CN112125918B - 芳香聚酮类化合物Talaromyoxaones A和B及其制备方法和应用 - Google Patents
芳香聚酮类化合物Talaromyoxaones A和B及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了两个芳香聚酮类化合物Talaromyoxaones A和B及其制备方法和在制备蛋白酪氨酸磷酸酶SHP1抑制剂、SHP2抑制剂、MEG2抑制剂和CD45抑制剂中的应用。所述的芳香聚酮类化合物的结构如式(Ⅰ)所示。Talaromyoxaones A和B是从Talaromyces purpureogenus SCSIO 41517的发酵提取物中分离得到的，经试验证明，本发明的芳香聚酮Talaromyoxaones A和B具有抑制蛋白酪氨酸磷酸酶SHP1、SHP2、MEG2和CD45的活性，它们可用于这四种酶抑制剂先导化合物的研究。
Description
技术领域
本发明属于海洋生物领域，具体涉及化合物Talaromyoxaones A和B及其制备方法和在 制备蛋白酪氨酸磷酸酶MEG2抑制剂、SHP1抑制剂、SHP2抑制剂或CD45抑制剂中的应用。
背景技术
蛋白质酪氨酸磷酸酶(PTP)在人体表达水平和活性的异常会导致糖尿病和癌症等人类 重大疾病，通过在PTP水平调解控制疾病以及筛选和发现PTP抑制剂具有很大的应用潜力。 PTPs的活性异常会导致酪氨酸磷酸化程度调控紊乱，是导致包括糖尿病、风湿性关节炎、 重症肌无力、紅斑狼疮和癌症、也血管疾病、神经性以及代谢方面疾病等诸多人类疾病的 重要原因。例如，生殖细胞或体细胞中的SHP2突变可显著激活SHP2的催化活性，导致Noonan综合征和各种儿童白血病。因此，PTPs被认为是治疗多种难点疾病的潜在靶标。发现高效的化学小分子PTPs抑制剂对开发与PTPs相关疾病治疗的新药具有重要意义。
海洋来源真菌能产生结构新颖、独特的次生代谢产物，是众多尚未被发掘和利用的新颖 生物活性物质的重要生产源，是人类寻找和开发新型功能产物和天然药物的宝库。有关海 洋真菌来源的PTPs抑制剂报道寥寥无几。
发明内容
本发明的第一个目的是提供对蛋白酪氨酸磷酸酶MEG2、SHP1、SHP2和CD45有抑制作用的新化合物Talaromyoxaones A和B。
本发明的新化合物Talaromyoxaones A和B，其结构式如式(I)所示，
本发明的第二个目的是提供化合物Talaromyoxaones A和B的制备方法，它是从真菌 Talaromyces purpureogenus SCSIO 41517的发酵液和菌丝体中分离得到的。
优选，具体步骤如下：
(a)制备真菌Talaromyces purpureogenus SCSIO 41517的发酵液和菌丝体；
(b)将步骤(a)得到的发酵液用大孔树脂吸附，接着用水冲洗大孔树脂去掉培养基成 分，再用甲醇或乙醇冲洗大孔树脂，浓缩有机相得到甲醇或乙醇提取物；或将步骤(a)得到的发酵液用乙酸乙酯、二氯甲烷或氯仿溶剂萃取，浓缩得到乙酸乙酯提取物、二氯甲烷提取物或氯仿提取物；菌丝体破碎后用丙酮浸泡提取，提取液减压浓缩除去丙酮，剩余水相用乙酸乙酯、二氯甲烷或氯仿萃取，浓缩得菌体的乙酸乙酯、二氯甲烷或氯仿提取物；
(c)将步骤(b)所述甲醇提取物、乙醇提取物、乙酸乙酯提取物、二氯甲烷提取物或氯仿提取物经过正相硅胶柱层析，依次用二氯甲烷:甲醇体积比为100:0，95:5，92:8，90:10， 85:15，80:20，70:30，50:50的溶剂系统梯度洗脱，收集二氯甲烷:甲醇体积比80:20冲洗下 来的样品得到组分Fr.6；Fr.6先经过凝胶Sephdex L-20柱层析，以CH3OH为洗脱液分离， 再经中压反相柱层析分离，以甲醇/水/TFA从体积比10:90:0.03-63:37:0.03为流动相梯度洗 脱，其中用体积分数26％甲醇洗脱得到的Fr.6-8和用体积分数32％甲醇洗脱得到的Fr.6-11 分别经过凝胶Sephdex L-20柱层析，以CH3OH为洗脱液，分离纯化获得Talaromyoxaone A 和Talaromyoxaone B。
进一步优选，步骤(a)中所述的发酵液和菌丝体是通过以下方法制备：用真菌适用的 平板培养基活化真菌T.purpureogenus SCSIO 41517，待真菌长出孢子后，将真菌接种到液 体发酵培养基中，摇床培养2-3天制成种子液，以每100mL培养基中添加1mL种子液的比例，将种子液再次接种于液体发酵培养基中，26℃静置培养28天得到发酵液和菌丝体，上述液体发酵培养基通过以下方法配制：按质量分数计，每升水中添加1％葡萄糖，1％淀粉，0.1％KH2PO4，0.1％MgSO4·7H2O，0.1％蛋白胨，3％海盐，培养基pH值调至6.5。
进一步优选，步骤(b)所述的浓缩是采用减压浓缩。
本发明的第三个目的是提供化合物Talaromyoxaones A或B或其药用盐在制备蛋白酪氨 酸磷酸酶MEG2抑制剂、SHP1抑制剂、SHP2抑制剂和CD45抑制剂中的应用。
本发明的第四个目的是提供一种蛋白酪氨酸磷酸酶MEG2抑制剂、SHP1抑制剂、SHP2 抑制剂或CD45抑制剂，所述的四种酶的抑制剂含有Talaromyoxaones A或B或其药用盐作 为活性成分。
本发明的第五个目的是提供真菌T.purpureogenus SCSIO 41517在制备化合物Talaromyoxaones A或B中的应用。
本发明从一株海洋真菌T.purpureogenus SCSIO 41517的发酵提取物中分离得到新化合 物Talaromyoxaones A和B，它们具有抑制蛋白酪氨酸磷酸酶MEG2、SHP1、SHP2和CD45 的活性，它们可用于这四种酶抑制剂先导化合物的研究。
本发明的真菌Talaromyces purpureogenus SCSIO 41517，于2020年5月22日保藏于广 东省微生物菌种保藏中心(GDMCC)，地址：广州市先烈中路100号大院59号楼5楼，其保藏编号为GDMCC No：61032。
附图说明
图1是化合物Talaromyoxaone A的关键HMBC和COSY相关；
图2是化合物Talaromyoxaones A和B的关键NOESY相关。
具体实施方式
以下实施例是对本发明的进一步说明，而不是对本发明的限制。
实施例1
(1)发酵培养基是通过以下方法配制的：按质量分数计，在自来水中添加1％葡萄糖， 1％淀粉，0.1％KH2PO4，0.1％MgSO4·7H2O，0.1％蛋白胨，3％海盐，用NaOH或HCl水溶液将培养基pH值调至6.5。配置发酵培养基50L，再分装入1L的三角烧瓶中，每瓶约300 mL培养基。经过115℃高压蒸汽灭菌25分钟制得。
(2)发酵液和菌丝体的制备：将真菌T.purpureogenus SCSIO 41517接种于含有PDA 培养基的平板中，待真菌长出孢子后，用竹签将孢子和菌丝体从平板上转移至盛有发酵培 养基的三角瓶中，摇床28℃培养2-3天制成种子液，用移液枪将种子液接种到发酵培养基 中(1L三角瓶中盛有300mL发酵培养基)，于26℃静置培养28天后收取发酵液和菌丝体。
(3)化合物分离纯化：将经上述发酵培养基培养得到的发酵液和菌丝体用纱布过滤分 离，其中50L发酵液用大孔树脂吸附，接着用水冲洗大孔树脂去掉培养基成分，再用乙醇 或甲醇冲洗大孔树脂收集有机相(发酵液也可用乙酸乙酯、二氯甲烷或氯仿萃取)，减压浓 缩得到菌液提取物；菌丝体破碎后用丙酮浸泡，重复提取三次，合并提取液，减压浓缩除去丙酮，剩余水相用乙酸乙酯萃取，回收乙酸乙酯相浓缩得菌体提取物；合并菌液和菌体提取物，用正相硅胶(100-200目)干法拌样后，装入玻璃层析柱(H细硅胶)，常温加压 柱层析，依次用二氯甲烷：甲醇体积比为100:0，95:5，92:8，90:10，85:15，80:20，70:30， 50:50的正相系统梯度洗脱，各洗脱液通过TLC和HPLC检测合并得到7个组分(Fr.1～Fr.7)， 收集二氯甲烷:甲醇体积比80:20冲洗下来的样品得到组分Fr.6；Fr.6经过凝胶SephdexL-20 柱层析(以CH3OH为洗脱液)分离，再经中压反相柱层析分离，以甲醇/水/TFA(体积比 10:90:0.03-63:37:0.03)为流动相梯度洗脱，得到14个组分Fr.6-1～Fr.6-14。其中用体积分数26％甲醇洗脱得到的Fr.6-8和用体积分数32％甲醇洗脱得到的Fr.6-11分别经过凝胶Sephdex L-20柱层析(以CH3OH为洗脱液)分离纯化获得Talaromyoxaone A(1)和Talaromyoxaone B(2)。
结构推定：
化合物Talaromyoxaone A(1)，浅黄色固体，高分辨质谱(HRESIMS)在m/z607.1088给出[M+H]+离子峰，结合NMR数据(表1)推测分子式为C30H23O14，不饱和度为20。1H NMR 和13CNMR谱图中分别存在两组类似的信号，推测化合物(1)可能是两个平面结构相同的 化合物的混合物，通过氢谱中质子的积分可确定这两个化合物的比例约为1:0.46(1a:1b)， 以下以含量较多的化合物1a为例进行结构解析。
1H NMR谱中，存在三个甲基单峰信号，其中两个甲基连氧(δH3.95,3.61)，另外一个连接在芳香环上(δH2.20)；一对互相耦合的次甲基质子二重峰δH5.19(d,J＝10.1Hz),7.70(d, J＝10.2Hz)，两个处于苯环间位的次甲基质子δH6.07(d,J＝1.8Hz),6.38(d,J＝1.8Hz)，一 个与羟基上的活泼氢δH8.13(d,J＝5.2Hz)互相耦合的次甲基质子δH5.36(d,J＝5.2Hz)，三 个芳香次甲基质子单峰δH6.70,7.17,7.35，以及四个低场的活泼氢信号δH10.94,12.04,13.19, 13.19。13C NMR和DEPT135显示存在3个甲基，6个sp2杂化的次甲基，2个被氧化的sp3杂化的次甲基，4个羰基和15个季碳。
对比文献并分析2D NMR信号，推测化合物1由两部分组成，其中片段A的谱图数据与文献报道的oxaphenalenone类化合物相似，含有一个naphtho[1,8-cd]pyran-3-one的基本骨 架，由三个环系组成，包括10个sp2杂化的碳、一个sp3杂化的次甲基碳和一个内酯键。进 一步分析HMBC信号(图1)，酚羟基质子δH12.04与C-4/5/3a相关，氧甲基δH3.95与C-6 相关，表明C-4和C-6分别被羟基和甲氧基取代；芳环上的甲基质子H-12(δH2.20)与C-8/9/9a相关，芳香质子H-8(δH7.17)与C-7/C-9a/C-6a/C-11(δC170.7)相关，表明C-9和C-7分 别被甲基和羧基取代；烯烃质子H-1′(δH5.19)与C-9a相关，且与H-1(7.07)存在COSY 相关，表明C-1与一个sp2杂化的次甲基相连。综合以上分析确定片段A的结构如图1所示 (红色标记)。
片段B由15个碳、8个氧和10个氢组成，共10个不饱和度，氢谱中存在一对苯环间位耦合的次甲基质子(δH6.07,6.38)，表明结构中有一个1,2,3,5-四取代苯环；HMBC谱中，氧甲基质子δH3.61与C-9′相关，芳香质子H-10′(δH6.38)与C-8′/9′/11′/11a′相关，H-8′(δH6.07)与C-9′/11a′/7′相关，推测苯环中C-9′和C-11′分别被一个甲氧基和羟基取代；此外，H-3′(δH7.35)分别与季碳C-4′/C-7′/C-14′相关，H-6′(δH5.36)与C-2′/C-7a′相关，烯烃质子H-1′与C-3′/C-7′相关，结合化学位移推测存在一个多取代的3,4-二氢吡喃环通过C-7′与苯 环的C-7a′相连，其中C-2′和C-4′分别被一对碳碳双键和羧基取代，由于活泼氢δH8.13(d,J＝ 5.2Hz)与H-6′存在COSY相关，确定C-6′被羟基取代。为满足该化合物的不饱和度和分子 式，推测C-7′和C-11a′之间通过一个内脂键相连组成片段B(图1中蓝色标记部分)。片段 A与B通过一个sp2杂化的次甲基碳C-1′结合在一起，从而确定化合物1a的平面结构如式 I所示。
含量较少的化合物1b的谱图与1a基本一致，主要区别是H-6′(1a:δH5.36；1b:δH5.45) 6′-OH(1a:δH8.13；1b:δH7.98)和C-7a′(1a:δC149.8；1b:δC151.1)的化学位移存在较明显 的差异，推测由于C-6′位的半缩醛羟基构型的改变导致该化合物中存在两套谱图，即化合 物1a与1b为一对C-6′构型不同的差向异构体，进一步通过手性柱拆分得到两个化合物， 分别测氢谱后发现两份谱图与拆分前的谱图完全相同，但比旋光值的符号相反，表明(±)-1a 和(±)-1b分别为一对对映体。最后通过单晶X射线衍射实验验证了上述推测，确定了该化 合物的绝对构型。
化合物Talaromyoxaone B(2)，白色固体，高分辨质谱(HRESIMS)在m/z607.1079给出[M+H]+离子峰，结合NMR数据(表1)推测分子式为C30H23O14，1H和13C NMR谱图 也存在两组信号，氢谱积分确定两组信号比例为1:0.6(2a:2b)，化合物2与化合物1的核 磁数据基本相同，主要区别是C-1′的化学位移差别较大(1:δC124.5,124.4；2:δC123.5, 123.0)，推测化合物2和1的平面结构相同，且两组信号(2a和2b)也是一对由于C-6′ 位的半缩醛羟基构型改变产生的差向异构体，主要区别是化合物2与1的C-1构型不同。 进一步分析NOESY相关(图2)和单晶X射线衍射实验证实了上述推测，化合物2通过手 性柱拆分也得到了两对比旋光值符号相反的化合物，确定化合物2也是四种异构体的混合 物，鉴定结构如式I所示。
表1化合物1-2的1H和13C NMR数据(分别500和125MHz,DMSO-d6,δppm)
实施例2化合物Talaromyoxaones A和B的蛋白酪氨酸磷酸酶活性测试
将人蛋白酪氨酸磷酸酶CDC25B、SHP2、MEG2、SHP1、TCPTP、CD45或PTP1B基因克 隆到大肠杆菌(Escherichia coli)中，然后进行表达，纯化蛋白。酶抑制活性的测定是在96孔板中使用对硝基苯磷酸(pNPP)作为底物，每孔板含100μL的反应混合物。分别将人类重组CDC25B、SHP2、MEG2、SHP1、TCPTP、CD45或PTP1B(0.05μg)添加到50μL含有50mM HEPES，100mMNaCl，1mM EDTA及1mM dithiothreitol(DTT)的反应缓冲液中(pH6.5)， 再在每个96孔板中分别添加待测的化合物样品(化合物1-2)。Na3VO4作为阳性对照，DMSO 作为阴性对照，用于评价此高通量筛选系统。在室温下预孵育15分钟后，添加50μL含有50mM pNPP的缓冲液，并继续在37℃下培养60分钟。磷酸酶活性是通过测定所产生的对硝基苯酚在 405nm处的吸光度来测定的。IC50值是使用Gen5软件计算(Synergy2 Multi-Mode Microplate Reader,BioTek Instruments,Inc.,headquartered in Winooski,VT,USA)。每个实验重复3次。
表1化合物1-2对七种蛋白酪氨酸磷酸酶的抑制活性
测试结果显示：化合物Talaromyoxaones A和B选择性抑制蛋白酪氨酸磷酸酶SHP1、 SHP2、MEG2和CD45，IC50值如表1所示，但对CDC25B、TCPTP和PTP1B没有显著抑 制活性。
以上仅是本发明的优选实施方式，应当指出的是，上述优选实施方式不应视为对本发明 的限制，本发明的保护范围应当以权利要求所限定的范围为准。对于本技术领域的普通技术 人员来说，在不脱离本发明的精神和范围内，还可以做出若干改进和润饰，这些改进和润饰 也应视为本发明的保护范围。
Claims (6)
1.化合物Talaromyoxaone A或B、或其可药用盐，化学结构如式(I)所示：
2.一种权利要求1所述的化合物Talaromyoxaone A或B的制备方法，其特征在于，包括以下步骤：
(a)制备真菌Talaromyces purpureogenus SCSIO 41517 GDMCC No：61032的发酵液和菌丝体；
(b)将步骤(a)得到的发酵液用大孔树脂吸附，接着用水冲洗大孔树脂去掉培养基成分，再用甲醇或乙醇冲洗大孔树脂，浓缩有机相得到甲醇或乙醇提取物；或将步骤(a)得到的发酵液用乙酸乙酯、二氯甲烷或氯仿溶剂萃取，浓缩得到乙酸乙酯提取物、二氯甲烷提取物或氯仿提取物；菌丝体破碎后用丙酮浸泡提取，提取液减压浓缩除去丙酮，剩余水相用乙酸乙酯、二氯甲烷或氯仿萃取，浓缩得菌体的乙酸乙酯、二氯甲烷或氯仿提取物；
(c)将步骤(b)所述甲醇提取物、乙醇提取物、乙酸乙酯提取物、二氯甲烷提取物或氯仿提取物经过正相硅胶柱层析，依次用二氯甲烷:甲醇体积比为100:0，95:5，92:8，90:10，85:15，80:20，70:30，50:50的溶剂系统梯度洗脱，收集二氯甲烷:甲醇体积比80:20冲洗下来的样品得到组分Fr.6；Fr.6先经过凝胶Sephdex L-20柱层析，以CH3OH为洗脱液分离，再经中压反相柱层析分离，以甲醇/水/TFA从体积比10:90:0.03-63:37:0.03为流动相梯度洗脱，其中用体积分数26％甲醇洗脱得到的Fr.6-8和用体积分数32％甲醇洗脱得到的Fr.6-11分别经过凝胶Sephdex L-20柱层析，以CH3OH为洗脱液，分离纯化获得Talaromyoxaone A和Talaromyoxaone B；
步骤(a)中所述的发酵液和菌丝体是通过以下方法制备：用真菌适用的平板培养基活化真菌Talaromyces purpureogenus SCSIO 41517，待真菌长出孢子后，将真菌接种到液体发酵培养基中，摇床培养2-3天制成种子液，以每100mL培养基中添加1mL种子液的比例，将种子液再次接种于液体发酵培养基中，26℃静置培养28天得到发酵液和菌丝体，上述液体发酵培养基通过以下方法配制：每升水中添加10g葡萄糖，10g淀粉，1g KH2PO4，1g MgSO4·7H2O，1g蛋白胨，30g海盐，pH值调至6.5。
3.根据权利要求2所述的制备方法，其特征在于，步骤(b)中所述的浓缩是采用减压浓缩。
4.权利要求1所述的化合物Talaromyoxaones A或B，或其药用盐在制备蛋白酪氨酸磷酸酶MEG2抑制剂、SHP1抑制剂、SHP2抑制剂和/或CD45抑制剂中的应用。
5.一种蛋白酪氨酸磷酸酶MEG2抑制剂、SHP1抑制剂、SHP2抑制剂或CD45抑制剂，其特征在于，其含有权利要求1所述的化合物Talaromyoxaones A或B或其药用盐作为活性成分。
6.真菌Talaromyces purpureogenus SCSIO 41517 GDMCC No：61032在制备权利要求1中化合物Talaromyoxaones A或B中的应用。
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