CN109824618A - 1-氧/硫/氮-4-氮杂螺醌类化合物及其用途 - Google Patents
1-氧/硫/氮-4-氮杂螺醌类化合物及其用途 Download PDFInfo
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Abstract
醌环与氧/硫/氨‑氮杂环组成的1‑氧/硫/氨‑4‑氮杂螺醌类化合物，其结构如通式(I)所示，式中各R基可表示相同或不同的基团，R1、R2、R3、R4、R7可同时或分别为氢、直链或支链的烷基或不饱和烃、卤素、烃氧基、酯基、羧基、氨基、硝基、羟基、芳环或杂环等；R5、R7可为氢、直链或支链的烷基或为葡萄糖、甘露糖、氨基糖、果糖等功能性基团、不饱和烃、烃氧基等；R6可为氢、直链或支链的烷基或不饱和烃、烃氧基、卤素、 葡萄糖、甘露糖、氨基糖、果糖等。Y为‑O‑、‑S‑、NH‑。实验显示，该类化合物显著抑制人非小细胞肺癌、人乳腺癌和人***细胞活性，具有作为抗肿瘤药物的应用价值。
Description
[技术领域]
本发明涉及医药技术领域，是一类具有抑制人类非小细胞肺癌(A549)、乳腺癌(MD-BMA-231)和***(Hela)等癌细胞生长活性的1-氧/硫/氨-4-氮杂螺醌类化合物，及该类化合物的用途。
[背景技术]
近年来新癌症病例和癌症死亡率逐年增加。由于伴随着化疗的广泛应用，很多抗肿瘤药物都产生耐药性，这使从事医药研发的工作者面临更为严峻的挑战。另外，小分子药物具有使用广泛、理论成熟等优势。而螺环醌类因具有改善醌类化合物抗肿瘤活性，改善药代动力学性质，提高醌类化合物稳定性等优点；同时，含有螺环和醌类衍生物的许多天然产物都表现出良好的抗肿瘤活性。因此，通过化学结构设计和活性筛选螺环醌类小分子先导化合物对发现新型活性高毒性低选择性更好的抗肿瘤化学药物具有重要意义。本专利通过合成一系列1-氧/硫/氨-4-氮杂螺醌类新化合物，并对其进行了体外抗肿瘤细胞活性筛选，证明该类1-氧/硫/氨-4-氮杂螺醌结构的化合物对肿瘤细胞有抑制增值活性作用。
[发明内容]
从以上所述内容可以看出，本发明提供了一种新的1-氧/硫/氨-4-氮杂螺醌结构，并在此结构上的进一步衍生化，包括合成取代基为烷基、芳环、芳杂环类化合物及其相应的一系列盐类。通过逐步的实验筛选提供具有良好的肿瘤抑制活性的药物，可将其应用于抗肿瘤治疗。本发明提供了一种可为烷基、芳环、芳杂环类取代的1-氧/硫/氨-4-氮杂螺醌化合物，其结构如式(I)所示：
式(I)中的R1、R2、R3、R4可以同时或分别为氢、直链或支链的烷基或不饱和烃、卤元素、烃氧基、酯基、羧基、氨基、硝基、羟基、芳环或杂环等；R5可以为氢、直链或支链的烷基或功能性(如TMS基团)基团、不饱和烃、烃氧基等；R6可以为氢、直链或支链的烷基或不饱和烃、烃氧基、卤素、 葡萄糖、甘露糖、氨基糖、果糖等。其中R7为氢原子、直链或支链的烷基、不饱和烃类、卤素、酯基、烃氧基、羧基、氨基、硝基、羟基、芳环或杂环、葡萄糖、甘露糖、氨基糖、果糖等基团。Y为-O-、-S-、NH-。当Y为氧，R5为氢，R6为氢、直链或支链的烃基基团、葡萄糖、甘露糖、氨基糖、果糖等一系列基团时，R1，R2，R3，R4可同时或分别为氢、甲基、卤素、酯基。其中R7为氢、直链或支链的烷基、不饱和烃类、卤素、酯基、烃氧基、羧基、氨基、硝基、羟基、芳环、杂环、葡萄糖、甘露糖、氨基糖、果糖等基团。结构如式(II)所示:
当R6为氢，R1，R2，R3，R4同时或分别为氢、甲基、卤素、酯基时，R5可为氢或烷基。结构如式(III)所示:
当R1，R2、R3、R4为氢，R5为氢或甲基时，R6可以表示直链或支链的烷基基团、不饱和烃类、葡萄糖、甘露糖、氨基糖、果糖等一系列基团，其中R7为氢、直链或支链的烷基、不饱和烃类、烃氧基、酯基、羧基、卤素、氨基、硝基、羟基、葡萄糖、甘露糖、氨基糖、果糖等基团。结构如式(Ⅳ)所示:
当R5为甲基，R6为直链或支链的烷基基团、不饱和烃类、 葡萄糖、甘露糖、氨基糖、果糖等一系列取代基时，R1，R2，R3，R4可同时或分别为甲基、卤素、酯基等一系列取代基。其中R7为氢、直链或支链的烷基、不饱和烃类、烷氧基、酯基、羧基、卤素、氨基、硝基、羟基、葡萄糖、甘露糖、氨基糖、果糖等基团。结构如式(Ⅴ)所示:
经初步的体外抗肿瘤细胞活性实验筛选，发现在上述通式(Ⅰ)的化合物中，所有化合物对肿瘤细胞都有不同程度的抑制作用。当R1，R2，R3，R4同时或分别为H、CH3、Cl，或其他基团，如酯基、环戊烷基、乙基或长链烷基、芳环或杂环；R5为H、CH3、乙基、苯环、芳环或其他杂环取代；R6为烷基取代或芳基、杂环取代，均表现出抑制肿瘤细胞生长活性(如式(Ⅱ、Ⅲ、Ⅳ、Ⅴ)所示)，本专利以其作为具体实例化合物：
其合成可采用以二环己基脲(DCC)为缩合剂，得到酰胺后在碘苯二乙酸(DIB)和过渡金属作用下，脱芳构化得到1-氧-4-氮杂螺醌结构母核，再在此基础上，进一步衍生化。其中，烃基化底物为末端炔烃、末端烯烃，或其他官能团时，可进一步衍生化，合成路线如下式：
具体操作过程如下：
1、4-氨基苯酚、α-羟酸在乙腈为溶剂，DCC为缩合剂的条件下脱水缩合成酰胺；
2、在氮气保护下，将原料酰胺、DIB、催化剂加入反应瓶中，再加入无水CH2Cl2室温反应，薄层层析(TLC)检测反应，生成1-氧-4氮杂螺醌，即得到相应的式(Ⅲ)结构产物；
3、氮气保护下，将1-氧-4氮杂螺醌溶于干燥THF中，加入碱后搅拌15min，再加入卤代烃，冰浴下反应半小时，生成4-取代-1-氧-4-氮杂螺醌，得到相应的式(Ⅳ)结构产物；
4、将含有活性基团的4-取代-1-氧-4-氮杂螺醌与叠氮化合物或其他基团，根据相关文献，生成如三氮唑、四氮唑、噁唑、噁唑林、咪唑类杂环的4-杂环取代-1-氧-4-氮杂螺醌，得到相应的式(Ⅴ)结构产物。
以下通过具体实施方式的实例再对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。在不脱离本发明上述技术思想情况下，根据本领域普通技术知识和惯用手段做出的各种替换或变更，均包括在本发明的范围内。
[具体实施方式]
实施例1：1-氧-4氮杂螺醌类化合物的合成
(1)4-氨基苯酚衍生物、α-羟酸在乙腈为溶剂，DCC为缩合剂的条件下脱水缩合成酰胺，经过过滤除去多余的DCC，减压浓缩后，用稀盐酸除掉未反应的4-氨基苯酚衍生物，浓缩后硅胶柱层析分离纯化，得到2-羟基-N-(4-羟基苯基)乙酰胺类化合物；
(2)在氮气保护下，将2-羟基-N-(4-羟基苯基)乙酰胺类化合物与DIB、催化剂溶于无水二氯甲烷中，室温下反应，TLC检测反应，反应完全后，经硅胶柱层析分离纯化，得到相应的式(Ⅱ或Ⅲ)结构产物；
7-methyl-1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione
1H NMR(400MHz,CDCl3)δ7.82(d,J＝6.8Hz,1H),6.69(d,J＝9.6Hz,1H),6.49(s,1H),6.20(d,J＝9.8Hz,1H),4.35(s,2H),1.89(s,3H).13C NMR(150MHz,CDCl3)δ184.8,173.4,143.9,139.3,136.9,129.6,84.8,66.4,15.5.HRMS(ESI)Calcd C9H9NO3{[M+H]+}:180.0661,Found 166.0658
7,9-dichloro-1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione
1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),7.59(d,J＝3.1Hz,2H),4.36(s,2H).13C NMR(100MHz,DMSO-d6)δ176.9,176.9,148.7,135.6,91.0,71.3.HR-MS(ESI)Calcd C8H5Cl2NO3{[M+H]+}:233.9725,Found 233.9721
1H NMR(400MHz,CDCl3)δ6.73-6.59(m,1H),6.54-6.39(m,1H),6.21(dd,J＝16.0,9.9Hz,1H),4.51(qd,J＝6.7,3.9Hz,1H),1.89(dd,J＝6.4,1.2Hz,3H),1.48(dd,J＝6.7,2.7Hz,3H).13C NMR(100MHz,CDCl3)δ184.9,175.5(175.49),175.5(175.46),145.3,144.1,140.6,139.6,137.6,136.2,130.2,129.0,82.9,82.9,73.3,73.2,18.5,18.4,15.6,15.5.HRMS(ESI)Calcd C10H11NO3{[M+H]+}:194.0817,Found194.0815。
实施例2：4-取代-1-氧-4-氮杂螺醌类化合物的合成
氮气保护下，将1-氧-4氮杂螺醌溶于干燥THF中，加入碱后搅拌15min，再加入卤代烃，冰浴下反应半小时，生成4-取代-1-氧-4-氮杂螺醌，得到相应的式(Ⅳ)结构产物
4-ethyl-2-methyl-1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione(4f)
1H NMR(400MHz,CDCl3)δ6.60(ddd,J＝32.7,10.0,2.8Hz,2H),6.37-6.25(m,2H),4.52(q,J＝6.6Hz,1H),3.23-3.15(m,2H),1.49(d,J＝6.7Hz,3H),1.14(d,J＝7.2Hz,3H).13CNMR(100MHz,CDCl3)δ184.00,171.77,145.61,144.4,131.3,130.3,85.9,73.3,35.2,18.7,14.6.HRMS(ESI)Calcd C11H14NO3{[M+H]+}:208.0974,Found 209.0969
4-(but-2-yn-1-yl)-2-methyl-1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione
1H NMR(400MHz,CDCl3)δ6.67(dd,J＝10.0,3.1Hz,1H),6.59(dd,J＝10.0,3.1Hz,1H),6.33(ddd,J＝15.9,10.1,2.0Hz,2H),4.54(q,J＝6.7Hz,1H),3.94(d,J＝2.4Hz,2H),1.72(t,J＝2.4Hz,3H),1.50(d,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ184.2,171.3,145.0,143.9,131.6,130.4,85.6,81.2,73.2,73.0,29.5,18.6,3.4.HRMS(ESI)Calcd C13H14NO3{[M+H]+}:232.0974,Found 232.0968
4-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione
1H NMR(400MHz,CDCl3)δ7.90(d,J＝7.5Hz,1H),7.47(dq,J＝15.4,6.9,6.3Hz,2H),7.34(dd,J＝12.5,6.6Hz,5H),7.28(s,2H),7.25(d,J＝4.1Hz,3H),7.04(d,J＝7.9Hz,2H),6.94(t,J＝8.7Hz,8H),6.34(d,J＝10.0Hz,2H),6.10(d,J＝10.0Hz,2H),4.43(s,2H),4.27(s,2H).HRMS(ESI)Calcd C41H31N5O3{[M+H]+}:642.2505,Found 642.2498
7-chloro-4-methyl-1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione
1H NMR(400MHz,CDCl3)δ6.79(d,J＝2.9Hz,1H),6.63(dd,J＝10.0,2.9Hz,1H),6.45(d,J＝10.0Hz,1H),4.42(s,2H),2.77(s,3H).13C NMR(100MHz,CDCl3)δ176.8,169.2,144.2,139.6,135.5,130.4,89.1,66.6,25.0.HRMS(ESI)Calcd C9H9ClNO3{[M+H]+}:214.0271,Found 232.0265
1H NMR(400MHz,CDCl3)δ7.09(d,J＝7.6Hz,2H),7.04(d,J＝7.8Hz,2H),6.50-6.46(m,2H),6.25(d,J＝9.8Hz,1H),4.51(d,J＝15.0Hz,1H),4.46(s,2H),4.27(d,J＝14.9Hz,1H),2.31(s,3H).HRMS(ESI)Calcd C16H14ClNO3{[M+H]+}:304.0740,Found 304.0732。
实施例3：4-杂环取代-1-氧-4-氮杂螺醌类化合物的合成
将4-炔丙基-1-氧-4-氮杂螺醌与叠氮化合物在混合溶剂DMSO:H2O＝2:1中，加入添加剂五水硫酸铜，维生素C钠，于室温下反应3h，可得到4-(1-R7-1H-1,2,3-***-4-基-甲基)-1-氧-4-氮杂螺醌，得到相应的式(Ⅴ)结构产物
4-((1-(2-oxo-2-phenylethyl)-1H-1,2,3-triazol-4-yl)methyl)-1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione
1H NMR(400MHz,CDCl3)δ7.98(d,J＝7.6Hz,2H),7.67(d,J＝8.3Hz,2H),7.55(t,J＝7.6Hz,2H),6.56(d,J＝10.0Hz,2H),6.27(d,J＝10.0Hz,2H),5.83(s,2H),4.53(s,2H),4.44(s,2H).13C NMR(150MHz,CDCl3)δ189.9,183.9,169.7,143.3,142.7,134.7,133.7,131.2,129.2,128.08,125.2,87.4,66.3,55.5,35.1.HRMS(ESI)Calcd C19H16N4O4{[M+H]+}:365.1250,Found 365.1244
4-((1-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione
1H NMR(400MHz,CDCl3)δ7.97(d,J＝7.5Hz,1H),7.53-7.44(m,3H),7.38-7.31(m,6H),7.24(d,J＝7.4Hz,6H),7.13(d,J＝7.7Hz,2H),6.98(d,J＝7.8Hz,2H),6.89(d,J＝8.0Hz,4H),6.53(d,J＝9.7Hz,2H),6.23(d,J＝9.7Hz,2H),5.33(s,2H),4.38(s,2H),4.32(s,2H).HRMS(ESI)Calcd C44H34N8O3{[M+H]+}:723.2832,Found 723.2822。
实施例4：MTT法测定化合物对肿瘤细胞的抑制活性
实验方法：
MTT法初步测定化合物对所筛选癌细胞株的抑制率：取对数生长期肺癌细胞系A549、人乳腺癌细胞MDA-BM-231和***细胞系Hela，用完全培养液稀释细胞浓度至2*104个/ml，接种于96孔板(每孔板加入100μL细胞液)，放入培养箱中培育24h后，更换不同浓度1-氧-4-氮杂螺醌类化合物(1μmol/Ml,10μmol/Ml)的完全培养基，空白对照为0.1％DMSO溶液，在恒温培养箱中继续培养72h后，加入MTT 10μL(5μg/mL)，孵育4好后，除去培养基，加入DMSO(150μL)，震荡15min，用酶标仪在570nm处测定吸光度，计算相对细胞抑制生长率，抑制率(％)＝(阴性组吸光度-加药组吸光度)/(阴性组吸光度-空白组吸光度)×100％，将肺癌细胞系A549、人乳腺癌细胞MDA-BM-231和***细胞系Hela常规地补充在有10％FBS,4mM谷氨酰胺，1mM丙酮酸钠,100IU/mL青霉素,100μg/mL链霉素和0.25μg/mL两性霉素的培养基里,置于37℃,5％CO2的培养箱内培养,以细胞每孔5×103的密度接种在96孔板中培养24h,分别按不同剂量浓度加入阳性对照药苯达莫司汀、伏立诺他及合成的目标化合物,孵育72h后加入20mL刃天青钠处理2h，使用Victor微量滴定荧光计(Perkin-Elmer，USA)在560nm(激发),590nm(发射)记录荧光，测定IC50值如下：
化合物的体外抗肿瘤活性
Claims (6)
1.1-氧/硫/氨-4-氮杂螺醌类化合物，结构如式(I)所示，式中各R基可表示相同或不同的基团，R1、R2、R3、R4可以同时或分别为氢、甲基、卤素、酯基；R5为氢或甲基；R6为氢、直链或支链的烷基基团或不饱和烃类、 葡萄糖、甘露糖、氨基糖、果糖等一系列基团等，其中R7为氢、直链或支链的烷基、不饱和烃类、卤素、酯基、烃氧基、羧基、氨基、硝基、羟基、芳环、杂环、葡萄糖、甘露糖、氨基糖、果糖等基团；Y为-O-、-S-、-NH-；(I)为
2.当R5为氢，R6为氢、直链或支链的烷基基团或不饱和烃类、 葡萄糖、甘露糖、氨基糖、果糖等一系列基团时，R1，R2，R3，R4可同时或分别为氢、甲基、卤素、酯基，其中R7为氢、直链或支链的烷基、不饱和烃类、卤素、酯基、烃氧基、羧基、氨基、硝基、羟基、芳环、杂环、葡萄糖、甘露糖、氨基糖、果糖等基团，结构如式(II)所示，
3.当R6为氢，R1，R2，R3，R4同时或分别为氢、甲基、卤素、酯基时，R5可为氢或甲基，结构如式(III)所示，
4.当R1，R2、R3、R4为氢，R5为氢或甲基时，R6可以表示直链或支链的烷基基团、不饱和烃类、葡萄糖、甘露糖、氨基糖、果糖等一系列基团，其中R7为氢、直链或支链的烷基、不饱和烃类、烃氧基、酯基、羧基、卤素、氨基、硝基、羟基、葡萄糖、甘露糖、氨基糖、果糖等基团，结构如式(Ⅳ)所示，
5.当R5为甲基，R6为直链或支链的烷基基团、不饱和烃类、 葡萄糖、甘露糖、氨基糖、果糖等一系列取代基时，R1，R2，R3，R4可同时或分别为甲基、卤素、酯基等取代基，其中R7为氢、直链或支链的烷基、不饱和烃类、烷氧基、酯基、羧基、卤素、氨基、硝基、羟基、葡萄糖、甘露糖、氨基糖、果糖等基团，结构如式(Ⅴ)所示，
6.权利要求1所述1-氧/硫/氨-4-氮杂螺醌类化合物用于制备抗肿瘤药物。
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