CN111187325B - 抗肿瘤(4′R)-甲基-α-L-呋喃苏糖核苷及其制备方法 - Google Patents
抗肿瘤(4′R)-甲基-α-L-呋喃苏糖核苷及其制备方法 Download PDFInfo
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- CN111187325B CN111187325B CN202010046069.3A CN202010046069A CN111187325B CN 111187325 B CN111187325 B CN 111187325B CN 202010046069 A CN202010046069 A CN 202010046069A CN 111187325 B CN111187325 B CN 111187325B
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Abstract
本发明公开了新型α‑L‑呋喃苏糖核苷膦酸酯类似物，具体涉及(4'R)‑甲基‑3'‑O‑甲基膦酸‑α‑L‑呋喃苏糖核苷类似物及其制备方法和用途，属于核苷化学及药物化学领域。其具有通式1所示结构：
其中，R'代表H、Na、K或NH4离子；B代表尿嘧啶、胸腺嘧啶、5‑氯尿嘧啶、5‑氟尿嘧啶、5‑溴尿嘧啶、5‑碘尿嘧啶、胞嘧啶、5‑氟胞嘧啶、腺嘌呤、2‑氟腺嘌呤、2‑氯腺嘌呤、2‑氨基腺嘌呤和鸟嘌呤。该类化合物具有抗肿瘤活性和良好的开发前景。
Description
技术领域
本发明属于核苷酸化学及药物化学领域，具体涉及新型L-苏糖核苷膦酸酯类似物、制备方法及其抗肿瘤活性。
背景技术
非天然核苷类药物是病毒类疾病的主要治疗药物，也是一类很重要的抗肿瘤药物。大多数具有生物活性的核苷类似物在细胞激酶的作用下发生磷酰化转化成单核苷酸而被激活，单核苷酸再经过两步磷酰化反应转化为5'-三磷酸核苷，作为病毒RNA或DNA聚合酶的底物表现出抗病毒作用，作为细胞RNA/DNA聚合酶底物表现出细胞毒性或抗肿瘤活性。膦酸酯核苷作为单核苷酸的生物电子等排体是单核苷酸的良好的替代物，既能提高单核苷酸的稳定性，又能提高其生物利用度。
糖环修饰或碱基修饰是获得新型核苷的有效手段。苏糖核苷相对于核糖核苷其结构更简单，相应的核苷酸能与天然RNA和DNA形成热稳定的双链，因此近年来苏糖核苷膦酸酯受到核酸化学家们的青睐。如：P.Herdewijn教授合成的L-2′-脱氧苏糖腺苷膦酸酯(PMDTA)和L-2′-脱氧苏糖胸苷膦酸酯(PMDTT)能选择性抑制HIV病毒而不影响正常组织细胞的增殖(Wu,T.；Froeyen,M.；Kempeneers,V.；Pannecouque,C.；Wang,J.；Busson,R.；DeClercq,E.；Herdewijn,P.J.Am.Chem.Soc.2005,127,5056)。
基于苏糖核苷膦酸酯的优势，对糖环作进一步修饰，合成新型苏糖核苷膦酸酯类似物有利于抗肿瘤药或抗肿瘤药物先导物的开发。
发明内容
本发明目的在于提供一类具有抗肿瘤活性的(4′R)-甲基-α-L-呋喃苏糖核苷膦酸酯类似物；另一目的在于提供其制备方法和应用。
为实现本发明目的，通过将市售D-木糖选择性1,2-羟基保护、脱5-羟基、3-羟基上引入磷酰甲基、1,2-羟基酰化、糖苷化、脱除各种保护基、酸解最终得到目标核苷膦酸酯类似物。
所述的新型(4′R)-甲基-α-L-呋喃苏糖核苷膦酸酯类似物以通式1表示：
其中，R代表H、Na、K或NH4离子；
B代表如下碱基：
优选如下化合物：
制备上述通式1所示的化合物首先制备(4R)-甲基-3-O-甲基磷酸酯-1,2-O-二酰基-α-L-呋喃苏糖2:
其中：R′为乙基或异丙基；acyl为乙酰基或苯甲酰基。
制备通式2所示中间体(acyl为乙酰基)的方法：
制备通式2所示中间体(acyl为苯甲酰基)的方法：
由中间体2通过如下步骤合成通式1所示化合物：
方法详述如下:
(1)将原料D-木糖悬浮于丙酮中，冰浴下加入硫酸，室温搅拌至澄清，加入碳酸氢钠水溶液，反应，反应结束，调pH至中性，浓缩，加入丙酮搅拌过滤，再浓缩得到油状液体I。
(2)中间体I溶于无水吡啶中，加入过量的对甲苯磺酰氯，反应，反应结束后加水淬灭反应，浓缩，柱层析分离得白色固体II。
(3)N2保护条件下，通过负氢转移还原反应脱除化合物II的磺酸酯基，还原结束后淬灭反应，柱层析分离得中间体III。负氢转移还原反应所使用的负氢转移试剂为四氢铝锂或硼氢化钠或硼氢化钠/路易斯酸，优选四氢铝锂。反应温度为-30℃到10℃。
(4)在碱的存在下，磷酰甲基化试剂处理中间体III，使中间体III的3-OH磷酰甲基化得到中间体IV。
所使用的磷酰甲基化试剂是氯甲基膦酸二乙酯、氯甲基膦酸二异丙酯、氯甲基膦酸二甲酯、对甲苯磺酰氧甲基膦酸二乙酯、对甲苯磺酰氧甲基膦酸二甲酯和对甲苯磺酰氧甲基膦酸二异丙酯中的一种。所使用的碱为氢化钠、甲醇钠或叔丁醇钾。
(5)酸水解3-O-膦酸酯-L-苏糖中间体IV的1,2-异丙叉基，得到1,2-二羟基中间体V。
酸水解可使用有机酸或无机酸的水溶液，有机酸水溶液的质量浓度为30％-80％，有机酸可使用乙酸或三氟乙酸。无机酸水溶液的质量浓度为2％-20％，无机酸为盐酸或硫酸。优选质量浓度60％的有机酸溶液。
(6)干燥的化合物V溶于无水吡啶，加入酰化试剂，氮气保护下室温反应。酰化结束后处理，柱层析分离得到重要中间体2(acyl为乙酰基)。
酰化试剂是乙酸酐或乙酰氯，优选乙酸酐。
(7)质子酸催化甲醇醇解中间体IV，柱层析分离得中间体VI的α和β构型的混合物。质子酸可以是硫酸或盐酸。
(8)中间体VI用苯甲酰氯/有机碱体系处理得到2-O-苯甲酰基中间体VII。有机碱可以是吡啶、三乙胺、或者二者的混合物。
(9)中间体VII溶于冰醋酸中，加入醋酸酐和催化量的硫酸，室温反应使1-甲氧基转化为1-乙酰氧基，柱层析分离得到中间体2(acyl为苯甲酰基)。
(10)将中间体2与硅烷化的碱基在路易斯酸的催化下通过Vorbrüggen反应得到核苷膦酸酯中间体VIII。
硅烷化碱基可以预先采用六甲基二硅胺烷在催化量的硫酸铵存在下处理碱基得到；或在反应体系中直接以N,O-双(三甲基甲硅烷基)乙酰胺(BSA)处理碱基。
路易斯酸使用三氟甲磺酸三甲基硅酯(TMSOTf)或四氯化锡。
(11)将上述所得的核苷膦酸酯中间体VIII在饱和氨甲醇溶液、饱和氨四氢呋喃溶液、饱和氨二氧六环溶液、氨水或甲醇钠甲醇溶液中脱除酰基保护基得到核苷膦酸酯中间体IX。
(12)将核苷膦酸酯IX溶于有机溶剂，在氮气保护下酸解酯基(乙酯或异丙基酯)，反应结束后倾入冷水、或冷的NaHCO3水溶液、或冷KHCO3水溶液、或冷氨水中，浓缩蒸干，柱层析分离分别得到相应的目标化合物的膦酸类似物、磷酸二钠类似物、膦酸二钾类似物或膦酸二铵类似物(化合物1)。
上述酸解反应中所使用的试剂为：三甲基溴硅烷(TMSBr)、三甲基碘硅烷(TMSI)、TMSI/2,6-卢剔啶、TMSBr/2,6-卢剔啶、TMSI/2,4,6-可力啶、TMSBr/2,4,6-可力啶中的一种。
上述反应使用的有机溶剂为：四氢呋喃、二氯甲烷或乙腈中的一种或两种。
本发明以D-木糖为原料，通过对糖环的修饰，得到膦酸苏糖中间体，进一步合成了4′-甲基-α-L-呋喃苏糖核苷膦酸酯类似物。通过体外抗肿瘤活性研究发现，部分化合物具有良好的抗肿瘤活性，尤其是抗乳腺癌细胞活性突出。因此该类化合物有望作为抗肿瘤药或作为抗肿瘤药物的先导物使用。
本发明的优点在于：
1、本发明提供的目标化合物兼具磷酰甲氧基呋喃糖核苷的优异的稳定性和抗溶核酶分解能力，同时可被酶识别进一步磷酸化为二磷酸酯(三磷酸核苷的生物电子等排体)作为DNA/RNA聚合酶的底物。
2、本发明提供了一类合成新型苏糖核苷膦酸酯的中间体4R-甲基-3-O-膦酸酯-1,2-O-二酰基-L-苏糖的方法。
3、该类化合物具有潜在的抗肿瘤活性和良好的开发前景。
4、本发明提供了一种原料价廉易得、操作简单的膦酸酯核苷合成新方法。
具体实施方式
以下结合实施例对本发明进行详细说明，并不局限于以下内容。
实施例1：制备(4R)-甲基-3-O-二乙氧基磷酰甲基-1,2-二-O-乙酰基-L-苏糖(化合物2a，通式2所示，acyl为乙酰基，R’为乙基)
将D-木糖(10g，0.068mol)和200mL丙酮混合，在冰浴条件下缓慢滴加浓硫酸(10.8Ml)。浓硫酸滴加完毕后撤掉冰浴，室温搅拌1h后反应体系完全澄清。滴加碳酸钠水溶液(12g/100mL水，0.110mol)，控制滴加速度，40min左右滴加完毕。继续常温搅拌2h，然后向反应体系中加入碳酸钠固体(6g，0.055mol)和10mL蒸馏水，抽滤后收集滤液，旋蒸，加入丙酮溶出有机物，滤除体系中残留的盐。减压蒸除溶剂，硅胶柱层析分离，减压浓缩得黄色油状液体(I)。
将化合物I(20.8g,0.098mol)溶解到200mL无水吡啶中。在冰浴和氮气保护下，分批加入对甲基苯磺酰氯(20.9g，0.108mol)，加完后升温至10℃反应14h。加水淬灭反应，减压蒸除溶剂得到黄色固体。硅胶柱层析分离(乙酸乙酯：石油醚＝1:3～2:1)，减压浓缩得白色固体(II)。
将化合物II(15g，0.044mol)溶于400mL干燥的四氢呋喃中，冰浴下分批加入LiAlH4(5g，0.132mol)，加完后逐渐升至室温，氮气保护下室温反应至原料消失。在冰浴和充分搅拌下逐滴加入5mL水，待其较粘稠时，加四氢呋喃稀释，然后再加入氢氧化钠水溶液(1.5g/10mL)，最后加水15mL，搅拌40min。过滤，蒸除溶剂，甲苯带水3次得粗产物。硅胶柱层析分离(乙酸乙酯:石油醚＝1:3～1:1)得无色液体(III)。
依次将化合物III(6g，0.034mol)、干燥的四氢呋喃(160mL)和氢化钠(2.5g，0.102mol)加入反应瓶中，在冰浴和N2保护的条件下缓慢加入对甲苯磺酰氧甲基膦酸二乙酯(21.9g，0.068mol)，撤掉冰浴至室温反应6h。反应结束后，缓慢滴加蒸馏水(30mL)淬灭反应，室温搅拌10min，减压蒸出THF，加入二氯甲烷用分液漏斗萃取，无水硫酸钠干燥，浓缩得粗产物。硅胶柱层析分离(乙酸乙酯:石油醚＝1:5～1:1)，减压浓缩得淡黄色油状液体(IV)。
将化合物IV(8g，0.025mol)溶于质量浓度60％醋酸水溶液(40mL)中，加热至70℃反应18h。待反应完毕后，减压蒸除溶剂。加入乙酸乙酯和饱和碳酸氢钠水溶液，萃取分层，无水硫酸钠干燥酯层，旋蒸得到黄色油状液体(V)。
将化合物V(4g，0.014mol)和无水吡啶(30mL)混合均匀，加入醋酐(8mL，0.07mol)，氮气保护下室温反应。原料消失后，加饱和NaHCO3水溶液淬灭反应，然后减压蒸除吡啶，用蒸馏水和乙酸乙酯分液，饱和NaCl水溶液洗涤乙酸乙酯层两次。无水硫酸钠干燥，过滤，浓缩得油状液体。硅胶柱层析分离(乙酸乙酯：石油醚＝1:4～3:1)，旋蒸得油状液体(2a，α-和β-构型的混合物)。
实施例2：制备(4R)-甲基-3-O-二乙氧基磷酰甲基-2-O-苯甲酰基-1-O-乙酰基-L-苏糖(化合物2b，通式2所示，acyl为苯甲酰基，R’为乙基)
将1.0g化合物IV溶于10mL无水甲醇，冰浴搅拌下缓慢加入200μL浓硫酸，冰浴搅拌14h。反应完成后加入过量碳酸氢钠固体，当不再产生气泡时停止搅拌，浓缩，用乙酸乙酯溶解，加少量无水硫酸钠干燥，过滤，浓缩，得无色透明油状液体VI(α、β两种构型的混合物)。
将1.0g化合物VI溶于10mL无水吡啶，冰浴搅拌下缓慢加入苯甲酰氯(2eq)，氮气保护，冰浴下搅拌4h，加入饱和碳酸氢钠水溶液终止反应，浓缩，用乙酸乙酯和饱和氯化钠溶液分层，有机层用无水Na2SO4干燥，减压浓缩，柱层析分离(石油醚:乙酸乙酯＝5:1-1:1)，得无色透明油状液体VII(α、β两种构型的混合物)。
将1.0g化合物VII溶于10mL冰醋酸，加入醋酸酐(4eq)，室温下搅拌；取1M硫酸的醋酸溶液120μL(硫酸0.05eq)，冰浴下加入反应体系，室温下搅拌8h。反应完后加入乙酸乙酯和饱和碳酸氢钠溶液及碳酸氢钠固体，冰浴下搅拌，产生大量气泡，至不再产生气泡时分液，有机层用无水Na2SO4干燥、浓缩，柱层析分离(石油醚:乙酸乙酯＝5:1-1:1，得无色透明油状液体2b(α和β两种构型的混合物)。
实施例3：制备化合物1a(通式1，R＝Na，B＝尿嘧啶)
分别将干燥的尿嘧啶(0.26g，0.0023mol)、甲苯15mL、六甲基二硅胺烷(5mL，0.023mol)和催化量的无水硫酸铵加入反应瓶中，氮气置换反应瓶中的空气，回流反应，直至体系变澄清，稍冷却，减压蒸除甲苯和多余的HMDS，得到类固体状物质。
将干燥的化合物2a(0.37g,0.001mol)溶于10mL无水四氢呋喃中，冰浴条件下加入到上述硅烷化尿嘧啶的四氢呋喃溶液中，再缓慢加入适量四氯化锡，待溶液澄清后撤掉冰浴。大约反应3h后，薄层色谱法检测2a完全消失，停止反应。加碳酸氢钠水溶液，搅拌20min，减压蒸除四氢呋喃，加二氯甲烷萃取，浓缩得粗产物(化合物VIIIa)，不用纯化直接投下步反应。
将上步得到的粗产物VIIIa溶于15mL饱和氨甲醇溶液中，室温反应8h，TLC监测原料消失，蒸除反应溶剂。硅胶柱层析分离(乙酸乙酯：甲醇＝10：1)，旋蒸得到淡黄色油状液体(IXa)。
将化合物IXa(100mg，0.26mmol)溶于无水乙腈中，在冰浴和N2保护条件下，依次加入2,6-二甲基吡啶(0.29mL，2.08mmol)和三甲基溴硅烷(TMSBr)(0.9mL，6.5mmol)，于25℃下反应过夜。TLC检测反应完全，停止反应，先减压蒸除易挥发物。加碳酸氢钠水溶液至pH为8.5，减压浓缩，ODS柱层析分离(水:甲醇＝4:1)，得白色固体(1a)。1H NMR(400MHz,D2O)δ7.74(d,J＝8.2Hz,1H),5.75–5.72(m,2H),4.44–4.37(m,1H),4.33(s,1H),3.72(d,J＝3.3Hz,1H),3.59(dd,J＝13.1,9.4Hz,1H),3.49(dd,J＝13.1,9.4Hz,1H),1.34(d,J＝6.5Hz,3H).
实施例4：制备化合物1b(通式1，R＝Na，B＝胸腺嘧啶)
分别将5mL无水乙腈，干燥的中间体2b(54mg，0.124mmol)，N,O-双三甲硅基乙酰胺(BSA，81μL，0.4mmol)以及胸腺嘧啶(23mg，0.18mmol)加入反应瓶中，氮气保护下于65℃油浴锅中反应直至体系澄清。冷却至室温，加三氟甲磺酸三甲基硅酯(TMSOTf，100μL)，加完后逐渐升至65℃，反应4h，TLC监测原料消失，停止反应，加碳酸氢钠水溶液淬灭，减压蒸除溶剂，再加甲醇溶解过滤，滤除无机盐，浓缩得VIIIb。
采用与实施例3相同的方法处理VIIIb，得到白色固体1b。1H NMR(400MHz,D2O)δ7.51(d,J＝1.1Hz,1H),5.77(d,J＝1.8Hz,1H),4.39(qd,J＝6.4,3.7Hz,1H),4.33(s,1H),3.77(d,J＝3.5Hz,1H),3.64(dd,J＝13.1,9.3Hz,1H),3.54(dd,J＝13.1,9.3Hz,1H),1.81(d,J＝0.8Hz,3H),1.36(d,J＝6.4Hz,3H).31P NMR(162MHz,D2O)δ15.13.
实施例5：制备化合物1c(通式1，R＝Na，B＝胞嘧啶)
采用与实施例4相同的方法，以N4-苯甲酰基胞嘧啶替换胸腺嘧啶，得到白色固体物1c。1H NMR(400MHz,D2O)δ7.73(d,J＝7.6Hz,1H),5.92(d,J＝7.6Hz,1H),5.78(d,J＝1.5Hz,1H),4.44–4.33(m,1H),4.29(s,1H),3.75(d,J＝3.3Hz,1H),3.44(dd,J＝19.2,8.9Hz,2H),1.32(d,J＝6.5Hz,3H).
实施例6：制备化合物1d(通式1，R＝Na，B＝5-氯尿嘧啶)
以5-氯尿嘧啶代替胸腺嘧啶,采用与实施例4相同的方法，得到白色固体物1d。1HNMR(400MHz,D2O)δ7.80(s,1H),5.77(d,J＝2.6Hz,1H),4.37(m,1H),4.32(s,1H),3.97(s,1H),3.45(m,2H),1.33(d,J＝6.3Hz,3H).
实施例7：制备化合物1e(通式1，R＝Na，B＝5-氟尿嘧啶)
以5-氟尿嘧啶代替5-氯尿嘧啶，采用与实施例6相同的方法，得到白色固体物1e。1H NMR(400MHz,D2O)δ7.85(d,J＝6.1Hz,1H),5.80(s,1H),4.41(m,1H),4.37(s,1H),3.88(s,1H),3.50(m,2H),1.38(d,J＝6.4Hz,3H).31P NMR(162MHz,D2O)δ13.62.19F NMR(376MHz,D2O)δ-164.61.
实施例8：制备化合物1f(通式1，R＝Na，B＝5-氟胞嘧啶)
以5-氟胞嘧啶代替5-氯尿嘧啶，采用与实施例6相同的方法，得到白色固体物1f。1H NMR(400MHz,D2O)δ7.84(d,J＝6.2Hz,1H),5.74(s,1H),4.40(m,1H),4.31(s,1H),3.82(s,1H),3.41(m,2H),1.36(d,J＝6.3Hz,3H).31P NMR(162MHz,D2O)δ13.43.
实施例9：制备化合物1g(通式1，R＝Na，B＝2-氟腺嘌呤)
以N6-苯甲酰基-2-氟腺嘌呤或2-氟腺嘌呤代替胸腺嘧啶，采用与实施例4所述相同的方法，得到白色固体物1g。1H NMR(400MHz,D2O)δ8.12(s,1H),5.72(d,J＝1.4Hz,1H),4.55(s,1H),4.52–4.42(m,1H),3.93–3.80(m,1H),3.59(dd,J＝13.0,9.3Hz,2H),1.33(d,J＝6.5Hz,3H).31P NMR(162MHz,D2O)δ12.93.19F NMR(376MHz,D2O)δ53.1.
实施例10：制备化合物1h(B＝腺嘌呤)
以N6-苯甲酰基腺嘌呤(或腺嘌呤)代替胸腺嘧啶，采用与实施例4相同的方法，得到白色固体物1h。1H NMR(400MHz,D2O)δ8.35(s,1H),8.05(s,1H),5.88(s,1H),4.68(s,1H),4.48(m,1H),3.96(s,1H),3.50(m,2H),1.34(d,J＝6.4Hz,3H).31P NMR(162MHz,D2O)δ12.95.
实施例11：化合物体外抗人乳腺癌细胞活性
采用MTT法对本发明化合物抗肿瘤活性进行初步筛选，其中化合物1g具有较强的抑制人乳腺癌细胞MCF-7和MDA-MB-231增殖活性，不同浓度和不同作用时间的半数抑制浓度IC50(μM)如下：
其它化合物72小时抑制人乳腺癌细胞MCF-7和MDA-MB-231增殖活性IC50(μM):
Claims (2)
1.(4′R)-甲基-3′-O-甲基膦酸-α-L-呋喃苏糖核苷类似物，其特征在于，具有通式1所示结构：
其中，R代表H、Na、K或NH4离子；
B代表如下碱基：
2.如权利要求1所述的(4′R)-甲基-3′-O-甲基磷酸-α-L-呋喃苏糖核苷类似物在药物制备中的应用，其特征在于，以其为活性成分，制备抗乳腺癌药物或作为制备抗肿瘤药物的中间体。
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