CN1283633A - 灵芝α－(1→3)－D－葡聚糖羧甲基化衍生物及其用途和制备方法 - Google Patents

灵芝α－(1→3)－D－葡聚糖羧甲基化衍生物及其用途和制备方法 Download PDF

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CN1283633A
CN1283633A CN 99116590 CN99116590A CN1283633A CN 1283633 A CN1283633 A CN 1283633A CN 99116590 CN99116590 CN 99116590 CN 99116590 A CN99116590 A CN 99116590A CN 1283633 A CN1283633 A CN 1283633A
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CN1133654C (zh
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张俐娜
陈敬华
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Wuhan University WHU
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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一葡聚糖羧甲基化衍生物的制备方法。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,该多糖不具有抗肿瘤活性。将α－(1→3)－D－葡聚糖溶解在NaOH水溶液中,用氯乙酸钠水溶液在80℃对其羧甲基化6-8小时制备了该多糖的羧甲基衍生物。这种衍生物是水溶性的,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。

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灵芝α-(1→3)-D-葡聚糖羧甲基化衍生物 及其用途和制备方法
本发明涉及一种具有抗肿瘤活性的α-(1→3)-D-葡聚糖羧甲基化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一种具有抗肿瘤活性的α-(1→3)-D-葡聚糖羧甲基化衍生物及其用途和制备方法，该方法将利用灵芝子实体中含量最多而又无生物活性的水不溶性α-(1→3)-D-葡聚糖(含量占3％)，通过羧甲基化后变为水溶性衍生物，从而使其具有明显抗肿瘤活性和免疫功能，并可用作保健品，而且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：
一种灵芝α-(1→3)-D-葡聚糖羧甲基化衍生物，它是将α-(1→3)-D-葡聚糖溶于NaOH水溶液，恒温80℃，在持续搅拌下缓慢滴加氯乙酸钠水溶液，反应6-8小时后，取出反应物溶液用盐酸中和至中性，并在甲醇中沉淀出产物，分别用甲醇水溶液和无水甲醇洗涤，得到的即为灵芝α-(1→3)D-葡聚糖羧甲基化衍生物。
所制得的羧甲基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)都具有明显的抑制作用。动物实验结果见附表1。因此，本发明的灵芝α-(1→3)-D-葡聚糖羧甲基化衍生物用于制备抗肿瘤药物或提高人体免疫机能的保健品。
制备本发明的灵芝α-(1→3)-D-葡聚糖羧甲基化衍生物方法是：首先从灵芝子实体中分离出水不溶性线型α-(1→3)-D-葡聚糖。其分子量为19.5×104，在1NNaOH中[α]D=170(degcm2g-1)。将其溶解在NaOH水溶液中，用氯乙酸钠水溶液于80℃，羧甲基化6-8小时，用甲醇沉淀出产物。接着用甲醇水溶液洗涤，最后用无水甲醇洗涤，真空干燥后得羧甲基化衍生物。
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羧甲基化衍生物的方法。动物体内试验证明，α-(1→3)-D-葡聚糖羧甲基化衍生物具有显著的抗肿瘤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，通过羧甲基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。
灵芝α-(1→3)-D-葡聚糖1克，溶于50mL NaOH水溶液。恒温80℃，在持续搅拌下缓慢滴加氯乙酸钠水溶液40mL，并于30分钟内滴加完。在反应6小时后取出反应物溶液，用盐酸中和至中性，在甲醇中沉淀出产物。将所得产物用甲醇水溶液洗涤6次，无水甲醇洗涤6次，真空干燥7天，由此得到白色粉状的羧甲基化衍生物。产率为80～85％。
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-葡聚糖羧甲基化衍生物     34.7×7     35.6
比较组：5-氟尿嘧啶     20.0×7     56.7

Claims (3)

1．一种灵芝α-(1→3)-D-葡聚糖羧甲基化衍生物，其特征在于它是将α-(1→3)-D-葡聚糖溶于NaOH水溶液，恒温80℃，在持续搅拌下缓慢滴加氯乙酸钠水溶液，反应6-8小时后，取出反应物溶液用盐酸中和至中性，并在甲醇中沉淀出产物，分别用甲醇水溶液和无水甲醇洗涤，得到的即为灵芝α-(1→3)-D-葡聚糖羧甲基化衍生物。
2．权利要求1所述的灵芝α-(1→3)-D-葡聚糖的羧甲基化衍生物用于制备抗肿瘤药物或提高人体免疫机能的保健品。
3．一种制备权利要求1所述的灵芝α-(1→3)-D-葡聚糖羧甲基化衍生物的方法，其特征在于：它是将α-(1→3)-D-葡聚糖溶于NaOH水溶液，恒温80℃，在持续搅拌下缓慢滴加氯乙酸钠水溶液，反应6-8小时后，取出反应物溶液用盐酸中和至中性，并在甲醇中沉淀出产物，分别用甲醇水溶液和无水甲醇洗涤，即得到灵芝α-(1→3)-D-葡聚糖羧甲基化衍生物。
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