CN116622007A - 一种乳糖基共轭6A,6D-双功能化β-环糊精衍生物及其制备方法和应用 - Google Patents
一种乳糖基共轭6A,6D-双功能化β-环糊精衍生物及其制备方法和应用 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本发明公开了一种乳糖基共轭6A,6D‑双功能化β‑环糊精衍生物，其制备方法包括如下步骤：S1.向3a、3b的混合溶液中加入半胱胺，在惰性气体氛围下加入NaH，室温搅拌反应，去除溶剂后，提纯得到4a、4b；然后向4a、4b和磺达肝癸钠的混合溶液中加入PyBOP和N,N‑二异丙基乙胺，搅拌反应，提纯得到R为磺达肝癸钠的产物1；或L1.向3a、3b的混合溶液中加入叶酸‑半胱胺缀合物，在惰性气体、黑暗环境下加入NaH，搅拌反应，提纯得到R为叶酸的产物2。本发明提供的环糊精衍生物可作为潜在的肝癌和其他抗癌药物载体，以提高抗癌药物的靶向能力、溶解度和稳定性，具有良好的应用前景。
Description
技术领域
本发明属于医药技术领域，特别涉及一种乳糖基共轭6A,6D-双功能化β-环糊精衍生物及其制备方法和应用。
背景技术
肝细胞癌占原发性肝癌的90％，近十年来肝癌发病率上升，死亡率每年攀升2％，肝癌患者5年生存率保持在2.4％。手术切除是肝癌根治性治疗的首选，但只有约15％的肝癌患者适合手术治疗，而化疗对延长大多数肝癌患者的生命无效。
索拉非尼作为一种VEGFR、PDGFR和RAF激酶抑制剂，于2007年被FDA批准为治疗晚期肝癌的靶向药物。然而，由于其水溶性差(3.59×10-2mg/L)，该药物只能延长肝癌患者三个月的生命。
化学合成具有癌细胞靶向能力的水溶性药物载体可能能够解决药物的水溶性、靶向能力和稳定性问题。将细胞表面受体的已知配体与载体分子结合是一种众所周知的靶向目标细胞的策略。在众多药物载体中，环糊精缀合物由于其天然来源而与众不同。由于环糊精能够提高药物的溶解度和稳定性，具有形成主客体包合物的能力，因此在制药工业中引起了全世界超分子化学应用各个领域的兴趣。这些环状低聚糖的选择性功能化可以显著提高它们与药物的络合能力和药物的靶向能力。
环糊精根据其具有6、7或8个吡喃葡萄糖单元的大环的大小分为α、β和γ。β-环糊精是许多抗癌药物的首选药物，因为它的成本相对较低，而且对于大多数药物而言具有理想的空腔尺寸。
静脉血栓栓塞在癌症患者中很常见，其治疗通常包括肝素、低分子肝素和磺达肝素或小分子抗凝剂。最近的一些报告表明，使用肝素治疗静脉血栓栓塞症可提高癌症患者的生存率。据推测，与环糊精结合的磺达肝癸钠可能在癌症化学疗法的靶向治疗中发挥重要作用。
此外，由于叶酸受体在许多癌细胞系中的过度表达，叶酸受体也是一个靶点，这一点已得到充分证实。叶酸受体(α亚基)在包括肝癌在内的多种肿瘤中过表达。已经有多个使用环糊精结合物来靶向所选癌细胞的例子。最近的例子中，β-环糊精缀合物被用作药物载体，已成功建立用于靶向癌细胞系。
综合而言，大多数已知的环糊精缀合物是单缀合或全缀合的环糊精衍生物，因为涉及的化学反应简单。令人惊讶的是，由于制备和纯化困难，关于环糊精的双重或双共轭的报道并不多，也由于具有挑战性的纯化和最终化合物的明确表征，双官能化环糊精衍生物的转化是一项艰巨的任务。
综上所述，有必要开发一种新的技术方案，以解决现有技术中存在的问题。
发明内容
基于此，为解决现有技术中存在的缺陷和不足，我们最近报道了一种合成双功能环糊精衍生物的有效方法，其中描述了D-半乳糖基和D-乳糖基双共轭β-环糊精衍生物的合成。有人认为D-半乳糖对存在于肝细胞上的凝集素和去唾液酸糖蛋白受体具有高亲和力，其结合的环糊精衍生物可用作靶向肝癌细胞的药物载体。在我们最近的工作中，描述了上述配体通过硫代接头或(1,2,3)-三唑接头与β-环糊精的双重偶联。接下来，我们假设双功能组除了随之增加的水溶性之外，还将增加测试药物的靶向能力。例如，β-环糊精的D-乳糖和磺达肝癸钠双偶联物可以增加癌细胞靶向能力，提高药物疗效，而β-环糊精的D-乳糖和叶酸双功能偶联物也可以增加抗癌药物递送到肝脏肿瘤部位癌细胞的机会。
本发明的一个目的在于，提供一种乳糖基共轭6A,6D-双功能化β-环糊精衍生物，具有如下结构：
其中，
X为氨基；
R选自碳原子数为1-40的烷基，或者碳原子数为1-40的烷基衍生物；
所述烷基衍生物上的一个或多个碳原子，被氢原子、氧原子、烯基、炔基、芳基、羟基、氨基、羰基、羧基、酯基、氰基、硝基的一种或多种所取代；
和/或，
所述烷基衍生物上的一个或多个氢原子，被氟原子、氯原子、溴原子、碘原子、烯基、炔基、芳基、羟基、氨基、羰基、羧基、酯基、氰基、硝基的一种或多种取代。
进一步地，所述R选自磺达肝癸钠或叶酸中的一种。
我们预计这些环糊精偶联物除了增加水溶性以及体外和体内稳定性外，还可以增强药物在癌症预防中的靶向能力。
本发明的另一个目的在于，提供上述乳糖基共轭6A,6D-双功能化β-环糊精衍生物的制备方法，包括如下步骤：
S1.向3a、3b的混合溶液中加入半胱胺溶液，在惰性气体氛围下加入NaH，室温搅拌反应，去除溶剂后，提纯得到中间产物4a、4b；然后向4a、4b和磺达肝癸钠的混合溶液中加入PyBOP和N,N-二异丙基乙胺，在惰性气体氛围、室温下搅拌反应，去除溶剂后，提纯得到R为磺达肝癸钠的产物1；
其中，所述4a、4b为6A,6D-二取代环糊精衍生物，是不可分离的异构体的混合物；
或
L1.向3a、3b的混合溶液中加入叶酸-半胱胺缀合物，在惰性气体氛围、黑暗环境、0-1℃下加入NaH，室温下搅拌反应，去除溶剂后，提纯得到R为叶酸的产物2。
进一步地，所述3a、3b为不可分离的同分异构体；
所述3a为6A,6D-双脱氧-6A-硫代-β-D-乳糖基-6D-碘代-β-环糊精；
所述3b为6A,6D-双脱氧-6A-碘代-6D-硫代-β-D-乳糖基-β-环糊精。
进一步地，所述PyBOP为六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷。
进一步地，步骤S1中，第一次搅拌反应的时间为2-5h，第二次搅拌反应的时间为3-5天。
进一步地，步骤L1中，所述室温下搅拌反应的时间为12-36h。
进一步地，步骤L1中，所述叶酸-半胱胺缀合物的制备方法包括如下步骤：
向无水二甲亚砜和三乙胺的溶液中加入叶酸、二环己基碳二亚胺和N-羟基-琥珀酰亚胺，在惰性气体氛围、黑暗环境、室温下搅拌反应，除去副产物后，加入半胱胺，搅拌反应后，提纯得到所述叶酸-半胱胺缀合物。
进一步地，第一次搅拌反应的时间为20-28h，第二次搅拌反应的时间为12-24h。
本发明的另一个目的在于，提供上述乳糖基共轭6A,6D-双功能化β-环糊精衍生物在肝癌药物载体中的应用。
本发明的有益效果如下：
本发明从单乳糖缀合的β-环糊精化合物，制备了相应的氨基衍生物。这些重要的中间体连接具有特定生物活性的其他分子以形成双功能环糊精。本发明通过连接磺达肝素或叶酸，获得乳糖基6A、6D-双功能化β-环糊精衍生物。这些环糊精衍生物可作为潜在的肝癌和其他抗癌药物载体，以提高抗癌药物的靶向能力、溶解度和稳定性，具有良好的应用前景。
附图说明
图1为β-环糊精衍生物1a、1b、1c和1d的合成路线示意图。
图2为β-环糊精衍生物2a、2b的合成路线示意图。
具体实施方式
为了更清楚地说明本发明的技术方案，列举如下实施例。实施例中所出现的原料、反应和后处理手段，除非特别声明，均为市面上常见原料，以及本领域技术人员所熟知的技术手段。
本发明中的词语“优选的”、“优选地”、“更优选的”等是指，在某些情况下可提供某些有益效果的本发明实施方案。然而，在相同的情况下或其他情况下，其他实施方案也可能是优选的。此外，对一个或多个优选实施方案的表述并不暗示其他实施方案不可用，也并非旨在将其他实施方案排除在本发明的范围之外。
应当理解，除了在任何操作实例中，或者以其他方式指出的情况下，表示例如说明书和权利要求中使用的成分的量的所有数字应被理解为在所有情况下被术语“约”修饰。因此，除非相反指出，否则在以下说明书和所附权利要求中阐述的数值参数是根据本发明所要获得的期望性能而变化的近似值。
本发明实施例中的3a、3b为不可分离的同分异构体；
所述3a为6A,6D-双脱氧-6A-硫代-β-D-乳糖基-6D-碘代-β-环糊精(6A,6D-dideoxy-6A-thio-β-D-lactosyl 6D-iodoβ-cyclodextrin)；
所述3b为6A,6D-双脱氧-6A-碘代-6D-硫代-β-D-乳糖基-β-环糊精(6A,6D-dideoxy-6A-iodo6D-thio-β-D-lactosylβ-cyclodextrin)。
本发明实施例中的叶酸-半胱胺缀合物的制备方法参考了“Chan,P.,Kurisawa,M.,Chung,J.E.,Yang,Y.,Synthesis and characterization of chitosan-g-poly(ethylene glycol)-folate as anon-viral carrier for tumor-targeted genedelivery,Biomaterials,28,540–549(2007).”，具体包括如下步骤：向无水二甲亚砜和三乙胺(20mL，10:1)的溶液加入0.25g叶酸、0.1g二环己基碳二亚胺和0.1g N-羟基-琥珀酰亚胺，将混合物在黑暗中、室温、氮气下搅拌24h，过滤除去二环己基脲副产物后，加入0.1g半胱胺，在黑暗中、室温、氮气下搅拌过夜，过滤得到黄色固体产物，用乙醚洗涤两次，即叶酸-半胱胺缀合物。
实施例1
一种乳糖基共轭6A,6D-双功能化β-环糊精衍生物，具有如下结构：
其中，
X为氨基；
R为磺达肝癸钠；
上述乳糖基共轭6A,6D-双功能化β-环糊精衍生物的制备方法包括如下步骤：
S1.向3a和3b(0.023mg，0.3mmol)的混合溶液中添加半胱胺(0.2g，0.1mmol)的无水DMF(5mL)溶液，在氮气下添加NaH(10mg，60％在矿物油中，0.25mmol)；在室温和氮气下搅拌3h后，在30℃下减压除去溶剂，将残余物在C-18反相柱上纯化(用H2O/CH3CN洗脱，100％至40％)，得到白色固体产物4a、4b，产率为90％。1H NMR(400MHz,D2O):δ5.20-5.10(m,7H),4.70(d,J＝8.0Hz,1H),4.50(d,J＝8.0Hz,1H),3.05-3.25(m,2H),2.80(m,2H)；ESI-MS:m/z1556[M+Na]+,1534[M+H]+,1532[MH]-(S-1,S-2)
向所述4a、4b(0.20g，0.13mmol)和磺达肝癸钠(0.12g，0.06mmol)在无水DMF(5mL)的混合溶液中加入PyBOP(0.15g，0.3mmol)和N,N-二异丙基乙胺(0.1mL)，并将混合物在氮气氛围、室温下搅拌四天；然后减压除去溶剂，并将残余物溶解于2mL水中，将溶液加载到C-18反相柱上并用H2O/CH3CN(100％至50％)洗脱，收集合适的级分(通过HPLC监测)，然后蒸发并冻干，得到白色固体产物1，为0.18g，70％。1H NMR(400MHz,D2O):δ5.57-5.67(m,2H),5.20-5.10(m,2H),5.05-5.10(m,14H),4.70-4.65(m,2H)；4.52-4.45(m,3H)；EIS-MS:m/z1144[M-6H-+2Na+]4-/4(S5,S6)
产物1为乳糖和磺达肝素共轭的6A,6D-二取代环糊精衍生物1a、1b、1c和1d，为不可分离的异构体的混合物。
EISMS中m/z 1144[M-6H-+2Na+]4-/4处的峰表明两个乳糖基结合的β-环糊精单元通过酰胺键连接到磺达肝素。在质子NMR谱中，两个H-1质子的四个峰从5.57ppm到5.67ppm，两个H-1质子的四个峰从5.20ppm到5.10ppm分配给磺达肝素部分，14个质子的5.05ppm至5.10ppm的宽峰分配给环糊精部分，三个H-1质子的4.70ppm至4.65ppm的峰分配给磺达肝素和乳糖基部分。
图1为β-环糊精衍生物1a、1b、1c和1d的合成路线示意图。
实施例2
一种乳糖基共轭6A,6D-双功能化β-环糊精衍生物，具有如下结构：
其中，
X为氨基；
R为叶酸；
上述乳糖基共轭6A,6D-双功能化β-环糊精衍生物的制备方法包括如下步骤：
L1.在室温、氮气氛围、黑暗中，向3a、3b(0.2g，0.13mmol)的无水DMF(5mL)溶液中添加叶酸-半胱胺缀合物(0.1g，0.2mmol)，然后在0℃加入NaH(40mg，60％矿物油分散液，2mmol)，氮气下室温避光搅拌24h后，减压蒸去溶剂，残余物溶于2ml水，将溶液加载到C-18反向柱上并用H2O/CH3CN(100％至40％)洗脱，收集、蒸发和冻干后，HPCL级分(通过HPLC监测)得到白色固体产物2(0.15g，60％)。1H NMR(400MHz,D2O):δ8.70ppm(1H,s),7.80(1H,d),7.70(2H,d),7.60(1H,d),7.40(2H,d),5.15ppm至5,10ppm(7H,m),4.80(1H,d),4.70(1H,d),4.50(1H,d),3.05(m,2H),2.75()(m,2H)；ESI-MS:m/z 1955[MH]-(S3,S4)。
产物2为叶酸和乳糖结合的β-环糊精衍生物2a和2b，为不可分离的异构体。
m/z 1955[MH]处的峰在其ESIMS光谱中符合所需产物的形成。在质子NMR光谱中，峰位于8.70ppm(1H,s)、7.80ppm(1H,d)、7.70ppm(2H,d)、7.60ppm(1H,d)、7.40ppm(2H,d)、4.50ppm(1H,d)分配给叶酸部分，而5.15ppm至5.10ppm(7H,m)、4.80(1H,d)、4.50(1H,d)的峰分配给环糊精和乳糖基部分。
图2为β-环糊精衍生物2a、2b的合成路线示意图。
对于本领域技术人员而言，显然本发明不限于上述示范性实施例的细节，而且在不背离本发明的精神或基本特征的情况下，能够以其他的具体形式实现本发明。因此，无论从哪一点来看，均应将实施例看作是示范性的，而且是非限制性的，本发明的范围由所附权利要求而不是上述说明限定，因此旨在将落在权利要求的等同要件的含义和范围内的所有变化囊括在本发明内。
此外，应当理解，虽然本说明书按照实施方式加以描述，但并非每个实施方式仅包含一个独立的技术方案，说明书的这种叙述方式仅仅是为清楚起见，本领域技术人员应当将说明书作为一个整体，各实施例中的技术方案也可以经适当组合，形成本领域技术人员可以理解的其他实施方式。
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Claims (8)
1.一种乳糖基共轭6A,6D-双功能化β-环糊精衍生物，其特征在于，具有如下结构：
其中，
X为氨基；
R选自碳原子数为1-40的烷基，或者碳原子数为1-40的烷基衍生物；
所述烷基衍生物上的一个或多个碳原子，被氢原子、氧原子、烯基、炔基、芳基、羟基、氨基、羰基、羧基、酯基、氰基、硝基的一种或多种所取代；
和/或，
所述烷基衍生物上的一个或多个氢原子，被氟原子、氯原子、溴原子、碘原子、烯基、炔基、芳基、羟基、氨基、羰基、羧基、酯基、氰基、硝基的一种或多种取代。
2.根据权利要求1所述乳糖基共轭6A,6D-双功能化β-环糊精衍生物，其特征在于，所述R选自磺达肝癸钠或叶酸中的一种。
3.权利要求1-2任一项所述乳糖基共轭6A,6D-双功能化β-环糊精衍生物的制备方法，其特征在于，包括如下步骤：
S1.向3a、3b的混合溶液中加入半胱胺溶液，在惰性气体氛围下加入NaH，室温搅拌反应，去除溶剂后，提纯得到中间产物4a、4b；然后向4a、4b和磺达肝癸钠的混合溶液中加入PyBOP和N,N-二异丙基乙胺，在惰性气体氛围、室温下搅拌反应，去除溶剂后，提纯得到R为磺达肝癸钠的产物1；
或
L1.向3a、3b的混合溶液中加入叶酸-半胱胺缀合物，在惰性气体氛围、黑暗环境、0-1℃下加入NaH，室温下搅拌反应，去除溶剂后，提纯得到R为叶酸的产物2；
其中，所述3a、3b为不可分离的同分异构体；
所述3a为6A,6D-双脱氧-6A-硫代-β-D-乳糖基-6D-碘代-β-环糊精；
所述3b为6A,6D-双脱氧-6A-碘代-6D-硫代-β-D-乳糖基-β-环糊精。
4.根据权利要求3所述乳糖基共轭6A,6D-双功能化β-环糊精衍生物的制备方法，其特征在于，步骤S1中，第一次搅拌反应的时间为2-5h，第二次搅拌反应的时间为3-5天。
5.根据权利要求3所述乳糖基共轭6A,6D-双功能化β-环糊精衍生物的制备方法，其特征在于，步骤L1中，所述室温下搅拌反应的时间为12-36h。
6.根据权利要求3所述乳糖基共轭6A,6D-双功能化β-环糊精衍生物的制备方法，其特征在于，步骤L1中，所述叶酸-半胱胺缀合物的制备方法包括如下步骤：
向无水二甲亚砜和三乙胺的溶液中加入叶酸、二环己基碳二亚胺和N-羟基-琥珀酰亚胺，在惰性气体氛围、黑暗环境、室温下搅拌反应，除去副产物后，加入半胱胺，搅拌反应后，提纯得到所述叶酸-半胱胺缀合物。
7.根据权利要求6所述乳糖基共轭6A,6D-双功能化β-环糊精衍生物的制备方法，其特征在于，第一次搅拌反应的时间为20-28h，第二次搅拌反应的时间为12-24h。
8.权利要求1-2任一项所述乳糖基共轭6A,6D-双功能化β-环糊精衍生物在肝癌药物载体中的应用。
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| CN107903342A (zh) * | 2017-11-22 | 2018-04-13 | 佛山科学技术学院 | 6A‑半乳糖基‑6D‑乳糖基‑β环糊精的合成方法 |
| CN108034012A (zh) * | 2018-01-23 | 2018-05-15 | 佛山科学技术学院 | 6A,6D-双官能化β环糊精衍生物的合成方法 |
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| CN107868141A (zh) * | 2017-11-22 | 2018-04-03 | 佛山科学技术学院 | 一种β环糊精衍生物的合成方法 |
| CN107903342A (zh) * | 2017-11-22 | 2018-04-13 | 佛山科学技术学院 | 6A‑半乳糖基‑6D‑乳糖基‑β环糊精的合成方法 |
| CN108034012A (zh) * | 2018-01-23 | 2018-05-15 | 佛山科学技术学院 | 6A,6D-双官能化β环糊精衍生物的合成方法 |
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