CN112538088A - 一类抗前列腺癌的瑞香烷型二萜及其制备方法 - Google Patents
一类抗前列腺癌的瑞香烷型二萜及其制备方法 Download PDFInfo
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- CN112538088A CN112538088A CN202011524327.0A CN202011524327A CN112538088A CN 112538088 A CN112538088 A CN 112538088A CN 202011524327 A CN202011524327 A CN 202011524327A CN 112538088 A CN112538088 A CN 112538088A
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- daphnane
- prostate cancer
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- C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
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Abstract
本发明公开了一类抗前列腺癌的瑞香烷型二萜及其制备方法。发明人研究发现
Description
技术领域
本发明涉及一种天然化合物及其制备方法和应用,特别涉及一类瑞香烷型二萜化合物及其制备方法和在制备抗去势抵抗性前列腺癌药物方面的应用。
背景技术
前列腺癌是中老年人高发恶性肿瘤,据美国癌症协会(ACS)2020年最新癌症统计数据,美国前列腺癌发病率在恶性肿瘤中高居首位,死亡率排第二位。在我国,随着生活水平和生活节奏的改变前列腺癌的发病率也逐年飙升。
前列腺癌后期演变为去势抵抗性前列腺癌,对激素治疗无效而发生转移,是导致病人死亡的重要因素。去势抵抗性前列腺癌与异常激活的雄激素受体(AR)信号通路密切相关,分别在2010年和2011年上市的抗雄激素药物恩杂鲁胺和阿比特龙能显著提高患者生存期,但由于获得性耐药,在治疗后期收效甚微。因此,开发新型抗去势抵抗性前列腺癌的新药具有重要的研究意义和应用价值。
天然产物因具有结构多样性和良好的生物兼容性是新药研发的重要来源。文献调研显示瑞香科植物中富含结构新颖的瑞香烷型二萜。它们是具有5/7/6三环碳骨架的复杂分子结构,含有多个手性中心,通常在C3、C4、C5、C9、C13、C14、C20等位置含有手性羟基;其中,诸多化合物在C9、C13、C14位置的手性羟基之间形成特定的原酸酯结构。据报道,瑞香烷型二萜具有抗HIV、抗白血病、抗肿瘤、神经保护、杀虫、细胞毒等活性。并且我们研究发现该类二萜对前列腺癌细胞具有非常显著的抑制活性,在细胞水平和动物水平强于现有临床靶向药物恩杂鲁胺。然而,该类二萜抗前列腺癌的深入药效学、构效关系及作用机制研究尚且匮乏。
发明内容
本发明的目的在于提供一类瑞香烷型二萜化合物及其制备方法和在制备治疗去势抵抗性前列腺癌药物方面的应用。
本发明所采取的技术方案是:
本发明的第一个方面,提供:
瑞香烷型二萜化合物在制备去势抵抗性前列腺癌治疗或联合治疗药物中的应用,所述瑞香烷型二萜化合物的通式如式Ⅰ或式II所示:
式I和式II中:C-1和C-2之间为双键或不为双键;C-6和C-7之间为双键或不为双键;C-15和C-16之间为双键或不为双键;
R1选自氢或羟基;
R2选自氢、羟基、羰基、苯甲酰基或乙酰基;
R3选自氢、羟基、乙酰基、异戊酰基、巴豆酰基或苯甲酰基;
R4选自氢、羟基、乙酰基、异丁酰基、2-噻吩甲酰基、苯甲酰基或棕榈酰基;
R5选自羟基、氟、氯、溴、碘,与R6形成三元环氧或与R6消除形成C6=C7双键;
R6选自氢、羟基、氟、氯、溴、碘,与R5形成三元环氧或与R5消除形成C6=C7双键;
式I中:R7选自甲基、苯基、壬烷基、(1E,3E)-壬二烯基、(1E,3Z)-壬二烯基或(1E,3E,5E)-壬三烯基;
式II中:R7选自氢、苯甲酰基、乙酰基、癸酰基、(2E,4E)-癸二烯酰基、(2E,4Z)-癸二烯酰基或(2E,4E,6E)-癸三烯酰基;
R8选自氢或羟基;
R9选自氢、羟基、乙酰基、苯甲酰基、异丁酰基、丁酰基或丙酰基。
在一些实例中,所述瑞香烷型二萜化合物选自:
在一些实例中,所述瑞香烷型二萜化合物选自YH-6、YH-11、YH-16、YH-17、YH-22、YH-35、YH-36、YH-47、YH-48、YH-49、YH-50、YH-52及YH-53中的至少一种。
在一些实例中,所述瑞香烷型二萜化合物还包括其药学上可接受的衍生物。
在一些实例中,所述药学上可接受的衍生物为其盐。
本发明的第二个方面,提供:
瑞香烷型二萜化合物及其药用衍生物,所述瑞香烷型二萜化合物如本发明第一个方面所述。
在一些实例中,所述瑞香烷型二萜化合物选自权利要求2中的化合物YH-8、YH-9、YH-10、YH-19、YH-20、YH-21、YH-24、YH-25、YH-26、YH-30、YH-33、YH-34、YH-37、YH-38、YH-39、YH-45、YH-46、YH-47、YH-48、YH-49、YH-50、YH-52、YH-53、YH-56、YH-57、YH-60、YH-61。
本发明的第三个方面,提供:
一种治疗或辅助治疗去势抵抗性前列腺癌的组合物,所述组合物的活性成分包括本发明第一个方面所述的瑞香烷型二萜化合物及其可接受的药用衍生物中的至少一种。
在一些实例中,所述药学上可接受的衍生物为其盐。
在一些实例中,所述瑞香烷型二萜化合物选自化合物YH-6、YH-11、YH-16、YH-17、YH-22、YH-35、YH-36、YH-8、YH-9、YH-10、YH-19、YH-20、YH-21、YH-24、YH-25、YH-26、YH-30、YH-33、YH-34、YH-37、YH-38、YH-39、YH-45、YH-46、YH-47、YH-48、YH-49、YH-50、YH-52、YH-53、YH-56、YH-57、YH-60、YH-61及其可接受的药用衍生物。
在一些实例中,所述组合物还包括至少一种对前列腺癌有治疗作用的化合物,优选的,所述对前列腺癌有治疗作用的化合物为恩杂鲁胺、阿比特龙、环磷酰胺、阿霉素、多烯紫杉醇、米托蒽醌。
本发明的有益效果是:
本发明的一些实例,首次分离或合成得到了一类瑞香烷型二萜化合物。该类化合物可以显著抑制多种前列腺癌细胞的增殖,特别是化合物YH-52在细胞水平和动物水平活性均强于现有临床靶向药物恩杂鲁胺,且其与恩杂鲁胺联合用药后具有较强的协同效果,有望成为治疗去势抵抗性前列腺癌的候选药物。
附图说明
图1是芫花提取分离流程图;
图2是化合物YH-52口服给药对前列腺癌22RV1异种移植小鼠的治疗作用;
图3是YH-52与恩杂鲁胺联合腹腔注射给药对前列腺癌22RV1异种移植小鼠的治疗作用。
具体实施方式
发明人从瑞香科植物芫花中分离得到34个天然瑞香烷型二萜,并对部分化合物进行结构修饰获得30个衍生物。将所得系列二萜进行抗前列腺癌细胞的相关测试,发现了一系列对该肿瘤细胞具有显著抑制活性的化合物,效果强于临床上现有靶向药物恩杂鲁胺,其中1个新化合物有望成为治疗去势抵抗性前列腺癌的候选药物。
下面结合实施例,进一步说明本发明的技术方案。除非特别说明,本发明采用的试剂、设备和方法为本技术领域常规市购的试剂、设备和常规使用的方法。
本发明中对瑞香科植物(以芫花为例)进行研究。
设备及试剂:NMR波谱采用Bruker AM-400/500spectrometer记录,TMS内标。柱色谱硅胶(300~400目):青岛海洋化工厂;GF254硅胶薄层色谱预制板:青岛海洋化工厂;MCI填料(CHP20P,75~150μm):日本Mitsubishi公司;葡聚糖凝胶(Sephadex LH-20):美国GE公司;ODS填料(12nm,S-50μm):日本YMC公司;其余溶剂和试剂:分析纯(AR),天津市百世化工有限公司。
瑞香烷型二萜类化合物的制备
取芫花20kg,粉碎成粗粉。加入3倍体积量的95%乙醇,浸泡1周,抽滤后减压回收乙醇。重复3次以上浸泡提取步骤,最终得到芫花乙醇提取物浸膏1500g,芫花浸膏用1L水分散后,用乙酸乙酯萃取三次。合并乙酸乙酯萃取液,减压浓缩,得到乙酸乙酯萃取物300g。
取上述乙酸乙酯萃取物载于硅胶柱上,用石油醚:乙酸乙酯,二氯甲烷:甲醇进行初步分段,然后用ODS、MCI、凝胶Sephadex LH-20等进一步分离,最后用半制备高效液相色谱手段在(乙腈:水)或(甲醇:水)条件下进一步纯化,得到34个单体化合物,具体分离流程图参考图1。
将所得部分瑞香烷型二萜化合物进行结构修饰制备其衍生物。
分离产物的鉴定
实施例1:通过半制备HPLC纯化得到化合物YH-30,其结构和数据如下:
YH-30:[α]25 D+7.8(c 0.230,CH2Cl2);UV(MeOH)λmax(logε)232(4.21)nm;ECD(c 3.3×10-4M,MeCN)λmax(Δε)252(-2.44)nm;IR(KBr)νmax 3445,2925,2856,1705,1632,1451,1401,1379,1301,1268,1108,1070,1026,938,913,863cm-1;1H NMR(CDCl3,400MHz)δH 7.55(1H,s,H-1),4.20(1H,s,H-5),3.61(1H,s,H-7),3.59(1H,d,J=2.4Hz,H-8),3.76(1H,m,H-10),2.52(1H,q,J=7.2Hz,H-11),5.18(1H,s,H-12),4.84(1H,d,J=2.4Hz,H-14),4.99(2H,s,H-16),1.84(3H,s,H3-17),1.37(3H,d,J=7.2Hz,H3-18),1.76(3H,br s,H3-19),3.81(1H,d,J=12.0Hz,H-20a),3.90(1H,d,J=12.0Hz,H-20b),1′-Me:1.70(3H,s);12-OBz:7.87(2H,m),7.44(2H,m),7.57(1H,m);13C NMR(CDCl3,100MHz)δC 160.3(C-1),136.9(C-2),209.4(C-3),72.2(C-4),71.8(C-5),60.7(C-6),64.1(C-7),35.5(C-8),77.8(C-9),47.4(C-10),44.0(C-11),78.9(C-12),83.9(C-13),80.5(C-14),143.0(C-15),113.5(C-16),18.6(C-17),18.3(C-18),9.8(C-19),64.8(C-20),118.9(C-1′),1′-Me:21.5,12-OBz:165.4,129.7,129.4×2,128.6×2,133.3;HRESIMS m/z 541.2070[M+H]+(calcd forC29H33O10 +,541.2068).
实施例2:通过半制备HPLC分离纯化得到化合物YH-60,其结构和数据如下:
YH-60:[α]25 D-14.2(c 0.148,CH2Cl2);UV(MeOH)λmax(logε)232(4.50)nm;IR(KBr)νmax 3418,2925,2855,1704,1631,1452,1379,1315,1270,1178,1108,1070,1026,1010,940,915cm-1;1H NMR(CDCl3,400MHz)δH 7.63(1H,s,H-1),4.13(1H,s,H-5),3.36(1H,s,H-7),4.22(1H,d,J=5.2Hz,H-8),3.51(1H,s,H-10),2.51(1H,m,H-11),5.22(1H,d,J=2.2Hz,H-12),6.19(1H,d,J=5.2Hz,H-14),5.04(1H,s,H-16a),5.34(1H,s,H-16b),1.88(3H,s,H3-17),1.40(3H,d,J=7.3Hz,H3-18),1.75(3H,br s,H3-19),3.34(1H,d,J=12.3Hz,H-20a),4.00(1H,d,J=12.3Hz,H-20b),12-OBz:7.97(2H,d,J=7.4Hz),7.49(2H,m),7.60(1H,m);14-OBz:8.07(2H,d,J=7.0Hz),7.28(2H,m),7.60(1H,m);13C NMR(CDCl3,100MHz)δC 159.6(C-1),137.0(C-2),208.6(C-3),72.4(C-4),69.5(C-5),63.1(C-6),62.8(C-7),40.3(C-8),75.8(C-9),51.0(C-10),42.9(C-11),79.9(C-12),75.2(C-13),73.7(C-14),144.5(C-15),114.9(C-16),19.6(C-17),16.2(C-18),9.9(C-19),65.5(C-20),12-OBz:165.8,129.4,129.6×2,128.6×2,133.3,14-OBz:166.6,129.8,130.0×2,128.4×2,133.4;HRESIMS m/z 619.2168[M-H]-(calcd for C34H35O11 -,619.2185).
衍生物的制备
实施例3:YH-7和YH-8的制备
取化合物YH-6(30mg)溶于2mL吡啶中,在N2保护下搅拌,然后用注射器打入100μL乙酸酐,50℃加热反应,薄层检测有两个产物,并且原料基本反应完时,加入3mL水使反应停止,之后用EtOAc(5mL)萃取三次,反应产物通过制备薄层(CH2Cl2/MeOH,50:1)纯化得YH-7(10mg)与YH-8(15mg),结构和数据如下:
YH-7:UV(MeOH)λmax(logε)240(3.70)nm;1H NMR(400MHz,CDCl3)δH 7.72(2H,m),7.49(1H,br s),7.39(3H,m),5.57(1H,s),5.05(2H,s,overlap),5.02(1H,s),4.91(1H,d,J=2.5Hz),4.80(1H,d,J=12.0Hz),4.06(1H,m),3.67(1H,d,J=2.5Hz),3.63(1H,d,J=12.0Hz),3.53(1H,s),3.07(1H,s),2.37(1H,q,J=7.3Hz),2.20(3H,s),2.03(6H,s),1.88(3H,s),1.75(1H,br s),1.31(3H,d,J=7.3Hz);13C NMR(100MHz,CDCl3)δC 10.0,18.1,18.8,20.6,20.7,21.1,35.4,43.9,47.9,59.5,64.2,66.3,68.4,71.8,78.1,78.3,80.5,84.1,113.5,117.9,126.0,128.0,129.7,135.1,137.1,143.0,158.2,168.8,169.6,170.6,205.6;MS m/z 625.2[M+H]+,659.2[M+Cl]-.
YH-8:[α]D 25+12.0(c 0.47,MeOH),UV(MeOH)λmax(logε)241(4.16)nm;IR(KBr)νmax3469,2929,1738,1698,1234,1082,and 1024cm-1;1H NMR(CDCl3,400MHz)δH 7.57(1H,br s,H-1),4.30(1H,s,H-5),3.51(1H,s,H-7),3.61(1H,d,J=2.6Hz,H-8),3.96(1H,m,H-10),2.46(1H,q,J=7.3Hz,H-11),5.07(1H,s,H-12),4.88(1H,d,J=2.6Hz,H-14),5.04(1H,s,H-16a),5.02(1H,s,H-16b),1.88(3H,s,H3-17),1.35(3H,d,J=7.3Hz,H3-18),1.78(3H,brs,H3-19),4.83(1H,d,J=12.0Hz,H-20a),3.92(1H,d,J=12.0Hz,H-20b).1′-Ph:7.71(2H,m),7.38(2H,m),7.38(1H,m),12-OAc:2.02(3H.s).20-OAc:2.09(3H,s);13C NMR(CDCl3,100MHz)δC160.1(C-1),136.9(C-2),209.2(C-3),72.2(C-4),69.8(C-5),59.4(C-6),64.0(C-7),35.3(C-8),78.6(C-9),47.3(C-10),44.0(C-11),78.2(C-12),84.0(C-13),80.7(C-14),143.0(C-15),113.5(C-16),18.8(C-17),18.3(C-18),9.9(C-19),65.7(C-20),117.9(C-1′).1′-Ph:135.2,126.0×2,128.0×2,129.6.12-OAc:169.6,21.1.20-OAc:170.6,20.8;HRESIMS m/z 583.2179[M+H]+(calcd for C31H35O11 +,583.2174).
实施例4:化合物YH-9的制备
取化合物YH-6(20mg)溶于2mL二氯甲烷中,搅拌情况下加入100μL三乙胺(Et3N),然后加入苯甲酰氯100μL,反应30分钟,待原料反应完,加入5mL H2O停止反应,随后用二氯甲烷(3×5mL)萃取,有机相浓缩后用凝胶(Sephadex LH-20,MeOH)和制备薄层(CH2Cl2/MeOH,50:1)纯化后得到化合物YH-9(11mg)。其结构和数据如下:
YH-9:[α]D 25+24(c 0.43,MeOH);UV(MeOH)λmax(logε)231(3.50)nm;IR(KBr)νmax3465,2925,1721,1274,1240,1082,and 1023cm-1;1H NMR(CDCl3,400MHz)δH 7.58(1H,br s,H-1),4.39(1H,s,H-5),3.59(1H,s,H-7),3.66(1H,d,J=2.3Hz,H-8),4.01(1H,br s,H-10),2.49(1H,q,J=7.3Hz,H-11),5.08(1H,s,H-12),4.90(1H,d,J=2.3Hz,H-14),5.03(1H,s,H-16a),5.05(1H,s,H-16b),1.88(3H,s,H3-17),1.37(3H,d,J=7.3Hz,H3-18),1.79(3H,br s,H3-19),5.13(1H,d,J=11.9Hz,H-20a),4.10(1H,d,J=11.9Hz,H-20b).1′-Ph:7.71(2H,m),7.38(2H,m),7.38(1H,m).12-OAc:2.02(3H.s).20-OBz:8.05(2H,d,J=7.7Hz),7.43(2H,t,J=7.7Hz),7.56(1H,m);13C NMR(CDCl3,100MHz)δC 160.1(C-1),136.9(C-2),209.2(C-3),72.3(C-4),69.8(C-5),59.7(C-6),64.2(C-7),35.3(C-8),78.6(C-9),47.3(C-10),44.0(C-11),78.3(C-12),84.1(C-13),80.7(C-14),143.0(C-15),113.5(C-16),18.8(C-17),18.3(C-18),9.9(C-19),66.6(C-20),117.9(C-1′).1′-Ph:135.2,126.0×2,128.0×2,129.6.12-OAc:169.6,21.1.20-OBz:166.2,129.8,129.7×2,128.4×2,133.2;ESIMS m/z 645.2[M+H]+,679.2[M+Cl]-;HRESIMS m/z 643.2184[M-H]-(calcd forC36H35O11 -,643.2185).
实施例5:化合物YH-10的制备
取化合物YH-6(20mg)溶于无水吡啶中,抽真空加氮气保护,然后用注射器加入100μL2-噻吩甲酰氯(2-Thiophenecarbonyl chloride),50度加热反应2h,反应完后加入5mL水淬灭,然后用EtOAc(3×5mL)萃取,有机相浓缩后通过制备薄层(CH2Cl2/MeOH,50:1)和凝胶(MeOH)纯化后得化合物YH-10(12mg)。其结构和数据如下:
YH-10:Colorless oil:[α]D 25+17.1(c 0.23,MeOH);UV(MeOH)λmax(logε)245(3.94)nm;IR(KBr)νmax 3476,2924,1706,1257,1230,1081,and 750cm-1;1H NMR(CDCl3,400MHz)δH7.57(1H,br s,H-1),4.36(1H,s,H-5),3.57(1H,s,H-7),3.64(1H,d,J=2.5Hz,H-8),3.98(1H,m,H-10),2.48(1H,q,J=7.2Hz,H-11),5.07(1H,s,H-12),4.90(1H,d,J=2.5Hz,H-14),5.05(1H,s,H-16a),5.02(1H,s,H-16b),1.88(3H,s,H3-17),1.36(3H,d,J=7.2Hz,H3-18),1.79(3H,br s,H3-19),5.12(1H,d,J=11.9Hz,H-20a),4.05(1H,d,J=11.9Hz,H-20b).1′-Ph:7.71(2H,m),7.38(2H,m),7.38(1H,m).12-OAc:2.02(3H.s).2-thenoyl:7.82(1H,dd,J=3.7,1.1Hz),7.09(1H,dd,J=4.8,3.9Hz),7.55(1H,dd,J=4.8,1.1Hz);13C NMR(CDCl3,100MHz)δC 160.2(C-1),137.0(C-2),209.2(C-3),72.3(C-4),69.7(C-5),59.7(C-6),64.0(C-7),35.3(C-8),78.6(C-9),47.3(C-10),44.0(C-11),78.2(C-12),84.1(C-13),80.7(C-14),143.0(C-15),113.6(C-16),18.9(C-17),18.3(C-18),10.0(C-19),66.6(C-20),117.9(C-1′).1′-Ph:135.2,126.0×2,128.1×2,129.7.12-OAc:169.7,21.2.2-thenoyl:161.8,133.1,133.9,127.9,132.8;ESIMS m/z 651.2[M+H]+,[M+Cl]-;HRESIMS m/z 651.1858(calcd for C34H35O11S+,651.1855).
实施例6:化合物YH-12和YH-13的制备
取化合物YH-11(30mg)溶于2mL吡啶中,在N2保护下搅拌,然后用注射器打入100μL乙酸酐,50℃加热反应,薄层检测有两个产物,并且原料基本反应完时,加入3mL水使反应停止,之后用EtOAc(5mL)萃取三次,反应产物通过制备薄层(CH2Cl2/MeOH,50:1)纯化得YH-12(13mg)与YH-13(10mg),结构和数据如下:
YH-12:[α]D 25+63.3(c 0.33,MeOH);UV(MeOH)λmax(logε)231(3.99)nm;IR(KBr)νmax3445,2925,1710,1268,1080,and 713cm-1;1H NMR(CDCl3,400MHz)δH 7.50(1H,br s,H-1),5.55(1H,s,H-5),3.59(1H,s,H-7),3.78(1H,d,J=2.5Hz,H-8),4.08(1H,m,H-10),2.55(1H,q,J=7.2Hz,H-11),5.28(1H,s,H-12),5.05(1H,d,J=2.5Hz,H-14),5.09(1H,s,H-16a),5.04(1H,s,H-16b),1.92(3H,s,H3-17),1.40(3H,d,J=7.2Hz,H3-18),1.74(3H,br s,H3-19),4.79(1H,d,J=12.0Hz,H-20a),3.64(1H,d,J=12.0Hz,H-20b).1′-Ph:7.75(2H,m),7.40(2H,m),7.40(1H,m).12-OBz:7.94(2H,m),7.48(2H,m),7.61(1H,m).5-OAc:2.14(3H,s).20-OAc:2.03(3H,s);13C NMR(CDCl3,100MHz)δC 158.0(C-1),137.2(C-2),205.4(C-3),71.7(C-4),68.4(C-5),59.6(C-6),64.2(C-7),35.9(C-8),78.4(C-9),47.9(C-10),44.0(C-11),78.9(C-12),84.3(C-13),80.6(C-14),142.9(C-15),113.8(C-16),18.9(C-17),18.2(C-18),10.0(C-19),66.4(C-20),118.0(C-1′).1′-Ph:135.1,126.0×2,128.1×2,129.7.12-OBz:165.4,129.7,129.5×2,128.6×2,133.4.5-OAc:168.8,20.7.20-OAc:170.6,20.3;ESIMS m/z 687.3[M+H]+;HRESIMS m/z 687.2420[M+H]+(calcd for C38H39O12 +,687.2436).
YH-13:white powder;[α]D 25+50.2(c 0.43,MeOH);UV(MeOH)λmax(logε)232(4.02)nm;IR(KBr)νmax 3446,2925,1908,1451,1365,1267,1241,978,713cm-1;1H NMR(CDCl3,400MHz)δH 7.59(1H,br s,H-1),4.28(1H,d,J=2.4Hz,H-5),3.59(1H,s,H-7),3.73(1H,d,J=2.5Hz,H-8),3.98(1H,m,H-10),2.64(1H,q,J=7.3Hz,H-11),5.32(1H,s,H-12),5.01(1H,d,J=2.5Hz,H-14),5.08(1H,s,H-16a),5.03(1H,s,H-16b),1.92(3H,s,H3-17),1.45(3H,d,J=7.3Hz,H3-18),1.77(3H,br s,H3-19),4.84(1H,d,J=12.0Hz,H-20a),3.92(1H,d,J=12.0Hz,H-20b).1′-Ph:7.75(2H,m),7.40(2H,m),7.40(1H,m).12-OBz:7.92(2H,m),7.47(2H,m),7.59(1H,m).20-OAc:2.09(3H,s);13C NMR(CDCl3,100MHz)δC 160.1(C-1),136.9(C-2),209.2(C-3),72.1(C-4),69.8(C-5),59.4(C-6),64.1(C-7),35.7(C-8),78.6(C-9),47.3(C-10),44.1(C-11),78.9(C-12),84.2(C-13),80.7(C-14),142.9(C-15),113.8(C-16),18.9(C-17),18.4(C-18),9.9(C-19),65.8(C-20),118.0(C-1′).1′-Ph:135.1,126.0×2,128.1×2,129.7.12-OBz:165.4,129.7,129.5×2,128.6×2,133.4.20-OAc:170.6,20.9;ESIMS m/z 645.3[M+H]+;HRESIMS m/z 645.2339[M+H]+(calcd forC36H37O11 +,645.2330).
实施例7:化合物YH-25的制备
取化合物YH-22(23mg),参照实施例4中的方法制备,所得产物经过凝胶(SephadexLH-20,MeOH)和制备薄层(CH2Cl2/MeOH,100:1)纯化后得YH-25(15mg)。其结构和数据如下:
YH-25:Colorless oil;[α]D 25+28.5(c 0.067,MeOH);UV(MeOH)λmax(logε)230(4.50)nm;IR(KBr)νmax 3459,2926,1719,1273,1230,1026,and 711cm-1;1H NMR(CDCl3,400MHz)δH7.57(1H,m,H-1),4.37(1H,s,H-5),3.52(1H,s,H-7),3.57(1H,d,J=2.5Hz,H-8),3.91(1H,m,H-10),2.40(1H,q,J=7.2Hz,H-11),4.99(1H,s,H-12),4.76(1H,d,J=2.5Hz,H-14),5.01(1H,s,H-16a),4.97(1H,s,H-16b),1.84(3H,s,H3-17),1.30(3H,d,J=7.2Hz,H-18),1.78(3H,br s,H3-19),5.12(1H,d,J=11.9Hz,H-20a),4.07(1H,d,J=11.9Hz,H-20b),5.64(1H,d,J=15.5Hz,H-2′),6.66(1H,dd,J=15.5,10.6Hz,H-3′),6.03(1H,dd,J=15.0,10.6Hz,H-4′),5.85(1H,dd,J=15.0,7.4Hz,H-5′),2.08(2H,m,H2-6′),1.37(2H,m,H2-7′),1.26(2H,m,H2-8′),1.26(2H,m,H2-9′),0.87(3H,t,J=6.9Hz,H-10′).12-OAc:1.99(3H.s).20-OBz:8.04(2H,d,J=7.3Hz),7.44(2H,m,),7.56(1H,m);13C NMR(CDCl3,100MHz)δC 160.2(C-1),136.9(C-2),209.2(C-3),72.3(C-4),69.7(C-5),59.7(C-6),64.1(C-7),35.2(C-8),78.1(C-9),47.3(C-10),43.9(C-11),78.2(C-12),83.6(C-13),80.3(C-14),143.1(C-15),113.3(C-16),18.7(C-17),18.2(C-18),9.9(C-19),66.6(C-20),117.1(C-1′),122.2(C-2′),135.0(C-3′),128.5(C-4′),139.3(C-5′),32.6(C-6′),28.7(C-7′),31.3(C-8′),22.5(C-9′),14.0(C-10′).12-OAc:169.7,21.1.20-OBz:166.2,129.7,129.7×2,128.4×2,133.1;ESIMS m/z 691.3[M+H]+,725.2[M+Cl]-;HRESIMS m/z689.2962[M-H]-(calcd for C39H45O11,689.2967).
实施例8:化合物YH-33的制备
取化合物YH-22(30mg)溶于3mL二氯甲烷中,加入10mg Grubbs二代催化剂,抽真空加氮气保护,用注射器加入200μL苯乙烯,然后在40℃加热搅拌反应1小时。过滤除掉催化剂,滤液浓缩后用HPLC(MeCN/H2O,75%,3mL/min)纯化得化合物YH-33(15mg,tR=10min)。其结构和数据如下:
YH-33:[α]D 25+4.2(c 0.33,MeOH);UV(MeOH)λmax(logε)286(4.26)nm;1H NMR(CDCl3,400MHz)δH 7.59(1H,br s,H-1),4.27(1H,s,H-5),3.57(1H,s,H-7),3.53(1H,d,J=2.5Hz,H-8),3.85(1H,m,H-10),2.39(1H,q,J=7.3Hz,H-11),5.00(1H,s,H-12),4.79(1H,d,J=2.5Hz,H-14),5.03(1H,br s,H-16a),4.97(1H,br s,H-16b),1.85(3H,s,H3-17),1.31(3H,d,J=7.3Hz,H3-18),1.80(3H,br s,H3-19),3.94(1H,d,J=12.4Hz,H-20a),3.81(1H,d,J=12.4Hz,H-20b),5.88(1H,d,J=14.9Hz,H-2′),6.86(1H,dd,J=14.9,10.0Hz,H-3′),6.77(1H,dd,J=15.1,10.0Hz,H-4′),6.69(1H,d,J=15.1Hz,H-5′),7.40(2H,m,H-7′/H-11′),7.32(1H,dd,J=7.5,7.5Hz,H-8′/H-10′),7.26(1H,m,H-9′);12-OAc:2.00(3H,s);13C NMR(CDCl3,100MHz)δC160.3(C-1),136.9(C-2),209.4(C-3),72.2(C-4),71.9(C-5),60.5(C-6),64.2(C-7),35.4(C-8),78.3(C-9),47.4(C-10),44.0(C-11),78.2(C-12),83.8(C-13),80.5(C-14),143.0(C-15),113.4(C-16),18.7(C-17),18.3(C-18),9.9(C-19),65.1(C-20),116.8(C-1′),124.9(C-2′),134.8(C-3′),127.0(C-4′),136.0(C-5′),136.7(C-6′),126.7(C-7′/C-11′),128.6(C-8′/10′),128.1(C-9′),12-OAc:169.7,21.2;HRESIMS m/z 615.2206[M+Na]+(calcd for,C33H36O10Na+,615.2201)and 627.1993[M+Cl]-(calcd for C33H36O10Cl-,627.2002).
实施例9:化合物YH-34的制备
取化合物YH-16(30mg),参照实施例8中的方法进行制备,所得产物经过HPLC(MeCN/H2O,80%,3mL/min)纯化得化合物YH-34(16mg,tR=14min)。其结构和数据如下:
YH-34:[α]D 25+27.8(c 0.13,MeOH);UV(MeOH)λmax(logε)285(4.24)nm;1H NMR(CDCl3,500MHz)δH 7.61(1H,br s,H-1),4.23(1H,s,H-5),3.66(1H,s,H-7),3.65(1H,d,J=2.7Hz,H-8),3.87(1H,m,H-10),2.58(1H,q,J=7.2Hz,H-11),5.24(1H,s,H-12),4.93(1H,d,J=2.7Hz,H-14),5.04(1H,br s,H-16a),5.02(1H,br s,H-16b),1.89(3H,s,H3-17),1.41(3H,d,J=7.2Hz,H3-18),1.79(3H,br s,H3-19),3.94(1H,d,J=12.2Hz,H-20a),3.83(1H,d,J=12.2Hz,H-20b),5.91(1H,d,J=15.2Hz,H-2′),6.90(1H,dd,J=15.2,10.5Hz,H-3′),6.78(1H,dd,J=15.4,10.5Hz,H-4′),6.73(1H,d,J=15.4Hz,H-5′),7.41(2H,d,J=7.6Hz,H-7′/H-11′),7.33(1H,dd,J=7.6,7.6Hz,H-8′/H-10′),7.26(1H,m,H-9′);12-OBz:7.90(2H,d,J=7.6Hz),7.46(2H,dd,J=7.6,7.6Hz),7.58(1H,dd,J=7.6,7.6Hz);13C NMR(CDCl3,125MHz)δC 160.2(C-1),137.0(C-2),209.3(C-3),72.2(C-4),71.8(C-5),60.6(C-6),64.0(C-7),35.8(C-8),78.4(C-9),47.4(C-10),44.1(C-11),78.9(C-12),84.0(C-13),80.5(C-14),142.9(C-15),113.7(C-16),18.8(C-17),18.3(C-18),9.9(C-19),64.7(C-20),116.9(C-1′),124.8(C-2′),134.8(C-3′),127.0(C-4′),136.1(C-5′),136.7(C-6′),126.7(C-7′/C-11′),128.6(C-8′/10′),128.1(C-9′),12-OBz:129.6,129.5×2,128.7×2,133.3;HRESIMS m/z 689.2147[M+Cl]-(calcd for C38H38O10Cl-,689.2159).
实施例10:化合物YH-37的制备
取化合物YH-22(20mg)溶于3mL甲醇中,加入钯碳催化剂20mg,抽真空后加氢气保护,然后常温下搅拌反应30分钟,过滤除掉钯碳,滤液浓缩后直接用HPLC(MeCN/H2O,95%,3mL/min)纯化得化合物YH-37(12mg,tR=14min)。其结构和数据如下:
YH-37:[α]D 25+87.0(c 0.033,MeOH);UV(MeOH)λmax(logε)243(4.03)nm;IR(KBr)νmax 3465,2925,1744,1698,1230,1027,and 936cm-1;1H NMR(CDCl3,400MHz)δH 7.53(1H,brs,H-1),4.23(1H,s,H-5),3.49(1H,s,H-7),3.34(1H,d,J=2.4Hz,H-8),3.73(1H,m,H-10),2.30(1H,q,J=7.3Hz,H-11),4.93(1H,s,H-12),4.44(1H,d,J=2.4Hz,H-14),1.85(1H,m,H-15),0.91(3H,d,J=6.9Hz,H3-16),0.93(3H,d,J=6.9Hz,H3-17),1.22(3H,d,J=7.3Hz,H3-18),1.78(3H,br s,H3-19),3.89(1H,d,J=12.4Hz,H-20a),3.79(1H,d,J=12.4Hz,H-20b),1.87(2H,m,H2-2′),1.54(2H,m,H2-3′),1.27-1.30(8H,m,H-4′-H-7′),1.30(2H,m,H2-8′),1.26(2H,m,H2-9′),0.87(3H,t,J=6.8Hz,H-10′);12-OAc:2.00(3H,s);13C NMR(CDCl3,100MHz)δC 160.9(C-1),136.6(C-2),209.7(C-3),72.2(C-4),72.0(C-5),60.4(C-6),64.5(C-7),35.5(C-8),77.2(C-9),47.5(C-10),44.0(C-11),77.5(C-12),83.6(C-13),80.0(C-14),31.3(C-15),16.6(C-16),15.9(C-17),18.1(C-18),9.8(C-19),65.2(C-20),119.9(C-1′),34.8(C-2′),23.4(C-3′),29.6(C-4′),29.5(C-5′),29.5(C-6′),29.3(C-7′),22.7(C-8′),31.8(C-9′),14.1(C-10′);12-OAc:169.9,21.2;HRESIMS m/z 593.3315[M+H]+(calcd for C32H49O10 +,593.3320).
实施例11:化合物YH-38的制备
取化合物YH-22(20mg)溶于3mL甲醇中,加入钯碳催化剂30mg,抽真空后加氢气保护,50摄氏度搅拌反应30分钟,过滤除掉钯碳,滤液浓缩后直接用HPLC(MeCN/H2O,95%,3mL/min)纯化得化合物YH-38(9mg,tR=15min)。其结构和数据如下:
YH-38:[α]D 25+76.8(c 0.67,MeOH);UV(MeOH)λmax(logε)202(3.50)nm;IR(KBr)νmax3463,2927,1742,1378,1229,1028,and 940cm-1;1H NMR(CDCl3,500MHz)δH 1.53(1H,m,H-1a),2.28(1H,m,H-1b)2.28(1H,m,H-2),4.07(1H,s,H-5),3.44(1H,s,H-7),3.32(1H,s,H-8),2.84(1H,m,H-10),2.25(1H,m,H-11),5.03(1H,s,H-12),4.40(1H,s,H-14),1.83(1H,m,H-15),0.93(3H,d,J=6.7Hz,H3-16),0.93(3H,d,J=6.7Hz,H3-17),1.25(3H,d,J=7.3Hz,H3-18),1.10(3H,d,J=5.5Hz,H3-19),3.87(1H,d,J=12.2Hz,H-20a),3.75(1H,d,J=12.2Hz,H-20b),1.84(2H,m,H2-2′),1.52(2H,m,H2-3′),1.25-1.31(8H,m,H-4′-H-7′),1.28(2H,m,H2-8′),1.26(2H,m,H2-9′),0.87(3H,t,J=6.7Hz,H-10′);12-OAc:2.00(3H,s);13CNMR(CDCl3,125MHz)δC 33.3(C-1),42.8(C-2),220.3(C-3),75.0(C-4),71.1(C-5),60.7(C-6),64.5(C-7),35.5(C-8),77.6(C-9),44.0(C-10),43.5(C-11),76.8(C-12),83.1(C-13),80.3(C-14),31.2(C-15),16.5(C-16),15.9(C-17),18.3(C-18),12.4(C-19),65.4(C-20),120.0(C-1′),34.9(C-2′),23.3(C-3′),29.6(C-4′),29.5(C-5′),29.5(C-6′),29.3(C-7′),22.6(C-8′),31.8(C-9′),14.1(C-10′);12-OAc:170.0,21.2;HRESIMS m/z 617.3316[M+Na]+(calcd for C32H50O10 +,617.3296).
实施例12:化合物YH-39的制备
取化合物YH-11,参照实施例11中的方法进行制备,所得产物经过HPLC(MeCN/H2O,70%,3mL/min)纯化得化合物YH-39(10mg,tR=17min)。其结构和数据如下:
YH-39:[α]D 25+64.5(c 0.067,MeOH);UV(MeOH)λmax(logε)230(4.08)nm;IR(KBr)νmax 3483,2968,1720,1272,1079,and 1025cm-1;1H NMR(CDCl3,400MHz)δH 2.36(1H,m,H-1α),1.61(1H,m,H-1β),2.25(1H,m,H-2),4.05(1H,s,H-5),3.62(1H,s,H-7),3.59(1H,d,J=2.4Hz,H-8),3.01(1H,dd,J=13.2,5.8Hz,H-10),2.54(1H,q,J=6.9Hz,H-11),5.42(1H,s,H-12),4.74(1H,d,J=2.4Hz,H-14),2.03(1H,m,H-15),1.04(3H,d,J=6.7Hz,H3-16),1.04(3H,d,J=6.7Hz,H3-17),1.46(3H,d,J=6.9Hz,H3-18),1.09(3H,d,J=6.6Hz,H3-19),3.86(1H,d,J=12.3Hz,H-20a),3.79(1H,d,J=12.3Hz,H-20b);1′-Ph:7.75(2H,m),7.39(2H,m),7.39(1H,m).12-OBz:7.94(2H,d,J=7.4Hz),7.47(2H,dd,J=7.4,7.4Hz),7.59(1H,dd,J=7.4,7.4Hz);13C NMR(CDCl3,100MHz)δC 33.4(C-1),42.8(C-2),220.1(C-3),74.9(C-4),71.2(C-5),60.7(C-6),64.4(C-7),36.1(C-8),78.9(C-9),44.1(C-10),43.8(C-11),77.3(C-12),84.1(C-13),81.0(C-14),31.6(C-15),16.7(C-16),16.2(C-17),18.6(C-18),12.4(C-19),65.1(C-20),118.1(C-1′).1′-Ph:135.7,125.9×2,128.0×2,129.5.12-OBz:165.6,129.8,129.5×2,128.6×2,133.3;HRESIMS m/z 605.2407[M-H]-(calcd forC34H37O10 -,605.2392).
实施例13:YH-47和YH-48的制备
取化合物YH-6(30mg)溶于2mL四氢呋喃(THF),搅拌的情况下加入200μL浓盐酸,反应20min左右,加入10mL水使反应停止,然后加入EtOAc(3×10mL)萃取。反应产物经过凝胶(MeOH)和制备薄层(CH2Cl2/MeOH,40:1)得化合物YH-47(13mg)和YH-48(10mg)。其结构和数据如下:
YH-47:[α]D 25+10.5(c 0.13,MeOH);UV(MeOH)λmax(logε)241(3.70)nm;IR(KBr)νmax3451,2925,1740,1691,1230,1078,and 697cm-1;1H NMR(CDCl3,400MHz)δH 7.61(1H,br s,H-1),4.38(1H,s,H-5),4.74(1H,s,H-7),3.60(1H,d,J=2.4Hz,H-8),4.04(1H,m,H-10),2.85(1H,q,J=7.3Hz,H-11),5.03(1H,s,H-12),4.96(1H,d,J=2.4Hz,H-14),5.03(1H,s,H-16a),5.06(1H,s,H-16b),1.87(3H,s,H3-17),1.35(3H,d,J=7.3Hz,H3-18),1.81(3H,brs,H3-19),4.01(1H,d,J=11.3Hz,H-20a),4.16(1H,d,J=11.3Hz,H-20b).1′-Ph:7.64(2H,m),7.41(2H,m),7.40(1H,m).12-OAc:1.98(3H.s);13C NMR(CDCl3,100MHz)δC 158.6(C-1),136.7(C-2),208.6(C-3),75.2(C-4),70.9(C-5),76.9(C-6),81.4(C-7),36.2(C-8),78.9(C-9),49.9(C-10),43.5(C-11),77.7(C-12),84.7(C-13),82.7(C-14),142.4(C-15),113.9(C-16),18.7(C-17),17.8(C-18),9.9(C-19),68.8(C-20),117.7(C-1′).1′-Ph:134.6,125.8×2,128.2×2,130.0.12-OAc:169.5,20.9;HRESIMS m/z 575.1685[M-H]-(calcd.for C29H32O10Cl-,575.1689).
YH-48:[α]D 25+15(c 0.1,MeOH);UV(MeOH)λmax(logε)241(3.70)nm;IR(KBr)νmax3451,2925,1740,1691,1230,1078,and 697cm-1;1H NMR(CDCl3,400MHz)δH 7.59(1H,br s,H-1),3.96(1H,s,H-5),4.89(1H,d,J=9.8Hz,H-7),3.06(1H,m,H-8),3.07(1H,m,H-10),2.85(1H,q,J=7.2Hz,H-11),5.02(1H,s,H-12),5.37(1H,d,J=2.4Hz,H-14),5.01(1H,s,H-16a),5.03(1H,s,H-16b),1.85(3H,s,H3-17),1.33(3H,d,J=7.2Hz,H3-18),1.80(3H,brs,H3-19),4.06(1H,d,J=10.4Hz,H-20a),4.46(1H,d,J=10.4Hz,H-20b).1′-Ph:7.67(2H,m),7.39(2H,m),7.39(1H,m).12-OAc:2.03(3H.s);13C NMR(CDCl3,100MHz)δC 158.9(C-1),137.6(C-2),208.5(C-3),73.3(C-4),81.7(C-5),79.0(C-6),66.9(C-7),36.8(C-8),78.4(C-9),50.6(C-10),42.8(C-11),77.9(C-12),84.2(C-13),79.1(C-14),142.8(C-15),113.7(C-16),18.8(C-17),18.1(C-18),10.0(C-19),61.8(C-20),117.4(C-1′).1′-Ph:134.8,125.9×2,128.1×2,129.8.12-OAc:169.7,21.0;HRESIMS m/z 575.1681[M-H]-(calcd.for C29H32O10Cl-,575.1689).
实施例14:YH-49和YH-50的制备
取化合物YH-11(40mg),用实施例13中相同的方法制备后经制备薄层(CH2Cl2/MeOH,50:1)纯化得化合物YH-49(20mg)和YH-50(12mg)。其结构和数据如下:
YH-49:[α]D 25+23.6(c 0.46,MeOH);UV(MeOH)λmax(logε)231(4.01)nm;IR(KBr)νmax3450,2924,1721,1268,1079,and 711cm-1;1H NMR(CDCl3,400MHz)δH 7.64(1H,s,H-1),4.40(1H,s,H-5),4.84(1H,s,H-7),3.79(1H,d,J=2.4Hz,H-8),4.08(1H,m,H-10),2.99(1H,q,J=7.3Hz,H-11),5.34(1H,s,H-12),5.10(1H,d,J=2.4Hz,H-14),5.07(1H,s,H-16a),5.03(1H,s,H-16b),1.91(3H,s,H3-17),1.45(3H,d,J=7.3Hz,H3-18),1.81(3H,br s,H3-19),4.16(1H,d,J=11.5Hz,H-20a),4.02(1H,d,J=11.5Hz,H-20b).1′-Ph:7.68(2H,m),7.42(2H,m),7.44(1H,m).12-OBz:7.97(2H,m),7.42(2H,m),7.55(1H,t,J=7.4Hz);13C NMR(CDCl3,100MHz)δC 158.6(C-1),136.9(C-2),208.6(C-3),75.1(C-4),70.9(C-5),77.0(C-6),81.6(C-7),36.6(C-8),79.1(C-9),49.9(C-10),43.8(C-11),78.0(C-12),85.1(C-13),82.9(C-14),142.4(C-15),114.2(C-16),18.8(C-17),18.0(C-18),9.9(C-19),68.9(C-20),117.9(C-1′).1′-Ph:134.6,125.8×2,128.3×2,130.1.12-OBz:165.1,129.4,129.6×2,128.4×2,133.4;HRESIMS m/z 637.18513[M-H]-(calcd for C34H34O10Cl-,637.18460).
YH-50:[α]D 25+16.7(c 0.35,MeOH);UV(MeOH)λmax(logε)230(4.10)nm;IR(KBr)νmax3431,2960,1721,1451,1268,and 1075cm-1;1H NMR(CDCl3,500MHz)δH 7.62(1H,br s,H-1),3.90(1H,s,H-5),4.90(1H,d,J=9.9Hz,H-7),3.12(1H,d,J=9.9Hz,H-8),3.06(1H,br s,H-10),2.99(1H,q,J=7.2Hz,H-11),5.28(1H,s,H-12),5.51(1H,s,H-14),5.06(1H,s,H-16a),5.01(1H,s,H-16b),1.88(3H,s,H3-17),1.44(3H,d,J=7.2Hz,H-18),1.78(3H,br s,H-19),4.33(1H,d,J=11.1Hz,H-20a),4.06(1H,d,J=11.1Hz,H-20b).1′-Ph:7.71(2H,d,J=7.3Hz),7.42(2H,m),7.43(1H,m).12-OBz:7.94(2H,d,7.4),7.47(2H,m),7.59(1H,t,J=7.4Hz);13C NMR(CDCl3,125MHz)δC 158.9(C-1),137.6(C-2),208.4(C-3),73.1(C-4),81.8(C-5),78.5(C-6),66.5(C-7),37.1(C-8),78.4(C-9),50.4(C-10),43.0(C-11),78.5(C-12),84.4(C-13),79.2(C-14),142.8(C-15),114.0(C-16),18.9(C-17),18.3(C-18),10.0(C-19),62.1(C-20),117.5(C-1′).1′-Ph:134.8,125.9×2,128.2×2,130.1.12-OBz:165.0,129.4,129.4×2,128.7×2,133.6;HRESIMS m/z 637.18536[M-H]-(calcd forC34H34O10Cl-,637.18460).
实施例15:YH-52和YH-53的制备
取化合物YH-11(100mg)溶于3mL二氯甲烷中,置于-60℃搅拌5分钟后,加入PBr3(50μL),薄层检测反应结束后,取出反应液加入5mL水淬灭,加入二氯甲烷萃取(3×5mL),合并有机层,减压浓缩后通过半制备高效液相(MeCN/H2O,80:20,3mL/min)纯化后得到YH-52(23mg,tR=15min)和YH-53(20mg,tR=12min)。其结构和数据如下:
YH-52:[α]D 25+56.3(c 0.35,MeOH);UV(MeOH)λmax(logε)232(3.96)nm;IR(KBr)νmax3445,2923,1720,1692,1268,1078,1008,and 710cm-1;1H NMR(CDCl3,400MHz)δH 7.64(1H,s,H-1),4.27(1H,s,H-5),4.98(1H,s,H-7),3.88(1H,d,J=2.4Hz,H-8),4.08(1H,s,H-10),3.00(1H,q,J=7.3Hz,H-11),5.33(1H,s,H-12),5.11(1H,d,J=2.4Hz,H-14),5.04(1H,s,H-16a),5.08(1H,s,H-16b),1.91(3H,s,H3-17),1.45(3H,d,J=7.3Hz,H3-18),1.81(3H,brs,H3-19),4.10(1H,d,J=12.0Hz,H-20a),4.21(1H,m,H-20b),12-OBz:8.01(2H,m),7.39(2H,m),7.55(1H,m);1′-Ph:7.68(2H,m),7.44(3H,m);13C NMR(CDCl3,100MHz)δC 158.6(C-1),136.9(C-2),208.7(C-3),75.1(C-4),70.5(C-5),75.8(C-6),82.5(C-7),37.8(C-8),79.2(C-9),50.0(C-10),43.8(C-11),78.1(C-12),85.1(C-13),82.8(C-14),142.4(C-15),114.2(C-16),18.8(C-17),18.0(C-18),9.9(C-19),69.9(C-20),117.9(C-1′),1′-Ph:134.5,125.8×2,128.4×2,130.1,12-OBz:165.1,129.3,129.8×2,128.3×2,133.4;HRESIMS m/z 705.1309[M+Na]+(calcd for,C34H35O10BrNa+,705.1306).
YH-53:[α]D 25+50.0(c 0.30,MeOH);UV(MeOH)λmax(logε)232(4.06)nm;IR(KBr)νmax3428,1701,1452,1268,1079,1026,and 712cm-1;1H NMR(CDCl3,500MHz)δH 7.57(1H,s,H-1),3.85(1H,s,H-5),5.06(1H,d,J=9.9Hz,H-7),3.12(1H,d,J=9.9Hz,H-8),3.07(1H,brs,H-10),3.00(1H,q,J=7.2Hz,H-11),5.28(1H,s,H-12),5.57(1H,d,J=1.3Hz,H-14),5.00(1H,s,H-16a),5.04(1H,s,H-16b),1.88(3H,s,H3-17),1.42(3H,d,J=7.2Hz,H3-18),1.73(3H,br s,H3-19),4.09(1H,d,J=10.9Hz,H-20a),4.39(1H,d,J=10.9Hz,H-20b),12-OBz:7.93(2H,d,J=7.5Hz),7.46(2H,dd,J=7.5,7.5Hz),7.56(1H,m);1′-Ph:7.71(2H,m),7.42(2H,m),7.41(1H,m);13C NMR(CDCl3,125MHz)δC 158.8(C-1),137.5(C-2),208.2(C-3),73.4(C-4),81.1(C-5),78.2(C-6),63.7(C-7),36.9(C-8),78.5(C-9),50.7(C-10),43.0(C-11),78.4(C-12),84.7(C-13),81.8(C-14),142.7(C-15),114.0(C-16),18.9(C-17),18.2(C-18),9.9(C-19),63.6(C-20),117.3(C-1′),1′-Ph:134.9,125.9×2,128.1×2,129.8,12-OBz:165.0,129.4,129.4×2,128.7×2,133.6;HRESIMS m/z 705.1289[M+Na]+(calcd for,C34H35O10BrNa+,705.1306).
瑞香烷型二萜化合物对去势抵抗性前列腺癌细胞的抑制活性
(1)细胞培养
所有前列腺癌细胞均用含有10%小牛血清、100单位每毫升的青霉素及100g/mL链霉素的RPMI-1640培养基,培养于含5%二氧化碳的饱和湿度为37℃恒温培养箱中。
(2)细胞毒活性测试
取对数生长期的细胞于96孔板中培养24小时(5×103cells/well),然后用不同浓度的待测化合物处理,用MTT法培养4小时,离心弃去上清液,加入DMSO溶解MTT结晶,以酶联免疫检测仪在570nm波长测吸光度值。用IC50表示待测化合物对癌细胞的细胞毒活性。
(3)实验结果
如表1所示,大部分瑞香烷型二萜均表现出不同程度的抑制多种前列腺癌细胞的活性,部分代表性化合物对前列腺癌细胞的抑制活性显著,IC50处于nM水平,强于阳性药阿霉素和恩杂鲁胺(ENZ),其中化合物YH-11、YH-22和YH-52等活性最为突出。初步构效关系分析表明,含有9,13,14-原酸酯的化合物(YH-11和YH-52等)的抑制活性显著高于不含原酸酯的化合物(YH-56、YH-60和YH-61),说明原酸酯为关键的药效基团。其次,20-OH被亲酯性基团取代后会导致活性明显降低,例如化合物YH-5、YH-9、YH-12、YH-19、YH-20、YH-25等;另外,6,7-环氧被开环形成双羟基产物YH-51时活性明显降低,而开环形成溴代产物YH-52时活性增强并且对正常人前列腺细胞RWPE-1的毒性比原型化合物YH-11显著降低。该类化合物1′-烯烃侧链的修饰对活性有着不可预见的影响,但总体而言,带有1′-烯烃侧链的化合物细胞毒性更强,例如化合物YH-16和YH-22细胞毒性强于YH-11和YH-6。YH-52被选为候选化合物进行动物体内药效学评价。
表1代表性瑞香烷型二萜化合物对几种人前列腺癌细胞及正常细胞的抑制活性
ENZ:阳性药恩杂鲁胺;DOX:阳性药阿霉素;NA:活性较低,未测试。
化合物YH-52动物体内药效学评价
(1)小鼠22RV1前列腺癌生长模型的构建
首先大量扩增22RV1细胞,为保证荷瘤的成功率需把细胞状态调整到最佳状态。待细胞数量足够时,消化细胞并用PBS缓冲液洗两遍去除培养基中的胎牛血清(FBS)以减少免疫排斥反应。血球计数板计数后将细胞调整到3000*104/mL。然后将22Rv1人前列腺癌细胞(100μL)皮下注射到4-5周龄的nod-scid重症免疫缺陷雄性小鼠。
(2)分组及给药
口服给药实验:
待肿瘤长到100mm3体积左右时,将小鼠分随机为3组(平均肿瘤体积相同),加药组小鼠每天口服灌胃0.5mg/kg及2mg/kg的化合物YH-52,对照组给予同样体积DMSO含量的生理盐水。每3天测量并记录小鼠体重及肿瘤的长与宽,持续给药的时间如图2所示,待实验结束后取皮下肿瘤,拍照。按照公式体积=长×宽2×π/6计算,统计肿瘤体积。
联合恩杂鲁胺腹腔注射给药实验:
待肿瘤长到100mm3左右时,将小鼠分随机为4组(平均肿瘤体积相同),加药组小鼠每天腹腔注射0.1mg/kg的化合物YH-52,阳性药组小鼠每天腹腔注射10mg/kg的恩杂鲁胺,联合用药组小鼠每天同时腹腔注射0.1mg/kg的化合物YH-52和10mg/kg恩杂鲁胺,对照组给予同样体积DMSO含量的生理盐水。每3天测量并记录小鼠体重及肿瘤的长与宽,持续给药的时间如图3所示,待实验结束后取皮下肿瘤,拍照。按照公式体积=长×宽2×π/6计算,统计肿瘤体积。
(3)实验结果
如图2所示,化合物YH-52可以在口服灌胃0.5mg/kg和2mg/kg剂量下明显抑制小鼠肿瘤的生长。与阳性药恩杂鲁胺(ENZ)比较,YH-52腹腔注射给药(剂量0.1mg/kg)表现出更强的疗效,并且在0.1mg/kg剂量下联合恩杂鲁胺(10mg/kg)腹腔注射给药有明显的协同增效(图3)。
可以预见,化合物药学上可接受的盐,可以产生相同或相近的活性。
Claims (10)
1.瑞香烷型二萜化合物在制备去势抵抗性前列腺癌治疗或联合治疗药物中的应用,其特征在于:所述瑞香烷型二萜化合物的通式如式Ⅰ或式II所示:
式I和式II中:C-1和C-2之间为双键或不为双键;C-6和C-7之间为双键或不为双键;C-15和C-16之间为双键或不为双键;
R1选自氢或羟基;
R2选自氢、羟基、羰基、苯甲酰基或乙酰基;
R3选自氢、羟基、乙酰基、异戊酰基、巴豆酰基或苯甲酰基;
R4选自氢、羟基、乙酰基、异丁酰基、2-噻吩甲酰基、苯甲酰基或棕榈酰基;
R5选自羟基、氟、氯、溴、碘,与R6形成三元环氧或与R6消除形成C6=C7双键;
R6选自氢、羟基、氟、氯、溴、碘,与R5形成三元环氧或与R5消除形成C6=C7双键;
式I中:R7选自甲基、苯基、壬烷基、(1E,3E)-壬二烯基、(1E,3Z)-壬二烯基或(1E,3E,5E)-壬三烯基;
式II中:R7选自氢、苯甲酰基、乙酰基、癸酰基、(2E,4E)-癸二烯酰基、(2E,4Z)-癸二烯酰基或(2E,4E,6E)-癸三烯酰基;
R8选自氢或羟基;
R9选自氢、羟基、乙酰基、苯甲酰基、异丁酰基、丁酰基或丙酰基。
3.根据权利要求2所述的应用,其特征在于:所述瑞香烷型二萜化合物选自YH-6、YH-11、YH-16、YH-17、YH-22、YH-35、YH-36、YH-47、YH-48、YH-49、YH-50、YH-52及YH-53中的至少一种。
4.根据权利要求1或2所述的应用,其特征在于:所述瑞香烷型二萜化合物还包括其药学上可接受的衍生物。
5.根据权利要求4所述的应用,其特征在于:所述药学上可接受的衍生物为其盐。
6.瑞香烷型二萜化合物及其药用衍生物,其特征在于:所述瑞香烷型二萜化合物如权利要求1所述。
7.根据权利要求6所述的瑞香烷型二萜化合物及其药用衍生物,其特征在于:所述瑞香烷型二萜化合物选自权利要求2中的化合物YH-8、YH-9、YH-10、YH-19、YH-20、YH-21、YH-24、YH-25、YH-26、YH-30、YH-33、YH-34、YH-37、YH-38、YH-39、YH-45、YH-46、YH-47、YH-48、YH-49、YH-50、YH-52、YH-53、YH-56、YH-57、YH-60、YH-61。
8.一种治疗或辅助治疗去势抵抗性前列腺癌的组合物,其特征在于:所述组合物的活性成分包括权利要求1~5任一项所述的瑞香烷型二萜化合物及其可接受的药用衍生物中的至少一种。
9.根据权利要求8所述的组合物,其特征在于:所述瑞香烷型二萜化合物选自权利要求2中的化合物YH-6、YH-11、YH-16、YH-17、YH-22、YH-35、YH-36、YH-8、YH-9、YH-10、YH-19、YH-20、YH-21、YH-24、YH-25、YH-26、YH-30、YH-33、YH-34、YH-37、YH-38、YH-39、YH-45、YH-46、YH-47、YH-48、YH-49、YH-50、YH-52、YH-53、YH-56、YH-57、YH-60、YH-61及其可接受的药用衍生物。
10.根据权利要求8所述的组合物,其特征在于:所述组合物还包括至少一种对前列腺癌有治疗作用的化合物,优选的,所述对前列腺癌有治疗作用的化合物为恩杂鲁胺、阿比特龙、环磷酰胺、阿霉素、多烯紫杉醇、米托蒽醌。
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