生物素-鬼臼毒素酯化衍生物及其药物组合物和其制备方法与应用转让专利
申请号 : CN201410338943.5
文献号 : CN104098594B
文献日 : 2016-05-11
发明人 : 蒋子华 , 字成庭 , 胡江苗 , 周俊 , 丁中涛 , 刘玉清 , 杨柳
申请人 : 中国科学院昆明植物研究所
摘要 :
权利要求 :
1.下述通式(I)所示的生物素-鬼臼毒素酯化衍生物,
其中:
R为CH3或H;
X为O,NH,S;或者结构片段
或者结构片段 其中Z为O,NH,S;m为0–6,r为0或1,Y为结构片段
2.如权利要求1所述的生物素-鬼臼毒素酯化衍生物,其特征在于为下述结构式所示的化合物3-6、8-11:。
3.药物组合物,其中含有治疗有效量的权利要求1或2所述的生物素-鬼臼毒素酯化衍生物和药学上可接受的载体。
4.权利要求1或2所述的生物素-鬼臼毒素酯化衍生物在制备抗肿瘤抑制剂中的应用。
5.权利要求1或2所述的生物素-鬼臼毒素酯化衍生物在制备抗肿瘤药物中的应用。
6.制备权利要求1所述的通式I的生物素-鬼臼毒素酯化衍生物的方法,其特征在于将鬼臼毒素、鬼臼毒素制备而成的4β-OH-鬼臼毒素、4β-OH-4'-O-去甲基鬼臼毒素与D-生物素溶解在DMF中,再加入4-二甲氨基吡啶DMAP和N,N'-二异丙基碳二亚胺DIC,在室温下搅拌反应,反应完后减压除去溶剂,得到的粗产物经硅胶柱层析,用氯仿:甲醇洗脱得到生物素-鬼臼毒素衍生物;或者用由鬼臼毒素制备而成的4β-氨基-鬼臼毒素、4β-氨基-4'-O-去甲基鬼臼毒素与D-生物素溶解在DMF中,再加入4-二甲氨基吡啶DMAP和N,N'-二异丙基碳二亚胺DIC,在室温下搅拌反应,反应完后减压除去溶剂,得到的粗产物经硅胶柱层析,用氯仿:甲醇洗脱得到生物素-鬼臼毒素衍生物;或者由鬼臼毒素制备而成的4'-O-甲基-4-脱氧-4β-叠氮化合物、4'-O-去甲基-4-脱氧-4β-叠氮化合物与端炔醇、端炔氨类化合物溶于四氢呋喃中,加入1:2的叔丁醇-水和醋酸铜,再滴加抗坏血酸水溶液经过Click反应后得到4β-(1,
2,3-三唑)鬼臼毒素衍生物,再用4β-(1,2,3-三唑)鬼臼毒素衍生物与D-生物素、6-生物素己酸溶解在DMF中,再加入4-二甲氨基吡啶DMAP和N,N'-二异丙基碳二亚胺DIC,在室温下搅拌反应,反应完后减压除去溶剂,得到的粗产物经硅胶柱层析,用氯仿:甲醇洗脱得到生物素-鬼臼毒素衍生物。
说明书 :
生物素-鬼臼毒素酯化衍生物及其药物组合物和其制备方法
与应用
技术领域
背景技术
发明内容
4.54(d,1H,J=5.2Hz),4.29(s,1H,C11-CHβ),4.26(d,1H,J=8.2Hz,C11-CHα),3.67(s,6H,
3',5'-OCH3),3.31(dd,1H,J=10.2Hz,17.3Hz,C2-H),2.87(m,1H,C3-H);13C NMR(CDCl3,
100MHz):δ175.6(C-12),148.7(C-7),147.9(C-3'),147.9(C-5'),147.7(C-6),135.9(C-
1'),134.2(C-9),133.0(C-10),131.5(C-4'),110.5(C-8),100.5(C-5),109.5(C-2'),
109.5(C-6'),102.1(C-13),68.3(C-11),66.7(C-4),56.6(3',5'-OCH3),44.6(C-1),41.1(C-2),39.4(C-3);MS-ESI m/z(%):400([M+H]+,100).
1H,C8-H),6.38(s,2H,C2',C6'-H),6.05(d,2H,J=0.6Hz,OCH2O),4.61(q,2H,J=3.7Hz,
5.3Hz,C4-H,C1-H),4.36(dd,2H,J=8.5Hz,10.3Hz,C11-CH2),3.66(s,6H,3',5'-OCH3),3.11
2 3 13
(dd,1H,J=4.7Hz,14.1Hz,C -H),2.96(m,1H,C -H);C NMR(CDCl3,100MHz):δ174.3(C-
12),148.9(C-3'),148.6(C-5'),148.0(C-7),148.0(C-6),136.0(C-1'),133.9(C-4'),
131.2(C-9),129.4(C-10),110.8(C-5),109.2(C-2'),109.2(C-6'),107.5(C-8),102.6(C-
13),70.9(C-11),63.9(C-4),56.4(3',5'-OCH3),45.7(C-1),44.4(C-2),38.6(C-3);MS-ESI m/z(%):448([M+Na]+,100).
1H,J=13.8Hz,C4-H),3.76(s,6H,C3',C5'-OCH3),3.72–3.70(m,1H,C1-H),3.64–3.57(m,C11-Hα),3.48–3.44(m,1H,C11-Hβ),3.31–3.30(m,1H,C3-H),2.73(dd,1H,J=6.2Hz,8.8Hz,C2-H),2.15(s,2H,NH2);13C-NMR(CD3OD,100MHz)δ181.1(C-12),149.3(C-3',C-5'),148.9(C-
7),147.4(C-6),136.7(C-9),136.4(C-1'),135.6(C-4'),130.3(C-10),112.6(C-5),107.7(C-8),107.2(C-2',C-6'),102.5(OCH2O),62.5(C-11),57.6(C-2),56.7(C3',C5'-OCH3),
52.7(C-4),47.3(C-1),46.6(C-3);MS-ESI m/z(%):422([M+Na]+,100).
5.91–5.87(m,2H,OCH2O),5.06(t,1H,J=12.0Hz,C1-H),4.52(d,1H,J=6.0Hz,C4-H),4.41–
4.39(m,1H,CHNH),4.34(t,1H,J=6.0Hz,C11-CHα),4.22–4.20(m,1H,CHNH),4.10(t,1H,J=
12.0Hz,C11-CHβ),3.70(s,6H,C3',C5'-OCH3),3.07–3.04(m,1H,CHS),2.83–2.79(m,2H,CH2S),2.69–2.64(m,1H,C3-H),2.57(t,2H,J=6.0Hz),2.23–2.19(m,1H,C2-H),1.66–1.59(m,2H),1.37–1.32(m,2H),1.21–1.19(m,2H);13C-NMR(CDCl3,150MHz)δ175.0(C-12),174.2(C=O),164.5(C=O),147.7(C-7),147.7(C-6),146.6(C-3',C-5'),134.7(C-1'),132.0(C-4'),131.6(C-9),130.7(C-10),110.4(C-5),109.2(C-2',C-6'),106.6(C-8),101.7
3' 5'
(OCH2O),71.8(C-11),69.7(C-4),61.9(CHNH),60.4(CHNH),57.1(C ,C -OCH3),56.1(CHS),53.9(CH2S),52.1(C-2),46.3(C-1),43.9(C-3),40.8,36.0,28.5,23.7;ESIMS:m/z660[M+Cl]-,HRESIMS:calcd for C31H35N3O9SH[M+H]+626.2167,found626.2145.[0048] 实施例3–15:
2.57–2.42(m,3H,CH2S,C3-H),2.16(t,2H,J=10.0Hz),1.58–1.52(m,2H),1.42–4.41(m,
13
2H),1.26–1.21(m,2H);C-NMR(CD3OD,100MHz)δ177.5(C-12),172.6(C=O),162.8(C=O),
152.7(C-3',C-5'),147.5(C-7),146.3(C-6),138.4(C-1'),136.0(C-4'),132.4(C-9),
126.8(C-10),109.2(C-5),108.2(C-8),105.6(C-2',C-6'),101.3(OCH2O),79.2(C-4),
72.1(C-11),61.0(CHNH),60.0(CHNH),59.2(C4'-OCH3),55.9(C3',C5'-OCH3),55.3(CHS),
43.6(C-2),43.5(C-1),39.7(C-3),33.4(CH2S),28.0,27.9,24.5,24.3;ESIMS:m/z641[M+H]+,HRESIMS:calcd for C32H36N2O10SH[M+H]+641.2138,found641.2163.
3.77(s,3H,C -OCH3),3.73(s,6H,C ,C -OCH3),3.20–3.17(m,2H,CHS,C-H),3.13–3.10(m,1H,CHaS),2.92(dd,1H,J=4.0Hz,16.0Hz,C2-H),2.79–2.69(m,2H),2.42(t,2H,J=
8.0Hz),2.18(t,2H,J=8.0Hz),1.68–1.64(m,4H),1.52–1.49(m,2H),1.40–1.35(m,2H),
1.31–1.29(m,2H),1.18–1.17(m,2H);13C-NMR(CDCl3,100MHz)δ174.1(C-12),173.8(C=O),
173.5(C=O),164.1(C=O),152.5(C-3',C-5'),148.1(C-7),147.5(C-6),136.9(C-1'),
134.9(C-4'),132.2(C-9),128.3(C-10),109.7(C-5),108.0(C-2',C-6'),106.9(C-8),
101.6(OCH2O),73.4(C-4),71.3(C-11),61.8(CHNH),60.7(CHNH),60.3(C4'-OCH3),56.1(C3',C5'-OCH3),55.7(CHS),45.4(C-2),43.6(C-1),40.5(C-3),39.2,38.7(CH2S),35.8,
34.1,29.2,28.2,28.0,26.4,25.3,24.5;ESIMS:m/z789[M+Cl]-,HRESIMS:calcd for C38H47N3O11SCl[M+Cl]-789.2625,found789.2625.确认所得化合物与文献报道一致(T.Saitoh,等,Bioorganic&Medicinal Chemistry,2008,16,5815–5825.)
5'),148.8(C-7),147.4(C-6),137.2(C-1'),134.6C-4'),132.9(C-9),127.8(C-10),110.2(C-5),109.5(C-8),108.0(C-2',C-6'),101.7(OCH2O),68.0(C-4),67.5(C-11),62.1(CHNH),60.7(C4'-OCH3),60.3(CHNH),56.2(C3',C5'-OCH3),55.4(CHS),43.8(C-2),41.5(C-+
1),40.4(C-3),36.7(CH2S),34.0,28.4,28.1,24.7;ESIMS:m/z663[M+Na] ,HRESIMS:calcd for C32H36N2O10SNa[M+Na]+663.1983,found663.1980.
3.79(s,3H,C -OCH3),3.73(s,6H,C ,C -OCH3),3.25–3.20(m,2H,CHS,C-H),3.15–3.14(m,1H,CHaS),2.89(dd,1H,J=4.0Hz,12.0Hz,C2-H),2.77–2.73(m,1H,CHbS),2.36(t,2H,J=8.0Hz),2.24(t,2H,J=4.0Hz),1.68–1.63(m,4H),1.53–1.50(m,2H),1.44–1.41(m,2H),
1.35–1.33(m,2H);13C-NMR(CDCl3,100MHz)δ174.3(C-12),173.7(C=O),173.3(C=O),
163.9(C=O),152.6(C-3',C-5'),148.9(C-7),147.4(C-6),137.2(C-1'),134.6(C-4'),
132.8(C-9),127.8(C-10),110.2(C-5),109.5(C-8),108.0(C-2',C-6'),101.7(OCH2O),
67.9(C-4),67.5(C-11),61.9(CHNH),60.7(C4'-OCH3),60.4(CHNH),56.2(C3',C5'-OCH3),
55.6(CHS),43.7(C-2),41.5(C-1),40.5(C-3),39.3(CH2S),36.7,35.7,34.1,29.1,28.0,- -
27.9,26.4,25.7,24.5;ESIMS:m/z788[M+Cl] ,HRESIMS:calcd for C38H47N3O11SCl[M+Cl]
788.2625,found788.2627.
1.28–1.26(m,2H);13C-NMR(C5D5N,125MHz)δ175.7(C-12),171.3(C=O),164.3(C=O),
152.3(C-3',C-5'),148.4(C-7),147.7(C-7),139.5(C-1'),136.1(C-4'),134.4(C-9),
132.0(C-10),110.6(C-5),110.4(C-8),108.5(C-2',C-6'),101.9(OCH2O),68.4(C-11),
3' 5'
66.3(C-4),62.5(CHNH),60.6(CHNH),56.3(C ,C -OCH3),56.2(CHS),44.7(C-2),41.1(C-
1),41.0(CH2S),39.7(C-3),33.9,29.1,28.8,25.4;ESIMS:m/z661[M+Cl]-,HRESIMS:calcd for C31H34N2O10SH[M+H]+627.2007,found627.1978.
8.0Hz),2.35–2.31(m,4H),2.17–2.12(m,2H),1.76–1.68(m,2H),1.66–1.58(m,2H),1.56–
1.48(m,2H),1.43–1.36(m,2H);13C-NMR(CDCl3,150MHz)δ175.8(C-12),173.8(C=O),171.9(C=O),163.9(C=O),151.5(C-3',C-5'),148.4(C-7),147.5(C-6),138.2(C-1'),132.3(C-4'),131.5(C-9),127.7(C-10),110.4(C-5),109.6(C-8),107.7(C-2',C-6'),101.7(OCH2O),68.1(C-4),66.3(C-11),62.1(CHNH),60.5(CHNH),56.3(C3',C5'-OCH3),55.6(CHS),44.1(C-2),40.7(C-1),40.5(C-3),39.4(CH2S),38.6,35.8,33.7,29.0,28.3,28.1,- +
26.2,25.6,24.6;ESIMS:m/z738[M-H] ,HRESIMS:calcd forC37H45N3O11SH[M+H]740.2848,found740.2809.
6.67(s,1H,C-H),5.96(d,2H,J=15.0Hz,OCH2O),4.84(s,1H,C-H),4.58(d,1H,J=2.3Hz,C1-H),4.56–4.52(m,2H,2×CHNH),4.37–4.34(m,1H,C11-CHα),4.32–4.28(m,1H,C11-CHβ),
3.90(s,3H,C4'-OCH3),3.69(s,6H,C3',C5'-OCH3),3.38(t,1H,J=5.0Hz,CHS),3.17–3.12(m,
1H,C3-H),3.02(s,2H,CH2S),2.94–2.89(m,1H,C2-H),2.18–2.13(m,2H),1.79–1.72(m,2H),
13
1.46–1.42(m,2H),1.40–1.37(m,2H);C-NMR(C5D5N,125MHz)δ178.1(C-12),173.2(C=O),
164.2(C=O),154.2(C-3',C-5'),148.0(C-7),146.5(C-6),141.3(C-1'),136.4(C-4'),
129.5(C-9),124.1(C-10),112.2(C-5),107.2(C-5,C-2',C-6'),101.7(OCH2O),64.2(C-
4),62.5(C-11),60.7(CHNH),60.6(CHNH),56.8(C4'-OCH3),56.4(C3',C5'-OCH3),56.3(CHS),
51.7(C-2),47.2(C-1),42.9(C-3),41.1(CH2S),34.1,29.0(2),25.3;ESIMS:m/z662[M+Na]+,HRESIMS:calcd for C32H37N3O9SNa[M+Na]+662.2143,found662.2145.
6.29(s,2H,C ,C -H),5.94-5.90(m,2H,OCH2O),4.50(s,1H,C-H),4.34-4.32(m,2H,C-H,C11-CHα),4.19-4.17(m,2H,2×CHNH),4.07(dd,1H,J=8.0Hz,12.0Hz,C11-CHβ),3.81(s,3H,C4'-OCH3),3.76(s,6H,C3',C5'-OCH3),3.19–3.13(m,3H,CHS,C3-H,CHaS),2.89–2.85(m,3H,CHbS,CH2NH),2.75–2.72(m,1H,C2-H),2.30–2.23(m,4H),1.69–1.64(m,4H),1.51–1.47(m,
4H),1.45–1.42(m,2H),1.27–1.24(m,2H);13C-NMR(CDCl3,100MHz)δ178.2(C-12),173.8(C=O),173.4(C=O),164.1(C=O),153.2(C-3',C-5'),147.6(C-7),146.0(C-6),140.0(C-
1'),136.7(C-4'),134.2(C-9),128.4(C-10),111.8(C-5),106.7(C-8),105.8(C-2',C-
6'),101.2(OCH2O),63.4(C-4),61.9(C-11),60.8(C4'-OCH3),60.4(CHNH),56.6(CHNH),
56.2(C3',C5'-OCH3),55.6(CHS),50.9(C-2),46.2(C-1),42.1(C-3),40.5(CH2S),39.3,
35.6,33.8,28.9,28.1,27.9,26.2,25.7,24.4;ESIMS:m/z775[M+Na]+,HRESIMS:calcd for C38H48N4O10SNa[M+Na]+753.3164,found753.3154.
1H,CHS),3.09–3.05(m,1H,C3-H),3.02–2.99(m,2H,CH2S),2.79(dd,1H,J=5.0Hz,10.0Hz,C2-H),2.54–2.51(m,2H),2.02(t,2H,J=5.0Hz),1.62–1.56(m,4H),1.50–1.44(m,2H),
1.42–1.38(m,2H),1.35–1.30(m,2H),1.29–1.21(m,2H);13C-NMR(CD3OD,125MHz)δ177.2(C-
12),171.9(C=O),170.8(C=O),162.7(C=O),151.4(C-3',C-5'),146.6(C-7),145.2(C-
6),143.4(C-1'),136.1(C-4'),128.4(C-9),126.7(C-10),111.1(C-5),106.9(C-8),105.4(C-2',C-6'),100.9(OCH2O),61.1(C-4),60.6(C-11),59.2(CHNH),55.9(C3',C5'-OCH3),
55.4(CHNH),54.9(CHS),50.1(C-2),45.6(C-1),44.8(C-3),38.2(CH2S),35.2,33.0,28.8,
28.2,28.0,25.6,25.3,24.3;ESIMS:m/z761[M+Na]+,HRESIMS:calcd for C37H46N4O10SH[M+Na]+761.2827,found761.2829.
4.53(m,1H,C11-CHα),4.43–4.35(m,2H,2×CHNH),4.21(t,1H,J=4.0Hz,C11-CHβ),3.81(s,
3H,C4'-OCH3),3.77(s,6H,C3',C5'-OCH3),2.25–2.23(m,1H,CHS),3.16–3.09(m,2H,CH2S),
2.95–2.90(m,1H,C3-H),2.79–2.75(m,1H,C2-H),2.38–2.35(m,2H),1.86–1.83(m,2H),
1.65–1.63(m,2H),1.42–1.40(m,2H);13C-NMR(CDCl3,100MHz)δ173.6(C-12),173.6(C=O),
164.0(C=O),152.7(C-3',C-5'),149.4(C-7),148.0(C-6),142.9(C-N=N),137.4(C-1'),
134.3(C-4'),133.2(C-9),124.5(C-10),124.3(CH-N),110.5(C-5),108.8(C-8),108.1(C-
2',C-6'),102.0(OCH2O),67.4(C-11),62.0(C-4),60.7(C4'-OCH3),60.3(CHNH),58.7
3' 5'
(CHNH),57.3(CH2O),56.3(C ,C -OCH3),55.4(CHS),43.6(C-2),41.5(C-1),40.4(CH2S),
37.1(C-3),33.6,28.1,25.6,24.6;ESIMS:m/z744[M+Na]+,HRESIMS:calcd for C35H39N5O10SNa[M+Na]+744.2310,found744.2356.
2H,CH2O),4.75(d,1H,J=4.7Hz,C1-H),4.52–4.49(m,1H,C11-CHα),4.38(s,2H,2×CHNH),
4.32-4.30(m,1H,C11-CHβ),3.79(s,3H,C4'-OCH3),3.75(s,6H,C3',C5'-OCH3),3.20–3.13(m,
2 3
3H,CHS,CH2S),2.88(dd,1H,J=4.0Hz,16.0Hz,C-H),2.74–2.71(m,1H,C-H),2.32(t,2H,J=8.0Hz),2.22(t,2H,J=8.0Hz),1.66–1.58(m,6H),1.49–1.46(m,2H),1.42–1.39(m,2H),
1.30–1.28(m,2H);13C-NMR(CDCl3,100MHz)δ173.7(C-12),173.5(C=O),173.3(C=O),
164.0(C=O),152.7(C-3',C-5'),149.4(C-7),148.0(C-6),142.9(C-N=N),137.4(C-1'),
134.3(C-1'),133.2(C-9),124.4(C-10),124.3(CH-N),110.5(C-5),108.8(C-8),108.1(C-
2',C-6'),102.0(C-8),67.4(C-11),61.8(C-4),60.7(C4'-OCH3),60.3(CHNH),58.7(CHNH),
57.2(CH2O),56.3(C3',C5'-OCH3),55.6(CHS),43.6(C-2),41.5(C-1),40.5(CH2S),39.2(C-
3),37.1,35.7,33.8,28.9,28.1,27.9,26.1,25.7,24.3;ESIMS:m/z857[M+Na]+,HRESIMS:
calcd for C41H50N6O11SH[M+H]+835.3331,found835.3338.
2H,2×CHNH),4.10(t,1H,J=8.0Hz,C11-CHβ),3.78(s,6H,C3',C5'-OCH3),3.30–3.24(m,1H,C3-H),3.03–2.99(m,3H,CHS,CH2S),2.79(dd,1H,J=8.0Hz,16.0Hz,C2-H),2.32(t,2H,J=
8.0Hz),1.65–1.55(m,4H),1.37–1.31(m,2H);13C-NMR(CDCl3,100MHz)δ173.6(C-12),173.5(C=O),164.0(C=O),148.5(C-7),147.9(C-7),146.8(C-3',C-5'),143.4(C-N=N),134.1(C-1'),132.5(C-4'),129.9(C-9),126.6(C-10),123.1(CH-N),110.2(C-5),107.5(C-2',C-6'),106.2(C-8),101.8(OCH2O),70.1(C-11),63.1(C-4),62.1(CHNH),60.2(CHNH),57.3(CH2O),56.3(C3',C5'-OCH3),55.4(CHS),45.8(C-2),43.6(C-1),40.2(CH2S),38.7(C-3),
33.5,28.2,28.1,24.5;ESIMS:m/z730[M+Na]+,HRESIMS:calcd for C34H37N5O10SH[M+H]+
708.2334,found708.2302.
3.64(s,6H,C3',C5'-OCH3),3.16(s,3H,CHS,CH2S),3.10–3.07(m,1H,C3-H),2.82(dd,1H,J=
4.0Hz,12.0Hz,C2-H),2.69–2.66(m,2H),2.53(t,2H,J=8.0Hz),2.15–2.12(m,2H),1.70–
1.65(m,2H),1.63–1.52(m,4H),1.50–1.45(m,2H),1.41–1.32(m,4H);13C-NMR(CDCl3,
100MHz)δ174.0(C-12),173.6(C=O),171.7(C=O),164.0(C=O),151.6(C-3',C-5'),
149.4(C-7),148.1(C-7),148.0(C-N=N),137.2(C-1'),132.8(C-4'),128.0(C-9),124.7(C-10),122.9(CH-N),110.5(C-5),108.9(C-8),107.6(C-2',C-6'),102.0(OCH2O),67.5(C-11),62.1(C-4),60.4(CHNH),58.7(CHNH),56.1(C3',C5'-OCH3),55.6(CH2O),55.4(CHS),
43.6(C-2),41.4(C-1),40.1(CH2S),39.3(C-3),37.0,35.4,33.5,28.7,28.1,27.8,26.0,
25.5,24.4;ESIMS:m/z843[M+Na]+,HRESIMS:calcd for C40H48N6O11SH[M+H]+821.3175,found821.3195.