CN111100141B - 一种倍半萜类化合物、含有其的真菌次生代谢产物提取物及其用途 - Google Patents
一种倍半萜类化合物、含有其的真菌次生代谢产物提取物及其用途 Download PDFInfo
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Abstract
本发明公开了一种具有脂肪酶抑制作用的倍半萜类化合物,这类倍半萜类化合物具有如式(I)和式(Ⅱ)所示结构:
Description
技术领域
本发明属于医药技术领域,特别涉及一种倍半萜类化合物和含有倍半萜类化 合物的真菌次生代谢产物提取物,及其在制备降血脂、抗肥胖药物或保健品中的 用途。
背景技术
肥胖是随着人们物质生活条件的逐渐改善带来的“文明病”之一,肥胖及其 因肥胖带来的一系列如高血压、高血脂等心血管疾病成为影响人们健康的主要危 害之一。肥胖发生的原因是多方面的,如遗传因素、环境因素、饮食习惯等,其 中高脂饮食是导致肥胖的重要原因。目前市场上的减肥药多数作用于大脑,通过 控制食欲来减少对食物的摄取,但由于这类药物可能对大脑或神经系统造成影响, 产生不良反应。食物中的脂肪在胃蛋白酶作用下糜化,在胰脂肪酶及肝脏和胆囊 分泌物的协助消化作用下,脂肪最终水解成甘油和脂肪酸,脂肪酸和甘油在小肠 处吸收入体内,然后在体内重新合成脂肪,造成脂肪堆积,最终可导致肥胖。应 用胰脂肪酶抑制剂可有效抑制肠道中胰脂肪酶对脂肪的分解,从而减少脂肪酸的 生成,达到减少脂肪的吸收,控制和治疗肥胖,降低血脂的目的。因而以胰脂肪酶抑制剂开发的新型减肥药仅在肠道作用于脂肪酶,抑制脂肪吸收,是一种相对 安全的药物。
天然产物结构和来源的多样性赋予其生物活性的多样性,从天然产物中探索 发现新型脂肪酶抑制剂具有极强的可行性。微生物次级代谢产物是天然脂肪酶抑 制剂的重要来源,微生物发酵方法生产的减肥用脂肪酶抑制剂已有产品上市,瑞 士罗氏公司于1987年从Streptomyces toxytricini中找到的有效脂肪酶抑制剂 lipstatin,其氢化后的产物orlistat性质更稳定,活性更强,是市售药品Xenical 的主要成分。
青霉属菌普遍存在于地球环境的各个角落,一个世纪以来,人们从青霉属菌 中获益匪浅,但相对于其庞大的家族,人们对青霉属菌的开发尚不完全。其次级 代谢产物的结构类型和生物活性也多种多样。其中一些骨架奇特的多元螺环倍半 萜类成分鲜有报道,对这类成分生物活性的研究主要集中在抗菌和抑制α葡萄糖 苷酶活性方面,尚未见到有关于该类倍半萜化合物对于脂肪酶抑制作用的报道。
发明内容
本发明解决的技术问题是提供一种倍半萜类化合物及其异构体以及其可药用盐,及含有该类化合物的真菌次生代谢产物提取物,其制备方法和及其在制备降 血脂、抗肥胖药物或保健品中的应用。
发明人经过大量研究惊奇地发现来自真菌Penicillium purpurogenum IMM003的多元螺环倍半萜类化合物具有优异的抑制脂肪酶活性的作用,可用于开发成降 血脂、抗肥胖药物或保健品。
为解决本发明的技术问题,本发明提供如下技术方案,概述如下:
本发明提供的真菌次生代谢产物提取物及倍半萜类化合物从结香的一株内生 真菌Penicillium purpurogenum IMM003的发酵产物中分离得到。所述真菌次生代 谢产物提取物及倍半萜类化合物对胰脂肪酶具有较强的抑制作用,提示该类化合 物可作为降血脂、抗肥胖药物或保健品成分。
本发明技术方案的第一个方面是提供了一种倍半萜类化合物,以及其在制备 降血脂、抗肥胖药物或保健品中的应用,所述的倍半萜类化合物具有如式(I)所 示结构:
其中:
R1为H,OH或OCOCH3;
其中,优选自如下化合物:
本发明技术方案的第一方面还提供了一种如式(II)所示的倍半萜类化合物, 及其在制备降血脂、抗肥胖药物或保健品中的应用,
本发明技术方案的第二方面是提供了一种药物组合物,其特征在于,含有上 述式(I)或式(Ⅱ)所示倍半萜类化合物及其可药用盐,和药学上可接受的载体 和/或赋形剂。
本发明技术方案的第三方面是提供了一种包含上述式(I)或式(Ⅱ)所示倍半 萜类化合物及其异构体以及其可药用盐的真菌次生代谢产物提取物,其特征在于, 所述的真菌次生代谢产物为青霉属真菌Penicillium purpurogenum IMM003以大米 为培养基进行发酵后,发酵物经乙酸乙酯超声提取而获得的真菌次生代谢产物提 取物。具体方法是:大米与纯净水按照1:0.25~1:6的重量体积比置于三角瓶中,于 115℃,68kPa下灭菌后,接种青霉属真菌Penicillium purpurogenum IMM003种子 液,于15~35℃培养7~100天,得到发酵物,每瓶发酵物用发酵物2~10倍量的 乙酸乙酯浸泡0.5~2小时后,再经超声提取0.2~3小时,提取三遍,合并提取液, 减压浓缩后获得该真菌次生代谢产物提取物。
本发明技术方案的第四方面是提供了上述式(I)或式(Ⅱ)所示倍半萜类化 合物及其可药用盐,和包含上述式(I)或式(Ⅱ)所示倍半萜类化合物的药用载 体或赋形剂,以及含上述式(I)或式(Ⅱ)所示倍半萜类化合物的真菌次生代谢 产物提取物在制备脂肪酶抑制剂以及在制备降血脂、抗肥胖药物或保健品中的应 用。
对于本领域普通技术人员而言,本发明倍半萜类化合物及真菌次生代谢产物 提取物可根据现有技术来制备成口服药物制剂、注射剂等。
本发明的优点:实验证明本发明的式(I)和式(Ⅱ)所示倍半萜类化合物可 通过真菌发酵获得,不仅产量高,而且绿色环保,利于可持续的工业化生产。实 验证明本发明的真菌次生代谢产物提取物在10μg/mL浓度下具有显著抑制脂肪酶 的活性,式(I)和式(Ⅱ)所示倍半萜类化合物在3~6μM浓度下具有显著抑制 脂肪酶的活性,提示本发明所述真菌次生代谢产物提取物及式(I)和式(Ⅱ)所 示倍半萜类化合物可用作降血脂、抗肥胖药物或保健品,具有良好的研究开发前 景。
附图说明:
图1:各化合物及阳性药山柰酚抑制脂肪酶后的残余酶活性
具体实施方式
下面结合实施例对本发明作进一步的详细描述,但本发明的实施方式不限于 此。
实施例1
真菌次生代谢产物提取物的制备,包括如下步骤:
(1)。
制备菌种液体种子液:培养液配方为马铃薯200g,酵母膏10g,蛋白胨6g, 葡萄糖30g,KH2PO4 2g,MgSO4 0.5g,定容至1L,调pH 6.8。分装至500mL三 角瓶,每瓶约装150mL,115℃,68kPa,灭菌30分钟。接种Penicillium purpurogenum IMM003菌种后,于28℃,155转/分钟,培养3天。随后培养液 稀释100倍后做种子液备用。
(2)菌株固体发酵:150g大米与180mL纯净水至于1L三角瓶中,于115℃, 68kPa下灭菌30分钟后,接种Penicillium purpurogenum IMM003种子液,于28℃ 培养40天,每瓶发酵物用500mL乙酸乙酯浸泡30分钟后,再经超声提取30分 钟,提取三遍,合并提取液,减压浓缩后获得该真菌次生代谢产物提取物。
实施例2
倍半萜类化合物的制备,包括如下步骤:
实施例1中获得的提取物经中压硅胶柱色谱(石油醚-丙酮50:1,20:1,5:1, 3:1,0:1)洗脱,得组分A-F。选取组分B再经常压硅胶柱色谱(石油-醚丙酮100:1, 50:1,20:1,10:1,7:1,5:1,3:1,2:1,1:1,丙酮,甲醇)洗脱,得组分B1-11。 组分B5经Flash C18柱色谱(20%,30%,50%,70%,90%甲醇-水梯度洗脱),得 组分B5-1~B5-5。B5-1经经SephadexLH-20柱色谱纯化得化合物1(45.0mg)。组 分B7经Flash C18柱色谱(20%,30%,50%,70%,90%甲醇-水梯度洗脱),得组 分B7-1~B7-5。组分B7-1经HPLC半制备色谱分离(ES-C18色谱柱,75%甲醇- 水,205nm)得化合物3(19min,6.0mg)。B7-2经Sephadex LH-20柱色谱分离得化合物4(26.0mg)和5(11.0mg)。组分B9经Sephadex LH-20柱色谱分离纯 化,随后经HPLC半制备色谱纯化(39%乙腈-水,205nm)得化合物Ⅱ(23min, 0.5mg)。组分B10经HPLC半制备色谱分离(43%乙腈-水,205nm)得化合物 2(19min,4.5mg)。
通过理化常数和现代波谱学手段(MS、NMR),结合文献相关数据,鉴定了 化合物1-5和Ⅱ的结构,如下式所示:
化合物1白色粉末;HR-ESI-MS:m/z 301.10397[M+Na]+(calcd for C15H18O5Na,301.10464);[α]20 D-122.2(c 0.1,MeOH);UV(MeOH)λmax(logε)210.2 (2.80);IR(KBr)νmax3448,2945,2881,1765,1339,1331,1008,943;1H NMR(600 MHz,CD3OD)和13C NMR(150MHz,CD3OD)数据见表1。
化合物2白色粉末;HR-ESI-MS:m/z 317.09903[M+Na]+(calcd for C15H18O6Na317.09956);[α]20 D-78.0(c 0.1,MeOH);UV(MeOH)λmax(logε)206.2 (2.57);IR(KBr)νmax3439,2946,2889,1792,1759,1340,1007,943;1H NMR(600 MHz,CD3OD)和13C NMR(150MHz,CD3OD)数据见表1。
化合物3无色晶体;HR-ESI-MS:m/z 331.11469[M+Na]+(calcd for C16H20O6Na,331.11521);[α]20 D-95.5(c 0.1,MeOH);mp 166.4-167.4℃;UV(MeOH) λmax(logε)206.4(2.71);IR(KBr)νmax 3508,2950,2884,2841,1790,1450,1331,1095, 1064,1006,960;1HNMR(600MHz,CD3OD)和13C NMR(150MHz,CD3OD) 数据见表1。
化合物4无色晶体;HR-ESI-MS:m/z 337.12741[M+H]+(calcd for C17H21O7337.12818);[α]20 D-73.0(c 0.1,MeOH);mp 152.4-153.4℃;UV(MeOH)λmax(log ε)206.2(2.71);IR(KBr)νmax 3541,2974,2934,1779,1720,1249,1075,1009,979, 947;1H NMR(600MHz,CD3OD)和13C NMR(150MHz,CD3OD)数据见表 2。
化合物5白色粉末;HR-ESI-MS:m/z 487.22968[M+Na]+(calcd for C25H36O8Na487.23024);[α]20 D-61.5(c 0.1,MeOH);UV(MeOH)λmax(logε)205.6 (2.84);IR(KBr)νmax3546,3292,2974,2930,2859,1796,1710,1332,1080,958;1H NMR(600MHz,CD3OD)和13C NMR(150MHz,CD3OD)数据见表2。
化合物Ⅱ白色粉末;HR-ESI-MS:m/z 361.12518[M+Na]+(calcd for C17H22O7Na,361,12577);[α]20 D-15.0(c 0.03,MeOH);UV,end absorption;IR(KBr) νmax 3393,3192,2921,2850,1791,1734,1647,1469,1420,1246,1120;1H NMR(600 MHz,CD3OD)和13C NMR(150MHz,CD3OD)数据见表2。
表1化合物1-3 1H-NMR(600MHz)和13C-NMR(150MHz)数据(CD3OD中测定)
表2化合物4-5和Ⅱ1H-NMR(600MHz)和13C-NMR(150MHz)数据(CD3OD中测定)
药理实验
实验例1:真菌次生代谢产物提取物以及化合物对胰脂肪酶活性抑制作用评价
仪器:金属孵育器、涡旋震荡仪、酶标仪
试剂:包括0.1M Buffer(柠檬酸-磷酸氢二钠)缓冲液(pH 7.4)、0.25mM的4-MUO(4-甲基伞形酮)及1mg/ml的lipase(溶于buffer)
实验步骤:
1)微粒体孵育系统包含以下成分(总体积200μl):
表3脂肪酶孵育体系及加入量
2)lipase+buffer缓冲液+Inhibitor/DMSO加于黑色96孔板上,振荡混匀后 置于金属浴/水浴37℃预孵10分钟;
3)加入2μl 4-MUO开始反应后进行荧光分析,即荧光酶标仪动力学检 测,时间为30min;
4)同时设置3个对照组,一个是无抑制剂(加等体积DMSO)组作为酶 活性的100%对照,第二个是无酶(加等体积Buffer)组用作测定本底荧光, 第三个为阳性抑制剂山奈酚。
5)荧光酶标仪的检测条件如下:
表4 lipase探针底物4-MUO及其代谢产物的检测条件
残余酶活性(%)=给药组荧光平均值/溶剂对照组荧光平均值(DMSO)×100%
按上述方法步骤,对获得的真菌次生代谢产物提取物对胰脂肪酶活性抑制作用进行评价,该提取物对胰脂肪酶活性抑制活性IC50为21.50±3.25μg/mL。
对制备获得的倍半萜类化合物对胰脂肪酶活性抑制作用进行评价,活性结果见图1和表5。
表5样品对脂肪酶抑制活性
本发明的化合物,按照常规技术手段,与药学上可接受的载体、和/或赋形剂, 制成适用于口服或注射等应用形式制剂,例如,按常规技术,加入药物可接受的 载体和/或赋形剂制成片剂、胶囊剂、粉剂、糖浆剂、针剂等。
含有本发明化合物的组合物具有药理活性。
以上实施例的说明只是用于帮助理解本发明的方法及其中心思想。应当指出, 对于本领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发 明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护。
Claims (10)
4.一种药物组合物,其特征在于,所述的药物组合物包含权利要求1-3任一项所述的倍半萜类化合物或其可药用盐,以及药用载体或赋形剂。
5.一种包含权利要求1-3任一项所述的倍半萜类化合物或其可药用盐的真菌次生代谢产物提取物,其特征在于,所述的真菌次生代谢产物提取物为青霉属真菌Penicilliumpurpurogenum以大米为培养基进行发酵后,发酵物经乙酸乙酯超声提取而获得的真菌次生代谢产物提取物。
6.根据权利要求5所述的真菌次生代谢产物提取物,其特征在于,所述提取物的提取方法具体如下:
大米培养基高温高压灭菌后,接种青霉属真菌Penicillium purpurogenum种子液,进行培养,培养后每瓶发酵物用发酵物2~10倍量的乙酸乙酯乙酸乙酯浸泡,再经超声提取2-5遍,合并提取液,减压浓缩后获得该真菌次生代谢产物提取物。
7.根据权利要求6所述的真菌次生代谢产物提取物,其特征在于,所述提取物的提取方法具体如下:
大米与纯净水按照1:0.25~1:6的重量体积比置于三角瓶中,于115℃,68kPa下灭菌后,接种青霉属真菌Penicillium purpurogenum种子液,于15~35℃培养7~100天,得到发酵物,每瓶发酵物用发酵物2~10倍量的乙酸乙酯浸泡0.5~2小时后,再经超声提取0.2~3小时,提取三遍,合并提取液,减压浓缩后获得该真菌次生代谢产物提取物。
8.权利要求1-3任一项所述的倍半萜类化合物或其可药用盐以及权利要求4的药物组合物在制备脂肪酶抑制剂药物中的应用。
9.权利要求1-3任一项所述的倍半萜类化合物或其可药用盐以及权利要求4的药物组合物在制备降血脂或抗肥胖药物中的应用。
10.权利要求5-6任一项所述的真菌次生代谢产物提取物在制备降血脂或抗肥胖药物中的应用。
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