CN115703788B - 一类肉桂链霉素及其应用 - Google Patents
一类肉桂链霉素及其应用 Download PDFInfo
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- CN115703788B CN115703788B CN202110931037.6A CN202110931037A CN115703788B CN 115703788 B CN115703788 B CN 115703788B CN 202110931037 A CN202110931037 A CN 202110931037A CN 115703788 B CN115703788 B CN 115703788B
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- streptomycin
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- cinnamyl
- lymphoma
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Classifications
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Abstract
本发明公开了一类从肉桂链霉菌Streptomyces cinnamoneus ATCC 21532中发酵获得的肉桂链霉素(Cinamomycin)及其制备方法和应用。本发明所述肉桂链霉素A‑D不但具有良好的抗肿瘤细胞增殖活性,而且具有明显的肿瘤细胞选择性,具备较好的安全性,可进一步制备成抗肿瘤药物,用于***及相关疾病。
Description
技术领域
本发明属于微生物制药技术领域,具体涉及一类抗肿瘤微生物天然产物肉桂链霉素及其应用。
背景技术
微生物次级代谢产物是药物先导化合物的重要来源,是新药发现的重要宝库。在过去近五十年中,发现了一大批骨架新颖、具有新药开发潜力的高活性先导化合物。
链霉菌属革兰氏阳性菌,次级代谢产物产物丰富,是微生物天然产物的重要来源。迄今为止,从微生物中发现的2.3万个抗生素中,超过40%来源于链霉菌。据保守估计,链霉菌至少可以产生15万种化合物,因此从链霉菌发现新型次级代谢产物成为拓展新活性化合物及药物来源的主要途径之一。
链霉菌Streptomyces cinnamoneus ATCC 21532是从日本札幌土壤中分离得到的一株放线菌。1972年从该菌株中分离纯化出一种具有广谱抗革兰氏阴性菌活性的抗生素双环霉素(bicyclomycin)。全基因组测序显示该菌株具有多样而新颖的次级代谢产物合成能力,可产生结构新颖的聚酮类化合物。
聚酮类化合物是微生物次级代谢产物中最具代表性的一类化合物。聚酮类化合物不仅在结构上具有多样性,同时具有丰富的生物活性,已有多种聚酮类化合物已成功作为药物用于临床治疗。在抗感染领域,直接作为抗生素批准上市的聚酮类化合物有红霉素(erthromycin)及其红霉素第三代衍生物泰利霉素(telithromycin);在抗肿瘤领域,大环内酯类抗生素埃博霉素(epothilone)以及蒽环类抗生素已成为广泛应用的化疗药物。发现具有生物活性的聚酮类化合物可以丰富先导化合物来源,进而开发成为***等疾病的药物。
发明内容
本发明首次从从肉桂链霉菌Streptomyces cinnamoneus ATCC 21532中发酵获得了一类新的抗肿瘤活性化合物,将其命名为肉桂链霉素(Cinamomycin)。该类化合物对肿瘤细胞具有显著抗细胞增殖活性,可制备成新颖的抗肿瘤药物。
本发明的另一个目的是提供一类特异、高效、安全并经不同给药途径的新型化合物,用于***及其相关疾病。
本发明技术方案具体如下:
一类肉桂链霉素化合物,具有如下结构式:
Cinnamomycin A,R1=OH,R2=CH3,R3=OH;
Cinnamomycin B,R1=H,R2=CH3,R3=OH;
Cinnamomycin D,R1=OH,R2=CH3,R3=OCH3;
Cinnamomycin C。
除本发明直接描述的化合物外,这些化合物的药学上可接受的盐、酯或溶剂化物也在本发明的保护范围中,本发明涉及化合物的药用型盐类包括与无机酸、有机酸或无机碱、有机碱所形成的各种盐。
本发明的另一目的在于提供上述的肉桂链霉素的制备方法。
本发明所述的肉桂链霉素是利用生物保藏编号为ATCC 21532的肉桂链霉菌Streptomyces cinnamoneus(美国典型培养物保藏中心(ATCC),10801,UniversityBoulevard,Manassas,VA.20110-2209,USA)通过液体发酵后提纯得到。具体包括以下步骤:
(1)将Streptomyces cinnamoneus ATCC 21532接种于种子培养基,优选30℃培养3天,作为种子液,将种子液转接于PYC培养基,优选30℃培养7天。所述的PYC培养基配方为40g/L黄豆粉,30g/L马铃薯淀粉,2.5g/L碳酸钙,溶剂为水。所述的种子培养基配方为15g/L葡萄糖,3g/L酪蛋白水解物,1g/L酵母提取物,1g/L牛肉提取物,溶剂为水。
优选所述的种子液与PYC培养基比例为1:50,转速为220rpm/min;
(2)将步骤(1)所得发酵液用乙酸乙酯萃取,取乙酸乙酯层,优选浓缩并干燥得到浸膏,使用反相硅胶柱层析进行洗脱,依次使用水/乙腈(v/v 40:60,30:70,20:80)进行洗脱,得到3个出峰组分;
(3)步骤(2)得到的第2和第3组分经过HPLC分离纯化制得本发明所述的Cinnamomycin A-D。
HPLC色谱条件如下:
仪器型号:Agilent 1260,色谱柱:YMC-Pack ODS-A(250mm×4.6mm,5μm)。
流动相A:水(含1‰甲酸);流动相B:乙腈(含1‰甲酸)。
柱温:30℃;流速:1mL/min;检测波长:280nm;进样量:10μL
洗脱梯度:10%B~100%B;梯度时间45min。
HPLC色谱图如图1所示(其中A-D分别对应肉桂链霉素Cinnamomycin A-D)。
本发明所述的PYC培养基是一种用于聚酮化合物合成的全新的培养基,有别于常规链霉菌发酵用培养基和培养条件。
本发明所述的化合物是一类由聚酮合酶合成具有全新骨架的新型大环内酯化合物,含有罕见于大环内酯类化合物中的苯醌药效团和六碳烷烃基团。
本发明所述的肉桂链霉素结构新颖,化学稳定性好。肉桂链霉素对于多种肿瘤细胞具有强效的抗细胞增殖活性,其活性显著强于抗肿瘤药5-氟尿嘧啶,而且具有令人意外的肿瘤细胞选择性。与人正常细胞相比,肉桂链霉素可以选择性地抗肿瘤细胞增殖,其对正常细胞增殖的半数抑制浓度(IC50)明显高于肿瘤细胞(3.7-29.7倍),具备良好的安全性,可进一步制备成抗肿瘤药物,用于临床***及相关疾病。
由此本发明的化合物特别适用于治疗和预防下述各种疾病:
发生在以下部位和组织的实体恶性肿瘤:乳腺、卵巢、结肠、肝、胆、肺、胃、***、胰腺、咽喉、膀胱、脑、皮肤等;
淋巴细胞型血液类肿瘤:急性淋巴细胞型血病、急性原始淋巴细胞型白血病、B细胞型白血病、T细胞型白血病、何杰金氏淋巴瘤、非何杰金氏淋巴瘤、毛状细胞淋巴瘤和Burkett氏淋巴瘤;
骨髓细胞型血液类肿瘤:急性骨髓细胞型白血病、慢性骨髓细胞型白血病、骨髓发育不全症和早幼粒细胞型白血病;
其它还包括发生在中枢神经***和外周神经***内的肿瘤。
本发明的化合物对任何影响细胞功能调控和细胞增生的疾病可能具有治疗和预防作用,这些疾病包括炎症、神经衰退性疾病、病毒感染及霉菌感染等。
本发明的另一目的在于提供上述的肉桂链霉素在***及相关疾病中的应用方式及其给药形式和剂型。
本发明所述的化合物可经由药用载体制备成为不同类型的制剂用于人体治疗,这些药用载体包括离子交换树脂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人体血清白蛋白)、缓冲物(如磷酸盐、甘氨酸、山梨酸、山梨酸钾等)、部分饱和植物油的甘油脂、水和盐的混合物或电解质(如硫酸精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠等)、锌盐、胶态硅胶、三聚硅酸镁、聚乙烯吡咯烷酮、纤维素类、聚乙烯甘油醇、羧酸甲基纤维素钠、聚酰化物、蜡类及羊毛脂等。
本发明所述的化合物可通过不同途径对人体给药,具体的给药途径包括口服、非胃肠道给药、口腔吸入、透过皮肤给药、直肠给药、鼻腔给药、舌下给药、面颊给药、***给药及通过植入性容器给药;非胃肠道给药又包括在皮下、静脉内、肌肉内、关节内、滑膜腔内、胸骨内、鞘内、肝内、损伤部位内和颅内注射或浸渗。
本发明所述的化合物可制成不同的剂型用于人体给药,具体的剂型有水溶液注射剂、油状混悬液注射剂、口服胶囊剂、口服片剂、口服水溶液、口服混悬液、直肠栓剂、滴眼液、眼膏、皮肤用软膏、皮肤用霜剂、皮肤用喷雾剂、口腔喷雾剂、口腔气雾剂、鼻腔喷雾剂和鼻腔气雾剂等,同时还包括这些不同剂型的缓释剂和控制释放速度和剂量的制剂。
本发明所述的化合物在用于人体进行肿瘤以及相关疾病治疗时,所用的剂量受多种因素的影响,这些因素包括年龄、体重、健康状况、性别、种族、饮食习惯、给药时间、排尿频率及是否使用其它药物,等等。
附图说明
图1为本发明肉桂链霉素Cinnamomycin A-D的HPLC色谱图。
具体实施方式
下面对本发明的实施例作详细说明,本实施例在以本发明技术方案为前提下进行实施,给出了详细的实施方式和具体的操作过程,但本发明的保护范围不限于下述的实施例。
实施例1 Streptomyces cinnamoneus ATCC 21532的液体发酵
在ISP2平板上活化Streptomyces cinnamoneus ATCC 21532,将新鲜的孢子500uL接种到50mL种子液培养基中(15g/L葡萄糖,3g/L酪蛋白水解物,1g/L酵母提取物,1g/L牛肉提取物,溶剂为水),置于摇床上30℃,220rpm培养3天,作为种子液。以每瓶1mL的接种量接种至100瓶含有50ml PYC培养基(40g/L黄豆粉,30g/L马铃薯淀粉,2.5g/L碳酸钙,溶剂为水)的摇瓶中,置于摇床中30℃,220rpm培养七天。
实施例2肉桂链霉素的提取与分离
实施例1所得的发酵液以1:1加入等体积的乙酸乙酯,充分萃取后离心并取乙酸乙酯层,真空浓缩干燥得浸膏A1。对浸膏A1进行反相硅胶柱层析,以水和乙腈作为流动相进行梯度洗脱(v/v 40:60,30:70,20:80,10:90,0:100)洗脱十个柱体积,收集得到5个组分,将第二和第三个组分经过HPLC纯化,制得本发明所述Cinnamomycin A-D。HPLC分析方法如下:
仪器型号:Agilent 1260,色谱柱:YMC-Pack ODS-A(250mm×4.6mm,5μm)。
流动相A:水(含1‰甲酸),流动相B:乙腈(含1‰甲酸)。
柱温:30℃;流速:1mL/min;检测波长:280nm;进样量:10μL
洗脱梯度:10%B~100%B;梯度时间45min。
HPLC色谱图如图1所示(其中A-D分别对应肉桂链霉素Cinnamomycin A-D)。
实施例3肉桂链霉素的结构鉴定
本发明所述肉桂链霉素的结构是基于其质谱、核磁共振谱和双齿配位手性溶剂BMBA法确定的。
肉桂链霉素A的结构如下:
H-H COSY
→Selected key HMBC
Selected key NOESY
肉桂链霉素A的质谱分析数据如下:
肉桂链霉素A:HR-ESI-MS(m/z):577.2643[M+H]+(calcd for C30H40O11,577.2643)。
肉桂链霉素A的1H和13C NMR数据见表1。
表1 Cinnamomycin A1H和13C NMR的数据归属
肉桂链霉素B的结构如下:
H-H COSY
→Selected key HMBC
Selected key NOESY
肉桂链霉素B的质谱学数据如下:
肉桂链霉素B:HR-ESI-MS(m/z):561.2706[M+H]+(calcd for C30H40O10,561.2694)。肉桂链霉素B的1H和13C NMR数据见表2。
表2.Cinnamomycin B 1H和13C NMR的数据归属
肉桂链霉素C的结构如下:
H-H COSY
→Selected key HMBC
Selected key NOESY
肉桂链霉素C的质谱学数据如下:
肉桂链霉素C:HR-ESI-MS(m/z):607.3124[M+H]+(calcd for C32H46O11,607.3113)。
肉桂链霉素C的1H和13C NMR数据见表3。
表3.Cinnamomycin C 1H和13C NMR的数据归属
肉桂链霉素D的结构如下:
H-H COSY
→Selected key HMBC
Selected key NOESY
肉桂链霉素D的质谱学数据如下:
肉桂链霉素D:HR-ESI-MS(m/z):591.2814[M+H]+(calcd for C31H42O11,591.2800)。
肉桂链霉素D的1H和13C NMR数据见表4。
表4.Cinnamomycin D 1H和13C NMR的数据归属
实施例4肉桂链霉素的抗细胞增殖活性
材料:人慢性髓系白血病细胞K562、人急性T细胞白血病细胞Jurkat、人乳腺癌细胞MDA-MB-231、人胰腺癌细胞PANC-1、人脐静脉内皮细胞HUVEC和人正常胰腺导管上皮细胞H6C7,5-氟尿嘧啶,CCK8试剂盒,DMSO。
方法:以CCK-8法测定抗细胞增殖活性,具体如下:
(1)取对数生长期细胞,进行细胞计数,制备细胞悬液;
(2)接种于96孔培养板中,每孔约2×104个细胞/150μl悬液,放置于37℃恒温培养箱培养4h,至细胞贴壁(K562、Jurkat悬浮细胞省略此步骤);
(3)每孔中加入不同浓度(含1‰DMSO)的化合物,继续细胞培养72h;
(4)72h后每孔加入10μl CCK-8试剂,放入37℃孵育1~2h;
(5)酶标仪检测波长450nm处的吸光度,计算IC50值;
(6)结果如表5所示。
表5抗细胞增殖作用的IC50值(μM)
结果表明,肉桂链霉素对多种肿瘤细胞具有较强的抗细胞增殖活性,对正常细胞影响较小。与抗肿瘤药5-氟尿嘧啶相比,肉桂链霉素A-D不但具有良好的抗肿瘤细胞增殖活性,而且具有明显的肿瘤细胞选择性,具备较好的安全性,可进一步制备成抗肿瘤药物,用于***及相关疾病。
Claims (6)
1.一类肉桂链霉素,其特征在于具有如下结构式:
或/>,
其中,R1=OH, R2=CH3, R3=OH;
或者,R1=H, R2=CH3, R3=OH;
或者,R1=OH, R2=CH3, R3=OCH3。
2.根据权利要求1所述的肉桂链霉素的制备方法,其特征在于利用生物保藏编号为ATCC 21532链霉菌属cinnamoneus菌种通过液体发酵提取分离获得,包括以下步骤:
(1)将保藏编号为ATCC 21532链霉菌属cinnamoneus菌种接种于种子培养基,培养获得种子液,将种子液转接于PYC培养基,培养获得发酵液,所述的种子培养基配方为15g/L葡萄糖,3g/L酪蛋白水解物,1g/L酵母提取物,1g/L牛肉提取物,溶剂为水;所述PYC培养基配方为:40g/L黄豆粉,30g/L马铃薯淀粉,2.5g/L碳酸钙,溶剂为水;
(2)将步骤(1)所得发酵液用乙酸乙酯萃取,取乙酸乙酯层,使用反相硅胶柱层析进行洗脱,依次使用水:乙腈,v/v,40:60,30:70,20:80,进行洗脱,得到3个出峰组分;
(3)步骤(2)得到的第2和第3个组分经过HPLC分离纯化制得本发明所述的肉桂链霉素。
3.根据权利要求2所述的制备方法,其特征在于所述步骤(1)种子液30℃培养3天,PYC培养基30℃培养7天。
4.根据权利要求2所述的制备方法,其特征在于所述步骤(3)HPLC色谱条件为:色谱柱:YMC-Pack ODS-A ,250 mm × 4.6 mm, 5 μm,流动相A:水+1‰甲酸,流动相B:乙腈+1‰甲酸,柱温:30℃,流速:1mL/min,检测波长:280 nm;洗脱梯度:10%B~100%B,梯度洗脱时间45min。
5.根据权利要求1所述的肉桂链霉素在制备***及相关疾病药物中的应用。
6.根据权利要求5所述的应用,其特征在于所述肿瘤选自:
(1)发生在以下部位和组织的实体恶性肿瘤:乳腺、卵巢、结肠、肝、胆、 肺、胃、***、胰腺、咽喉、膀胱、脑、皮肤:
(2)淋巴细胞型血液类肿瘤:急性淋巴细胞型血病、急性原始淋巴细胞型白血病、B细胞型白血病、T细胞型白血病、何杰金氏淋巴瘤、非何杰金氏淋巴瘤、毛状细胞淋巴瘤和Burkett氏淋巴瘤;
(3)骨髓细胞型血液类肿瘤:急性骨髓细胞型白血病、慢性骨髓细胞型白血病、骨髓发育不全症和早幼粒细胞型白血病;
(4)发生在中枢神经***和外周神经***内的肿瘤;
所述相关疾病选自炎症、神经衰退性疾病、病毒感染或霉菌感染。
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CN107556300A (zh) * | 2017-09-27 | 2018-01-09 | 中国科学院南海海洋研究所 | 一类吲哚细胞松弛素类化合物及其制备方法和在制备抗肿瘤药物中的应用 |
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