CN103553957B - 含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物及制备方法和用途 - Google Patents
含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物及制备方法和用途 Download PDFInfo
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- CN103553957B CN103553957B CN201310450208.9A CN201310450208A CN103553957B CN 103553957 B CN103553957 B CN 103553957B CN 201310450208 A CN201310450208 A CN 201310450208A CN 103553957 B CN103553957 B CN 103553957B
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- histone deacetylase
- acid
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Abstract
本发明提供了一种通式I所示的含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物及其药学上可接受的盐及其制备方法和用途。在通式I中，X为羰基、亚甲基、取代的亚甲基、亚乙基以及取代的亚乙基；Y为芳香环、取代的芳香环、芳杂环以及取代的芳杂环；Z为氢、芳香环、取代的芳香环、芳杂环以及取代的芳杂环。该类化合物具有良好的抗肿瘤活性，在临床上可以进行口服、静脉注射、肌肉注射等方式应用。
Description
技术领域
本发明涉及一类作用于微管及组蛋白去乙酰化酶的多靶点抑制剂以及制备这些化合物的方法和用途。更具体地说，涉及具有以下结构的新型秋水仙碱衍生物(I)以及它们的制备方法和这些化合物在抗肿瘤领域中的应用。
背景技术
微管是一种具有极性的细胞骨架，是维持细胞形态的重要因素，也是一类重要的抗肿瘤靶点。秋水仙碱(1)是代表性的作用于微管秋水仙碱结合位点的具有抗肿瘤活性的化合物，但因毒性强、副作用大而使其应用受到限制。
联合用药和发展单分子多靶点药物是抗肿瘤药物研究领域的一个方向，通过不同靶点之间的协同作用从而起到增加药效以及降低副作用的效果。前者已在实际临床上有了大量的应用实例，但往往会因为药物的分布、半衰期不同以及给药方式复杂等因素给临床研究带来不便；而后者能在保持协同作用的同时克服上述缺陷，故而成为当今药物化学家研发新型抗肿瘤药物的一条重要分支。由于阻断了肿瘤细胞生存的多条途径，此类小分子药物能够克服传统的药物容易产生耐药性的缺点。例如，第一代酪氨酸激酶抑制剂伊马替尼作用靶点较为单一，主要抑制酪氨酸激酶Bcr-Abl。病人服用一段时间的伊马替尼后容易产生耐药性。第二代酪氨酸激酶抑制剂尼罗替尼和达沙替尼具有abl和src双重激酶抑制的能力，能够治疗对伊马替尼产生耐药的患者，从而显示出比第一代药物更好的治疗效果。
哺乳动物的蛋白去乙酰化酶(HDAC)是一类含有锌离子的酰胺水解酶，可以分为第一类(HDAC-1、HDAC-2、HDAC-3和HDAC-8)、第二类(HDAC-4、HDAC-5、HDAC-7、HDAC-9、HDAC-10)和第四类(HDAC-11)。组蛋白去乙酰化酶抑制剂(HDACi)可以抑制白血病和实体肿瘤细胞增殖，并诱导细胞分化。
本发明将HDAC抑制剂和秋水仙碱类化合物进行有机的融合，发展了新型杂化分子，具有双靶点的抗肿瘤活性。
发明内容
本发明的目的是寻找一类新型的含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物及其药学上可接受的盐，这类化合物具备微管及组蛋白去乙酰化酶双重抑制作用。
本发明的另一目的是提供一种制备所述含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物及其药学上可接受的盐的方法。
本发明的另一目的是提供一种用于治疗癌症的组合物，该组合物包含治疗有效量的一种或多种所述含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物及其药学上可接受的盐以及药学上可接受的载体。所述药学上可接受的盐包括但不限于该化合物与盐酸、硫酸、磷酸、甲磺酸、琥珀酸、马来酸、富马酸、酒石酸、柠檬酸等的加成盐。
本发明的再一目的是提供一种所述含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物及其药学上可接受的盐在制备抗肿瘤药物中的应用。这类多靶点抗肿瘤药物比原有药物具有更广的抗肿瘤谱，克服某些肿瘤株对这两种药物的耐药性。
本发明是关于含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物，这些化合物是在去甲基秋水仙碱的N端引入组蛋白去乙酰化酶的锌离子螯合片段，并进行合理的连接。它们具有良好的抗肿瘤活性。
本发明所述的含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物及其药学上的盐具体结构如通式(I)所示：
其中，
X为羰基、亚甲基、取代的亚甲基、亚乙基以及取代的亚乙基；优选为亚甲基；
Y为芳香环，取代的芳香环，芳杂环以及取代的芳杂环；优选为苯环；
Z为氢、芳香环，取代的芳香环，芳杂环以及取代的芳杂环；优选为氢。
本发明提供了一种所述的含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物及其药学上可接受盐的制备方法，该方法包括如下步骤：
i)化合物II在氯化亚砜作用下生成酰氯中间体，该中间体在碱性条件下与Boc保护的邻苯二胺衍生物反应，得化合物III；碱为碳酸钠、碳酸铯、碳酸钾、三乙胺、吡啶、二异丙基乙基胺等，优选为三乙胺；反应溶剂为甲苯、二氯甲烷、四氢呋喃等，优选为二氯甲烷；反应温度为0-80℃，优选为20-30℃；
ii)在碱作用条件下，化合物III发生水解反应生成羧酸中间体，本步碱为氢氧化锂，氢氧化钠，氢氧化钾，优选为氢氧化锂，溶剂为乙醇、甲醇、四氢呋喃与水的混合，优选为甲醇水溶液，反应温度为20-80℃，优选为20-30℃;在缩合剂与碱存在的条件下,该中间体与去乙酰秋水仙碱进行反应得到化合物IV，缩合剂为DCC、EDCI、CDI、HATU等，优选为HATU;碱为三乙胺、吡啶、二异丙基乙基胺，优选为二异丙基乙基胺;反应溶剂为四氢呋喃、二氯甲烷等，优选为四氢呋喃，反应温度为0-50℃，优选为20-30℃；
iii)在酸作用条件下，化合物IV脱除保护基得化合物I-1，本步反应溶剂为二氯甲烷、甲醇、乙酸乙酯、四氢呋喃等，优选为二氯甲烷;酸为氯化氢、甲磺酸、苯磺酸、三氟乙酸等，优选为三氟乙酸;反应温度为0-40℃，优选为20-30℃。
i)化合物V在氯化亚砜作用下生成酰氯中间体，该中间体在碱性条件下与Boc保护的邻苯二胺衍生物反应，得化合物VI；碱为碳酸钠、碳酸铯、碳酸钾、三乙胺、吡啶、二异丙基乙基胺等，优选为三乙胺；反应溶剂为甲苯、二氯甲烷、四氢呋喃等，优选为二氯甲烷；反应温度为0-80℃，优选为20-30℃；
ii)在碱和催化剂共同作用下，化合物VI与去乙酰秋水仙碱反应得化合物VII；本步碱为碳酸钾、碳酸钠、叔丁醇钾、叔丁醇钠、碳酸钠、碳酸铯、乙酸钠、三乙胺、吡啶、二异丙基乙基胺，优选为乙酸钠，催化剂为碘化钾、碘化纳等；溶剂为二氯甲烷、四氢呋喃、甲苯等，优选为四氢呋喃；反应温度为20-100℃，优选为60-80℃；
iii)在酸作用条件下，化合物VII脱除保护基得化合物I-2，本步反应溶剂为二氯甲烷、甲醇、乙酸乙酯、四氢呋喃等，优选为二氯甲烷；酸为氯化氢、甲磺酸、苯磺酸、三氟乙酸等，优选为三氟乙酸；反应温度为0-40℃，优选为20-30℃。
本发明所涉及的化合物具有良好的抗肿瘤活性，在临床上可以进行口服、静脉注射、肌肉注射等方式应用。
具体实施方式
本发明的新型含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物和制备方法在如下实施例中更详细地叙述，但实施例不构成对本发明的限制。
实施例1
1.1化合物3的制备
将900mg对苯二甲酸单甲酯溶于10mL甲苯中，室温滴加氯化亚砜2.1mL后升温至60-70℃反应2h，减压除去溶剂及过量的氯化亚砜后得无色液体。将此液体溶于5mL二氯甲烷中，滴加入溶有1.1mL三乙胺和832mg叔丁基2-氨基苯基氨基甲酸酯的二氯甲烷溶液中，室温反应30分钟后停止反应。经二氯甲烷萃取，1N盐酸洗，饱和碳酸钠洗后有机相干燥旋干。粗产品在石油醚-乙酸乙酯中结晶既得白色固体1.28克，收率86.5%。1H NMR(400MHz,DMSO)δ9.98(s,1H),8.71(s,1H),8.15–8.03(m,4H),7.55(dd,J=13.6,7.8Hz,2H),7.27–7.08(m,2H),3.91(s,3H),1.44(s,9H)。
实施例2
1.2化合物4的制备
室温下，将50mg化合物3、11mg一水合氢氧化锂溶于3mL乙醇与0.27mL水的混合液中，反应1小时后加入1N盐酸调节pH至弱酸性，减压去除溶剂。将所得固体、53mg去乙酰秋水仙碱、43mg二异丙基乙基胺、44mg2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯溶于5mL二氯甲烷中，室温反应两小时后以二氯甲烷萃取，1N盐酸洗涤，水洗后有机相转干，以二氯甲烷-甲醇为展开剂过柱分离，得浅黄色固体62mg，产率81.1%。1H NMR(400MHz,CDCl3)δ9.38(s,1H),7.84–7.67(m,6H),7.63(s,1H),7.41–7.35(m,2H),7.23–7.13(m,3H),6.90(d,J=10.9Hz,1H),6.58(s,1H),4.97–4.81(m,1H),4.00(d,J=12.6Hz,3H),3.98–3.87(m,6H),3.61(s,3H),2.68–2.55(m,1H),2.53–2.31(m,2H),2.20–2.06(m,1H),1.45(s,9H)。
实施例3
1.3化合物5的制备
将化合物4溶于20mL二氯甲烷中，加入3mL三氟乙酸，室温反应3小时。加入饱和碳酸钠溶液淬灭反应后，用二氯甲烷萃取，有机相用水洗，饱和食盐水洗，无水硫酸钠干燥并减压蒸馏。所得粗产品以二氯甲烷-石油醚打浆，得白色固体31mg，产率69.6%。1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.50(d,J=6.3Hz,1H),7.78(s,1H),7.70(d,J=8.0Hz,2H),7.51(d,J=7.8Hz,2H),7.37(d,J=10.8Hz,1H),7.26–7.23(m,1H),7.00(t,J=7.4Hz,1H),6.94(d,J=11.0Hz,1H),6.84–6.68(m,2H),6.56(s,1H),4.98–4.83(m,1H),4.02(s,3H),3.92(s,3H),3.90(s,3H),3.55(s,3H),2.61–2.47(m,1H),2.42–2.25(m,2H),2.21–2.09(m,1H).HPLC:room temperature;tR=9.35min,UV254=95.6%;HRMS(ESI):m/z calcd forC34H33N3O7Na(M+Na+):618.2216,found:618.2224。
实施例4
1.4化合物7的制备
将5.0g对羟甲基苯甲酸溶于50mL甲苯中，室温下滴加氯化亚砜6.0mL后升温至60-70℃反应3小时，减压除去溶剂及过量的氯化亚砜后得无色液体。将此液体溶于15mL二氯甲烷中，滴加入溶有8.3mL三乙胺和4.16g叔丁基2-氨基苯基氨基甲酸酯的二氯甲烷溶液中，室温反应1小时后停止反应。经二氯甲烷萃取，1N盐酸洗，饱和碳酸钠洗后有机相干燥旋干。粗产品在石油醚乙酸乙酯中结晶既得白色固体6.5克，收率82.0%。1H NMR(400MHz,CDCl3)δ9.24(s,1H),7.97(d,J=8.1Hz,2H),7.83(d,J=7.8Hz,1H),7.49(d,J=8.2Hz,2H),7.26–7.14(m,3H),6.73(s,1H),4.64(s,2H),1.52(s,9H)。
实施例5
1.5化合物8的制备
将1.16g去乙酰秋水仙碱，1.33g化合物7,1.01g醋酸钠，610mg碘化钾溶于50mL四氢呋喃中回流15小时。反应结束后用乙酸乙酯萃取，有机相经10%硫代硫酸钠洗涤，食盐水洗涤后干燥旋干。以二氯甲烷甲醇为淋洗剂柱层析，得白色固体1.52g，产率80%。1H NMR(400MHz,CDCl3)δ9.10(s,1H),7.89–7.80(m,3H),7.75(dd,J=7.8,1.3Hz,1H),7.36–7.29(m,3H),7.25–7.11(m,3H),6.99(s,1H),6.80(d,J=11.0Hz,1H),6.52(s,1H),3.98(s,3H),3.91(s,3H),3.90(s,3H),3.79–3.74(m,1H),3.59(s,3H),3.52–3.43(m,2H),2.53–2.31(m,2H),2.30–2.14(m,1H),1.70–1.65(m,1H),1.50(s,9H)。
实施例6
1.6化合物9的制备
将1.15g化合物8溶于6mL二氯甲烷中，滴加入1.9mL三氟乙酸，室温下反应3小时。反应完全后加入碳酸氢钠水溶液淬灭反应，并以二氯甲烷萃取，有机相干燥后转干。以二氯甲烷甲醇为淋洗剂柱层析，得白色固体400mg，产率41%。1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.83(s,1H),7.76(d,J=6.9Hz,2H),7.41–7.29(m,3H),7.23(d,J=10.7Hz,1H),7.07(t,J=7.4Hz,1H),6.91–6.75(m,3H),6.52(s,1H),3.96(s,3H),3.91(s,3H),3.90(s,3H),3.73(d,J=13.5Hz,1H),3.60(s,3H),3.54(d,J=13.5Hz,1H),3.47–3.41(m,1H),2.50–2.34(m,2H),2.28–2.15(m,1H),1.77–1.65(m,1H).HPLC:room temperature;tR=7.89min,UV254=100.0%。
实施例7：HDAC抑制活性测试：
以Ac-Lys-Tyr-Lys(Ac)-AMC为底物，采用荧光检测法，在96孔或384孔平底微孔板中检测酶活性。底物Ac-Lys-Tyr-Lys(Ac)-AMC分别经HDAC1，HDAC2，HDAC3去乙酰化后，利用胰酶水解得到的产物AMC在荧光检测仪的355nm激发460nm发射光下可被检测到荧光信号。通过检测随时间荧光信号的变化，计算得到反应初速度。
以Boc-lys(Ac)-AMC为底物，采用荧光检测法，在96孔或384孔平底微孔板中检测酶活性。底物Boc-lys(Ac)-AMC经HDAC6去乙酰化后，利用胰酶水解得到的产物AMC在荧光检测仪的355nm激发460nm发射光下可被检测到荧光信号。通过检测随时间荧光信号的变化，计算得到反应初速度。
表1.对HDAC的抑制活性
上表显示了本发明所述的化合物对HDAC具有良好的抑制活性。
实施例8：该类化合物的细胞毒活性测试都在相应的肿瘤细胞株上进行，每100μL的培养液中有4000个肿瘤细胞，置于96孔板中(Falcon，CA)。肿瘤细胞分成三份，用梯度浓度的药物处理，在37℃下培养72h，采用MTT法测试。50％的肿瘤细胞生长抑制时药物的浓度即IC50使用量效曲线来计算的。
表1.对HCT116细胞的生长抑制活性
上表显示了本发明所述的化合物对HCT116细胞株具有良好的抑制活性。
实施例9：选取该类化合物中化合物9测试其体外微管活性。
在冰浴的比色杯中加入微管蛋白，然后加入GTP（母液5μL），使其终浓度为100mmol/L。在4℃于340nm处迅速调零，放入37℃水浴中恒温，每间隔1min取出测吸光度（A），根据所测得的Ａ的变化绘制微管蛋白聚合曲线。实验结果证明化合物9能明显促使微管解聚，且能力与秋水仙碱相当。
Claims (7)
1.一种通式I所示的含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物及其药学上可接受的盐：
其中，
X为羰基或亚甲基；
Y为苯环；
Z为氢。
2.含有组蛋白去乙酰化酶抑制活性的秋水仙碱化合物，选自以下化合物：
或其药学上可接受的盐。
3.一种通式I-1所示的含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物及其药学上可接受的盐的制备方法，该方法包括如下步骤：
式中，Z为氢；
ⅰ)化合物II在氯化亚砜作用下生成酰氯中间体，该中间体在碱性条件下与Boc保护的邻苯二胺衍生物反应，得化合物III；其中，碱为碳酸钠、碳酸铯、碳酸钾、三乙胺、吡啶或二异丙基乙基胺；反应溶剂为甲苯、二氯甲烷或四氢呋喃，反应温度为0-80℃；
ⅱ)在碱作用条件下，化合物III发生水解反应生成羧酸中间体；其中，碱为氢氧化锂，氢氧化钠或氢氧化钾；溶剂为乙醇、甲醇或四氢呋喃与水的混合；反应温度为20-80℃；在缩合剂与碱存在的条件下，该中间体与去乙酰秋水仙碱进行反应得到化合物IV；其中，缩合剂为DCC、EDCI、CDI或HATU；碱为三乙胺、吡啶或二异丙基乙基胺；反应溶剂为四氢呋喃或二氯甲烷；反应温度为0-50℃；
ⅲ)在酸作用条件下，化合物IV脱除保护基得化合物I-1，其中，反应溶剂为二氯甲烷、甲醇、乙酸乙酯或四氢呋喃；酸为氯化氢、甲磺酸、苯磺酸或三氟乙酸；反应温度为0-40℃。
4.一种通式I-2所示的含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物及其药学上可接受的盐的制备方法，该方法包括如下步骤：
式中，Z为氢
ⅰ)化合物V在氯化亚砜作用下生成酰氯中间体，该中间体在碱性条件下与Boc保护的邻苯二胺衍生物反应，得化合物VI；其中，碱为碳酸钠、碳酸铯、碳酸钾、三乙胺、吡啶或二异丙基乙基胺；反应溶剂为甲苯、二氯甲烷或四氢呋喃；反应温度为0-80℃；
ⅱ)在碱和催化剂共同作用下，化合物VI与去乙酰秋水仙碱反应得化合物VII；其中，碱为碳酸钾、碳酸钠、叔丁醇钾、叔丁醇钠、碳酸钠、碳酸铯、乙酸钠、三乙胺、吡啶或二异丙基乙基胺；催化剂为碘化钾或碘化纳；溶剂为二氯甲烷、四氢呋喃或甲苯；反应温度为20-100℃；
ⅲ)在酸作用条件下，化合物VII脱除保护基得化合物I-2，其中，反应溶剂为二氯甲烷、甲醇、乙酸乙酯或四氢呋喃；酸为氯化氢、甲磺酸、苯磺酸或三氟乙酸；反应温度为0-40℃。
5.一种用于治疗癌症的组合物，该组合物包含治疗有效量的一种或多种如权利要求1或2所述的含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物或其药学上可接受的盐以及药学上可接受的载体。
6.一种权利要求1或2所述的含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物或其药学上可接受的盐在制备抗肿瘤药物中的应用。
7.一种权利要求1或2所述的含有组蛋白去乙酰化酶抑制活性的秋水仙碱衍生物或其药学上可接受的盐在制备治疗结肠癌或肺癌的药物中的应用。
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| Biological Effects of Modified Colchicines. 2. Evaluation of Catecholic Colchicines, Colchifolines, Colchicide, and Novel N-Acyl- and N- Aroyldeacetylcolc hicines;Arnold Brossi et al.;《Journal of Medicinal Chemistry》;19831231;第26卷(第10期);第1365页第1段至第1369页倒数第1段 * |
| Synthesis and Biological Evaluation of Colchicine B‑Ring Analogues Tethered with Halogenated Benzyl Moieties;Laura Cosentino et al.;《Journal of Medicinal Chemistry》;20121126;第55卷;第11062页第1段至第11066页倒数第1段 * |
| 具有体内抗肿瘤活性的新型微管蛋白聚合抑制剂:发现、结构优化及机理研究;龙亚秋等;《中国化学会第28界学术年会第3分会场摘要集》;20120413;全文 * |
| 几种杭瘤生物碱对微管作用的研究进展;吴虹等;《国外医学 药学分册》;19881231;第140页第1段至第143页倒数第1段 * |
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