CN116621909B 雷公藤红素衍生物及其制备方法与医药用途 （中国药科大学）

雷公藤红素衍生物及其制备方法与医药用途本发明公开了结构如式Ⅳ所示的雷公藤红发明雷公藤红素衍生物对多种肿瘤细胞的增殖22)n_2)n_35.一种权利要求1所述的雷公藤红素衍生物的制备方法，其特征在于：当R选自H或者n为2～5的整数；4步骤(2)、以无水二氯甲烷为反应溶剂，中间体b与雷公藤红素的2＝36.权利要求1_4任一项所述的雷公藤红素衍生5已有大量针对雷公藤红素的结构修饰研究，但尚未得到能够进入临床实验的候选化合物。嘧啶及嘌呤类化合物对细胞周期蛋白依赖性激酶(CDK)和组蛋白去乙酰化酶(HDAC)等表现6)n_)n)n_2)3_)n)3_，72＝32＝32＝Br389所示的二胺反应得到中间体b；[0050]步骤(2)中，雷公藤红素与中间体b的摩尔比为1:2～1:3；雷公藤红素与EDCI、2＝3[0059]本发明的另一个目的是提供所述的雷公藤红素衍生物在制备抗肿瘤药物的医药[0064]本发明雷公藤红素嘧啶/嘌呤类衍生物的结构新颖，制备方法简单，反应条件温[0065]药理实验表明，本发明雷公藤红素嘧啶/嘌呤类衍生物对多种肿瘤细胞的增殖具(ESI)calculatedforC38H49N3O5[M+H]+6210.30.LC_TOF_MS(ESI)calculatedforC39H51N3O5[M+H]+[0078]4_(3_吡啶基)_2_氨基嘧啶(344.4mg复溶，经硅胶柱层析(洗脱剂为二氯甲烷:甲醇＝100:1～80:1V/V)纯化得到中间体a3[0079]雷公藤红素(90mg,0.2mmol)、中间体a1(134.1mg,0.4mmol)和NaHCO3(67mg,H_NMR(400MHz,CDCl3,TMS)δ9.25(s,1H),8.78–8.72(m,157.89,151.98,148.51,146.07,134.70,134.19,131.96,127.41,123.88,119.63,118.16,21.34,18.53,10.28.LC_TOF_MS(ESI)calculatedforC43H52N4O5[M+H]+705.39,found705.7.H_NMR(400MHz,CDCl3,TMS)δ9.26(s,1H),8.74(d,J=151.96,148.52,146.14,134.75,134.42,132.02,127.39,123.86,119.57,118.23,117.51,21.55,18.40,10.29.LC_TOF_MS(ESI)calculatedforC44H54N4O5[M+H]+719.41,found719.7.[0087]将2_氯嘧啶(229mg,2mmol)溶于8m_NMR(500MHz,CDCl3)δ178.43,170.38,164.76,162.99,162.53,158.05,146.11,134.08,127.39,119.66,118.03,117.19,111.10,calculatedforC35H46N4O3[M+H]177.78,170.25,164.75,162.81,158.08(C×2),146.08,133.99,127.44,119.60,118.TOF_MS(ESI)calculatedforC36H48N4O3[M+H]+585.37,30.21,29.46,28.70,26.97,26.58,21.81,18.34,10.29.LC_TOF_MS(ESI)calculatedforC37H50N4O3[M+H]+599.39,[0101]雷公藤红素(90mg,0.2mmol)、中间体c1(116.2mg,0.4mmol)和NaHCO3(67mg,_NMR29.65,28.74,28.65,21.61,18.68,10.30.LC_TOF_MS(ESI)calculatedforC37H46ClN5O4[M+H]+661.33,found661.6.calculatedforC38H48ClN5O4[M+H]+674.3413C_NMR(500MHz,CDCl3159.19,153.88,151.32,146.06,142.16,134.29,127.41,125.28,119.47,118.23,117.34,TOF_MS(ESI)calculatedforC39H50ClN5O4[M+H]+688.36,[0114]雷公藤红素(90mg,0.2mmol)、中间体c4(128mg,0.4mmol)和NaHCO3(67mg,169.65,164.62,152.03,150.63,146.06,144.82,143.38,134.33,134.02,127.50,119.62,TOF_MS(ESI)calculatedforC37H45BrN4O4[M+H]+689.26,C_NMR(500MHz,CDCl3)δ178.35,178.20,169.86,164.71,151.99,150.63,146.06,144.90,143.32,134.31,134.11,127.46,119.57,118.22,TOF_MS(ESI)calculatedforC38H47BrN4O4[M+H]+705.28,164.74,151.90,150.66,146.03,144.98,143.23,134.22,134.16,127.41,119.48,118.21,10.28.LC_TOF_MS(ESI)calculatedforC39H49BrN4O4[M+H]+[0134]用培养基将化合物溶液和空白对照组溶液稀释到待测浓度后加入至96孔板(共5次初筛结果平均值为其最终抑制率。受试化合物进一步浓度梯度筛选，计算其IC50值[0