CN109180594A - C15漆酚基三氮唑衍生物的合成 - Google Patents

C15漆酚基三氮唑衍生物的合成 Download PDF

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CN109180594A
CN109180594A CN201811165444.5A CN201811165444A CN109180594A CN 109180594 A CN109180594 A CN 109180594A CN 201811165444 A CN201811165444 A CN 201811165444A CN 109180594 A CN109180594 A CN 109180594A
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laccol
synthesis
triolefin
diol
benzene
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王成章
齐志文
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Nanjing Zhongsen Biotechnology Co Ltd
Institute of Chemical Industry of Forest Products of CAF
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Nanjing Zhongsen Biotechnology Co Ltd
Institute of Chemical Industry of Forest Products of CAF
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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Abstract

本发明涉及一种以东亚地区传统生漆漆酚中的C15三烯漆酚(3‑((8Z，11E，13Z)‑pentadeca‑8，11，13‑trien‑1‑yl)benzene‑1，2‑diol)或C15单烯漆酚((Z)‑3‑(pentadec‑8‑en‑1‑yl)benzene‑1，2‑diol)为原料，基于基团叠加原理，将三氮唑结构引入C15漆酚芳基醚中。其中，漆酚基三氮唑衍生物显著降低甚至消除了C15三烯漆酚的致敏性，对肝癌细胞增殖的抑制达到了减毒增效的效果；该发明将扩大C15三(单)烯漆酚的医运用领域。

Description

C15漆酚基三氮唑衍生物的合成
技术领域
本发明涉及C15漆酚基三氮唑衍生物的合成，特别是一种有机合成的漆酚林化产品，具体本发明是通过基于Cu(I)AAC重氮环化反应的合成方法，利用本发明的方法可以合成一些新的、生物活性较高的漆酚林化产品。
背景技术
超过1/3的植物来源的抗肿瘤药物。大量证据表明，肿瘤的发生和转移与细胞程序性死亡有关。化学治疗药物如紫杉醇，顺铂，阿霉素与此类肿瘤细胞凋亡有关。漆酚作为漆的主要成分，刺激小鼠某些细胞的活性，并降低小鼠脂肪肝的风险。它调节SIRT抑制剂的活性，具有显着的抗肿瘤活性，肿瘤血管生成抑制作用和核转录因子-κB抑制活性等。它还在清除，抑制DPPH和ABTS等自由基，抗氧化剂变形链球菌，并抑制食物腐败和微生物生长。但是漆酚的致敏作用与细胞膜上的角蛋白或蛋白质结合形成完整的抗原，这些抗原攻击苯环的4，5和6位碳原子。新的漆酚衍生物具有抗血小板凝集活性，显着降低TNF-α和IL-1β，通过防止肿瘤细胞增殖并诱导肿瘤细胞分化以及酒精诱导的程度在肝，肺和乳腺癌中的抗肿瘤病毒小鼠脂肪变性；它可以提高小鼠的免疫能力，并可能治疗ALD。
三唑类化合物可以抑制肿瘤细胞增殖，诱导白血病和乳腺癌细胞凋亡。三唑已经成为各种阴离子和中性分子，甚至生物大分子受体化合物因为主要结构中的重要组成部分，氮与其富电子络合物易与金属离子结合，并具有更强的捕获能力阳离子。三唑环还可通过氢键与阴离子形成超分子。
发明内容
本发明的目的是在现有纯化的C15三烯漆酚(3-((8Z，11E，13Z)-pentadeca-8，11，13-trien-1-yl)benzene-1，2-diol)或C15单烯漆酚((Z)-3-(pentadec-8-en-1-yl)benzene-1，2-diol)基础上，合成三(单)不饱和漆酚三氮唑衍生物，从而达到减毒增效的效果，其方法简单、一步反应、产率高、成本低，利用该方法可以得到抗肝癌效果较好的C15三(单)烯漆酚基衍生物，对国内生漆产业的发展意义重大。
附图说明
图1为产物1的1H NMR图
图2为产物1的13C NMR图
图3为产物2的1H NMR图
图4为产物2的13C NMR图
图5为产物1的MS图
图6为产物2的MS图
具体实施方式
漆酚炔醚的合成：漆酚与溴丙炔在60℃、24h条件下，在Bronsted碱条件下(K2CO3)，反应生成漆酚炔醚，继而生成化合物1和2。具体为：漆酚炔醚的合成：将三烯或单烯漆酚(0.5mmolL)溶解在干丙酮(3mL)中，加入碳酸钾(0.5mmol/L)和溴丙炔(100μL，5.25mmol)。将混合物在60℃搅拌24小时，在0℃浴中用水(50mL)猝灭。将该溶液旋蒸浓缩除去丙酮，用二氯甲烷(2×30mL)萃取。用饱和碳酸氢钠和饱和食盐水洗涤有机层，用硫酸镁干燥，过滤，浓缩。用氯仿-甲醇(100∶5)柱层析纯化浓缩产物，分别得到化合物漆酚炔醚。
2-叠氮乙胺的合成：2-溴乙胺氢溴酸(500mg，2.44mmol)和叠氮钠(475.9mg，7.32mmol)溶于水(2mL)中，溶液加热至75℃，搅拌21h，冷却至0℃，加入氢氧化钾(800mg)和乙醚(2mL)，用乙醚(2×10mL)萃取，旋蒸浓缩。经氯仿-甲醇(20∶1)柱层析纯化得到2-叠氮乙胺(171mg，82％)。
化合物1和2的合成：单烯漆酚炔醚或三烯漆酚炔醚(0.1mmol)分别在水/叔丁醇(2mL，1∶1)中加入2-叠氮乙胺(22μL，0.25mmol)，然后加入硫酸铜(3.0mg)和抗坏血酸钠溶液(50μL，1M溶液)。混合液在室温下搅拌15h，旋蒸浓缩，用氯仿-甲醇(50∶1)柱层析纯化产物，得到化合物1和2。
化合物1：(2，2′-((((3-((8Z，11E，13Z)-pentadeca-8，11，13-trien-1-yl)-1，2-phenylene)bis(oxy))bis(meth-ylene))bis(1H-1，2，3-triazole-4，1-diyl))bis(ethan-1-amine))Yellow liquid.Yield：33mg，27％.1H NMR(400MHz，CDCl3)δ7.47-7.45(trizole，-CH＝)，6.58-6.62(Ar，m，3H)，6.28(t，1H)，5.90(t，1H)，5.56(m，1H)，5.32(m，3H)，5.27(s，4H，-O-CH2-)，4.69(-CH2-)，4.06，4.04，3.87，3.85，1.54(t，4H，-NH2).13CNMR(101MHz，CDCl3)δ143.71，142.71，132.35，131.18，129.94，129.93，126.89，125.63，121.62，119.56，112.69，77.42，76.90，60.45(-C-N)，31.86，30.68，29.90，29.81，29.76，29.64，29.54，29.36，29.05，27.28，22.74，21.03.ESIMS m/z 429.0[M-C10H16]+。
化合物2：((Z)-2，2′-((((3-(hexadec-9-en-1-yl)-1，2-phenylene)bis(oxy))bis(methylene))bis(1H-1，2，3-triazole-4，1-diyl))bis(ethan-1-amine))Yellowliquid.Yield：31mg，73％.1H NMR(400MHz，CDCl3)δ7.54-7.52(trizole，-CH＝，2H)，7.00(m，1H)，6.89-6.84(dd，2H)，5.34(t，2H)，5.26(-O-CH2-)，4.73-4.72(-CH2-N)，3.67，2.62，2.24，1.54(t，4H，-NH2)，0.88(t，-CH3).13C NMR(101MHz，CDCl3)δ143.20，142.07，131.76，130.32，129.36，128.82，123.57，120.99，118.97，112.05，59.86，31.27.ESIMS，m/z441.2[M-C9H18]+。

Claims (3)

1.一种漆酚基系列化合物的合成，其特征在于：以两种漆酚化合物为原料，与诸多化学试剂在有机溶剂中反应生成漆酚基系列化合物；部分新型C15三烯漆酚衍生物具备更优的抗肝癌活性。
2.根据权利要求1所述合成的漆酚基系列化合物，其特征在于：所述漆酚原料Urushiol(Rhus vernicifluum China)分别为C15三烯漆酚(3-((8Z，11E，13Z)-pentadeca-8，11，13-trien-1-yl)benzene-1，2-diol)和C15单烯漆酚((Z)-3-(pentadec-8-en-1-yl)benzene-1，2-diol)，结构式如图。
3.根据权利要求1所述合成的漆酚基系列化合物，其特征在于：所述合成的漆酚基系列侧链三氮唑胺基化合物1和2具有以下结构特征，结构如。
CN201811165444.5A 2018-09-29 2018-09-29 C15漆酚基三氮唑衍生物的合成 Pending CN109180594A (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116375698A (zh) * 2023-06-05 2023-07-04 中国林业科学研究院林产化学工业研究所 具有靶向抗肿瘤活性的新型漆酚基异羟肟酸型hdac抑制剂及其制备方法和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101805246A (zh) * 2010-04-16 2010-08-18 中国科学院昆明植物研究所 漆酚化合物,其药物组合物及其制备方法和应用

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116375698A (zh) * 2023-06-05 2023-07-04 中国林业科学研究院林产化学工业研究所 具有靶向抗肿瘤活性的新型漆酚基异羟肟酸型hdac抑制剂及其制备方法和应用
CN116375698B (zh) * 2023-06-05 2023-08-01 中国林业科学研究院林产化学工业研究所 具有靶向抗肿瘤活性的漆酚基异羟肟酸型hdac抑制剂及其制备方法和应用

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Application publication date: 20190111