CN111303095B - 一种基于α-亚甲基-γ-内酯环结构的硫化氢供体及其制备方法和应用 - Google Patents
一种基于α-亚甲基-γ-内酯环结构的硫化氢供体及其制备方法和应用 Download PDFInfo
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- CN111303095B CN111303095B CN202010138850.3A CN202010138850A CN111303095B CN 111303095 B CN111303095 B CN 111303095B CN 202010138850 A CN202010138850 A CN 202010138850A CN 111303095 B CN111303095 B CN 111303095B
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Abstract
本发明涉及一种基于α‑亚甲基‑γ‑内酯环结构的硫化氢供体化合物及其制备方法和应用，其系由α‑亚甲基‑γ‑内酯环结构同硫形成的二聚体结构，该系列化合物能够持续释放硫化氢，可以作为硫化氢供体应用，本发明的一些化合物具有明显的肿瘤抑制活性，为抗肿瘤药物的开发奠定了基础。
Description
技术领域
本发明属于生物医药技术领域，具体涉及一种基于α-亚甲基-γ-内酯环结构的硫化氢供体及其制备方法和应用。
背景技术
硫化氢(H2S)是继一氧化氮(NO)和一氧化碳(CO)后发现的第三种内源性信号转导分子，在多种生理及病理过程中发挥重要的调控作用。体内H2S水平的降低会导致高血压、动脉粥样硬化、胃肠溃疡、肝硬化、糖尿病、炎症、阿尔兹海默症、癌症等多种疾病的发生及发展，因此外源性H2S的供给无疑是解决上述问题的有效途径。但是由于H2S的毒理效应浓度与生理和药理有效浓度接近，而该气体易挥发的特性又使其可控性不佳，难以精确控制其在体内的有效浓度，这极大限制了H2S气体本身作为药物在基础研究和临床试验中的应用。因此寻找安全、缓释可控的H2S供体药物，不仅具有广阔的市场应用前景，而且对于更加深入地阐明H2S的生物效应机制也具有重要意义。
目前，H2S供体药物的研究尚处于起步阶段，根据来源及设计策略，可以将现有的H2S供体分为无机硫化物、人工合成H2S供体、天然有机含硫化合物、H2S供体-药物/天然活性产物拼合物及H2S供体-高分子材料/载体结合物五类。
有研究报道α-亚甲基-γ-内酯环是木香倍半萜类化合物为对肿瘤细胞毒性的必需官能团，蓝功财等也合成了一系列α-亚甲基-γ-内酯类化合物，并验证了其抗癌作用。除此以外，对α-亚甲基-γ-内酯类化合物的抗炎等多种作用也相继展开，但是目前尚未见有基于α-亚甲基-γ-内酯环结构的硫化氢供体的报告。
发明内容
本发明的目的之一在于提供一种基于α-亚甲基-γ-内酯环结构的硫化氢供体化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药，其具备较好的H2S释放性能。
本发明的又一目的在于提供所述化合物的合成方法。
本发明的再一目的在于提供所述化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药在作为硫化氢供体的应用，尤其在制备抗肿瘤或相关病患方面的药物中的应用。
本发明的另一目的在于提供所述化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药在作为活性成分的药物组合物或药物制剂。
术语定义
在本文中用于本发明描述中的术语仅是为了描述具体实施方案而不作为对本发明的限制。本文所用命名和在本文所述的有机化学、药物化学、生物学中的实验室操作是本领域熟知的和常用的。除非另外提及，本文所用的全部技术和科学术语与本领域所属技术领域的一般技术人员通常所理解的具有相同的含义。
如在本发明实施方案和所附权利要求的描述中所用，单数形式的“一”、“一种”、“该”“其””用于是指该冠词的单数和复数，除非上下文另外明确提及。例如，一种化合物包括一种或多于一种化合物。
如本文所用，“和/或”是指和包括一或多个相关的所列项目的任意和所有可能的组合。
如本文所用，术语“疾病”或“病患”是指身体状态或一些器官的任意改变，中断或干扰其功能的实施和/或引起症状。
如本文所用，术语“肿瘤”是指机体在各种致病因素作用下,细胞异常增殖而形成的局部肿块，包括良性肿瘤、恶性肿瘤和交界肿瘤。包括但不局限于乳腺癌、卵巢癌、结直肠癌、黑色素瘤、非小细胞肺癌、小细胞肺癌、胃肠道间质瘤、宫颈癌、胰腺癌、前列腺癌、胃癌、慢性髓样白细胞过多症、肝癌、淋巴瘤、腹膜癌和软组织肉瘤。
如本文所用，术语“治疗”目的是减轻或消除所针对的疾病状态或病症。如果受试者按照本文所述方法接受了治疗量的化合物或其药学上可接受的盐、异构体、多晶型物、溶剂合物、同位素标记的化合物、代谢物或前药，或其药物组合物，该受试者一种或多种指征和症状表现出可观察到的和/或可检测出的降低或改善，则受试者被成功地“治疗”了。还应当理解，所述的疾病状态或病症的治疗的不仅包括完全地治疗，还包括未达到完全地治疗，但实现了一些生物学或医学相关的结果。
技术主题一
本发明提供了一种基于α-亚甲基-γ-内酯环结构的硫化氢供体化合物，系由α-亚甲基-γ-内酯环结构(II)同硫形成的二聚体结构，其具有式(I)所示的结构：
其中，
n选自1、2、3、4或5；
R1和R2分别为取代或未取代的C1-C8烃基；或由所述R1、R2和他们共同连接的原子形成环状结构。
在本发明的一些优选实施方式中，还包括式(I)所示的结构的药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药。
在本发明的一些优选实施方式中，所述环状结构为单环或双环结构。
在本发明的一些优选实施方式中，所述环状结构为十元单环、十元双环。
在本发明的一些优选实施方式中，所述α-亚甲基-γ-内酯环结构(II)选自土木香内酯、异土木香内酯或小白菊内酯。
在本发明的一些优选实施方式中，所述结构选自如下：
本文所用，“取代的取代基”选自：卤素、氧、氧桥、羟基、C1-C8烃基、卤素取代的C1-C8烃基、氨基取代的C1-C8烃基、C1-C8烃氧基、卤素取代的C1-C8烃氧基、氨基取代的C1-C18烃氧基、芳基、取代芳基，所述取代芳基由一个或多个如下基团取代：卤素、C1-C8烃基、卤素取代的C1-C8烃基、氨基、C1-C8烃基单取代或双取代氨基、C1-C8烃氧基、卤素取代的C1-C8烃氧基。
如本文所用，“烃基”可以是但不限于是碳原子数在1-8的直链，环状或支链烃基，可以为饱和或不饱和，例如，甲基、乙基、异丙基、正丙基、正丁氧基、异丁基、仲丁基、叔丁基、正戊基、异戊基、正己基、异己基、环已甲基，环丙基甲基，烯丙基，苄基、芳基、烷基取代的苄基、烷基取代的芳基等。
如本文所用，“烃氧基”可以是但不限于是碳原子数在1-8的直链，环状或支链烃氧基，可以为饱和或不饱和，例如，甲氧基、乙氧基、异丙氧基、正丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、异戊氧基、正己氧基、异己氧基、环已甲氧基，环丙基甲氧基，烯丙氧基，苄氧基、芳氧基、烷基取代的苄氧基、烷基取代的芳氧基等。
如本文所用，“药用盐”是指保留目标化合物的所需生物活性并表现出最小的不希望的毒理学效应的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与本发明化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱包括无机碱及有机碱制备的盐，所述的无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。所述的有机无毒碱的盐，包括伯胺、仲胺和叔胺的盐，包括取代胺和环状胺。例如：N,N'－二苄基乙二胺、二乙胺、2一二乙基氨基乙醇、2一二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N一乙基吗啉、N一乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺等。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例盐酸、氢溴酸、氢碘酸、硫酸、磷酸或硝酸等；有机酸例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)-苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡萄糖酸、3-羟基-2-萘甲酸、烟酸、巴莫酸、果胶酯酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、胺基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对-甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、海藻酸、马来酸、富马酸、D-葡萄糖酸、扁桃酸、抗坏血酸、葡庚糖酸、甘油磷酸、天冬胺酸、磺基水杨酸等包括钠、钾、镁、锂、铝、钙、锌、N,N’-二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因等形成的盐。
如本文所用，“药用酯”是指，本发明所提供的化合物中存在的-OH与适当的酸(例如，羧酸或含氧无机酸)形成的酯。适宜的酯基团包括但不限于，甲酸酯、乙酸酯、丙酸酯、丁酸酯、丙烯酸酯、乙基琥珀酸酯、硬脂肪酸酯或棕榈酸酯。
如本文所用，“异构体”是指式(I)化合物含有一个或多个不对称中心和/或双键的情况下，本发明的化合物能够以外消旋物、外消旋混合物、单一对映异构体、非对映异构体混合物、单一非对映异构体、几何异构体等的形式存在。这些化合物可以由符号“R”或“S”表示，这取决于立体碳原子周围的取代基的构型，还可能由符号“Z”或“E”表示，这取决于碳-碳双键周围的取代基的排列，或者碳-碳双键周围的取代基可被称为“顺式”或“反式”。本文公开的化合物可以互变异构体存在，并且两种互变异构形式均旨在包括在本发明的范围内，即使仅描绘了一种互变异构结构，例如酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。
如本文所用，“多晶型”是指式(I)化合物也可以各类晶型的形式存在，通过将化合物或其药学上可接受的盐在溶剂中重结晶，得到它们的不同单一晶型以及多晶型混合物。
如本文所用，“溶剂合物”是指式(I)化合物可以溶剂化物(如水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
如本文所用，“同位素”是指式(I)化合物也意在包括区别仅在于存在一种或多种同位素富集原子的化合物。例如，具有本发明结构的化合物，但用氘(2H)或氚(3H)代替氢，或用13C-或14C-碳原子代替碳，在本发明的范围内。这种化合物可用作，例如，分析工具、生物测定中的探针或治疗剂。
如本文所用，“前药”是指式(I)化合物还可以是前药的形式或可在体内代谢变化后释放出所述活性成分的形式。选择和制备适当的前药衍生物是本领域技术人员公知技术。
技术主题二
本发明还提供了式(I)所示化合物的合成方法。
路线一微生物合成
取大鼠新鲜排出的粪便与生理盐水混匀，离心后取上层混悬液与厌氧培养液混合，形成肠道菌培养液；向式(II)化合物加入CMC-Na溶液，配成式(II)化合物混悬液，然后将式(II)化合物混悬液与肠道菌培养液混合，充入N2后密封，放入厌氧培养袋，恒温孵育，孵育结束后，用有机溶液进行萃取，减压蒸干得到微生物转化样品，然后通过分离纯化得到式(I)化合物。
路线二化学合成
当n为1和2时，其他基团如权利要求1定义时，采用路线A所示的方法：
路线A
当n为3、4和5时，其他基团如权利要求1定义时，采用路线B所示的方法：
路线B
技术主题三
本发明提供一种药物组合物，其包含式(I)所示的硫化氢供体化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药，以及药学上可以接受的载体或赋形剂。
如本文所用，“药物组合物”其中含有治疗有效量的所述式(I)硫化氢供体化合物其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药，以及一种或多种药学上可接受的载体，制备成片剂、胶囊、颗粒剂、散剂、混悬剂、乳剂、粉剂、溶液、凝胶剂、糖浆剂、丸剂、酊剂、酒剂、煎膏剂、锭剂、合剂、栓剂、注射剂、吸入剂或喷雾剂等形式。该药物组合物优选含有重量比为0.1％-99.5％的本发明的硫化氢供体化合物或其药用盐作为活性成分，更优选含有重量比为0.5％-99.5％的活性成分。
如本文所用，“药学上可接受的载体或赋形剂”包括：稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、粒化剂、包衣剂、润湿剂、溶剂、共溶剂、助悬剂、乳化剂、增甜剂、调味剂、掩味剂、着色剂、防结块剂、保湿剂、螯合剂、增塑剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂，本领域技术人员将理解，某些药学上可接受的赋形剂可以以多于一种功能和以替代性功能来使用，取决于所述赋形剂在制剂中存在多少和在制剂中存在何种其它成分。例如：当用于口服时，可以制成口服制剂，如片剂、胶囊剂、颗粒剂和丸剂等，包含填充剂(例如糖类衍生物如乳糖、蔗糖、葡萄糖、甘露糖醇和山梨糖醇；淀粉衍生物如玉米淀粉、土豆淀粉、糊精和羧甲基淀粉；纤维素衍生物如结晶纤维素、羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠；阿拉伯胶；右旋糖酐；硅酸盐衍生物如偏硅酸镁铝；磷酸盐衍生物如磷酸钙；碳酸盐衍生物如碳酸钙；硫酸盐衍生物如硫酸钙等)、粘合剂(例如明胶、聚乙烯吡咯烃酮和聚乙二醇)、崩解剂(例如纤维素衍生物如羧甲基纤维素钠、聚乙烯吡咯烃酮)、润滑剂(例如滑石、硬脂酸钙、硬脂酸镁、鲸蜡、硼酸、苯甲酸钠、亮氨酸)、稳定剂(对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等)、矫味剂(例如常用的甜味剂、酸味剂和香料等)。当用于肠胃外时，可以制成注射剂，包括注射用无菌粉末与注射用溶剂，所用载体或赋形剂包含无菌水、林格氏液和等渗氯化钠溶液，也可根据药物的性质加入适宜的附加剂例如抗氧化剂、缓冲剂和抑菌剂。当用于直肠给药时，所述药物可以制成栓剂等。用于经肺给药时，所述药物可以制成吸入剂或喷雾剂等。有许多本领域技术人员可用的资源，这些资源描述了药学上可接受的赋形剂且其可用于选择合适的药学上可接受的赋形剂，例如《雷明登药学大全》、《中国药学年鉴》、《药剂学》等书籍。
本发明可以通过本领域已知的任何合适的方法来施用，例如，口服、静脉内、腹膜内、肌肉内、局部、透皮、经眼、经鼻、吸入、皮下、肌内、口含、舌下、直肠给予等方式，可以以1μg～2000mg/kg受试者体重的任何量施用如上所述的化合物，例如以1μg～1000mg/kg体重/天，50μg～1000mg/kg体重/天，100μg～1000mg/kg体重/天，1～500mg/kg体重/天，2～200mg/kg体重/天，5～100mg/kg体重/天量施用如上所述的化合物。在本发明的一些的实施方案中，可以以每日4次、每日3次、每日2次、每日1次、每两日1次、每周1次或其他间隔的方式施用如上所述的化合物，任选地酌情每周或每月重复如上所述的给药方案。在本发明中，所述化合物的给药剂量可根据患者或受试者的病情轻重、年龄、体重、性别、给药方式及疗程等因素进行调整。
本发明化合物可以单独使用，经也可以和另一种或多种其它活性成分联合用于治疗、预防、抑制或者改善疾病或者病状，其中药物的联合使用比任何一种药物的单独使用更为安全或者更为有效。这种其它药物可以以对此通常使用的途径和量与本发明的化合物同时或者依次给药。当本发明的化合物与一种或者多种其它药物同时使用时，在单位剂型中含有该其它药物和本发明的化合物的药物组合物是优选的，特别是与药学可接受的载体联合。然而，联合治疗还可以包括在不同重叠日程中给予本发明的化合物和一种或者多种其它药物的治疗。还可以预期，当与一种或者多种其它活性成分联合使用时，本发明化合物和其它活性成分可以以比各自单独使用时更低的剂量使用。因此，除了本发明的化合物外，本发明药物组合物还包括含有一种或者多种其它活性成分的那些组合物。
技术主题四
本发明还提供了式(I)所示结构的化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药作为硫化氢供体的应用，尤其在制备抗肿瘤药物中的应用。
本发明研究了所述式(I)化合物的体外H2S的释放性能，对肿瘤细胞的抑制活性，其能够持续释放硫化氢，并具有显著的抗肿瘤活性。
在本发明的一些实施方案中，将式(I)化合物、其药用盐或酯、溶剂合物、异构体、多晶型物、同位素标记的化合物、代谢物或前药在治疗性治疗中的用途。在本发明的一些实施方案中，所述治疗性治疗用于治疗肿瘤疾病。在一些实施方案中，肿瘤疾病是指机体在各种致病因素作用下,细胞异常增殖而形成的局部肿块，包括良性肿瘤、恶性肿瘤和交界肿瘤。包括但不局限于乳腺癌、卵巢癌、结直肠癌、黑色素瘤、非小细胞肺癌、小细胞肺癌、胃肠道间质瘤、宫颈癌、胰腺癌、前列腺癌、胃癌、慢性髓样白细胞过多症、肝癌、淋巴瘤、腹膜癌和软组织肉瘤。
发明的有益效果
本申请的发明人通过大量研究及筛选发现了一系列基于α-亚甲基-γ-内酯环结构的硫化氢供体，该系列化合物能够持续释放硫化氢，可以作为硫化氢供体应用，本发明的一些化合物具有明显的肿瘤抑制活性，为抗肿瘤药物的开发奠定了基础。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图是本发明的一些实施方式，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其它的附图。
图1为小白菊内酯硫二聚体的硫化氢释放图；
图2为L-cys催化下小白菊内酯硫二聚体的硫化氢释放图；
图3为异土木香内酯硫二聚体的硫化氢释放图；
图4为L-cys催化下异土木香内酯硫二聚体的硫化氢释放图；
图5为土木香内酯硫二聚体的硫化氢释放图；
图6为L-cys催化下土木香内酯硫二聚体的硫化氢释放图；
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，下面结合具体实施例对发明进行清楚、完整的描述。
以下结合具体实施例阐述本发明，这些实施例不旨在限制本发明的范围，而是为本领域技术人员制备和使用本发明化合物、组合物和方法提供指导。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1
小白菊内酯一硫二聚体PA2-S
厌氧培养液的配制如下：1000mL烧杯中，加入37.5mL溶液A(0.78％K2HPO4)，37.5mL溶液B(1.2％(NH4)2SO4，0.47％KH2PO4，0.25％MgSO4·H2O，0.12％CaCl2，1.18％NaCl)，50mL8％Na2CO3，10g牛肉膏，10g蛋白胨以及适量超纯水，加热煮沸15min溶解，冷却至室温后加入0.5g L-cystine·H2O和0.5g L-ascorbic acid，加超纯水至近1L，1mM盐酸调pH至7.1～7.3，最后用超纯水定容至1L。
取大鼠新鲜排出的粪便与生理盐水按照1g:4mL的比例混匀，2000rpm离心5min。取上层混悬液与厌氧培养液混合，比例为50mL厌氧培养液中加1g粪便粗提液，得肠道菌培养液。将0.6g小白菊内酯研成细粉，加入30mL CMC-Na(0.5％)溶液，配成PA混悬液。然后将PA混悬液与600mL肠道菌培养液混合，充入N2后密封，放入厌氧培养袋，37℃鼓风干燥箱中孵育48h。孵育结束后，于培养液中加入600mL乙酸乙酯萃取三次，合并萃取液，35℃减压蒸干得PA微生物转化样品约0.642g。
将上述PA微生物转化样品加适量乙酸乙酯溶解，加2g硅胶(200-300目)拌样，35g硅胶装柱用于分离，石油醚-乙酸乙酯2:1.1洗脱。TLC检识，合并相似流份。其中组分1-2(约150mg)采用硅胶GF254分离，氯仿-丙酮96：4洗脱，得组分2。采用制备液相对组分2进行纯化，流动相为乙腈-0.1％甲酸水，流速为20mL/min，检测波长为210nm。组分2经分离纯化得目标化合物。
实施例2
小白菊内酯二硫二聚体PA2-S2
微生物合成方法同实施例1，经分离得到目标化合物。
实施例3
小白菊内酯三硫二聚体PA2-S3
在250mL三口瓶中加入5mL95％乙醇，0.6gNa2Sn溶液和0.04gNaOAc溶解，0-5℃冰水浴。在分液漏斗中加入50mL无水乙醇，0.15gH3PO4溶液和0.3g小白菊内酯，溶解后逐滴滴加至三口瓶中，反应约3h至经TLC检识无小白菊内酯母药。反应液35℃减压旋蒸至无乙醇，剩余部分加适量水和等体积乙酸乙酯萃取3次，萃取液减压蒸干得粗品约430mg。
粗品用乙酸乙酯溶解后加0.8g硅胶拌样，20g硅胶(300-400目)装柱分离，氯仿-丙酮系统洗脱，洗脱梯度为98:2和96:4。经TLC检识合并相似流分，得主要组分约193mg。该组分经Pre-HPLC制备得目标化合物，流动相为乙腈-0.1％甲酸水系统。
实施例4
土木香内酯一硫二聚体AL2-S
取大鼠的新鲜粪便，将粪便按照1g:50mL的比例与厌氧培养液混合均匀，即得肠道菌培养液。在其中充入充足的N2后放入MGC厌氧培养袋中，于37℃培养30min。之后，将溶于1mL乙酸乙酯的20mg土木香内酯加入到250mL该培养液中，于37℃温孵48h。温孵结束后，用等量的乙酸乙酯萃取3次，合并，在35℃下减压浓缩。
将上述浓缩后的残留物溶于少量乙酸乙酯，与等质量的硅胶拌样，按样品与上样硅胶1:60装柱。洗脱剂为石油醚-乙酸乙酯，按20:1→3:1的梯度进行洗脱。经TLC检识，将相同流份合并，减压浓缩。粗分后的混合物晶体溶于色谱甲醇，经制备HPLC分离得到目标化合物，流动相为甲醇-水(90:10)，流速为4mL/min，检测波长为215nm。
实施例5
土木香内酯二硫二聚体AL2-S2
微生物合成方法同实施例4，经分离得到目标化合物。
实施例6
土木香内酯三硫二聚体AL2-S3
在250mL三口瓶中加入5mL95％乙醇，0.6gNa2Sn溶液和0.04gNaOAc溶解，0-5℃冰水浴。在分液漏斗中加入50mL无水乙醇，0.15gH3PO4溶液和0.28g土木香内酯，溶解后逐滴滴加至三口瓶中，反应约3h至经TLC检识无AL母药。反应液35℃减压旋蒸至无乙醇，剩余部分加适量水和等体积二氯甲烷萃取3次，萃取液减压蒸干得粗品约380mg。
粗品用二氯甲烷溶解后加0.5g硅胶拌样，20g硅胶(300-400目)装柱分离，石油醚-乙酸乙酯系统(20:1→3:1)反复洗脱，得目标化合物。
实施例7
异土木香内酯一硫二聚体IAL2-S
取大鼠的新鲜粪便，将粪便按照1g:50mL的比例与厌氧培养液混合均匀，即得肠道菌培养液。在其中充入充足的N2后放入MGC厌氧培养袋中，于37℃培养30min。之后，将溶于1mL乙酸乙酯的20mg异土木香内酯加入到250mL该培养液中，于37℃温孵48h。温孵结束后，用等量的乙酸乙酯萃取3次，合并，在35℃下减压浓缩。
将上述浓缩后的残留物溶于少量乙酸乙酯，与等质量的硅胶拌样，按样品与上样硅胶1:60装柱。洗脱剂为石油醚-乙酸乙酯，按20:1→3:1的梯度进行洗脱。经TLC检识，将相同流份合并，减压浓缩。粗分后的混合物晶体溶于色谱甲醇，经制备HPLC分离得到目标化合物，流动相为甲醇-水(85:15)，流速为4mL/min，检测波长为215nm。
实施例8
异土木香内酯二硫二聚体IAL2-S2
微生物合成方法同实施例7，经分离得到目标化合物。
实施例9异土木香内酯三硫二聚体IAL2-S3
在250mL三口瓶中加入5mL95％乙醇，0.6gNa2Sn溶液和0.04gNaOAc溶解，0-5℃冰水浴。在分液漏斗中加入50mL无水乙醇，0.15gH3PO4溶液和0.28g异土木香内酯，溶解后逐滴滴加至三口瓶中，反应约3h至经TLC检识无IAL母药。反应液35℃减压旋蒸至无乙醇，剩余部分加适量水和等体积二氯甲烷萃取3次，萃取液减压蒸干得粗品约400mg。
粗品用二氯甲烷溶解后加0.5g硅胶拌样，20g硅胶(300-400目)装柱分离，石油醚-乙酸乙酯系统(20:1→3:1)反复洗脱，得目标化合物。
实施例10
化学法合成小白菊内酯一硫二聚体PA2-S和二硫二聚体PA2-S2：
称取约0.5gPA于250mL三口瓶中，加入120mL95％乙醇溶解，加150mg醋酸钠(NaOAc·3H2O)。于分液漏斗中装入33％的H2SO4溶液，逐滴滴入装有FeS固体的锥形瓶中，以生成H2S气体。H2S气体通过导管导入三口瓶中，多余的H2S通入NaOH溶液中吸收处理。三口瓶中的反应液于80℃水浴加热回流约3h，磁力搅拌，至经TLC检识没有PA母药，停止反应。40℃下将反应液减压旋蒸至无乙醇，加入120mL水混悬后加入等体积乙酸乙酯萃取三次，合并乙酸乙酯层，35℃减压蒸干得合成粗品约0.6g。
粗品用乙酸乙酯溶解后加0.7g硅胶(100-200目)拌样，20g硅胶(300-400目)装柱分离，石油醚-乙酸乙酯系统洗脱，洗脱梯度依次为3:1,2:1和1:1。分离得主要组分约294mg。然后经Pre-HPLC制备得化合物PA2-S和PA2-S2，流动相系统为乙腈-0.1％甲酸水。
实验例1结构表征
对实施例1-9得到的化合物进行结构表征，具体见表1-3。
表1 AL2-S,AL2-S和AL2-S3的1H和13C核磁数据
表2 IAL2-S,IAL2-S和IAL2-S3的1H和13C核磁数据
表3 PA2-S,PA2-S和PA2-S3的1H和13C核磁数据
实验例2 H2S释放测定
1.1溶液配制和测定条件
CTAB储备液(5mM)：5.87mgCTAB溶于3.225mL无水乙醇；CTAB-PBS溶液(100μM)：0.5mLCTAB储备液加24.5mLPBS(pH＝7.4)；L-Cys溶液(4mM)：0.97mgL-Cys溶于2mLPBS；WSP-5溶液(1mM)：0.63mgWSP-5溶于760μL；DADS和样品均用二甲基亚砜(DMSO)配制，浓度为2mM。
采用荧光分光光度计测定荧光强度随时间的变化情况，仪器设置如下：激发波长为502nm，发射波长为525nm，激发/发射狭缝均为2.5nm，扫描时间为60min。
1.2样品测定
20μL WSP-5溶液加1.92mL CTAB-PBS溶液混合，分别加入20μL DMSO或待测样品(DADS，化合物PA2-S，PA2-S2，PA2-S3，AL2-S，AL2-S2，IAL2-S，IAL2-S2和PA2-S3，)，以及40μLPBS或L-Cys溶液混匀作为测定溶液，WSP-5、待测样品和L-Cys的测定终浓度分别为10μM，20μM和80μM。溶液装入3cm比色池中，扫描1h内荧光强度随时间的变化曲线。
本实验用DADS作为阳性对照考察各化合物的H2S释放水平，具体见图1-图6。
经测定，PA2-S3和PA2-S2在PBS中可缓慢释放H2S，同时PA2-S3比PA2-S2释放要多。在L-cys的催化下，PA2-S3在5min内快速释放H2S；PA2-S2缓慢释放H2S，但比不加L-cys时释放要快。AL2-S2加入L-cys后，有缓慢释放H2S的迹象。IAL2-S3在加入L-cys后，20min内快速释放H2S。
实验例3抗肿瘤活性测定
将细胞接种在25cm2的细胞培养瓶中，加入配制好的含血清和双抗的培养基，饱和湿度下37℃、5％CO2培养箱中培养，常规传代培养。
初筛实验：细胞计数后接种到96孔板，每孔100μl，细胞数大约1×104个，设空白、对照各一组，空白组为空白培养基，对照组为培养基和细胞悬液各100μl，实验组为6组，每组设3个复孔，先加入细胞悬液，在培养箱中培养，待细胞贴壁后加入药品，在培养箱中培养46小时，取出后每孔加入20μlCCK-8，继续培养2小时后，取出，在450nm下测量吸光度值(OD值)，计算药物抑制率[抑制率(％)＝1-(实验组OD值-空白组OD值)/(对照组OD值-空白组OD值)×100％]。
IC50实验：将其待测化合物配制成0.2μM/μl、2μM/μl、20μM/μl、200μM/μl的实验用液，其他实验步骤同上，结果见表4。
表4代表化合物的抗肿瘤活性
最后应说明的是：以上实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明实施例技术方案的精神和范围。
Claims (5)
1.一种基于α-亚甲基-γ-内酯环结构的硫化氢供体化合物，其特征在于，为如下结构：
2.一种制备所述权利要求 1 所述的化合物的方法，其特征在于，包括如下路线：
路线一 微生物合成
取大鼠新鲜排出的粪便与生理盐水混匀，离心后取上层混悬液与厌氧培养液混合，形成肠道菌培养液；将小白菊内酯加入CMC-Na溶液，配制成小白菊内酯混悬液，然后将小白菊内酯混悬液与肠道菌培养液混合，充入N2后密封，放入厌氧培养袋，恒温孵育，孵育结束后，用有机溶液进行萃取，减压蒸干得到微生物转化样品，然后通过分离纯化得到基于α-亚甲基-γ-内酯环结构的硫化氢供体化合物；
路线二 化学合成
当n为2时，采用路线A所示的方法：
路线A
当n为3时，采用路线B所示的方法：
路线B
3.药物组合物，其包含权利要求1所述的化合物以及任选地，一种或多种药学上可接受的载体或赋形剂。
4.根据权利要求1所述结构的化合物在制备硫化氢供体药物中的应用。
5.根据权利要求1所述结构的化合物在制备抗肿瘤药物中的应用。
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