四环三萜类衍生物的合成及应用的制作方法

本发明涉及两种四环三萜类天然产物衍生物、合成方法、应用、药物，属于化学及药物领域。

背景技术：

组蛋白的乙酰化与去乙酰化在真核细胞的染色质重组和基因表达中发挥着重要的作用，而组蛋白乙酰化酶(hat)和组蛋白去乙酰化酶(hdac)调节着机体中核心组蛋白乙酰化和去乙酰化的动态平衡。hdac是治疗癌症(t细胞淋巴瘤、多发性骨髓瘤)的成功药物靶点，也参与神经紊乱、感染和炎症，hdac抑制剂在免疫紊乱中的潜在治疗效果已成为关注的焦点。hdac2是脂多糖诱导巨噬细胞炎症反应的关键。然而，hdac抑制和炎症之间的关系是复杂的，结果取决于实验系统、研究途径和化合物的用量，还有待众多药物化学家进一步探索。

五味子科植物以其显著的药用作用引起了药理学家和植物化学家的广泛关注，其作为传统中药用于缓解疲劳、护肝、强心、降血、治疗失眠已有2000多年的历史，nigranoicacid(na)和manwuweizicacid(ma)是从五味子科植物中分出来的两种具有代表性的四环三萜类化合物，据文献报道这两个化合物具有多种生物活性，包括抗hiv、抗癌、促进精神和智力功能、抗凋亡和保护肝脏等。

经查阅相关资料得知，关于na和ma及其衍生物的专利报道较少，文献也集中于对癌细胞的抑制作用的研究，鲜有对其作为hdac抑制剂并与炎症联系的相关报道。根据对hdac抑制活性与抗炎活性的研究，本发明设计并半合成了一系列新型的四环三萜类衍生物。

技术实现要素：

本发明提供了na衍生物和ma衍生物及其制备方法和在hdac抑制和抗炎方面的应用。

本发明提供了如下所示结构的四环三萜类衍生物ⅰ和ⅱ，具体包括ⅰa,ⅰb,ⅱa,ⅱb所示的化合物

上式中ⅰa按照结构式二所示的方法制备：不同取代基的胺与nigranoicacid在tbtu的缩合条件下，以三乙胺作碱，乙腈作溶剂，室温反应得到ⅰa。

上式中ⅰb按照结构式三所示的方法制备：nigranoicacid与碘甲烷在碳酸钾作碱，dmf作溶剂，室温的反应条件下得到甲酯化产物a，a与50％羟胺水溶液在氢氧化钾作碱，四氢呋喃和甲醇作溶剂，室温的反应条件下得到ⅰb。

上式中ⅱa按照结构式四所示的方法制备：不同取代基的胺与manwuweizicacid在tbtu的缩合条件下，以三乙胺作碱，乙腈作溶剂，室温反应得到ⅱa；

上式中ⅱb按照结构式五所示的方法制备：manwuweizicacid与碘甲烷在碳酸钾作碱，dmf作溶剂，室温的反应条件下得到甲酯化产物b，b与50％羟胺水溶液在氢氧化钾作碱，四氢呋喃和甲醇作溶剂，室温的反应条件下得到ⅱb；

以上通式及结构中：

r代表通式ⅰa,ⅰb,ⅱa,ⅱb中所示的取代基；

在通式ⅰa中，r1代表：1-9个碳的直链烷基或烷氧基，1-9个碳支链烷基或烷氧基，1-9个碳环烷基或烷氧基，1-9个碳碳链上含有双键、三键、含硫含氧取代基、苯基或取代苯基、杂芳基或取代杂芳基的烷基或烷氧基，苯基或取代苯基，杂芳基或取代杂芳基；

在通式ⅰb中，r2代表：羟基，羟胺基；

在通式ⅱa中，r1代表：1-9个碳的直链烷基或烷氧基，1-9个碳支链烷基或烷氧基，1-9个碳环烷基或烷氧基，1-9个碳碳链上含有双键、三键、含硫含氧取代基、苯基或取代苯基、杂芳基或取代杂芳基的烷基或烷氧基，苯基或取代苯基，杂芳基或取代杂芳基；

在通式ⅱb中，r2代表：羟基，羟胺基。

本发明的有益效果为，本发明结构通式和取代结构式中的取代基设置多样，可以根据不同的条件制备得到。本发明的四环三萜类衍生物表现出了一定的组蛋白去乙酰化酶抑制活性和抗炎活性，可以用于制备组蛋白去乙酰化酶抑制剂药物和抗炎药物。

附图说明

图1为本发明部分na衍生物和ma衍生物对比结构式图。

具体实施方式

本发明提供的更具体na衍生物和ma衍生物如图1所示。

下述的实施例和测试结果可用来进一步说明本发明，但不意味着限制本发明。

实施例1：nigranoicacid类衍生物n1的合成

在一个10ml的圆底烧瓶中加入nigranoicacid(47mg,0.1mmol),tbtu(71mg,0.22mmol)和三乙胺(40mg,0.4mmol)，用5ml重蒸的乙腈溶解，室温搅拌30min，加入甲氧基胺盐酸盐(19mg,0.23mmol)，室温搅拌3h，tlc监测反应完毕后，加入15ml水稀释反应液，用二氯甲烷萃取(3×10ml)，合并有机层，饱和食盐水洗，无水硫酸钠干燥，抽滤后得到滤液，减压蒸馏去除溶剂后得到粗品。柱层析(石油醚：乙酸乙酯＝1:1)后得到白色固体，收率53％，熔点104-107℃；irνmax(kbr)3443,2924,2854,1643,1457,1383,1262,1076,1053cm^-1；¹hnmr(cdcl3,400mhz)δ8.31,8.25(2h,s,conh(a)andconh(b)),5.58(1h,t,j＝7.2hz,h-24),4.81(1h,s,ha-28),4.73(1h,s,hb-28),3.82(3h,s,och3(a)),3.73(3h,s,och3(b)),1.88,1.67(6h,s,ch3-26,ch3-29),2.50-1.04(24h,m,nigranoicacidscaffold),0.94,0.91(6h,s,ch3-18,ch3-30),0.87(3h,d,j＝6.4hz,ch3-21),0.73(1h,d,j＝4.5hz,hβ-19),0.40(1h,d,j＝4.5hz,hα-19)；¹³cnmr(cdcl3,100mhz)δ172.8(c,c-3),168.1(c,c-27),149.8(c,c-4),136.1(ch,c-24),128.5(c,c-25),111.5(ch2,c-28),64.6(oc(a)h3),64.5(oc(b)h3),52.0(ch,c-17),48.9(c,c-14),47.4(ch,c-8),46.1(ch,c-5),45.1(c,c-13),36.1(ch2,c-11),35.9(ch,c-20),35.5(ch2,c-12),33.0(ch2,c-15),29.7(ch2,c-2),29.6(ch2,c-19),29.3(ch2,c-1),28.0(ch2,c-16),27.6(ch2,c-6),27.1(c,c-10),27.9(ch2,c-22),26.5(ch2,c-23),24.9(ch2,c-7),21.3(c,c-9),20.5(ch3,c-26),19.7(ch3,c-29),19.3(ch3,c-30),18.1(ch3,c-21),17.9(ch3,c-18)；hrms-esi:m/zcalcdforc32h52n2nao4(m+na)⁺551.3819,found551.3817.

实施例2：nigranoicacid类衍生物n2的合成

化合物n2的合成参照化合物n1的合成方法，原料为相应原料。

n2：白色固体，收率82％，熔点132-134℃；irνmax(kbr)3439,3309,2924,2878,1652,1617,1531,1382,1146,999cm^-1；¹hnmr(cdcl3,400mhz)δ5.91-5.72(2h,overlap,ch(a)＝ch2andch(b)＝ch2),5.72-5.58(2h,overlap,conh(a)andconh(b)),5.49(1h,t,j＝7.5hz,h-24),5.26-5.03(4h,overlap,ch＝ch2(a)andch＝ch2(b)),4.79(1h,s,ha-28),4.71(1h,s,hb-28),3.98-3.86(2h,m,ch2(a)-ch＝ch2),3.86-3.75(2h,m,ch2(b)-ch＝ch2),1.88,1.66(6h,s,ch3-26,ch3-29),2.46-1.02(24h,m,nigranoicacidscaffold),0.92,0.89(6h,s,ch3-18,ch3-30),0.84(3h,d,j＝6.4hz,ch3-21),0.70(1h,d,j＝4.5hz,hβ-19),0.37(1h,d,j＝4.5hz,hα-19)；¹³cnmr(cdcl3,100mhz)δ173.0(c,c-3),170.0(c,c-27),149.8(c,c-4),134.3(ch,c-24),134.2(c(a)h＝ch2),134.1(c(b)h＝ch2),131.4(c,c-25),116.5(ch＝c(a)h2),116.1(ch＝c(a)h2),111.4(ch2,c-28),52.0(ch,c-17),49.0(c,c-14),47.4(ch,c-8),45.9(ch,c-5),45.1(c,c-13),41.8(c(a)h2-ch＝ch2),41.7(c(b)h2-ch＝ch2),36.2(ch2,c-11),35.8(ch,c-20),35.5(ch2,c-12),33.8(ch2,c-15),32.9(ch2,c-2),29.9(ch2,c-19),29.7(ch2,c-1),28.0(ch2,c-16),27.6(ch2,c-6),27.1(c,c-10),26.9(ch2,c-22),26.3(ch2,c-23),24.9(ch2,c-7),21.3(c,c-9),20.9(ch3,c-26),19.6(ch3,c-29),19.2(ch3,c-30),18.1(ch3,c-21),17.9(ch3,c-18)；hrms-esi:m/zcalcdforc36h56n2nao2(m+na)⁺571.4234,found571.4238.

实施例3：nigranoicacid类衍生物n3的合成

化合物n3的合成参照化合物n1的合成方法，原料为相应原料。

n3：白色固体，收率54％，熔点93-98℃；irνmax(kbr)3440,2924,2854,1640,1495,1458,1402,1324,1263,1039cm^-1；¹hnmr(cdcl3,400mhz)δ8.30,8.23(2h,s,conh(a)andconh(b)),5.56(1h,t,j＝7.2hz,h-24),4.81(1h,s,ha-28),4.72(1h,s,hb-28),4.17-3.97(2h,m,j＝6.4hz,och2(a)ch3),3.96-3.77(2h,m,j＝6.3hz,och2(b)ch3),1.87,1.67(6h,s,ch3-26,ch3-29),2.49-1.04(30h,m,nigranoicacidscaffold,och2ch3(a),och2ch3(b)),0.93,0.90(6h,s,ch3-18,ch3-30),0.86(3h,d,j＝6.4hz,ch3-21),0.72(1h,d,j＝4.5hz,hβ-19),0.40(1h,d,j＝4.5hz,hα-19)；¹³cnmr(cdcl3,100mhz)δ171.4(c,c-3),168.3(c,c-27),149.8(c,c-4),135.8(ch,c-24),128.5(c,c-25),111.4(ch2,c-28),72.3(oc(a)h2ch3),72.1(oc(b)h2ch3),52.0(ch,c-17),48.9(c,c-14),47.5(ch,c-8),46.1(ch,c-5),45.1(c,c-13),36.1(ch2,c-11),35.9(ch,c-20),35.5(ch2,c-12),33.0(ch2,c-15),29.7(ch2,c-2),29.7(ch2,c-19),29.7(ch2,c-1),28.0(ch2,c-16),27.7(ch2,c-6),27.2(c,c-10),27.0(ch2,c-22),26.5(ch2,c-23),24.9(ch2,c-7),21.3(c,c-9),20.6(ch3,c-26),19.7(ch3,c-29),19.2(ch3,c-30),18.1(ch3,c-21),17.9(ch3,c-18),13.5(och2c(a)h3),13.4(och2c(b)h3)；hrms-esi:m/zcalcdforc34h56n2nao4(m+na)⁺579.4132,found579.4129.

实施例4：nigranoicacid类衍生物n4的合成

化合物n4的合成参照化合物n1的合成方法，原料为相应原料。

n4：白色固体，收率67％，熔点114-118℃；irνmax(kbr)3442,2923,2853,1652,1545,1457,1382,1233,1151cm^-1；¹hnmr(cdcl3,400mhz)δ5.53-5.30(3h,overlap,conh(a),conh(b),h-24),4.81(1h,s,ha-28),4.73(1h,s,hb-28),3.35-3.21(2h,m,j＝6.8,2.6hz,ch2(a)ch2ch3),3.21-3.11(2h,m,j＝6.6hz,ch2(b)ch2ch3),1.88,1.68(6h,s,ch3-26,ch3-29),2.49-1.04(28h,m,nigranoicacidscaffold,ch2ch2(a)ch3,ch2ch2(b)ch3),1.03-0.87(12h,overlap,ch3-18,ch3-30,ch2ch2ch3(a),ch2ch2ch3(b)),0.86(3h,d,j＝6.5hz,ch3-21),0.72(1h,d,j＝4.2hz,hβ-19),0.37(1h,d,j＝4.5hz,hα-19)；¹³cnmr(cdcl3,100mhz)δ173.2(c,c-3),170.3(c,c-27),150.0(c,c-4),133.3(ch,c-24),132.0(c,c-25),111.3(ch2,c-28),52.0(ch,c-17),48.9(c,c-14),47.5(ch,c-8),46.0(ch,c-5),45.1(c,c-13),41.1(c(a)h2ch2ch3),41.0(c(b)h2ch2ch3),36.3(ch2,c-11),35.9(ch,c-20),35.5(ch2,c-12),34.0(ch2,c-15),33.0(ch2,c-2),30.0(ch2,c-19),29.7(ch2,c-1),28.0(ch2,c-16),27.7(ch2,c-6),27.1(c,c-10),27.0(ch2,c-22),26.3(ch2,c-23),24.9(ch2,c-7),22.9(ch2c(a)h2ch3),22.8(ch2c(b)h2ch3),21.3(c,c-9),20.9(ch3,c-26),19.7(ch3,c-29),19.2(ch3,c-30),18.1(ch3,c-21),17.9(ch3,c-18),11.4(ch2ch2c(a)h3),11.3(ch2ch2c(b)h3)；hrms-esi:m/zcalcdforc36h60n2nao2(m+na)⁺575.4547,found575.4546.

实施例5：nigranoicacid类衍生物n5的合成

化合物n5的合成参照化合物n1的合成方法，原料为相应原料。

n5：白色固体，收率71％，熔点119-122℃；irνmax(kbr)3425,2955,2923,2867,1655,1625,1548,1433,1454,1385,1275,1159,1072,1034cm^-1；¹hnmr(cdcl3,400mhz)δ5.59(1h,t,j＝5.2hz,conh(a)),5.56-5.49(1h,t,j＝5.6hz,conh(b)),5.44(1h,t,j＝7.3hz,h-24),4.80(1h,s,ha-28),4.71(1h,s,hb-28),3.20-3.07[2h,m,j＝4.3,2.0hz,ch2(a)ch(ch3)2],3.07-2.94[2h,m,j＝6.3,1.4hz,ch2(b)ch(ch3)2],1.87,1.66(6h,s,ch3-26,ch3-29),2.47-1.02[26h,m,nigranoicacidscaffold,ch2ch(a)(ch3)2,ch2ch(b)(ch3)2],0.94-0.85[18h,overlap,ch3-18,ch3-30,ch2ch(ch3(a))2,ch2ch(ch3(b))2],0.84(3h,d,j＝6.6hz,ch3-21),0.70(1h,d,j＝4.0hz,hβ-19),0.37(1h,d,j＝4.4hz,hα-19)；¹³cnmr(cdcl3,100mhz)δ173.2(c,c-3),170.3(c,c-27),149.9(c,c-4),133.2(ch,c-24),132.0(c,c-25),111.3(ch2,c-28),52.0(ch,c-17),48.9(c,c-14),47.4(ch,c-8),46.7[c(a)h2ch(ch3)2],46.6[c(b)h2ch(ch3)2],45.9(ch,c-5),45.1(c,c-13),36.2(ch2,c-11),35.9(ch,c-20),35.5(ch2,c-12),34.0(ch2,c-15),32.9(ch2,c-2),30.1(ch2,c-19),29.7(ch2,c-1),28.5[ch2c(a)h(ch3)2],28.4[ch2c(a)h(ch3)2],28.0(ch2,c-16),27.6(ch2,c-6),27.1(c,c-10),26.9(ch2,c-22),26.4(ch2,c-23),24.9(ch2,c-7),21.3(c,c-9),20.9(ch3,c-26),20.1[2c,ch2ch(c(a)h3)2],20.0[2c,ch2ch(c(a)h3)2],19.6(ch3,c-29),19.2(ch3,c-30),18.1(ch3,c-21),17.9(ch3,c-18)；hrms-esi:m/zcalcdforc38h64n2nao2(m+na)⁺603.4860,found603.4856.

实施例6：nigranoicacid类衍生物n6的合成

化合物n6的合成参照化合物n1的合成方法，原料为相应原料。

n6：白色固体，收率76％，熔点177-179℃；irνmax(kbr)3356,2925,2874,1653,1539,1456,1407,1278,1238,1155cm^-1；¹hnmr(cdcl3,400mhz)δ5.61-5.37(3h,overlap,conh(a),conh(b),h-24),4.80(1h,s,ha-28),4.72(1h,s,hb-28),2.87(2h,d,j＝4.8hz,conhch3(a)),2.76(2h,d,j＝4.5hz,conhch3(b)),1.87,1.67(6h,s,ch3-26,ch3-29),2.47-1.04(24h,m,nigranoicacidscaffold),0.94,0.91(6h,s,ch3-18,ch3-30),0.86(3h,d,j＝6.4hz,ch3-21),0.72(1h,d,j＝3.3hz,hβ-19),0.38(1h,d,j＝3.7hz,hα-19)；¹³cnmr(cdcl3,100mhz)δ173.9(c,c-3),170.9(c,c-27),149.9(c,c-4),134.0(ch,c-24),131.6(c,c-25),111.3(ch2,c-28),52.0(ch,c-17),49.0(c,c-14),47.5(ch,c-8),46.0(ch,c-5),45.1(c,c-13),36.3(ch2,c-11),35.9(ch,c-20),35.5(ch2,c-12),33.8(ch2,c-15),33.0(ch2,c-2),29.9(ch2,c-19),29.7(ch2,c-1),28.0(ch2,c-16),27.7(ch2,c-6),27.2(c,c-10),27.0(ch2,c-22),26.4(ch2,c-23),26.2(conhc(a)h3),26.0(conhc(b)h3),24.9(ch2,c-7),21.4(c,c-9),20.9(ch3,c-26),19.7(ch3,c-29),19.3(ch3,c-30),18.1(ch3,c-21),17.9(ch3,c-18)；hrms-esi:m/zcalcdforc32h53n2o2(m+h)⁺497.4102,found497.4107.

实施例7：nigranoicacid类衍生物n7的合成

化合物n7的合成参照化合物n1的合成方法，原料为相应原料。

n7：白色固体，收率53％，熔点140-141℃；irνmax(kbr)3306,3073,2924,2873,1650,1535,1454,1374,1323,1264,1239,1148,890cm^-1；¹hnmr(cdcl3,400mhz)δ5.54-5.42(2h,overlap,conh(a),h-24),5.40-5.32(1h,m,conh(b)),4.81(1h,s,ha-28),4.73(1h,s,hb-28),3.42-3.30(2h,m,j＝6.6,1,3hz,ch2(a)ch3),3.29-3.20(2h,m,j＝6.9,1,5hz,ch2(b)ch3),1.88,1.68(6h,s,ch3-26,ch3-29),2.47-1.22(24h,m,nigranoicacidscaffold),1.18(3h,t,j＝7.3hz,ch2ch3(a)),1.11(3h,t,j＝7.2hz,ch2ch3(b)),0.94,0.91(6h,s,ch3-18,ch3-30),0.87(3h,d,j＝6.3hz,ch3-21),0.72(1h,d,j＝4.2hz,hβ-19),0.39(1h,d,j＝4.4hz,hα-19)；¹³cnmr(cdcl3,100mhz)δ173.1(c,c-3),170.2(c,c-27),150.0(c,c-4),133.5(ch,c-24),131.9(c,c-25),111.4(ch2,c-28),52.0(ch,c-17),49.0(c,c-14),47.5(ch,c-8),46.0(ch,c-5),45.1(c,c-13),36.3(ch2,c-11),35.9(ch,c-20),35.5(ch2,c-12),34.3(c(a)h2ch3),34.2(c(b)h2ch3),34.0(ch2,c-15),33.0(ch2,c-2),30.0(ch2,c-19),29.7(ch2,c-1),28.1(ch2,c-16),27.7(ch2,c-6),27.2(c,c-10),27.0(ch2,c-22),26.3(ch2,c-23),24.9(ch2,c-7),21.4(c,c-9),20.9(ch3,c-26),19.7(ch3,c-29),19.3(ch3,c-30),18.2(ch3,c-21),17.9(ch3,c-18),15.0(ch2c(a)h3),14.9(ch2c(b)h3)；hrms-esi:m/zcalcdforc34h57n2o2(m+h)⁺525.4415,found525.4412.

实施例8：nigranoicacid类衍生物n8的合成

化合物n8的合成参照化合物n1的合成方法，原料为相应原料。

n8：白色固体，收率52％，熔点110-112℃；irνmax(kbr)3442,2925,1640,1453,1262,1031,929cm^-1；¹hnmr(cdcl3,400mhz)δ8.16(2h,s,conh(a)andconh(b)),6.06-5.88(2h,overlap,och2ch(a)＝ch2andoch2ch(b)＝ch2),5.57(1h,t,j＝7.5hz,h-24),5.41-5.26(4h,overlap,och2ch＝ch2(a)andoch2ch＝ch2(b)),4.82(1h,s,ha-28),4.74(1h,s,hb-28),4.51-4.41(2h,m,och2(a)-ch＝ch2),4.41-4.28(2h,m,och2(b)-ch＝ch2),1.88,1.68(6h,s,ch3-26,ch3-29),2.50-1.05(24h,m,nigranoicacidscaffold),0.95,0.92(6h,s,ch3-18,ch3-30),0.88(3h,d,j＝6.0hz,ch3-21),0.73(1h,d,j＝3.2hz,hβ-19),0.41(1h,d,j＝3.2hz,hα-19)；¹³cnmr(cdcl3,100mhz)δ171.3(c,c-3),168.2(c,c-27),149.8(c,c-4),136.0(ch,c-24),132.2(och2c(a)h＝ch2),129.9(och2c(b)h＝ch2),128.5(c,c-25),120.8(och2ch＝c(a)h2),120.7(och2ch＝c(b)h2),111.5(ch2,c-28),77.5(overlap,oc(a)h2ch＝ch2),77.2(overlap,oc(b)h2ch＝ch2),52.1(ch,c-17),49.0(c,c-14),47.5(ch,c-8),46.1(ch,c-5),45.2(c,c-13),36.2(ch2,c-11),35.9(ch,c-20),35.5(ch2,c-12),33.0(ch2,c-15),33.0(ch2,c-2),29.8(ch2,c-19),29.3(ch2,c-1),28.1(ch2,c-16),27.7(ch2,c-6),27.2(c,c-10),27.0(ch2,c-22),26.6(ch2,c-23),24.9(ch2,c-7),21.4(c,c-9),20.6(ch3,c-26),19.7(ch3,c-29),19.3(ch3,c-30),18.2(ch3,c-21),18.0(ch3,c-18)；hrms-esi:m/zcalcdforc36h56n2nao4(m+na)⁺603.4132,found603.4129.

实施例9：nigranoicacid类衍生物n9的合成

n9的合成路线如下：

在一个10ml的圆底烧瓶中加入nigranoicacid(94mg,0.2mmol),k2co3(111mg,0.8mmol),用2ml的dmf溶解，室温搅拌2h，加入碘甲烷(85mg,0.6mmol)，室温搅拌3h，tlc监测反应完毕后，加入15ml水稀释反应液，用乙酸乙酯萃取(3×10ml)，合并有机层，饱和食盐水洗，无水硫酸钠干燥，抽滤后得到滤液，减压蒸馏去除溶剂后得到粗品。柱层析(石油醚：乙酸乙酯＝6:1)后得到化合物a，透明油状液体，收率88％，irνmax(kbr)2962,1741,1721,1644,1435,1375,1261,1197,1095,1028,866,800cm^-1；¹hnmr(cdcl3,400mhz)δ5.92(1h,t,j＝7.2hz,h-24),4.80(1h,s,ha-28),4.72(1h,s,hb-28),3.73,3.64(6h,s,och3(a)andoch3(b)),1.88,1.67(6h,s,ch3-26,ch3-29),2.55-1.04(24h,m,nigranoicacidscaffold),0.95,0.92(6h,s,ch3-18,ch3-30),0.89(3h,d,j＝6.4hz,ch3-21),0.72(1h,d,j＝4.6hz,hβ-19),0.40(1h,d,j＝4.4hz,hα-19)；¹³cnmr(cdcl3,100mhz)δ174.5(c,c-3),168.7(c,c-27),149.6(c,c-4),144.3(ch,c-24),126.6(c,c-25),111.6(ch2,c-28),52.3(ch,c-17),51.6(oc(a)h3),51.3(oc(b)h3),49.1(c,c-14),47.8(ch,c-8),46.0(ch,c-5),45.3(c,c-13),36.1(ch,c-20),36.0(ch2,c-11),35.8(ch2,c-12),33.2(ch2,c-15),31.6(ch2,c-2),30.1(ch2,c-19),29.2(ch2,c-1),28.2(ch2,c-16),27.9(ch2,c-6),27.2(c,c-10),27.1(ch2,c-22),26.8(ch2,c-23),25.1(ch2,c-7),21.5(c,c-9),20.8(ch3,c-26),19.9(ch3,c-29),19.4(ch3,c-30),18.3(ch3,c-21),18.2(ch3,c-18)；hrms-esi:m/zcalcdforc32h50nao4(m+na)⁺521.3601,found521.3599.

将化合物a(88mg,0.18mmol)加入10ml圆底烧瓶，用1ml甲醇和1ml四氢呋喃的混合溶剂溶解，加入50％羟胺水溶液(0.46ml,7.2mmol)和koh(81mg,1.44mmol)，室温搅拌3h，反应完毕后，反应液用1n盐酸中和至ph值为7，用乙酸乙酯萃取(3×10ml)，合并有机层，饱和食盐水洗，无水硫酸钠干燥，抽滤后得到滤液，减压蒸馏去除溶剂后得到粗品。柱层析(二氯甲烷：甲醇＝13:1)后得到化合物n9，白色固体，收率38％，熔点116-121℃；irνmax(kbr)3440,3217,2931,1687,1633,1542,1457,1375,1259,1073,993,891cm^-1；¹hnmr(pyridine-d5,400mhz)δ6.07(1h,t,j＝6.9hz,h-24),4.93(1h,s,ha-28),4.79(1h,s,hb-28),2.17,1.70(6h,s,ch3-26,ch3-29),2.97-1.14(24h,m,nigranoicacidscaffold),0.99(3h,d,j＝6.3hz,ch3-21),0.95,0.85(6h,s,ch3-18,ch3-30),0.67(1h,d,j＝4.0hz,hβ-19),0.37(1h,d,j＝4.0hz,hα-19)；¹³cnmr(pyridine-d5,100mhz)δ171.2(c,c-3),171.2(c,c-27),150.6(c,overlap,c-4),143.2(ch,c-24),129.2(c,c-25),112.4(ch2,c-28),52.9(ch,c-17),49.6(c,c-14),48.2(ch,c-8),46.4(ch,c-5),45.8(c,c-13),36.9(ch2,c-11),36.9(ch,c-20),36.3(ch2,c-12),33.7(ch2,c-15),31.7(ch2,c-2),31.1(ch2,c-19),30.5(ch2,c-1),28.8(ch2,c-16),28.4(ch2,c-6),28.3(c,c-10),27.7(ch2,c-22),27.5(ch2,c-23),25.7(ch2,c-7),22.0(c,c-9),22.0(ch3,c-26),20.5(ch3,c-29),19.9(ch3,c-30),18.9(ch3,c-21),18.7(ch3,c-18)；hrms-esi:m/zcalcdforc30h47nnao4(m+na)⁺508.3397,found508.3397.

实施例10：manwuweizicacid类衍生物m1的合成

在一个10ml的圆底烧瓶中加入manwuweizicacid(47mg,0.1mmol),tbtu(71mg,0.22mmol)和三乙胺(40mg,0.4mmol)，用5ml重蒸的乙腈溶解，室温搅拌30min，加入甲氧基胺盐酸盐(19mg,0.23mmol)，室温搅拌3h，tlc监测反应完毕后，加入15ml水稀释反应液，用二氯甲烷萃取(3×10ml)，合并有机层，饱和食盐水洗，无水硫酸钠干燥，抽滤后得到滤液，减压蒸馏去除溶剂后得到粗品。柱层析(石油醚：乙酸乙酯＝1:1)后得到白色固体，收率49％，熔点124-125℃；irνmax(kbr)3440,2923,2853,1640,1402,1323,1263,1038cm^-1；¹hnmr(cdcl3,400mhz)δ8.66,844(2h,s,conh(a)andconh(b)),5.58(1h,t,j＝7.1hz,h-24),4.88(1h,s,ha-28),4.68(1h,s,hb-28),3.80(3h,s,och3(a)),3.73(3h,s,och3(b)),1.87,1.75(6h,s,ch3-26,ch3-29),2.33-1.01(23h,m,manwuweizicacidscaffold),0.94(3h,s,ch3-18),0.92-0.79(6h,overlap,ch3-30,ch3-21),0.72(3h,s,ch3-19)；¹³cnmr(cdcl3,100mhz)δ171.7(c,c-3),168.2(c,c-27),147.4(c,c-4),139.1(c,c-9),136.0(ch,c-24),129.6(c,c-8),128.4(c,c-25),113.8(ch2,c-28),64.5(oc(a)h3),64.5(oc(b)h3),50.8(c,c-14),50.2(ch,c-17),47.0(ch,c-5),44.4(c,c-13),40.5(c,c-10),36.3(ch,c-20),36.2(ch2,c-11),36.2(ch2,c-1),31.1(ch2,c-2),31.1(ch2,c-6),31.0(ch2,c-7),28.1(ch2,c-12),26.5(ch2,c-15),25.9(ch2,c-16),25.2(ch3,c-30),24.0(ch2,c-22),23.0(ch3,c-19),22.3(ch3,c-18),21.8(ch2,c-23),20.5(ch3,c-21),18.6(ch3,c-26),16.0(ch3,c-29)；hrms-esi:m/zcalcdforc32h52n2nao4(m+na)⁺551.3819,found551.3820.

实施例11：manwuweizicacid类衍生物m2的合成

化合物m2的合成参照化合物m1的合成方法，原料为相应原料。

m2：白色固体，收率71％，熔点123-125℃；irνmax(kbr)3432,2925,1640,1546,1401,1323,1267cm^-1；¹hnmr(cdcl3,400mhz)δ5.91-5.74(2h,overlap,ch(a)＝ch2andch(b)＝ch2),5.73-5.63(2h,overlap,conh(a)andconh(b)),5.48(1h,t,j＝7.4hz,h-24),5.23-5.05(4h,overlap,ch＝ch2(a)andch＝ch2(b)),4.87(1h,s,ha-28),4.66(1h,s,hb-28),3.98-3.86(2h,m,ch2(a)-ch＝ch2),3.86-3.78(2h,m,ch2(b)-ch＝ch2),1.87,1.73(6h,s,ch3-26,ch3-29),2.30-1.01(23h,m,manwuweizicacidscaffold),0.93(3h,s,ch3-18),0.91-0.84(6h,overlap,ch3-30,ch3-21),0.69(3h,s,ch3-19)；¹³cnmr(cdcl3,100mhz)δ173.3(c,c-3),170.0(c,c-27),147.5(c,c-4),138.7(c,c-9),134.4(ch,c-24),134.2(c(a)h＝ch2),134.1(c(b)h＝ch2),131.4(c,c-8),129.5(c,c-25),116.5(ch＝c(a)h2),116.2(ch＝c(b)h2),113.6(ch2,c-28),50.7(c,c-14),50.2(ch,c-17),46.9(ch,c-5),44.3(c,c-13),41.8(c(a)h2-ch＝ch2),41.7(c(b)h2-ch＝ch2),40.3(c,c-10),36.2(ch2,c-1),36.2(ch,c-20),33.2(ch2,c-2),31.7(ch2,c-6),31.0(ch2,c-7),30.9(ch2,c-11),28.0(ch2,c-12),26.4(ch2,c-15),25.8(ch2,c-16),25.2(ch3,c-30),23.9(ch2,c-22),22.9(ch3,c-19),22.3(ch3,c-18),21.7(ch2,c-23),20.9(ch3,c-21),18.5(ch3,c-26),15.9(ch3,c-29)；hrms-esi:m/zcalcdforc36h57n2o2(m+h)⁺549.4415,found549.4413.

实施例12：manwuweizicacid类衍生物m3的合成

化合物m3的合成参照化合物m1的合成方法，原料为相应原料。

m3：白色固体，收率57％，熔点115-120℃；irνmax(kbr)3445,2924,1640,1401,1052cm^-1；¹hnmr(cdcl3,400mhz)δ8.35,8.23(2h,s,conh(a)andconh(b)),5.55(1h,t,j＝7.2hz,h-24),4.88(1h,s,ha-28),4.68(1h,s,hb-28),4.09-3.79(4h,overlap,och2(a)ch3andoch2(b)ch3),1.87,1.75(6h,s,ch3-26,ch3-29),1.28(3h,t,j＝6.8hz,och2ch3(a)),1.24(3h,t,j＝7.0hz,och2ch3(b)),2.33-1.05(23h,m,manwuweizicacidscaffold),0.94(3h,s,ch3-18),0.92-0.86(6h,overlap,ch3-30,ch3-21),0.71(3h,s,ch3-19)；¹³cnmr(cdcl3,100mhz)δ171.6(c,c-3),168.3(c,c-27),147.4(c,c-4),139.0(c,c-9),135.8(ch,c-24),129.5(c,c-8),128.6(c,c-25),113.7(ch2,c-28),72.3(oc(a)h2ch3),72.1(oc(b)h2ch3),50.7(c,c-14),50.2(ch,c-17),47.0(ch,c-5),44.3(c,c-13),40.4(c,c-10),36.2(ch,c-20),36.1(ch2,c-11),36.0(ch2,c-1)31.1(ch2,c-2),31.1(ch2,c-6),30.9(ch2,c-7),28.0(ch2,c-12),26.5(ch2,c-15),25.8(ch2,c-16),25.2(ch3,c-30),24.0(ch2,c-22),22.9(ch3,c-19),22.3(ch3,c-18),21.7(ch2,c-23),20.6(ch3,c-21),18.5(ch3,c-26),15.9(ch3,c-29)；hrms-esi:m/zcalcdforc34h56n2nao4(m+na)⁺579.4132,found579.4132.

实施例13：manwuweizicacid类衍生物m4的合成

化合物m4的合成参照化合物m1的合成方法，原料为相应原料。

m4：白色固体，收率56％，熔点108-111℃；irνmax(kbr)3441,2964,2925,1641,1545,1460,1403,1323,1262,1101,1026,802cm^-1；¹hnmr(cdcl3,400mhz)δ5.53-5.32(3h,overlap,conh(a),conh(b),h-24),4.89(1h,s,ha-28),4.68(1h,s,hb-28),3.36-3.24(2h,m,j＝7.2,2.4hz,ch2(a)ch2ch3),3.23-3.09(2h,m,j＝6.8hz,ch2(b)ch2ch3),1.88,1.76(6h,s,ch3-26,ch3-29),2.31-1.14(27h,overlap,manwuweizicacidscaffold,ch2ch2(a)ch3,ch2ch2(b)ch3),0.99-0.86(15h,overlap,ch3-18,ch3-30,ch3-21,ch2ch2ch3(a),ch2ch2ch3(b)),0.72(3h,s,ch3-19)；¹³cnmr(cdcl3,100mhz)δ173.4(c,c-3),170.3(c,c-27),147.6(c,c-4),138.8(c,c-9),133.4(ch,c-24),132.0(c,c-8),129.6(c,c-25),113.7(ch2,c-28),50.7(c,c-14),50.2(ch,c-17),47.0(ch,c-5),44.3(c,c-13),41.2(c(a)h2ch2ch3),41.0(c(b)h2ch2ch3),40.4(c,c-10),36.3(ch2,c-1),36.3(ch,c-20),33.3(ch2,c-2),31.9(ch2,c-6),31.1(ch2,c-7),31.0(ch2,c-11),28.0(ch2,c-12),26.4(ch2,c-15),25.8(ch2,c-16),25.2(ch3,c-30),24.0(ch2,c-22),23.0(ch3,c-19),23.0(ch2c(a)h2ch3),22.9(ch2c(b)h2ch3),22.4(ch3,c-18),21.8(ch2,c-23),20.9(ch3,c-21),18.6(ch3,c-26),15.9(ch3,c-29),11.5(ch2ch2c(a)h3),11.3(ch2ch2c(b)h3)；hrms-esi:m/zcalcdforc36h60n2nao2(m+na)⁺575.4547,found575.4554

实施例14：manwuweizicacid类衍生物m5的合成

化合物m5的合成参照化合物m1的合成方法，原料为相应原料。

m5：白色固体，收率57％，熔点103-105℃；irνmax(kbr)3442,2959,2926,1639,1548,1466,1372,1264,1158,1031cm^-1；¹hnmr(cdcl3,400mhz)δ5.54-5.35(3h,overlap,conh(a),conh(b),h-24),4.90(1h,s,ha-28),4.69(1h,s,hb-28),3.22-3.10[2h,m,j＝4.1,2.4hz,ch2(a)ch(ch3)2],3.10-3.01[2h,m,j＝6.6hz,ch2(b)ch(ch3)2],1.89,1.76(6h,s,ch3-26,ch3-29),2.30-1.07[25h,m,manwuweizicacidscaffold,ch2ch(a)(ch3)2,ch2ch(b)(ch3)2],1.01-0.79[21h,overlap,ch3-18,ch3-30,ch3-21,ch2ch(ch3(a))2,ch2ch(ch3(b))2],0.72(3h,s,ch3-19)；¹³cnmr(cdcl3,100mhz)δ173.4(c,c-3),170.3(c,c-27),147.7(c,c-4),138.8(c,c-9),133.4(ch,c-24),132.0(c,c-8),129.6(c,c-25),113.6(ch2,c-28),50.8(c,c-14),50.3(ch,c-17),47.0(ch,c-5),46.8[c(a)h2ch(ch3)2],46.7[c(b)h2ch(ch3)2],44.4(c,c-13),40.4(c,c-10),36.3(ch,c-20),36.3(ch2,c-21),33.4(ch2,c-2),32.0(ch2,c-6),31.1(ch2,c-7),31.0(ch2,c-11),28.6[ch2c(a)h(ch3)2],28.5[ch2c(a)h(ch3)2],28.0(ch2,c-12),26.5(ch2,c-15),25.9(ch2,c-16),25.2(ch3,c-30),24.0(ch2,c-22),23.0(ch3,c-19),22.4(ch3,c-18),21.8(ch2,c-23),21.0(ch3,c-21),20.2[2c,ch2ch(c(a)h3)2],20.1[2c,ch2ch(c(a)h3)2],18.6(ch3,c-26),15.9(ch3,c-29)；

实施例15：manwuweizicacid类衍生物m6的合成

化合物m6的合成参照化合物m1的合成方法，原料为相应原料。

m6：白色固体，收率66％，熔点164-167℃；irνmax(kbr)3423,3320,2963,2926,2881,1654,1633,1560,1467,1408,1323,1274,1160,1026cm^-1；¹hnmr(cdcl3,400mhz)δ5.60-5.43(3h,overlap,conh(a),conh(b),h-24),4.88(1h,s,ha-28),4.67(1h,s,hb-28),2.86(2h,d,j＝4.4hz,conhch3(a)),2.78(2h,d,j＝4.4hz,conhch3(b)),1.87,1.75(6h,s,ch3-26,ch3-29),2.26-1.03(23h,m,manwuweizicacidscaffold),0.94(3h,s,ch3-18),0.92-0.84(6h,overlap,ch3-21,ch3-30),0.71(3h,s,ch3-19)；¹³cnmr(cdcl3,100mhz)δ174.1(c,c-3),170.6(c,c-27),147.6(c,c-4),138.8(c,c-9),134.0(ch,c-24),131.6(c,c-8),129.6(c,c-25),113.7(ch2,c-28),50.7(c,c-14),50.3(ch,c-17),47.0(ch,c-5),44.4(c,c-13),40.4(c,c-10),36.3(ch2,c-1),36.2(ch,c-20),33.2(ch2,c-2),31.7(ch2,c-6),31.1(ch2,c-7),31.0(ch2,c-11),28.0(ch2,c-12),26.4(ch2,c-15),26.3(conhc(a)h3),26.1(conhc(b)h3),25.8(ch2,c-16),25.2(ch3,c-30),24.0(ch2,c-22),23.0(ch3,c-19),22.3(ch3,c-18),21.8(ch2,c-23),20.9(ch3,c-21),18.6(ch3,c-26),15.9(ch3,c-29)；hrms-esi:m/zcalcdforc32h53n2o2(m+h)⁺497.4102,found497.4100.

实施例16：manwuweizicacid类衍生物m7的合成

化合物m7的合成参照化合物m1的合成方法，原料为相应原料。

m7：白色固体，收率63％，熔点136-139℃；irνmax(kbr)3425,2963,2924,2853,1642,1402,1323,1262,1097,1030,802cm^-1；¹hnmr(cdcl3,400mhz)δ5.56-5.37(3h,overlap,conh(a),conh(b),h-24),4.88(1h,s,ha-28),4.68(1h,s,hb-28),3.40-3.29(2h,m,j＝7.1hz,ch2(a)ch3),3.29-3.20(2h,m,j＝7.2hz,ch2(b)ch3),1.87,1.75(6h,s,ch3-26,ch3-29),2.30-1.19(23h,m,manwuweizicacidscaffold),1.17(3h,t,j＝7.1hz,ch2ch3(a)),1.11(3h,t,j＝7.2hz,ch2ch3(b)),0.94,0.71(6h,s,ch3-18,ch3-19),0.92-0.84(6h,overlap,ch3-21,ch3-30)；¹³cnmr(cdcl3,100mhz)δ173.3(c,c-3),170.1(c,c-27),147.6(c,c-4),138.7(c,c-9),133.4(ch,c-24),131.9(c,c-8),129.7(c,c-25),113.6(ch2,c-28),50.7(c,c-14),50.3(ch,c-17),47.0(ch,c-5),44.4(c,c-13),40.4(c,c-10),36.3(ch2,c-1),36.3(ch,c-20),34.3(c(a)h2ch3),34.1(c(b)h2ch3),33.3(ch2,c-2),31.8(ch2,c-6),31.1(ch2,c-7),31.0(ch2,c-11),28.0(ch2,c-12),26.3(ch2,c-15),25.8(ch2,c-16),25.2(ch3,c-30),24.0(ch2,c-22),23.0(ch3,c-19),22.3(ch3,c-18),21.8(ch2,c-23),20.8(ch3,c-21),18.6(ch3,c-26),15.9(ch3,c-29),14.9(ch2c(a)h3),14.9(ch2c(b)h3)；hrms-esi:m/zcalcdforc34h57n2o2(m+h)⁺525.4415,found525.4417.

实施例17：manwuweizicacid类衍生物m8的合成

化合物m8的合成参照化合物m1的合成方法，原料为相应原料。

m8：白色固体，收率55％，熔点103-105℃；irνmax(kbr)3440,2923,1640,1402,1324,1029,929cm^-1；¹hnmr(cdcl3,400mhz)δ8.06(2h,s,conh(a)andconh(b)),6.12-5.81(2h,overlap,och2ch(a)＝ch2andoch2ch(b)＝ch2),5.57(1h,t,j＝7.3hz,h-24),5.43-5.22(4h,overlap,och2ch＝ch2(a)andoch2ch＝ch2(b)),4.89(1h,s,ha-28),4.67(1h,s,hb-28),4.51-4.41(2h,m,och2(a)-ch＝ch2),4.41-4.26(2h,m,och2(b)-ch＝ch2),1.87,1.75(6h,s,ch3-26,ch3-29),2.31-1.04(23h,m,manwuweizicacidscaffold),0.95,0.72(6h,s,ch3-18,ch3-19),0.93-0.84(6h,overlap,ch3-21,ch3-30)；¹³cnmr(cdcl3,100mhz)δ171.6(c,c-3),168.2(c,c-27),147.5(c,c-4),139.1(c,c-9),136.0(ch,c-24),132.2(och2c(a)h＝ch2),129.9(och2c(b)h＝ch2),129.5(c,c-8),128.5(c,c-25),120.8(och2ch＝c(a)h2),120.8(och2ch＝c(b)h2),113.8(ch2,c-28),77.5(overlap,oc(a)h2ch＝ch2),77.2(overlap,oc(b)h2ch＝ch2),50.8(c,c-14),50.3(ch,c-17),47.1(ch,c-5),44.4(c,c-13),40.5(c,c-10),36.3(ch2,c-1),36.2(ch,c-20),29.8(ch2,c-2),29.3(ch2,c-6),31.1(ch2,c-7),31.0(ch2,c-11),28.1(ch2,c-12),26.6(ch2,c-15),25.9(ch2,c-16),25.3(ch3,c-30),24.0(ch2,c-22),23.0(ch3,c-19),22.3(ch3,c-18),21.8(ch2,c-23),20.6(ch3,c-21),18.6(ch3,c-26),16.0(ch3,c-29)；hrms-esi:m/zcalcdforc36h56n2nao4(m+na)⁺603.4132,found603.4128.

实施例18：manwuweizicacid类衍生物m9的合成

m9的合成路线如下：

在一个10ml的圆底烧瓶中加入manwuweizicacid(94mg,0.2mmol),k2co3(111mg,0.8mmol),用2ml的dmf溶解，室温搅拌2h，加入碘甲烷(85mg,0.6mmol)，室温搅拌3h，tlc监测反应完毕后，加入15ml水稀释反应液，用乙酸乙酯萃取(3×10ml)，合并有机层，饱和食盐水洗，无水硫酸钠干燥，抽滤后得到滤液，减压蒸馏去除溶剂后得到粗品。柱层析(石油醚：乙酸乙酯＝6:1)后得到化合物b，透明油状液体，收率85％，irνmax(kbr)2963,1746,1714,1681,1646,1571,1415,1261,1093,1025,800cm^-1；¹hnmr(cdcl3,400mhz)δ5.93(1h,t,j＝7.4hz,h-24),4.89(1h,s,ha-28),4.67(1h,s,hb-28),3.73,3.65(6h,s,och3(a)andoch3(b)),1.89,1.75(6h,s,ch3-26,ch3-29),2.55-1.08(23h,m,manwuweizicacidscaffold),0.95(3h,s,ch3-18),0.94-0.89(6h,overlap,ch3-30,ch3-21),0.73(3h,s,ch3-19)；¹³cnmr(cdcl3,100mhz)δ174.8(c,c-3),168.6(c,c-27),147.4(c,c-4),144.1(ch,c-24),139.1(c,c-9),129.4(c,c-8),126.4(c,c-25),113.8(ch2,c-28),51.5(oc(a)h3),51.2(oc(b)h3),50.8(c,c-14),50.3(ch,c-17),46.8(ch,c-5),44.4(c,c-13),40.3(c,c-10),36.4(ch,c-20),35.9(ch2,c-1),32.5(ch2,c-2),31.1(ch2,c-6),31.0(ch2,c-7),29.4(ch2,c-11),28.0(ch2,c-12),26.7(ch2,c-15),25.9(ch2,c-16),25.2(ch3,c-30),24.0(ch2,c-22),23.0(ch3,c-19),22.3(ch3,c-18),21.7(ch2,c-23),20.7(ch3,c-21),18.6(ch3,c-26),15.9(ch3,c-29)；hrms-esi:m/zcalcdforc32h50nao4(m+na)⁺521.3601,found521.3597.

将化合物b(85mg,0.17mmol)加入10ml圆底烧瓶，用1ml甲醇和1ml四氢呋喃的混合溶剂溶解，加入50％羟胺水溶液(0.45ml,7mmol)和koh(76mg,1.36mmol)，室温搅拌3h，反应完毕后，反应液用1n盐酸中和至ph值为7，用乙酸乙酯萃取(3×10ml)，合并有机层，饱和食盐水洗，无水硫酸钠干燥，抽滤后得到滤液，减压蒸馏去除溶剂后得到粗品。柱层析(二氯甲烷：甲醇＝13:1)后得到化合物m9，白色固体，收率30％，熔点114℃；irνmax(kbr)3443,2925,1640,1401,1323,1265cm^-1；¹hnmr(pyridine-d5,400mhz)δ6.07(1h,t,j＝6.9hz,h-24),4.96(1h,s,ha-28),4.88(1h,s,hb-28),2.16,1.79(6h,s,ch3-26,ch3-29),3.05-1.12(23h,m,manwuweizicacidscaffold),1.03(3h,d,j＝5.2hz,ch3-21),0.98,0.86,0.76(9h,s,ch3-18,ch3-30,ch3-19)；¹³cnmr(pyridine-d5,100mhz)δ171.5(c,c-3),171.2(c,c-27),148.3(c,c-4),143.2(ch,c-24),139.2(c,c-9),130.7(c,c-8),129.2(c,c-25),114.7(ch2,c-28),51.5(c,c-14),51.1(ch,c-17),47.4(ch,c-5),45.0(c,c-13),41.2(c,c-10),37.2(ch,c-20),36.9(ch2,c-1),34.7(ch2,c-2),31.8(ch2,c-6),31.8(ch2,c-7),29.5(ch2,c-11),28.8(ch2,c-12),27.5(ch2,c-15),26.6(ch2,c-16),25.8(ch3,c-30),24.8(ch2,c-22),23.9(ch3,c-19),23.0(ch3,c-18),22.5(ch2,c-23),22.0(ch3,c-21),19.4(ch3,c-26),16.7(ch3,c-29)；hrms-esi:m/zcalcdforc30h48no4(m+h)⁺486.3578,found486.3578.

实施例19：组蛋白去乙酰化酶抑制活性的测定

1.测定程序如下：

saha作为hdac1，hdac2，hdac6和hdac8的阳性对照化合物，tmp269作为hdac4的阳性对照化合物。初步筛选阶段，用单一化合物100μm浓度测定抑制率。ic50的测定，每个化合物测定了6个浓度，起始浓度为50μm，梯度稀释5倍。

1.活性测试结果

表a.部分na和ma衍生物的hdac活性抑制数据

与na和ma相比，衍生物n9和m9对hdac的抑制活性提高，而其他化合物没有表现出显著的抑制活性(ic50>50μm)。

实施例20：抗炎活性及细胞毒性的测定

1.测定程序如下：

将小鼠巨噬细胞j774a.1置于六孔板中培养过夜，细胞密度为1×10⁶/ml，然后将六孔板上的上清液全部弃去。将含有200ng/ml的lps(脂多糖)的opti-mem(1ml/孔)加入剩余部分进行预刺激，整个刺激过程持续3小时。3小时后，再次丢弃所有上清液，加入opti-mem(500μl/孔)，其中包含需要测试的化合物或阳性对照化合物，预孵育0.5小时，然后加入nlrp3炎症小体刺激剂nig(500μl/孔)，最终浓度为10μm，与化合物孵育1小时，然后收集所有上清液，测量ldh和il-1β的释放。

将细胞j774a.1处于对数生长期，计数后接种于96孔板培养过夜，细胞密度为4×10⁴/孔，将细胞分为6组，每组3个复制孔。其中有1个正常组和5个化合物19个浓度梯度实验组，从低到高，化合物浓度分别为2.5μm,5μm,10μm,20μm和40μm。培养后弃置上清。在正常组加入200μl每孔的dmem细胞培养基(10％胎牛血清，1％p+/s+)，将含有不同浓度化合物的dmem细胞培养液(10％胎牛血清，1％p+/s+)200μl每孔分别加入5个实验组。各组培养48小时，在每孔中加入150μldmso。待晶体充分溶解后，在波长540nm和630nm处检测吸光度，计算细胞存活率。

2.活性测试结果

表b.部分na和ma衍生物的抗炎活性数据

化合物n1，n6，n8，m8，n9对ldh和il-1β蛋白表达有抑制作用，但不降低细胞活力，m9对j774a.1具有细胞毒性。其他化合物没有表现出显著的抑制活性(ic50>50μm)。

以上所述的仅是本发明的部分具体实施例，方案中公知的具体内容或常识在此未作过多描述。应当指出，上述实施例不以任何方式限制本发明，对于本领域的技术人员来说，凡是采用等同替换或等效变换的方式获得的技术方案均落在本发明的保护范围内。本申请要求的保护范围应当以其权利要求的内容为准，说明书中的具体实施方式等记载可以用于解释权利要求的内容。