为19.5×104,在1N NaOH中[α]D=170(degcm2g-1)。分离方法如下:
灵芝子实体经粉碎、脱脂、再用磷酸盐缓冲液于100℃下提取出水溶性多糖后,用1M NaOH水溶液提取出水不溶性α-(1→3)-D-葡聚糖。将它的NaOH溶液在流水中透析7天,再对蒸馏水透析3天。此时NaOH被透析掉,多糖沉淀出来。然后将浑浊液进行离心,收集固体并进行真空干燥。由此得到白色粉末状灵芝α-(1→3)-D-葡聚糖。
本发明建立了以灵芝子实体水不溶性线型α-(1→3)-D-葡聚糖为原料制备出水溶性硫酸酯化衍生物的方法。动物体内试验证明,α-(1→3)-D-葡聚糖硫酸酯化衍生物都具有显著的抗肿瘤EAC活性,且无毒副作用,可用作保健品,作为抗肿瘤天然药物也具有应用前景。本发明与已有技术相比有实质性不同,而且科技含量较高,有明显的技术进步。
本发明首次用灵芝α-(1→3)-D-葡聚糖为原料,通过衍生化使水不溶性且无生物活性的多糖变为水溶性,且抗肿瘤活性明显的多糖衍生物。此法工艺简单,操作方便,效果显著。
以下结合具体的实施例对本发明的技术方案作进一步的说明:
实施例1
灵芝子实体经粉碎、脱脂、再用磷酸盐缓冲液于100℃下提取出水溶性多糖后,用1M NaOH水溶液提取出水不溶性α-(1→3)-D-葡聚糖。将它的NaOH溶液在流水中透析7天,再对蒸馏水透析3天。此时NaOH被透析掉,多糖沉淀出来。然后将浑浊液进行离心,收集固体并进行真空干燥。由此得到白色粉末状灵芝α-(1→3)-D-葡聚糖。
将灵芝α-(1→3)-D-葡聚糖200mg,溶于40mL含0.25M LiCl的二甲基亚砜(0.25M LiCl-DMSO)混合溶剂中。在冰浴条件下,将4.9mL氯磺酸缓慢地滴加到24mL吡啶中,制成磺化试剂。在持续搅拌下,将磺化试剂慢慢滴加到上述多糖的LiCl-DMSO溶液中,反应4-6小时。然后,用NaOH水溶液中和至中性。最后,加入大量丙酮沉淀出反应产物。用丙酮水溶液洗涤反应产物6次,以除去其中的无机盐和小分子,再用无水丙酮洗涤6次,真空干燥7天,得到白色的硫酸酯化衍生物。产率为70-80%。
附表1.灵芝α-(1→3)-D-葡聚糖及其衍生物抗EAC肿瘤活性
样品 | 剂量(mg/kg/day) | 抑制率(%) |
灵芝α-(1→3)-D-葡聚糖 | 12.0×7 | 0 |
灵芝α-(1→3)-D-葡聚糖硫酸酯化衍生物 | 14.8×729.7×7 | 34.841.5 |
比较组:5-氟尿嘧啶 | 20.0×7 | 31.4 |
Claims (3)
1.一种灵芝α-(1→3)-D-葡聚糖硫酸酯化衍生物,其特征在于:它是将灵芝子实体中水不溶性的线性α-(1→3)-D-葡聚糖溶于含0.25M LiCl的二甲基亚砜混合溶剂中,在搅拌下滴加磺化试剂,反应4-6小时,最后用NaOH水溶液中和至中性,再用丙酮沉淀并用丙酮和水混合溶液洗涤后得到的硫酸酯化衍生物;
2.按权利要求1所述的灵芝α-(1→3)-D-葡聚糖硫酸酯化衍生物用于制备抗肿瘤药物或保健品;
3.一种制备权利要求1所述的灵芝α-(1→3)-D-葡聚糖硫酸酯化衍生物的方法,其特征在于:它是将灵芝子实体中水不溶性的线性α-(1→3)-D-葡聚糖溶于含0.25M LiCl的二甲基亚砜混合溶剂中,在搅拌下滴加磺化试剂,反应4-6小时,最后用NaOH水溶液中和至中性,再用丙酮沉淀并用丙酮和水混合溶液洗涤后,即得到灵芝α-(1→3)-D-葡聚糖硫酸酯化衍生物。
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CN110128565A (zh) * | 2019-05-06 | 2019-08-16 | 上海市农业科学院 | 一种灵芝β-葡聚糖硫酸酯及其合成方法和应用 |
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WO2014099724A1 (en) * | 2012-12-20 | 2014-06-26 | E. I. Du Pont De Nemours And Company | Preparation of poly alpha-1,3-glucan ethers |
WO2014105698A1 (en) * | 2012-12-27 | 2014-07-03 | E. I. Du Pont De Nemours And Company | Preparation of poly alpha-1,3-glucan esters and films therefrom |
CN103804512B (zh) * | 2014-01-16 | 2016-05-04 | 昆山京昆油田化学科技开发公司 | 一种半乳糖基葡聚糖衍生物的制备方法 |
CN117624404B (zh) * | 2024-01-25 | 2024-03-29 | 默普生物科技(山东)有限公司 | 一种提升葡聚糖硫酸钠化学稳定性与生物活性的合成工艺 |
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JPS5171668A (ja) * | 1974-12-18 | 1976-06-21 | Matsushita Electric Ind Co Ltd | Inkyokusenkan |
JPS5893702A (ja) * | 1981-12-01 | 1983-06-03 | Sankyo Co Ltd | β−1,3−グルカンおよびその製法 |
US4769363A (en) * | 1984-03-08 | 1988-09-06 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Beta-glucan |
ES2043529A1 (es) * | 1991-11-08 | 1993-12-16 | Taya Miguel Margarit | Procedimiento para la obtencion de un polisacarido sulfato alcalino. |
JPH0826173A (ja) * | 1994-07-15 | 1996-01-30 | Sanyo Electric Co Ltd | 電動自転車 |
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JPS5171668A (ja) * | 1974-12-18 | 1976-06-21 | Matsushita Electric Ind Co Ltd | Inkyokusenkan |
JPS5893702A (ja) * | 1981-12-01 | 1983-06-03 | Sankyo Co Ltd | β−1,3−グルカンおよびその製法 |
US4769363A (en) * | 1984-03-08 | 1988-09-06 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Beta-glucan |
US5512672A (en) * | 1988-07-07 | 1996-04-30 | Ajinomoto Co., Inc. | Curdlan sulfate |
ES2043529A1 (es) * | 1991-11-08 | 1993-12-16 | Taya Miguel Margarit | Procedimiento para la obtencion de un polisacarido sulfato alcalino. |
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CN110128565A (zh) * | 2019-05-06 | 2019-08-16 | 上海市农业科学院 | 一种灵芝β-葡聚糖硫酸酯及其合成方法和应用 |
CN110128565B (zh) * | 2019-05-06 | 2021-02-26 | 上海市农业科学院 | 一种灵芝β-葡聚糖硫酸酯及其合成方法和应用 |
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