CN107903246A - 一种磺酰胺衍生物、制备方法及其抗肿瘤中的应用 - Google Patents
一种磺酰胺衍生物、制备方法及其抗肿瘤中的应用 Download PDFInfo
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Abstract
本发明公开了一种磺酰胺衍生物式（Ⅰ），式（Ⅰ）为新结构，还公开了式（Ⅰ）的制备方法及其作为烟酰胺磷酸核糖转移酶抑制剂在抗肿瘤药物中的应用。在抑制烟酰胺磷酸核糖转移酶的活性实验和MTT法测定式（Ⅰ）对不同肿瘤细胞的抑制作用的实验中都表现出了很好的活性。式（Ⅰ）结构为
Description
技术领域
本发明涉及一种磺酰胺衍生物、制备方法及其抗肿瘤中的应用。
背景技术
烟酰胺磷酸核糖转移酶（nicotinamide phosphoribosyl transferase，NAMPT)又名内脏脂肪素visfatin或前B细胞克隆增强因子PBEF，调控哺乳动物细胞内必需能量物质NAD的水平。癌细胞具有很高的NAD消耗和代谢速率，因而NAD合成途径的限速酶NAMPT成为癌症治疗的新靶标，其酶抑制剂FK866和CHS-828是典型的NAMPT抑制剂，在癌症治疗领域进行了广泛的临床研究。
FK866((E)-N-[4-(1-苯甲酰基哌啶-4-基)丁基]-3-(吡啶-3-基)丙烯酰胺)在HepG2细胞中诱导细胞凋亡，但对细胞能量代谢不具有初始作用。FK866可被用于治疗牵涉细胞凋亡失调的疾病例如癌症。现有技术已证明，FK866干扰烟酰胺腺嘌呤二核苷酸的生物合成并诱导凋亡细胞死亡而无任何DNA损伤效应。FK866抑制NAMPT并耗尽NAD的细胞但不引起即刻细胞毒性，这暗示，对于抗依赖烟酰胺来合成NAD的癌细胞来说，FK866是有前景的药物。在小鼠乳癌模型中，FK866也诱导肿瘤生长延迟和肿瘤放射敏感性增强，伴随着NAD水平、pH和能量状态的剂量依赖性降低。在THP-1和K562白血病细胞系中，已观察到FK866对抗肿瘤药1-甲基-3-硝基-1-亚硝基胍鎓(MNNG)-诱导的细胞死亡的化学增敏作用。在异种移植物模型中评价GMX1777的效力且通过液相色谱/质谱测量GMX1778的药代分布及其对烟酰胺腺嘌呤二核苷酸细胞水平的作用。
以上所述表明NAMPT抑制剂具有很好的成药性，可用于制备通过抑制烟酰胺磷酸核糖转移酶来预防和/或治疗的疾病的药物，也可用于防治癌症等疾病。新型的NAMPT抑制剂的开发也是药学研究的热点。
发明内容
本发明的目的之一在于提供一种磺酰胺衍生物、制备方法及其抗肿瘤中的应用。其结构式（Ⅰ）为
。
本发明的另一目的在于提供所述式（Ⅰ）的合成路线：
。
本发明的另一目的在于提供所述式（Ⅰ）的合成步骤：
（1）吡咯烷-3-碳酰氯和4,5-二氢-1H-咪唑-1-磺酰氯在甲苯中反应生成1-((4,5-二氢-1H-咪唑-1-基)磺酰基)吡咯烷-3-羰酰氯，后处理分别用水和盐酸溶液洗涤，然后柱色谱分离得到产品；
（2）1-((4,5-二氢-1H-咪唑-1-基)磺酰基)吡咯烷-3-羰酰氯和4-氨基-2,6-二氯吡啶低温下反应，经过水和盐的水溶液洗涤，最后重结晶得到式（Ⅰ）。
进一步的，磺酰氯的反应后处理所用的盐酸溶液浓度为1-5 mol/L，优选2-3 mol/L，最优选2 mol/L。
进一步的，式（Ⅰ）的生成反应中，反应温度为-30-0℃，优选0℃；洗涤有机相的盐包括碳酸氢钠、碳酸钠、碳酸氢钾，磷酸氢二钠等盐的水溶液，优选碳酸氢钠和碳酸钠，最优选碳酸氢钠；重结晶所用的溶剂为乙酸乙酯/正己烷（1:5）。
本发明的另一目的在于提供所述式（Ⅰ）的用途，作为烟酰胺磷酸核糖转移酶抑制剂的应用。
进一步的，所述式（Ⅰ）在制备烟酰胺磷酸核糖转移酶抑制剂药物中的应用。
本发明的另一目的在于提供所述式（Ⅰ）的另一方面的用途，在抗肿瘤药物中的应用。
进一步的，所述式（Ⅰ）在制备抗肿瘤药物中的应用。所述的肿瘤类型包括肺癌，肝癌，胃癌，乳腺癌，慢性髓系白血病。
本发明所涉及的化合物式（Ⅰ）为新结构，在抑制烟酰胺磷酸核糖转移酶的活性实验和MTT法测定式（Ⅰ）对不同肿瘤细胞的抑制作用的实验中都表现出了很好的活性。
显然，根据本发明的上述内容，按照本领域的普通技术知识和手段，在不脱离本发明上述基本技术思想前提下，还可以做出其他多种形式的修改、替换或变更。
具体实施方式
实施例1：1-（（4,5-二氢-1H-咪唑-1-基）磺酰基）吡咯烷-3-羰酰氯的合成
将吡咯烷-3-碳酰氯（16.8ml，0.2mol）在无水甲苯（40ml）中的溶液滴加到4,5-二氢-1H-咪唑-1-磺酰氯（33.72g，0.2mol）在甲苯（30ml）中的冷（-10℃）溶液中，使得内部温度不超过-5°C。一旦添加完成，将混合物在-5℃下搅拌三十分钟，然后加水（50ml）。分层，有机层用HCl（2mol/l，50ml）洗涤，用无水MgSO4干燥，真空蒸发得到澄清油状物（9.6g）。该油是所需氨磺酰氯和1-（（4,5-二氢-1H-咪唑-1-基）磺酰基）吡咯烷-3-羰酰氯的2:1混合物。柱色谱分离得到1-（（4,5-二氢-1H-咪唑-1-基）磺酰基）吡咯烷-3-羰酰氯42.4g，产率80%。1H-NMR (400 MHz, CDCl3) δ:1.77(m,1H), 2.07(m, 1H), 2.80(m, 1H), 3.55-3.64(m,4H), 3.73(m, 1H), 3.84(m, 1H), 3.95-3.98(t, 2H), 7.98(s, 1H).13C-NMR (125 MHz,CDCl3) δ: 31.92,43.81, 45.34, 46.45, 50.02, 55.87, 136.36, 174.48.LC-MS(ESI,pos, ion) m/z: 266[M+1].
实施例2：N-（2,6-二氯吡啶-4-基）-1-（（4,5-二氢-1H-咪唑-1-基）磺酰基）吡咯烷-3-甲酰胺的合成
将1-（（4,5-二氢-1H-咪唑-1-基）磺酰基）吡咯烷-3-羰酰氯（53.14g，0.2mol）在无水CH2Cl2（36mL）中的溶液在0℃小心地加入到2,6-二氯-4-氨基吡啶（32.60g，0.2mol）和三乙胺（27mL）的无水CH2Cl2（90mL）溶液）。将反应混合物在冰浴中搅拌1小时，然后温热至室温并搅拌过夜。加入冷水（100mL），并从水溶液中分离CH2Cl2层。有机相用饱和NaHCO3溶液（2×40mL）和水洗涤，用无水MgSO4干燥，过滤并浓缩，得到粗品，将其从乙酸乙酯/正己烷（1:5）中重结晶，得到白色针状物N-（2,6-二氯吡啶-4-基）-1-（（4,5-二氢-1H-咪唑-1-基）磺酰基）吡咯烷-3-甲酰胺66.68g，产率为85％。1H-NMR (400 MHz, CDCl3) δ: 1.79(m,1H),2.06(m, 1H), 2.77(m, 1H), 3.17(m, 1H), 3.57-4.06(m, 7H), 7.79(s, 1H), 8.01(s,2H), 8.84(s, 1H). 13C-NMR (125 MHz, CDCl3) δ: 31.21, 43.24, 43.81, 45.14,45.34, 55.87, 117.50, 136.36, 148.76, 149.0, 1173.83. LC-MS(ESI, pos, ion) m/z: 392[M+1].
效果例1：式（Ⅰ）抑制烟酰胺磷酸核糖转移酶的活性
1、酶的制备：将转化有重组质粒(Nampt-pET28a+)的BL21(DE3)plysS细胞接种于2×YT培养基(37ug/ml氯霉素和75ug/ml卡那霉素)中，37℃振摇过夜，收集菌体后用20倍于原体积的新鲜培养基重悬，37℃培养至OD600约0.6，在0.3mM IPTG、28℃条件下诱导5h。离心收集菌体，并重悬于lysis buffer(20mM Tris-HCl pH8.0，300mM NaCl)中，200W超声裂解细胞，超声1s间隙9s，共进行30min。将裂解液于12500rpm、4℃离心50min吸取上清液。该上清液与Ni-NTA柱(购自QIAGEN公司)在冰上振摇孵育1h，再依次用binding buffer(5mMimidazole，0.5M NaCl，20mMTris-Hcl，pH＝7.5)、wash buffer(40mM imidazole，0.5MNaCl，20mM Tris-HCl，pH＝7.5)依次洗去杂蛋白，最后用Elution buffer(200mMimidazole，0.5MNaCl，20mM Tris-Hcl，pH＝7.5)洗脱目的蛋白，并进行SDS-PAGE检测。将洗脱的目的蛋白转移到透析袋中，在4℃冰箱中用灭菌的Tris-HCl(20mM pH＝7.5)透析4～5次，20％PEG20000浓缩后，用Bradford方法测定蛋白浓度。
2、酶反应体系为25μl，其中各种组分的浓度为：50mM Tris-HCl(pH7.5)、0.02％BSA、12mM MgCl2、2mM ATP、0.4mM PRPP、2mM DTT、2μg/mlNampt、0.2μM NAM、2％DMSO和倍比稀释的化合物。先将0.5μl化合物的不同浓度的DMSO溶液加于96孔板，再加入20μl酶反应混合溶液(除底物之外的酶反应组分)，37℃预孵育5min后，加入4.5μl底物NAM溶液以启动反应，37℃反应15min后于95℃加热1min终止酶反应。
3、待酶反应液在冰上冷却后，依次加入10μl 20％苯乙酮和2M KOH，涡旋混合仪上混匀后于0℃作用2min，加入45μl88％甲酸，70℃加热5min，冰上冷却。
4、使用酶标仪测定激发波长382nm、发射波长445nm处的荧光值。
5、根据公式：E＝R/(1+(C/IC50)S)+B(其中E为酶活性，C为化合物浓度，R、IC50、S、B为待拟合的参数)，在origin软件中将酶活性对化合物浓度的曲线进行拟合，求出式（Ⅰ）的IC50为3.34±0.27 nM。
由此可以得出，本发明所公开的式（Ⅰ）具有抑制烟酰胺磷酸核糖转移酶的活性，可以作为烟酰胺磷酸核糖转移酶抑制剂，可以用于烟酰胺磷酸核糖转移酶相关疾病的治疗。
效果例2：MTT（噻唑蓝）法测定式（Ⅰ）对不同肿瘤细胞的抑制作用
1、所采用的肿瘤细胞为：人肺癌细胞A549，人肝癌细胞SMMC-7721，人肝癌细胞Bel-7402，人胃腺癌细胞SGC-7901，人乳腺癌细胞MCF-7，人慢性髓系白血病细胞K562。
2、实验步骤
1.取对数生长期的细胞，胰蛋白酶消化，RPMI 1640细胞培养液调细胞悬液浓度为6×104个/mL。在96孔培养板中每孔加细胞悬液100μL，置37℃，5% CO2培养箱中培养24h，细胞贴壁。
2.移走RPMI 1640细胞培养液，加入浓度梯度的待测药物的RPMI 1640细胞培养液100μL，每个浓度设6个平行孔。将加药后的96孔板置于37℃，5% CO2培养箱中培养48h，倒置显微镜下观察药物的作用效果。
3.96孔板离心后弃去培养液，小心用PBS冲2~3遍后，再加入含0.5% MTT的RPMI1640细胞培养液100μL，继续培养4h。
4.移走上清，每孔加入150μL二甲基亚砜，置摇床上低速振荡10min，使formazan结晶充分溶解。
5.在酶联免疫检测仪490nm处测量各孔的光密度（OD值）。
6.平行孔OD值以mean±SD表示，计算抑制率公式：[(OD对照组-OD空白组)-(OD药物实验组-OD空白组)]/(OD对照组-OD空白组)*100%。
7.采用GraphPad Prism 5数据处理软件，通过绘制量效曲线计算半数抑制浓度（IC50）。
表1 式（Ⅰ）人肿瘤细胞IC50值
由此可以得出，本发明所公开的式（Ⅰ）对六种人肿瘤细胞具有抑制作用，可以作为癌症预防和/或治疗的备选药物进行更加深入的研发，提示了本发明所公开的式（Ⅰ）可以用于制备抗肿瘤药物。
Claims (5)
1.一种磺酰胺衍生物、制备方法及其抗肿瘤中的应用，其结构式（Ⅰ）为
。
2.如权利要求1所述的式（Ⅰ），合成路线为
。
3.如权利要求2所述的式（Ⅰ）的合成路线，其合成步骤为：
（1）吡咯烷-3-碳酰氯和4,5-二氢-1H-咪唑-1-磺酰氯在甲苯中反应生成1-((4,5-二氢-1H-咪唑-1-基)磺酰基)吡咯烷-3-羰酰氯，后处理分别用水和盐酸溶液洗涤，然后柱色谱分离得到产品；
（2）1-((4,5-二氢-1H-咪唑-1-基)磺酰基)吡咯烷-3-羰酰氯和4-氨基-2,6-二氯吡啶低温下反应，经过水和盐的水溶液洗涤，最后重结晶得到式（Ⅰ）。
4.如权利要求1所述的式（Ⅰ），作为烟酰胺磷酸核糖转移酶抑制剂的应用。
5.如权利要求1所述的式（Ⅰ），在抗肿瘤药物中的应用。
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| US20060205941A1 (en) * | 2004-12-16 | 2006-09-14 | Bressi Jerome C | Histone deacetylase inhibitors |
| CN103384668A (zh) * | 2010-09-03 | 2013-11-06 | 福马Tm有限责任公司 | 用于抑制nampt的新化合物和组合物 |
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| US20060205941A1 (en) * | 2004-12-16 | 2006-09-14 | Bressi Jerome C | Histone deacetylase inhibitors |
| CN103384668A (zh) * | 2010-09-03 | 2013-11-06 | 福马Tm有限责任公司 | 用于抑制nampt的新化合物和组合物 |
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