CN116514858A - 一种去氢骆驼蓬生物碱衍生物、制备方法及其应用 - Google Patents
一种去氢骆驼蓬生物碱衍生物、制备方法及其应用 Download PDFInfo
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- CN116514858A CN116514858A CN202310504156.2A CN202310504156A CN116514858A CN 116514858 A CN116514858 A CN 116514858A CN 202310504156 A CN202310504156 A CN 202310504156A CN 116514858 A CN116514858 A CN 116514858A
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
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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
- A61K47/54—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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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种去氢骆驼蓬生物碱衍生物、制备方法及其应用。将去氢骆驼蓬碱与4‑溴丁基邻苯二甲酰亚胺在活化剂的作用下反应,得到第一中间体,经肼处理脱去邻苯二甲酰基,得到第二中间体,与4‑羧基苯硼酸在催化剂的作用下反应,得到一种去氢骆驼蓬碱衍生物。本发明以去氢骆驼蓬碱为原料修饰苯硼酸,通过对N9位引入4个碳链长度的烷基链,有效提高了化合物的抗肿瘤活性;再在烷基链上通过酰胺化反应引入靶向基团苯硼酸,实现了对肿瘤细胞的靶向选择,提高药物递送和作用效率,可有效提高药物对多种癌症的治疗效果,并降低原化合物的毒副作用。本发明采用的制备方法步骤较短,处理方便,产率较高,为工业化生产提供了切实可行的途径。
Description
技术领域
本发明涉及化合物合成技术领域,尤其涉及一种以β-咔波啉类生物碱为原型的衍生物、合成及其应用,属于医药制备技术领域。
背景技术
目前,癌症仍是导致除老龄人口外人类死亡的主要原因,但现有的大部分肿瘤治疗药物毒副作用仍较大,治疗指数偏低,所以亟需高效低毒肿瘤靶向药物的研发。去氢骆驼蓬碱(Harmine,HM)是一类三环β-咔波啉类生物碱,提取自蒺藜科植物骆驼蓬种子,具有抗炎、抗菌、抗寄生虫、抗糖尿病等多种药理作用以及广谱抗肿瘤作用。作为一种潜在的抗肿瘤药物,其抗肿瘤活性近年来备受国内外学者关注。由于其具有一定的神经毒性,使其在抗肿瘤方面的应用受到限制。通过合理修饰其化学结构,能够有效降低甚至消除其毒副作用,充分发挥或增强其抗肿瘤作用。
苯硼酸能与多元醇形成可逆环状硼酯结构,常作为配体与含1,2-二醇、1,3-二醇或多元醇的聚糖分子进行结合。在肿瘤弱酸性微环境中,非游离型苯硼酸与其他糖基不能形成稳定结构,但可与唾液酸特异性结合,形成稳定复合物。唾液酸是一类包含9个碳原子兼吡喃糖结构的糖残基总称,属于一类神经氨酸衍生物,常位于聚糖链末端。大量研究报道唾液酸在肿瘤组织中表达显著高于正常组织。唾液酸的高分布有助于肿瘤细胞间粘附性降低,创造便于肿瘤转移的有利条件,是肿瘤转移率高的原因之一。基于以上特征,以唾液酸作为靶向位点设计以苯硼酸作配体修饰的靶向药物。通过识别肿瘤表面高分布的唾液酸从而实现对肿瘤细胞的靶向选择,提高药物递送和作用效率。
发明内容
本发明的目的在于提供一种合成工艺简单,生产成本低,产率较高,所得产物纯度高,具广泛抗肿瘤作用的新结构去氢骆驼蓬碱衍生物、制备方法及其应用。
实现本发明目的采用的技术方案是提供一种去氢骆驼蓬碱衍生化合物,它的结构式为:
。
本发明技术方案所述的一种去氢骆驼蓬碱衍生化合物的制备方法,包括以下步骤:
(1)以摩尔质量比计,将1份去氢骆驼蓬碱在无水溶剂中用5~10份的氢化钠活化后,加入到2~10份4-溴丁基邻苯二甲酰亚胺中,在氮气保护、室温条件下反应2~4 h后,用有机溶剂稀释萃取,再经淬灭、洗涤、干燥、过滤、浓缩后得到浓缩液,加入浓缩液50~300倍体积的低极性有机溶剂石油醚,静置,析出后再过滤,得到第一中间体N9-(4-(1,3-二氧异吲哚啉-2-基)丁基)去氢骆驼蓬碱;
(2)氮气保护条件下,将1份第一中间体溶解于无水试剂中,加热回流搅拌,加入10~50份水合肼处理脱去邻苯二甲酰基,反应完全后冷却,再经过滤,浓缩后得到浓缩液,加入浓缩液20~200倍体积的低极性有机溶剂二氯甲烷,静置,析出得到第二中间体N9-(4-氨基丁基)去氢骆驼蓬碱;
(3)以摩尔质量比计,将1.2~5份4-羧基苯硼酸与1.2~5份(1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(EDC)和1.2~5份N-羟基琥珀酰亚胺(NHS)在冰浴条件下活化羧基处理1~3 h后,加入1份量的第二中间体,室温下避光反应24小时以上,反应液经柱层析纯化,得到一种去氢骆驼蓬碱衍生化合物。
上述制备方法,步骤(1)中以二氯甲烷为反应液萃取剂,经饱和氯化铵淬灭,饱和食盐水洗涤后,以二氯甲烷与石油醚的体积比1:50~300为混合溶媒,采用混合溶媒法析出第一中间体。
本发明技术方案还包括一种去氢骆驼蓬碱衍生物的应用,将制备得到的去氢骆驼蓬碱衍生物制成药物制剂,用于癌症的靶向治疗。
本发明提供的一种去氢骆驼蓬碱衍生物,利用羧基苯硼酸上的羧基与氨基衍生化后的去氢骆驼蓬碱发生酰胺化反应,将苯硼酸修饰在去氢骆驼蓬碱上;通过对N9位引入4个碳链长度的烷基链,有效提高化合物的抗肿瘤活性;再在烷基链上通过酰胺化反应引入靶向基团苯硼酸,苯硼酸可以通过识别肿瘤细胞表面高分布的唾液酸从而实现对肿瘤细胞的靶向选择,提高药物递送和作用效率;同时,苯硼酸的芳脂基结构也能有效增强化合物的抗肿瘤活性。
与现有技术相比,本发明技术方案的有益效果在于:
1. 本发明将去氢骆驼蓬碱与苯硼酸修饰结合后,药物可靶向富集于肿瘤发生组织,提高药物的治疗效果,经与多种肿瘤细胞作用后,结果表明该衍生物保留并增强了对多种肿瘤细胞的增殖抑制效果。
2.本发明得到的去氢骆驼蓬碱衍生化合物分子量增加,极性增大,神经毒性减弱,通过小鼠急性毒性预实验表明,去氢骆驼蓬碱修饰后,毒性反应大大减少,口服给药剂量达20g/kg时仍未出现明显的毒性反应,属于安全范畴。
3. 本发明提供的去氢骆驼蓬碱衍生化合物生产成本低,合成工艺简单,以多次混合溶媒法重结晶得产物纯度高,易于实现工业化生产。
附图说明
图1、2分别为本发明实施例提供的去氢骆驼蓬碱衍生化合物的核磁共振(1H-NMR、13C-NMR)谱图;
图3为本发明实施例提供的去氢骆驼蓬碱衍生化合物的质谱图;
图4、5、6、7分别为本发明实施例提供的去氢骆驼蓬碱衍生化合物(HP)及原料药去氢骆驼蓬碱(HM)作用于人肺癌A549细胞、人肝癌HepG2细胞、人宫颈癌Hela细胞、人乳腺癌M231细胞的增殖抑制结果对比图。
实施方式
下面结合附图和实施例对本发明技术方案作进一步的阐述。
实施例1
本实施例提供一种去氢骆驼蓬碱衍生化合物,其反应式如下:
。
具体的制备方法包括如下步骤:
(1)将去氢骆驼蓬碱(a)、氢化钠及搅拌子投入双口瓶中,抽真空,充入氮气进行保护,注入无水DMF作溶剂,室温搅拌1 h,充分活化去氢骆驼蓬碱N9位上的H,继续搅拌,并缓慢注入4-溴丁基邻苯二甲酰亚胺(DMF作溶剂),持续搅拌反应2 h,用薄层色谱法对反应进行监测(二氯甲烷:甲醇=10:1)。反应结束后将反应液转移至分液漏斗中,加入二氯甲烷对反应液进行稀释后,用饱和氯化铵溶液淬灭反应,经饱和食盐水洗3遍,取有机相旋转蒸发浓缩,加入石油醚静置过夜,过滤,得到第一中间体(b),分子量为413g/mol,产率约90%,反应中,去氢骆驼蓬碱,氢化钠,4-溴丁基邻苯二甲酰亚胺的摩尔比为1:10:2。
(2)将步骤(1)中得到的第一中间体与搅拌子投入双口瓶,装入油浴锅及冷凝循环装置,抽真空,充入氮气保护,注入无水乙醇,加热至78℃,充分搅拌溶解,随后缓慢注入85%水合肼溶液,维持78℃下搅拌反应4 h,利用硅胶薄层色谱法(TLC)监测反应(二氯甲烷:甲醇:甲酸=10:1:0.1),反应液过滤,待反应液冷却至常温后加入二氯甲烷混合,冰浴静置过夜,析出第二中间体(c),过滤,自然挥干,产率约为85%,反应中第二中间体和水合肼的摩尔比为1:10。
(3)将4-羧基苯硼酸溶于无水DMF中,置冰浴条件下与活化剂EDC和NHS混合搅拌1.5 h,缓慢滴入第二中间体的DMF混合溶液,室温避光反应24-48 h,反应经后处理后通过柱层析法分离纯化得到最终产物(d)(以下缩写HM-N-PBA,HP)。其中,HM-N-PBA的分子量为431g/mol;混合前,4-羧基苯硼酸、EDC、NHS与第二中间体的摩尔比为1.2 : 1.2 : 1.2 :1。
对本实施例所得化合物进行表征及产物的性能测定。
将10mg产物溶解于600μL的氘代DMSO中,经600MHz核磁共振仪检测。
参见附图1,为1H-NMR图谱:1H NMR (600 MHz, DMSO-d6) δ 8.47 (t, J = 5.8Hz, 1H), 8.20 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H),7.88 (d, J = 5.2 Hz, 1H), 7.86 – 7.79 (m, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.21(d, J = 2.1 Hz, 1H), 6.86 (dd, J = 8.6, 2.1 Hz, 1H), 4.58 (t, J = 7.7 Hz,2H), 3.87 (s, 3H), 3.17 (s, 1H), 2.93 (s, 3H), 1.81 – 1.76 (m, 2H), 1.64 (p,J = 6.9 Hz, 2H).;
参见附图2,为13C-NMR图谱: 13C NMR (151 MHz, DMSO-d6) δ 166.88, 161.05,143.27, 140.80, 137.89, 136.35, 134.91, 134.33, 129.03, 126.42, 122.86,114.57, 112.74, 109.66, 94.12, 56.01, 44.28, 39.08, 28.16, 26.87, 23.29.;
参见附图3,为本实施例提供的去氢骆驼蓬碱衍生化合物的质谱图;
由图1、2和3的结果表明,本实施例所述结构的去氢骆驼蓬碱衍生化合物产物成功合成。
将本实施例制备的去氢骆驼蓬碱衍生化合物进行体外抑瘤作用考察。
去氢骆驼蓬碱具有广泛的抗肿瘤活性,但由于其具有较大的神经毒性使得临床作用受到很大限制。通过对去氢骆驼蓬碱进行适当的结构修饰,能有效增强其抗肿瘤活性并降低神经毒性。为考察该新型去氢骆驼蓬碱衍生物的抗肿瘤活性,采用CCK-8试剂进行细胞增殖抑制实验,通过与去氢骆驼蓬碱原药的IC50值比较,初步判断衍生化后药效有效增加。实验方案如下:
(1)培养基的配制:将50 mLFBS和 5 mL双抗(青霉素、链霉素)加至500 mL DMEM培养基中均匀混合,储存于4℃ 冰箱。
(2)PBS溶液的配制:天平分别称取0.72 g磷酸氢二钠(Na2HPO4·12H2O)、0.12 g磷酸二氢钾(KH2PO4)、4 g氯化钠(NaCl)溶于400 mL 无菌蒸馏水,滴加盐酸将溶液pH值调节至7.4,转移至500 mL容量瓶继续加蒸馏水定容即得500 mL 0.01 M磷酸盐缓冲液。
(3)细胞培养和传代:根据细胞特性,将人肝癌HepG2细胞、 肺癌人类肺泡基底上皮A549细胞、人乳腺癌MDA-MB-231细胞及人宫颈癌Hela细胞分别培养于含血清及双抗的DMEM培养基中,放置于37℃、5%CO2的培养箱中培养;每1~2天换一次培养液,细胞单层长满培养皿后进行传代:①消化:吸出原培养基,培养皿中加入2 mL PBS润洗;弃去后加入2 mL胰酶消化2~7分钟,使细胞分离为单个细胞;②离心:加入旧培养基终止消化,转移至15 mL离心管中以1500转/分钟离心5分钟;③弃去上清液,加入1 mL 新鲜培养基并吹打均匀,注意枪尖伸入液面以下,避免吹出泡沫;④将以上细胞悬液均匀分配至3个培养皿中,再加入10 mL 新鲜培养基,十字交叉轻晃使细胞均匀分散,显微镜下观察细胞状态呈单个分散圆润状,形态分明,轮廓清晰,最后放入CO2培养箱中继续培养。以此传3次后进行CCK-8实验。
(4)铺板:取一96孔板,最外围加入200 mL PBS溶液,防止板内有效孔中液体蒸发。取对数生长期的肿瘤细胞,调整细胞悬浮液至相应细胞密度。以1*104个/mL,200 mL/孔接种于96孔板;放置在37℃、5%CO2的培养箱中继续培养24 h至细胞稳定且完全贴壁。
(5)化合物储存液的配制:精确称取目标产物溶于1 ml DMSO溶液,配制成100mmol/L母液,过滤后分装,标记后密封储存于4℃冰箱内。
(6)实验分组:设置三组对照组(完全空白组:只含培养基;实验空白组:含细胞和培养基;阴性对照组:含0.1 %DMSO的培养基)和六个浓度梯度工作溶液(50 mM、40 mM、30mM、20 mM、10 mM、5 mM),每组设5个平行孔;加药完毕做好标记置培养箱中培养48小时,每8~10小时观察细胞生长状况。
(7)加CCK-8:移液枪吸弃96孔板中原含药培养基,重新添加100 μL新培养基,避光加入10 μL CCK-8,轻平行振摇5下,放入培养箱继续孵育1小时。
(8)检测:取出后将96孔板平行摇匀,放置于酶标仪中,设置450 nm波长下检测其各孔吸光度。
(9)计算细胞增殖抑制率及IC50值:IC50值为抑制率为50%时对应的药物浓度。
(10)实验结果参见附图4、5、6和7。
图4为本实施例提供的去氢骆驼蓬碱衍生化合物(HP)及原料药去氢骆驼蓬碱(HM)对人肺癌肺泡基底上皮A549细胞的增殖抑制结果对比图;图5为HP和HM对人肝癌HepG2细胞的增殖抑制结果对比图;图6为HP和HM对人宫颈癌Hela细胞的增殖抑制结果对比图;图7为HP和HM对人乳腺癌MDA-MB-231细胞的增殖抑制结果对比图。
实验结果表明,本实施例提供的去氢骆驼蓬碱衍生物保留并有效增加了去氢骆驼蓬碱的广谱抗肿瘤作用,且初步的急性毒性实验表明其神经毒性大大减弱,本发明的新化合物较原化合物有良好的减毒增效效果,可以更好地适用于抗肿瘤药物应用。
本发明通过与靶向分子苯硼酸相连,使去氢骆驼蓬碱衍生物能更有选择性地作用于肿瘤细胞,且由于其分子量及分子极性相对增加,作用于神经的毒性将有效减弱。为增强其水溶性,考虑将药物进一步制成包合物或纳米粒作为新型抗癌药物进行开发或与其他常规抗肿瘤药物,如顺铂、氟尿嘧啶、喜树碱、阿霉素等联合用药,将具有很大的潜力和应用前景。
Claims (4)
1.一种去氢骆驼蓬碱衍生化合物,其特征在于它的结构式为:
。
2.如权利要求1所述的一种去氢骆驼蓬碱衍生化合物的制备方法,其特征在于包括以下步骤:
(1)以摩尔质量比计,将1份去氢骆驼蓬碱在无水溶剂中用5~10份的氢化钠活化后,加入到2~10份4-溴丁基邻苯二甲酰亚胺中,在氮气保护、室温条件下反应2~4 h后,用有机溶剂稀释萃取,再经淬灭、洗涤、干燥、过滤、浓缩后得到浓缩液,加入浓缩液50~300倍体积的低极性有机溶剂石油醚,静置,析出后再过滤,得到第一中间体N9-(4-(1,3-二氧异吲哚啉-2-基)丁基)去氢骆驼蓬碱;
(2)氮气保护条件下,将1份第一中间体溶解于无水试剂中,加热回流搅拌,加入10~50份水合肼处理脱去邻苯二甲酰基,反应完全后冷却,再经过滤,浓缩后得到浓缩液,加入浓缩液20~200倍体积的低极性有机溶剂二氯甲烷,静置,析出得到第二中间体N9-(4-氨基丁基)去氢骆驼蓬碱;
(3)以摩尔质量比计,将1.2~5份4-羧基苯硼酸与1.2~5份(1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和1.2~5份N-羟基琥珀酰亚胺在冰浴条件下活化羧基处理1~3 h后,加入1份量的第二中间体,室温下避光反应24小时以上,反应液经柱层析纯化,得到一种去氢骆驼蓬碱衍生化合物。
3.根据权利要求2所述的一种去氢骆驼蓬碱衍生化合物的制备方法,其特征在于:步骤(1)中以二氯甲烷为反应液萃取剂,经饱和氯化铵溶液淬灭,饱和食盐水洗涤后,以二氯甲烷与石油醚的体积比1:50~300为混合溶媒,采用混合溶媒法析出第一中间体。
4.权利要求1所述的一种去氢骆驼蓬碱衍生物的应用,其特征在于:将去氢骆驼蓬碱衍生物制成药物制剂,用于癌症的靶向治疗。
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