CN107954987A - 一种磺酰胺衍生物及其在抗肿瘤药物中的应用 - Google Patents
一种磺酰胺衍生物及其在抗肿瘤药物中的应用 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，其中，R1选自NO2或CF3。
Description
技术领域
本发明涉及一种磺酰胺衍生物及其在抗肿瘤药物中的应用。
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及其在抗肿瘤药物中的应用。其结构式（Ⅰ）为
，其中，R1选自NO2或CF3。
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一类磺酰胺衍生物的合成方法，其合成过程中用到了磺酰氯和胺的缩合及酰氯和胺的缩合。反应利用的是磺酰氯以及酰氯与胺的缩合反应，反应物反应活性较高，反应条件相对温和，有很强的可操作性。所得产物也具有很强的可扩展性，在原有的药理基础上容易合成具有改性结构的药理结构。
在缩合反应过程中所用溶剂可以为二氯甲烷、三氯甲烷、四氢呋喃、乙腈、石油醚、乙醚、甲苯等惰性的极性或者非极性溶剂，优选乙腈和四氢呋喃；反应温度从0-50℃皆可，优选0-10℃。本发明从经济效益出发，对反应条件和反应路线进行了优化，无论是溶剂的用量、反应物的种类及用量、还是反应温度的选择都进行了条件优化，所得的反应路线和条件是我们挑选的路线中最具有原子经济性和环保性的路线。
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：中间体1-[(1氢苯并[d]咪唑-1基)磺酰基]吡咯烷-3-甲酰氯的合成
将1氢苯并[d]咪唑-1-磺酰氯溶液（2.2mmol，2.2当量）冷却至0℃，将四氢吡咯-3-甲酰氯（2.2mmol，2.2当量）加入到剧烈搅拌的磺酰氯溶液中。在0℃下搅拌5分钟后，将反应容器从冰浴中取出，温热至室温，并搅拌1.5小时。然后将反应混合物用EtOAc稀释，并通过硅胶垫过滤，盖上硅藻土层，将其用另外的EtOAc洗涤。将滤液浓缩，所得残余物通过快速色谱法纯化（使用具有SNAP 25g柱的Biotage Isolera Four系统），得到0.50g白色固体1-[(1氢苯并[d]咪唑-1基)磺酰基]吡咯烷-3-甲酰氯，产率为72％）。1H-NMR (400 MHz, CDCl3) δ:1.78(m, 1H), 2.07(m, 1H), 2.80(m, 1H), 3.56-3.71(m, 2H), 3.87(m, 1H), 4.29(m,1H), 7.17-7.28(m, 2H), 7.52-7.59(m, 2H), 9.16(s, 1H). 13C-NMR (125 MHz, CDCl3)δ: 31.92, 45.34, 46.45, 50.02, 113.79, 121.33, 124.89, 127.37, 129.52,131.68, 143.81, 174.48. LC-MS(ESI, pos, ion) m/z: 314[M+H]。
实施例2：1-[(1氢苯并[d]咪唑-1-基)磺酰基]-N-(3-硝基吡啶-4-基)吡咯-3-甲酰胺的合成
将溶解在DCM（50mL）中的1-[(1氢苯并[d]咪唑-1基)磺酰基]吡咯烷-3-甲酰氯（2.2mmol）溶液缓慢加入到冷却到温度为0℃的3-硝基吡啶-4-胺（2.2mmol）和三乙胺（2.2mmol）的（100mL）溶液中。加完后，除去冰浴，将所得混合物在室温下搅拌过夜，然后将反应混合物倒入水中，用CH2Cl2溶液萃取。将有机萃取物用MgSO4干燥并减压浓缩。残余物用DCM/Et2O 1/10研磨，通过过滤收集得到棕褐色固体1-[(1氢苯并[d]咪唑-1-基)磺酰基]-N-(3-硝基吡啶-4-基)吡咯烷-3-甲酰胺0.80g，产率为87％。1H-NMR (400 MHz, CDCl3) δ:1.76(m, 1H), 1.98(m, 1H), 2.84(m, 2H), 3.51-3.76(m, 3H), 4.69(dd, 1H), 7.17-7.22(m, 2H), 7.50-7.56(m, 2H), 8.13(d, 1H), 8.62(d, 1H), 8.65(s, 1H), 9.16(s,1H), 9.34(s, 1H).13C-NMR (125 MHz, CDCl3) δ: 31.21, 43.24, 45.14, 45.34,113.79, 118.54, 121.33, 124.89, 127.37, 129.52, 131.68, 138.00, 139.77,143.81, 147.09, 151.36, 174.23. LC-MS(ESI, pos, ion) m/z: 417[M+H]。
实施例:3：1-[(1氢苯并[d]咪唑-1-基)磺酰基]-N-(3-(三氟甲基)吡啶-4-基)吡咯-3-甲酰胺的合成
将溶解在DCM（50mL）中的1-[(1氢苯并[d]咪唑-1基)磺酰基]吡咯烷-3-甲酰氯（2.2mmol）溶液缓慢加入到冷却到温度为0℃的3-(三氟甲基)吡啶-4-胺（2.2mmol）和三乙胺（2.2mmol）的（100mL）溶液中。加完后，除去冰浴，将所得混合物在室温下搅拌过夜，然后将反应混合物倒入水中，用CH2Cl2溶液萃取。将有机萃取物用MgSO4干燥并减压浓缩。残余物用DCM/Et2O 1/10研磨，通过过滤收集得到棕褐色固体1-[(1氢苯并[d]咪唑-1-基)磺酰基]-N-(3-(三氟甲基)吡啶-4-基)吡咯烷-3-甲酰胺0.80g，产率为83％。1H-NMR (400 MHz,CDCl3) δ: 1.76(m, 1H), 2.00(m, 1H), 2.80(m, 1H), 3.64-3.83(m, 2H), 3.95(m,1H), 4.18(m, 1H), 7.16-7.27(m, 2H), 7.51-7.58(m, 2H), 7.67(s, 1H), 7.89(d,1H), 8.25(d, 1H), 8.40(s, 1H), 9.27(s, 1H). 13C-NMR (125 MHz, CDCl3) δ:31.21,43.24, 45.14, 45.34, 113.79, 119.48, 121.33, 121.66, 123.78, 124.89, 127.37,129.52, 131.68, 141.17, 143.81, 148.28, 150.59, 174.23. LC-MS(ESI, pos, ion)m/z: 440[M+H]。
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。
表1 式（Ⅰ）NAMPT 抑制的IC50值
| IC50（nM） | |
| 实施例2 | 4.36±0.32 |
| 实施例3 | 4.08±0.26 |
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2 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 (4)
1.一种磺酰胺衍生物及其在抗肿瘤药物中的应用，其结构式（Ⅰ）为
，其中，R1选自NO2或CF3。
2.如权利要求1所述的式（Ⅰ），合成路线为
。
3.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。
4.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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| WO2013130943A1 (en) * | 2012-03-02 | 2013-09-06 | Genentech, Inc. | Alkyl-and di-substituted amido-benzyl sulfonamide derivatives |
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