CN102816197B - 一种新的嘧啶并嘧啶类核苷类似物、制备方法及其形成的超分子结构和应用 - Google Patents
一种新的嘧啶并嘧啶类核苷类似物、制备方法及其形成的超分子结构和应用 Download PDFInfo
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- JOZPEVMCAKXSEY-UHFFFAOYSA-N pyrimido[5,4-d]pyrimidine Chemical compound N1=CN=CC2=NC=NC=C21 JOZPEVMCAKXSEY-UHFFFAOYSA-N 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 229940127073 nucleoside analogue Drugs 0.000 title 3
- 239000003814 drug Substances 0.000 claims abstract description 27
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Classifications
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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
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种新的嘧啶并嘧啶类核苷类似物、制备方法,尤其涉及式I所示的核苷类似物、其制备方法及其在抗肿瘤和抗病毒等方面的应用,属药物化学领域。此类化合物及其盐和形成的纳米结构在药载、再生医学以及催化等方面的应用。
Description
技术领域
本发明涉及一种新的嘧啶并嘧啶类核苷类似物、制备方法,此类化合物形成的纳米结构在药载、再生医学以及催化等方面的应用。
背景技术
DNA和RNA分子在纳米技术领域,因其具有良好的生物功能、纳米尺度、生物相容性、生物降解性、分子识别能力、热稳定性好且长度可控等特性,被证明是最易裁剪和用途广泛的通用材料。科学家已经成功地使用DNA和RNA构建了各种各样的令人惊叹的纳米结构,比如规则的栅格、折纸、超分子聚集体、甚至是三维结构。除此之外,DNA和RNA的基本组成单位脱氧核糖核苷和核糖核苷也被用于构建各式各样的超分子结构。除了经典的嘌呤和嘧啶核苷,结构修饰的核苷也被广泛用于构建不同形状的超分子结构。为了寻找生更好的纳米材料,我们首次设计并合成了一系列的具有自组装能力的嘧啶并嘧啶类核苷化合物,希望此类化合物能为开发新型的药物递送***提供新的途径,同时希其作为支架材料在再生医学及催化等方面有新的应用。
发明内容
本发明目的在于提供在碱基或糖部分进行修饰的新的核苷类似物。下面将更详细地说明下述定义的通式(I)的各个基团:
其中A选自O、S、CH2;R2、R2’、R3、和R3’独立选自H、F、OH、NH2、SH、CN、N3和R,其中R为低级烷基、低级链烯基、低级链炔基或低级酰基,并且任选含有至少一个杂原子;R4为H、OH、NH2、SH、CN、N3、和R,其中R为低级烷基、低级链烯基、低级链炔基或低级酰基,并且任选含有至少一个杂原子;R5为H、OH、OR6、SH、SR7、R8、OP(O)(OH)2、OP(O)(OR")2、SP(O)(OH)2、SP(O)(OR")2其中R6、R7、R8、R"为功能化基团;而B为选自式(II):
其中X、Y、Z、U独立选自H、卤素、SH、SR、NH2、NHR、NHC(O)OR、OH或OR,其中R为低级烷基、低级酰基。
其中所述的低级烷基、低级链烯基、低级链炔基或低级酰基是指:
低级烷基包括:甲基、乙基、丙基、异丙基、丁基等C18以内的烷基。
低级烯烃包括:乙烯、丙烯等C18以内的烯烃。
低级炔基包括:乙炔、丙炔等C18以内的炔烃。
低级酰基包括:乙酰基等C18以内的酰基。
所述的杂原子是指:O、S、N
所述的功能化基团是指:如荧光基团(香豆素、氟硼荧)。
同时需要说明的是上述三个取代基可以为R,这三个取代基同为R时,取代基可以不相同。
具体而言,所述的嘧啶并嘧啶类核苷类似物为:
本发明目的还在于提供上述类核苷的制备方法;
本发明目的还在于提供通过下述合成方法得到编号1-6的上述核苷类化合物;
本发明目的还在于提供由上述类化合物构成的超分子结构,如纳米管、纳米管构成的纳米棒以及纳米花;
本发明目的还在于提供此类纳米结构在药物载体***、作为支架在再生医学及在催化等方面的应用;
附图说明
图1:嘧啶并嘧啶核苷类似物在水溶液中形成的花状和管状纳米结构,其中分别为核苷1-6在水溶液中形成的超分子结构。
图2:药物包裹SEM对比图,其中分别为核苷2和6的药物包裹对比图。
图3:药物包裹UV对比图,其中分别为核苷2和6的药物包裹对比图。
具体实施方式
下述实施例将更详细地说明本发明,而不是在任何意义上限制其范围
实施例一:4,7-二氨基-1-(D-呋喃核糖)-5-甲氧基-嘧啶并[4,5-d]嘧啶-2,5(1H,2H)-二酮(化合物1)
将4,7-二氨基-1-(2’,3’-O-异亚丙基-D-呋喃核糖)-5-甲氧基-嘧啶并[4,5-d]嘧啶-2(1H)-酮3.8g(购买,10mmol)溶于丙酮中,加入4.5g碘化钠和3.3g(30mmol)四甲基氯硅烷,室温搅拌20小时。虑得反应生成的沉淀,用乙腈(30ml*3)和丙酮(30ml*3)洗。接着将得到的黄色沉淀在冰浴条件下加入30ml三氟醋酸,搅拌20分钟后,减压蒸去三氟醋酸。所得产物反复用乙醇共蒸,以除去残留的酸。最后将得到的产物加热溶解到水中,静置若干小时,可得到纯净的白色固体产物4,7-二氨基-1-(D-呋喃核糖)-5-甲氧基-嘧啶并[4,5-d]嘧啶-2,5(1H,2H)-二酮(3g,91%产率)。
λmax(MeOH)/nm(ε/dm3mol-1cm-1):228(2359),283(1216).δH(400MHz;d6-DMSO):3.41-3.45(1H,m,4’H),3.59-3.65(2H,t,5’CH2),4.19(1H,s,3’H),4.54-4.56(1H,d,J=8.0Hz,3’OH),4.68(1H,s,2’OH),4.80-4.81(1H,bd,J=2.0Hz,2’H),5.02(1H,s,5’OH),6.47(1H,s,1’H),7.57-8.25(4H,m,NH2×2),11.72(1H,br,NH).HRMS(ESI-)m/z:Calc.for C11H14N6O6:325.0896[M-H]-.Found325.0891[M-H]-
实施例二:制备5-氨基-8-(2,3,5-三-氧-苯甲酰基-D-呋喃核糖)嘧啶并[4,5-d]嘧啶-2,4(3H,8H)-二酮
将600mg碱基(3.3mmol)加入30mL六甲基二硅烷胺(HMDS)中,140℃下搅拌大约2-3分钟,随后加入三甲基氯硅烷(TMSCl)。回流状态下反应18小时。然后,除去剩余的HMDS,得到硅烷化碱基。立即将其用于下一步糖基化反应。将20ml无水1,2-二氯乙烷加入含有化合物的反应器中,常温搅拌溶解,随后将溶解于20ml无水乙腈的630mg 3,5-二-O-苯甲酰基-β-D-呋喃核糖(购买)加入上述反应器中。550μL(mmol)四氯化锡作为催化剂加入上述混合物中。直到3,5-二-O-苯甲酰基-β-D-呋喃核糖消失。加入40ml饱和NaHCO3水溶液用来终止反应。加入二氯甲烷萃取有机相(40×3),合并有机相并用无水硫酸钠干燥,最后减压旋蒸。旋蒸后的产物使用柱层析进行分离,硅胶柱4×8cm,真空干燥后得到为白色粉末的核糖核苷:5-氨基-8-(2,3,5-三-氧-苯甲酰基-D-呋喃核糖)嘧啶并[4,5-d]嘧啶-2,4(3H,8H)-二酮940mg(45%)。λmax(MeOH)/nm(ε/dm3mol-1cm-1):225(95658),251(27263),273(15395),278(14355);1H-NMR(DMSO-d6,600MHz):δ4.73~4.75(2H,t,J=6Hz,5’-H2),4.82~4.84(1H,t,J=6Hz,4’-H),6.12~6.13(1H,d,J=6Hz,3’-H),6.17-6.20(1H,t,J1=12Hz,J2=6Hz,2’-H),6.51(1H,s,1’-H),7.40~7.99(15H,m,H-arom),8.66(1H,s,CH),9.07(1H,s,NHα)9.14(1H,s,NHβ),10.87(1H,s,NH).13C NMR(600MHz;DMSO-d6)δ64.41,71.12,74.68,80.25,87.59,129.00,129.05,129.13,129.20,129.62,129.73,129.78,129.89,133.98,134.27,134.37,153.06,156.72,157.70,162.03,164.99,165.13,165.31。
实施例三:制备5-氨基-8-(D-呋喃核糖)嘧啶并[4,5-d]嘧啶-2,4(3H,8H)-二酮(化合物2)
将80mg经由实施例一制备获得的5-氨基-8-(2,3,5-三-氧-苯甲酰基-D-呋喃核糖)嘧啶并[4,5-d]嘧啶-2,4(3H,8H)-二酮(0.13mmol),溶于10ml 0.5M NaOMe/MeOH,反应物由悬浊状态变为胶状物,冷却至室温后,用稀释后的冰醋酸中和,过滤,用甲醇洗三遍,真空干燥后得到淡黄色粉末5-氨基-8-(D-呋喃核糖)嘧啶并[4,5-d]\嘧啶-2,4(3H,8H)-二酮(32mg,80%)。λmax(MeOH)/nm(ε/dm3mol-1cm-1)251(25943),277(5681);1H-NMR(DMSO-d6,600MHz):δ3.60~3.80(2H,m,5’-H2),3.94~3.97(1H,m,4’-H),4.08~4.17(2H,m,3’-H,2’-H),5.08~5.09(1H,d,J=6Hz,5’-OH),5.27~5.29(1H,t,J=6Hz,3’-OH),5.55~5.56(1H,d,J=6Hz,2’-OH),6.17~6.18(1H,d,J=6Hz,1’-H),8.88(1H,s,CH),8.92(1H,s,NHα)8.98(1H,s,NHβ),10.77(1H,s,NH).13C NMR(600MHz;DMSO-d6)δ60.04,69.04,74.98,85.06,87.44,90.26,151.88,157.00,158.18,162.00,165.44。
实施例四:4,6-二氯嘧啶-5甲醛肟
将1.8g 4,6-二氯嘧啶-5甲醛(购买)溶于20ml冰乙酸,然后滴入40ml盐酸羟胺乙醇溶液(1.4g),常温反应15小时。溶液旋干后,用饱和NaHCO3和水洗有机相,最后用无水硫酸钠干燥有机相,旋干得到白色产物4,6-二氯嘧啶-5甲醛肟(1.8g,84%产率)。1H NMR(400MHz;DMSO-d6):δ=8.19(s,1H),8.91(s,1H),12.27(s,1H).13C NMR(600MHz;DMSO-d6)δ=113.63,142.03,149.50,154.25.Anal.Calcd for C5H3Cl2N3O:C,31.28;H,1.57;N,21.89.Found C,31.44;H,1.46;N,22.17.
实施例五:4-(5’-O乙酰基-2’,3’-O-异亚丙基-β-D呋喃核糖)胺-5氰基-6-氯嘧啶
将1.7g化合物4,6-二氯-5氰基嘧啶(购买),溶解在50ml干燥四氢呋喃(THF)中。依次加入7.2g 2,3-O-异亚丙基-D-呋喃糖胺对甲苯磺酸盐(购买),1.7g NaHCO3,3.4ml ipr2EtN(N,N-二异丙基乙胺,购买)。混合溶液在室温反应10分钟后加热到60℃,继续反应60分钟。冷却后,用50ml二氯甲烷(DCM)重新溶解产物。产物再分别用水和稀盐酸(0.1N)洗两次,无水硫酸钠干燥,旋干得到粗品4d。将未经纯化的4d溶解到50ml DCM中,加入2.6ml ipr2EtN,1.4ml乙酸酐,12.2mgDMAP(4-二甲氨基吡啶,下同)。反应约10分钟后,加入1ml稀盐酸终止。得到的溶液用DCM稀释至150ml,再用稀盐酸和水洗,无水硫酸钠干燥,旋干得泡沫状产物粗品。柱层析分离(洗脱剂:DCM,Rf=0.9)得到无色产物4-(5’-O乙酰基-2’,3’-O-异亚丙基-β-D呋喃核糖)胺-5氰基-6-氯嘧啶(2.1g,58%产率)。1H NMR(400MHz;DMSO-d6)δ=1.295(s,3H),1.462(s,3H),2.021(s,3H),4.125-4.185(m,3H)4.753-4.775(m,1H)4.998-5.019(m,1H),5.861-5.885(m,1H),8.619(s,1H),8.996-9.015(d,1H,);13C NMR(600MHz;DMSO-d6)δ=21.06,25.56,27.21,64.48,81.80,83.13,83.84,87.91,113.20,159.97,162.23,170.57.HR-MS(ESI+):calcd for C15H17ClN4O5:368.0877Found:369.0973[M+H]。
实施例六:4-氨基-1-(2’,3’-O-异亚丙基-β-D呋喃核糖)-5-甲氧基嘧啶并[4,5-d]嘧啶-2(1H)-酮
将3.7g经由实施例4制备获得的4-(5’-O乙酰基-2’,3’-O-异亚丙基-β-D呋喃核糖)胺-5氰基-6-氯嘧啶溶于100ml干燥DCM,在冰浴条件下加入6.5ml ipr2EtN(N,N-二异丙基乙胺,购买)。搅拌一段时间后,滴加入5.2ml CCI(N-(氯甲酰)异氰酸酯,购买)。CCI完全加入后,之后加入5ml HCl(0.1N)终止反应,过滤沉淀后,将滤液用水洗两次,无水硫酸钠干燥,旋干得到加脲产物粗品。将该粗品在50ml甲醇钠(0.15N)中反应,即得到成环产物。所得的混合物经柱层析分离得到白色产物4-氨基-1-(2’,3’-O-异亚丙基-β-D呋喃核糖)-5-甲氧基嘧啶并[4,5-d]嘧啶-2(1H)-酮(1.1g,30%产率)。1H NMR(400MHz;DMSO-d6)δ=1.280(s,3H),1.492(s,3H),3.474-3.33(m,1H),3.579-3.636(m,1H),3.956-3.997(m,1H),4.104(s,3H),4.720-4.749(t,1H),4.871-4.898(t,1H),5.197-5.217(m,1H),6.852(s,1H),7.818(s,1H),8.521(s,1H),8.716,8.729(s,1H);13C NMR(600MHz;DMSO-d6)δ=25.74,27.68,55.84,62.68,82.67,84.53,88.21,112.96,154.09,159.42,160.12,161.10,166.85.HR-MS(ESI-):calcdfor[C15H19N5O6]:365.1335Found:364.0982[M-H]。
实施例七:4-氨基-1-(β-D呋喃核糖)嘧啶并[4,5-d]嘧啶-2,5(1H,6H)-二酮(化合物3)
将3.6g经由实施例4制备获得的化合物4-氨基-1-(2’,3’-O-异亚丙基-β-D呋喃核糖)-5-甲氧基嘧啶并[4,5-d]嘧啶-2(1H)-酮溶于30ml丙酮。加入4.5g碘化钠和3.3gTMSi-Cl(三甲基氯硅烷,购买),室温搅拌20小时。滤得反应生成的沉淀,将沉淀用30ml乙腈洗3次,30ml丙酮洗3次。之后将所得黄色沉淀(3.3g,94%产率)在冰浴条件下加入30ml三氟醋酸(含10%水)。搅拌20分钟后,减压蒸去三氟醋酸。所得产物反复用乙醇共蒸,以除去残留的酸。最后将得到的产物加热溶于水中,室温静置若干小时后,可得到纯净的白色固体产物沉淀4-氨基-1-(β-D呋喃核糖)嘧啶并[4,5-d]嘧啶-2,5(1H,6H)-二酮(2.66g,91%产率)1H NMR(400MHz;DMSO-d6)δ=3.45(br,1H);3.608-3.699(m,2H);4.196(s,1H);4.561(s,1H);4.636(s,1H);4.838(s,1H);5.042(s,1H);6.512(s,1H);8.221-8.304(t,1H);8.400-8.419(d,2H);13.150(br,1H).HR-MS(ESI-):calcd for[C11H13N5O6]:311.0866Found 310.0782[M-H].
实施例八:5-氨基-8-(2-脱氧-D-呋喃核糖)嘧啶并[4,5-d]嘧啶-2,4.(3H,8H)-二酮(化合物5)
按照实施例二类似的方法利用产物4-氨基嘧啶并[4,5-d]嘧啶-5,7(6H,8H)-二酮(按文献1合成)得到5-氨基-8-(2-脱氧-D-呋喃核糖)嘧啶并[4,5-d]嘧啶-2,4.(3H,8H)-二酮。λmax(MeOH)/nm(ε/dm3mol-1cm-1),251(28571),277(6158);1H-NMR(DMSO-d6,600MHz):δ2.18~2.22(1H,m,2’-Hα),2.35-2.39(1H,m,2’-Hβ),3.59~3.61(1H,d,J=12Hz,5’-Hα),3.67-3.69(1H,d,J=12Hz,5’-Hβ),3.89~3.91(1H,t,J=6HZ,4’-H),4.27(1H,s,3’-H),5.20(1H,s,5’-OH),5.34(1H,s,3’-OH),6.41~6.43(1H,t,J=6Hz,1’-H),8.77(1H,s,CH),8.89~8.93(2H,2s,NH2),10.76(1H,s,NH).13C NMR(600MHz;DMSO-d6).13C NMR(600MHz;DMSO-d6)δ41.60,60.95,69.99,86.75,87.46,88.59,151.39,157.11,157.78,162.07,165.43。
实施例九:5-氨基-1-(2-脱氧-D-呋喃核糖)嘧啶并[4,5-d]嘧啶-2,4.(1H,3H)-二酮(化合物六)
按照实施例二类似的方法利用产物4-氨基嘧啶并[4,5-d]嘧啶-5,7(6H,8H)-二酮(按文献1合成)得到5-氨基-1-(2-脱氧-D-呋喃核糖)嘧啶并[4,5-d]嘧啶-2,4.(1H,3H)-二酮.1H NMR(400MHz,d6-DMSO)δ(ppm):2.31-2.38(1H,m,2’-CH),2.51-2.63(1H,m,2’-CH),3.36-3.60(2H,m,5’-CH2),4.07-4.14(2H,m,3’-CH and 4’-CH),4.61-4.63(1H,t,J=5.2Hz,5’-OH),5.16-5.18(1H,d,J=2.4Hz,3’-OH),6.48-6.50(1H,t,J=7.6Hz,1’-CH),8.22-8.23(2H,d,J=5.2Hz,-NH2),8.25(1H,s,7-CH),11.89-11.90(1H,d,J=2.4Hz,-NH);13C NMR(100MHz,d6-DMSO)δ(ppm):36.39,61.81,70.89,81.45,86.06,89.56,150.26,157.68,161.95,162.66,163.56;UV(H2O):λmax(ε):227(10000);289(1559);HRMS(ESI)calcd for(M+Na+)/z:318.0815,found:318.0807。
实施例十:5-氨基-1-(D-呋喃核糖)嘧啶并[4,5-d]嘧啶-2,4(1H,3H)-二酮(化合物4)
按照实施例二类似的方法利用产物4-氨基嘧啶并[4,5-d]嘧啶-5,7(6H,8H)-二酮(按文献1合成)得到5-氨基-1-(D-呋喃核糖)嘧啶并[4,5-d]嘧啶-2,4(1H,3H)-二酮。1H NMR(600MHz,d6-DMSO)δ(ppm):3.18(1H,s,3’-CH),3.44-3.47(1H,m,4’-CH),3.61-3.72(4H,m,5’-CH2,2’-CH and 5’-OH),4.17(1H,t,J=6Hz,3’-OH),4.52-4.54(1H,q,J=3.6Hz,2’-OH),6.17(1H,d,J=3.6Hz,1’-CH),7.79-8.19(2H,m,-NH2),8.14(1H,s,7-CH);13C NMR(150MHz,d6-DMSO)δ(ppm):22.83,48.09,62.90,70.73,71.58,84.86,89.87,161.77,163.18,173.30;UV(H2O):λmax(ε):227(10412);289(1777);HRMS(ESI)calcd for(M+Na+)/z:334.0764,found:334.0766.
实施例十一:此类核苷化合物在水溶液中均能通过自组装形成很好的纳米结构,分别称取上述结构图中核苷1-60.2mg溶于水中,然后加热至沸腾,在室温下静置48h,扫描电镜、透射电镜结果如图1所示。
实施例十二:这些纳米结构均可以用于包裹药物。
分别称取化合物2和6(如之前的结构图所示,其他另外的化合物和这两个化合物一样都具有双面碱基的结构且在水中能够自我聚集,初步的扫描电镜以表明此类核苷化合物均能形成类似的超分子结构。如图一所示)0.2mg,加热溶于水中,然后静置24h,分别加入1mg和厚朴酚,然后放置室温2天,扫描电镜药物包裹前后结果如图2所示,包裹药物前后UV对比图如图3所示。
而且通过MTT细胞毒性实验,证实此类核苷化合物的IC50均大于3000umol,表明生物毒性很低,可以用于体内。(不需要详细说明实验方案,采用引用文献的方式即可文献2),同时,利用NMR研究药物的载药量,表明化合物2、6的载药量达40%(见表1)。
表1:药物的载药量研究
包药比例 | 5:1 | 5:3 | 5:5 | 5:7 |
包药前积分 | 0.3 | 1.0 | 2.5 | 4.5 |
包药后积分 | 0.2 | 0.6 | 1.5 | 2.65 |
平均载药量 | 33.3% | 40% | 40% | 41% |
上述实验初步表明此类核苷化合物具有较好的药物包裹能力,且毒性较低,因此作为新型的药载***具有较好的应用前景,同时此类化合物在再生医学、催化等方面也具有较大的应用潜力。
文献:
1 Y.Tominaga,S.Ohno,S.Kohra,H.Fujito,H.Mazurae,J.Heterocycl.Chem.1991,28,1039-1042.
2 Geise Ribeiro et al.Polyhedron,2008,27,1131-1137.
Claims (3)
1.一种嘧啶并嘧啶类核苷类似物,其特征在于具有如下结构:
2.由权利要求1所述的嘧啶并嘧啶类核苷类似物构成的超分子结构,所述超分子结构为:纳米管、纳米管构成的纳米棒以及纳米花。
3.权利要求2所述的超分子结构在药物载体***方面的应用。
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