CN115093462B - 一种环肽类化合物及其制备方法和用途 - Google Patents
一种环肽类化合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明从卷柏(S.tamariscina)中分离得到1个新环6肽，为卷柏属(Selaginella)植物的药效物质基础研究提供理论依据，对该化合物进行了细胞活性实验，可为卷柏的深入开发与利用提供参考。
Description
技术领域
本发明涉及一种肽类化合物及其制备方法和用途领域。
背景技术
卷柏(Selaginella tamariscina(Beauv.)Spring)为卷柏科(Selaginellaceae)卷柏属 (Selaginella)的一味草本植物。卷柏因生命力顽强、耐旱、耐寒等特点又称作九死还魂草、万年青、石莲花等，广泛分布于我国东北、华北、华东、陕西、四川等地。卷柏(S.tamariscina) 为2020年版《中国药典》收载药材，最早记载于《神农本草经中》，列为上品。全草入药，味辛、涩、性平。卷柏具有破血散瘀、活血通经之效，可用于经闭痛经，症瘕痞块，跌扑损伤。
为了进一步完善卷柏药效物质基础，本发明拟对其进行化合物的分离纯化研究。
发明内容
长久以来对卷柏的研究主要集中在双黄酮类化学成分。本发明首次从卷柏植物中分离得到了具有抗肿瘤活性的环肽类成分。本发明对卷柏的75％乙醇提取物乙酸乙酯部位经多种柱色谱分离纯化，运用高分辨质谱、核磁共振等波谱技术对其进行结构确证，从中分离得到了 1个新的环肽化合物，如式I所示：
本发明从卷柏(S.tamariscina)中分离得到1个新环6肽，为卷柏属(Selaginella)植物的药效物质基础研究提供理论依据，对该化合物进行了细胞活性实验，可为卷柏的深入开发与利用提供参考。
本发明还提供了式I所述环肽的制备方法，它包括如下内容：
卷柏乙醇提取物，依次采用水-石油醚、水-氯仿、水-乙酸乙酯萃取；乙酸乙酯萃取部位过小孔树脂柱，依次用5～15％、25～35％甲醇水溶液洗脱；30％洗脱部位采用聚酰胺柱色谱分离，依次以二氯甲烷：甲醇30:1、10:1、5:1洗脱；收集二氯甲烷：甲醇5:1洗脱部位，再用反相半制备或制备液相分离，流动相为50～70％甲醇水，即得式I环肽。
所述“小孔树脂”，简称MCI，是聚苯乙烯基的反相树脂填料，其是在大孔吸附树脂基础上设计的，粒径比大孔树脂小，而且兼有反相色谱的作用。
本发明还提供了式I所述环肽在制备抗皮肤恶性肿瘤产品中的用途。
所述皮肤恶性肿瘤选自基底细胞癌、鳞状细胞癌、恶性黑素瘤及帕哲病(Paget病)等。
本发明还提供了一种药物，它包括式I所示的环肽。
本发明药物中还包括药学上可接受的辅料，“药学上可接受的辅料”是药物中除主药以外的一切附加材料的总称，辅料应当具备如下性质：(1)对人体无毒害作用，几无副作用；(2) 化学性质稳定，不易受温度、pH、保存时间等的影响；(3)与主药无配伍禁忌，不影响主药的疗效和质量检查；(4)不与包装材料相互发生作用。
本发明中辅料包括但不仅限于填充剂(稀释剂)、润滑剂(助流剂或抗粘着剂)、分散剂、湿润剂、粘合剂、调节剂、增溶剂、抗氧剂、抑菌剂、乳化剂、崩解剂等。粘合剂包含糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶、纤维素及其衍生物(如微晶纤维素、羧甲基纤维素钠、乙基纤维素或羟丙甲基纤维素等)、明胶浆、糖浆、淀粉浆或聚乙烯吡咯烷酮等；填充剂包含乳糖、糖粉、糊精、淀粉及其衍生物、纤维素及其衍生物、无机钙盐(如硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙等)、山梨醇或甘氨酸等；润滑剂包含微粉硅胶、硬脂酸镁、滑石粉、氢氧化铝、硼酸、氢化植物油、聚乙二醇等；崩解剂包含淀粉及其衍生物(如羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、玉米淀粉等)、聚乙烯吡咯烷酮或微晶纤维素等；湿润剂包含十二烷基硫酸钠、水或醇等；抗氧剂包含亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、二丁基苯酸等；抑菌剂包含0.5％苯酚、0.3％甲酚、0.5％三氯叔丁醇等；调节剂包含盐酸、枸橼酸、氢氧化钾(钠)、枸橼酸钠及缓冲剂(包括磷酸二氢钠和磷酸氢二钠)等；乳化剂包含聚山梨酯-80、没酸山梨坦、普流罗尼克F-68，卵磷酯、豆磷脂等；增溶剂包含吐温-80、胆汁、甘油等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物同样可以用于注射制剂。其中，所述注射剂选自液体注射剂(水针)、注射用无菌粉末(粉针)或注射用片剂(系指药物用无菌操作法制成的模印片或机压片，临用时用注射用水溶解，供皮下或肌肉注射之用)。
其中，所述注射用粉剂的中除含有上述化合物外，还至少含有赋形剂。本发明中所述赋形剂，为有意加到药物中的成分，其在所用的量上不应具有药理学特性，但是，赋形剂可以有助于药物的加工、溶解或溶出、通过靶向给药途径递药或有助于稳定性。
本发明所述赋形剂可以选自碳水化合物、无机盐、聚合物中的一种或两种以上的组合。其中碳水化合物包括单糖、寡糖或多糖类等。
附图说明
图1式I环肽的HMBC,NOESY和1H-1H COSY谱
具体实施方式
实施例1
1仪器和材料
P850型旋光仪(中国海能公司)；Bruker AV 600NMR型核磁共振波谱仪(德国Bruker 公司)；Agilent 6545型高分辨率质谱仪(美国Agilent公司)；闪式提取器JHBE-50T(郑州赛克斯玻璃仪器有限公司)；Waters 515-2996高效液相色谱仪(美国Waters公司)；YMC-Pack ODS-A反相半制备色谱柱(250×10mm,5μm)。柱色谱聚酰胺(100-200目，国药试剂集团)； GF254硅胶(青岛海洋化工厂)；HP-20吸附树脂(日本三菱公司)。氘代盐酸(99％,C12098 808,Macklin)；DMSO-d6(99％,102356410,Sigma-Aldrich)；甲醇(色谱纯，美国费希尔公司)；石油醚、氯仿、乙酸乙酯、正丁醇、95％乙醇(分析纯，天津富宇精细化工有限公司) 和甲醇(色谱纯，山东禹王化学试剂有限公司)。
卷柏全草药材采自黑龙江省尚志市，经鉴定为卷柏科卷柏属卷柏(S.tamariscina)的干燥全草。
2提取与分离
卷柏(S.tamariscina)干燥全草15.0kg，采用闪式提取器以75％乙醇水溶液12:1的液料比进行提取，提取三次每次1.5min，合并提取液减压干燥至无醇味，得卷柏总浸膏(783.0g)。浸膏用水混悬，分别依次用石油醚、氯仿、乙酸乙酯和正丁醇各萃取3次。减压回收溶剂得石油醚层(80.5g)、氯仿层(170.6g)、乙酸乙酯层(178.0g)、正丁醇层(160.0g)和水层 (110.0g)。
乙酸乙酯部位通过HP-20色谱柱进行分离，流动相依次用10％、30％、50％、70％、90％甲醇-水以及纯甲醇进行梯度洗脱，得到6个流份(E-1～E-6)。E-2部分通过聚酰胺柱色谱进行分离，以二氯甲烷：甲醇(30:1、10:1、5:1、1:1)为流动相，梯度洗脱得四个流分(E-2-1～E-2-4)。 E-2-3通过反相半制备液相分离，流动相为60％甲醇水，流速为2.5mL/min，得到式I环肽(tR＝35min，5.2mg)。
3氨基酸绝对构型的确定
式I环肽(0.5mg)用6N的氘代盐酸(1.2mL)在110℃减压密闭水解24h，减压干燥并用氮气吹干。水解产物通过HPLC-ESI-MS/MS采用MRM技术进行分析(Nexera LCMS-8050)(日本京都岛津公司)。
在+ESI离子源模式下，MS条件参数如下：雾化气：3L/min；加热气：5L/min；干燥气：15L/min；接口温度：250℃；脱溶剂管温度：250℃；加热块温度：250℃和接口电压：4kV。色谱柱为CROWNPAK CR-I(+)和CR-I(-)(3.0mm i.d.×150mm,5mm)手性柱(日本大阪 DaicelCPI公司)。进样体积为1μL，温度为25℃。流动相为ACN,EtOH,Water和TFA (80/15/5/0.5)，流速为0.6mL/min进行等梯度洗脱。使用LabSolutions(岛津)软件对LC-MS/MS 数据采集和处理分析，得到不同构型(D/L)氨基酸的保留时间。
4结构鉴定
式I环肽:白色无定型粉末，HR-ESI-MS显示其准分子离子峰为m/z 703.3435[M+Na]+(Calcd.703.3431，C35H48N6O8Na)，m/z 405.2138[M-Phe-4-OHLeu +H]+，提示式I环肽的分子式为C35H48N6O8，不饱和度为15。
1H-NMR(DMSO-d6,600MHz)和13C-NMR(DMSO-d6,150MHz)谱中显示有6个酰胺羰基碳信号(δC 169.2,169.9,170.9,171.2,171.5,172.5)，6个氨基酸α碳信号(δC 43.0,53.2,54.5, 55.3,58.2,60.6)提示为含有6个氨基酸片段的肽类化合物。通过酸水解和MS分析确定式I 环肽是由2个苯丙氨酸(Phe)、1个缬氨酸(Val)、1个苏氨酸(Thr)、1个甘氨酸(Gly)、1个亮氨酸(Leu)衍生物构成。结合135°DEPT、HSQC、HMBC谱图分析，6个氨基酸片段的NMR数据得到了明确的归属(表1)。
在1H-1H COSY谱中，亮氨酸(Leu)衍生物片段中H-α/H-β，H-β/H-γ，H-γ/H-δ,H-ε和H-ε/-OH的相关，提示存在-CH-CH2-CH(CH3)-CH2-OH片段，为Leu中的一个角甲基被-OH 取代。
在HMBC谱中，3.12,2.83(Phe1β-H)/170.9(Phe1 C＝O)和128.5(Phe1δ-C)有相关，2.91,2.66(Phe2β-H)/128.5(Phe2δ-C)有相关，4.23(Phe2α-H)/171.2(Phe2 C＝O)有相关，且4.36(Phe1α-H)/171.2(Phe2 C＝O)有远程相关，提示存在-Phe1-Phe2-片段；3.81 (Valα-H)/171.5(Val C＝O)和169.9(Thr C＝O)有远程相关，4.25(Thrα-H)/169.9(Thr C＝O)有相关，提示存在-Val-Thr-片段；3.90,3.57(Glyα-H)/172.5(Gly C＝O)和169.2 (5-OH LeuC＝O)有远程相关，3.98(5-OH Leuα-H)/169.2(5-OH Leu C＝O)有相关，提示存在-Gly-5-OH Leu-片段。在NOESY谱中，8.31(5-OH Leu-NH)/4.36(Phe1α-H)有相关，7.71(Phe1-NH)/4.23(Phe2α-H)有相关，8.00(Phe2-NH)/3.81(Valα-H)有相关， 7.81(Val-NH)/4.25(Thrα-H)有相关，8.07(Thr-NH)/3.90(Glyα-H)有相关，8.50(Gl y-NH)/3.98(5-OH Leuα-H)有相关，结合m/z 405.2138[Phe+Val+Thr+Gly+H]+的肽链片段，不饱和度15等信息推断式I环肽为cyclo[-Phe1-Phe2-Val-Thr-Gly-5-OH Leu-]。氨基酸的绝对构型是通过氘代盐酸水解后与HPLC-MS/MS标准品保留时间tR比对确定的，其Phe 1，Phe2(tR＝1.81min)，Val(tR＝1.323min)，Thr(tR＝1.386min)的绝对构型均为L。 5-OH Leu结构中有2个手性C，无法确定其片段构型。
表1式I环肽的1H-NMR(600MHz)和13C-NMR(150MHz)数据
综上所述，式I环肽的结构为cyclo[L-Phe1-L-Phe2-L-Val-L-Thr-Gly-5-OH Leu]，为未见文献报道的新化合物。
5MTT细胞毒活性测定
采用MTT法初步研究式I环肽对小鼠皮肤黑色素瘤细胞B16F10、人乳腺癌细胞MDA-MB-231和MDA-MB-468的抑制作用。待测细胞加入0.25％胰酶消化液使贴壁细胞消化脱落，形成细胞混悬液，对细胞进行记数，并将细胞稀释到1×104个/ml。将细胞悬液接种在96孔板上，每孔加入180μL，放置在37℃、5％CO2的恒温箱中培养，培养12h使细胞贴壁。更换新鲜培养液，加入待测化合物和阳性对照药5-氟尿嘧啶，40μM/孔和100μM/孔，在恒温箱中培养48h。吸去上清，加入100μL新鲜DMEM高糖培养液，再加入配置好的10 μL MTT溶液(5mg/mL，0.5％MTT)，继续在恒温箱中培养4h。吸去上清液后，每孔加入 100μL的formazan溶解液，置摇床上低速振荡10min，在37℃条件下孵育3～4h。待结晶物充分溶解后，在酶联免疫检测仪570nm处测量各个孔的吸光值。
结果显示，式I环肽在40μM浓度下对B16F10细胞系的抑制率为51.57±4.34％，在100μM 浓度下对MDA-MB-231、MDA-MB-468细胞系没有抑制活性。
Claims (8)
1.如式I所示的环肽：
2.权利要求1所述式I所示环肽在制备抗黑色素瘤产品中的用途。
3.一种药物，其特征在于：它包括权利要求1所述式I所示的环肽。
4.权利要求1所述式I所示环肽的制备方法，其特征在于：它包括如下内容：
卷柏乙醇提取物，依次采用水-石油醚、水-氯仿、水-乙酸乙酯萃取；乙酸乙酯萃取部位过小孔树脂柱，依次用5％～15％、25％～35％甲醇水溶液洗脱；30％洗脱部位采用聚酰胺柱色谱分离，依次以二氯甲烷：甲醇30:1、10:1和5:1洗脱；收集二氯甲烷：甲醇5:1洗脱部位，再用反相半制备或制备液相分离，流动相为50％～70％甲醇水，即得式I环肽。
5.根据权利要求4所述的制备方法，其特征在于：所述乙醇提取物为70％～80％乙醇提取物。
6.根据权利要求4所述的制备方法，其特征在于：所述小孔树脂选自HP-20。
7.根据权利要求4所述的制备方法，其特征在于：小孔树脂柱依次用10％和30％甲醇水溶液洗脱。
8.根据权利要求4所述的制备方法，其特征在于：反相半制备或制备液相的流动相采用60％甲醇水。
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