CN114349730B - 柚皮素衍生物及其用途 - Google Patents
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Abstract
本发明公开了柚皮素衍生物及其用途,特点是具有I式所示结构式的化合物,其中,R1、R2和R3均为H、CH3、CH2F、CHF2、CF3、碳原子位数为1‑5的直链烷烃、酯基、硅醚、碳原子位数为1‑5的三氟或多氟代烷烃,碳原子位数为1‑6的直链端炔烷烃,n=1,2,3,4或5,m=1,2,3,4、5或6,该柚皮素衍生物在制备治疗化疗痛药物、化疗痛诱发的脊髓胶质细胞激活抑制剂和减轻炎性疼痛和神经病理性疼痛药物方面的用途,优点是具有显著镇痛效果。
Description
技术领域
本发明涉及一种柚皮素衍生物及其用途。
背景技术
在临床抗肿瘤治疗中,化疗药物(如紫杉醇(paclitaxel,PTX)类和铂类药物)常见的副作用之一为化疗诱发周围神经病变(Chemotherapy-induced peripheralneuropathy, CIPN)并伴随神经病理性疼痛和神经炎症,严重影响癌症患者的生存质量,临床上也缺乏有效药物和疗法。有文献报道,PTX产生的周围神经病理性疼痛在化疗结束后的第一个月影响68%的患者,在化疗后6个月仍有约30%的患者存在疼痛症状。
柚皮素(Naringenin,Nar)属于二氢黄酮类化合物,主要存在于芸香科植物葡萄柚、西红柿、葡萄以及柑橘类水果中。研究表明,柚皮素具有抗炎、抗氧化、抗肿瘤作用和镇痛作用。利用动物模型的基础研究发现柚皮素可减轻炎性痛和神经病理性疼痛。有研究指出,柚皮素可能通过抑制炎症因子(IL-33,TNF-α和IL-1β)和激活NO-cGMP-PKG-KATP通道减轻炎性疼痛。目前还未有人公开柚皮素衍生物的结构及其用于镇痛方面的应用的相关内容。
发明内容
本发明所要解决的技术问题是提供一种具有显著镇痛效果的柚皮素衍生物及其用途。
本发明解决上述技术问题所采用的技术方案为:柚皮素衍生物,为具有以下结构式的化合物:
(I),
其中R1、R2和R3均为H、CH3、CH2F、CHF2、CF3、t-Bu、MOM、EE、THP、碳原子位数为1-5的直链或支链烷烃、酯基(Ac、t-BuCO、PhCO、Ts、Ms、Tf、PO(OR`)2: R`= Alkyl or Ar、etc.)、硅醚(TMS、TES、TBS、 TIPS、TBDPS etc.)、碳原子位数为1-5的三氟或多氟代烷烃,碳原子位数为1-6的直链端炔烷烃/>,n=1,2,3,4或5,m=1,2,3,4、5或6,当一个基团为端炔时,另外两个基团为烷烃或氟代烷烃。
上述柚皮素衍生物在制备治疗化疗痛药物方面的用途。
上述柚皮素衍生物在制备化疗痛诱发的脊髓胶质细胞激活抑制剂方面的用途。
上述柚皮素衍生物在制备减轻炎性疼痛和神经病理性疼痛药物方面的用途。
与现有技术相比,本发明的优点在于:本发明柚皮素衍生物及其用途,利用常见化疗药物紫杉醇(PTX)建立CIPN诱发神经病理性疼痛(即化疗痛)小鼠模型,发现鞘内注射柚皮素衍生物显著减低PTX诱发的疼痛。本发明显示柚皮素衍生物减轻化疗痛的起效浓度显著优于柚皮素,提示柚皮素衍生物在镇痛治疗上有良好的应用前景。
附图说明
图1为在PTX诱发的化疗痛小鼠模型中,单次鞘内注射柚皮素衍生物在48小时内有显著镇痛作用;(A-F)柚皮素衍生物溶液(Y1,Y2,Y3,Y5,Y7或Y8)对小鼠疼痛阈值的作用。Ctrl:正常对照;PTX:紫杉醇;NAR:柚皮素;** P < 0.01 VS.PTX +DMSO 组;
图2为在PTX诱发的化疗痛小鼠模型中,单次鞘内注射柚皮素在48小时内的镇痛作用。PTX:紫杉醇;Nar:柚皮素;*P < 0.05, ** P < 0.01 VS.PTX +DMSO 组;
图3为单次鞘内注射柚皮素衍生物Y3或生理盐水(Saline)24小时后,PTX处理或DMSO对照(ctrl)小鼠脊髓胶质细胞活化标记物GFAP和Iba-1的表达水平。(A)脊髓背角星形胶质细胞标记物GFAP免疫荧光染色图和相对荧光强度统计图 (n = 4)。(B)A)脊髓背角小胶质细胞标记物Iba-1免疫荧光染色图和相对荧光强度统计图(n = 4)。双因素方差分析,***P < 0.005 VS. Ctrl + Saline组; ## P < 0.01 VS. PXT + Saline组。
具体实施方式
以下结合附图实施例对本发明作进一步详细描述。
一、具体实施例
柚皮素衍生物具有以下结构式的化合物:
(I),
其中R1、R2和R3均为H、CH3、CH2F、CHF2、CF3、t-Bu、MOM、EE、THP、碳原子位数为1-5的直链或支链烷烃、酯基(Ac、t-BuCO、PhCO、Ts、Ms、Tf、PO(OR`)2: R`= Alkyl or Ar、etc.)、硅醚(TMS、TES、TBS、 TIPS、TBDPS etc.)、碳原子位数为1-5的三氟或多氟代烷烃,碳原子位数为1-6的直链端炔烷烃/>,n=1,2,3,4或5,m=1,2,3,4、5或6,当一个基团为端炔时,另外两个基团为烷烃或氟代烷烃,以下例举化合物及其制备方法。
实施例1:化合物Y1的制备
将柚皮素 (100 mg,0.37 mmol, 1.0 eq.)溶于1 mL DMF中,加入K2CO3(153 mg,1.11 mmol, 3 eq.) 室温下搅拌15 min, 加入MeI (131 mg, 0.93 mmol, 2.5 eq.)室温下搅拌过夜,TLC和LCMS监控反应。过滤,过flash(反相)(H2O/0.05%FA)/MeCN:25%-65%, 20min)得到黄色固体1.5 mg,收率1.4%。化合物结构数据表征:1H NMR (500 MHz, DMSO-d6)δ 12.15 (d, J = 8.8 Hz, 1H), 9.55 (s, 1H), 7.22 -7.30 (m, 2H), 6.70 – 6.79(m, 2H), 6.15 (d, J = 11.0 Hz, 1H), 5.40 (dt, J = 12.3, 2.3 Hz, 1H), 3.62 –3.79 (m, 4H), 2.62 – 2.76 (m, 1H), 1.83 (d, J = 10.0 Hz,3H)。MS(ESI):C17H16O5,Calcd for [M+H]+ 301.1071; Found: 301.1。
实施例2:化合物Y2(柚皮素三甲醚)的制备
将柚皮素 (100 mg,0.37 mmol, 1.0 eq.)溶于1 mL DMF中,加入K2CO3(153 mg,1.11 mmol, 3 eq.) 室温下搅拌15 min, 加入MeI (131 mg, 0.93 mmol, 2.5 eq.)室温下搅拌过夜,TLC和LCMS监控反应。过滤,过flash(反相)(H2O/0.05%FA)/MeCN:25%-65%, 20min)得到黄色油状物13.7 mg,收率11.8%。化合物结构数据表征:1H NMR (500 MHz, DMSO-d6) δ 7.40 – 7.47 (m, 2H), 6.93 – 7.00 (m, 2H), 6.17 – 6.23 (m, 2H), 5.46(dd, J = 12.7, 2.9 Hz, 1H), 3.75 – 3.84 (m, 9H), 3.01 – 3.11 (m, 1H), 2.56 –2.63 (m, 1H)。MS(ESI): C18H18O5,Calcd for [M+H]+ 315.1227;Found: 315.1。
实施例3:化合物Y3(4',7-二甲基柚皮素)的制备
将柚皮素 (100 mg,0.37 mmol, 1.0 eq.)溶于1 mL DMF中,加入K2CO3(153 mg,1.11 mmol, 3 eq.) 室温下搅拌15 min, 加入MeI (131 mg, 0.93 mmol, 2.5 eq.)室温下搅拌过夜,TLC和LCMS监控反应。过滤,过flash(反相)(H2O/0.05%FA)/MeCN:25%-65%, 20min)得到3黄色固体3.8mg,收率3.4%。化合物结构数据表征:1H NMR (500 MHz, DMSO-d6)δ 12.04 (s, 1H), 7.35 – 7.42 (m, 2H), 6.88 – 6.95 (m, 2H), 6.03 (dd, J =15.2, 2.3 Hz, 2H), 5.49 (dd, J = 12.7, 3.0 Hz, 1H), 3.71 (d, J = 8.2 Hz, 6H),3.22 – 3.29 (m, 1H), 2.66 – 2.73 (m, 1H)。MS(ESI): C17H16O5,Calcd for [M+H]+301.1071; Found: 301.1。
实施例4:化合物Y4(樱花素)的制备
将柚皮素(100 mg, 0.37 mmol, 1.0 eq.)溶于1 mL DMF中,加入K2CO3(51 mg,0.37 mmol, 1 eq.) 室温下搅拌15 min, 加入MeI (52 mg, 0.37 mmol, 1 eq.)室温下搅拌过夜,TLC和LCMS监控反应。过滤,过flash(反相)(H2O/0.05%FA)/MeCN:20%-65%, 20min)得到类白色固体18.2 mg,收率17.3%。化合物结构数据表征:1H NMR (500 MHz, DMSO-d6) δ 12.05 (s, 1H), 9.54 (s, 1H), 7.22 – 7.28 (m, 2H), 6.69 – 6.76 (m, 2H),5.99 – 6.05 (m, 2H), 5.41 (dd, J = 12.9, 2.9 Hz, 1H), 3.71 (s, 3H), 3.20 –3.29 (m, 1H), 2.61 – 2.69 (m, 1H)。MS(ESI): C16H14O5,Calcd for [M+H]+ 287.0914;Found: 287.1。
实施例5:化合物Y5的制备
将柚皮素(100 mg, 0.37 mmol, 1.0 eq.)溶于1 mL DMF中,加入K2CO3(61 mg,0.44 mmol, 1.1 eq.) 室温下搅拌15 min, 加入2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethyl ethanesulfonate(84.58 mg, 0.37 mmol, 1.1 eq.)。50°C下搅拌过夜,TLC和LCMS监控反应。加水淬灭,EA萃取三遍,合并有机相,饱和食盐水洗,干燥,过滤,旋干, 过flash(反相)(H2O/0.05%FA)/MeCN:20%-65%, 20 min)得到黄色固体13.2 mg,收率9.2%。化合物结构数据表征:1H NMR (500 MHz, DMSO-d6) δ 12.03 (s, 1H), 9.55 (s, 1H),7.23 – 7.29 (m, 2H), 6.69 – 6.76 (m, 2H), 5.97 – 6.04 (m, 2H), 5.39 – 5.46(m, 1H), 3.82 (t, J = 6.2 Hz, 2H), 3.24 (d, J = 12.8 Hz, 1H), 2.75 (q, J =2.4 Hz, 1H), 2.62 – 2.70 (m, 1H), 1.92 – 1.98 (m, 2H), 1.75 – 1.81 (m, 2H),1.53 – 1.62 (m, 2H)。MS(ESI):C22H20N2O5,Calcd for [M-H]- 391.1445; Found: 391.1。
实施例6:化合物Y6的制备
将柚皮素(100 mg, 0.37 mmol, 1.0 eq.)溶于1 mL DMF中,加入K2CO3(51 mg,0.37 mmol, 1.0 eq.) 室温下搅拌15 min, 加入7-iodohept-1-yne (82 mg, 0.37 mmol,1.0 eq.)室温下搅拌过夜,TLC和LCMS监控反应。过滤,过flash(反相)(H2O/0.05%FA)/MeCN:20%-65%, 20 min)得到类白色固体16.8 mg,收率12.4%。化合物结构数据表征:1HNMR (500 MHz, DMSO-d6) δ 12.07 (s, 1H), 10.77 (s, 1H), 7.35 (d, J = 8.4 Hz,2H), 6.89 (d, J = 8.5 Hz, 2H), 5.80 – 5.85 (m, 2H), 5.43 (dd, J = 12.6, 3.0Hz, 1H), 3.91 (t, J = 6.4 Hz, 2H), 3.20 (dd, J = 17.1, 12.7 Hz, 1H), 2.68 (t,J = 2.7 Hz, 1H), 2.65 (dd, J = 17.1, 3.1 Hz, 1H), 2.08 – 2.15 (m, 2H), 1.61 –1.70 (m, 2H), 1.37 – 1.47 (m, 4H)。MS(ESI):C22H22O5,Calcd for [M+H]+ 367.1540;Found: 367.1。
实施例7:化合物Y7的制备
将樱花素Y4(100 mg, 0.35 mmol, 1.0 eq.)溶于1 mL DMF中,加入1 M NaOH(419ul) 室温下搅拌15 min, 加入7-iodohept-1-yne (77 mg, 0.35 mmol, 1.0 eq.). 室温下搅拌过夜,TLC和LCMS监控反应。加水淬灭,EA萃取三遍,合并有机相,饱和食盐水洗,干燥,过滤,旋干, 过flash(反相)(H2O/0.05%FA)/MeCN:20%-75%, 20 min)得到黄色固体6.6mg,收率5.0%。化合物结构数据表征:1H NMR (500 MHz, DMSO-d6) δ 12.11 (s, 1H),7.41 – 7.47 (m, 2H), 6.94 – 7.00 (m, 2H), 6.07 – 6.14 (m, 2H), 5.52 – 5.58(m, 1H), 3.98 (t, J = 6.4 Hz, 2H), 3.79 (d, J = 1.9 Hz, 3H), 2.72 – 2.78 (m,1H), 2.50 (d, J = 2.0 Hz, 2H), 2.15 – 2.22 (m, 2H), 1.68 – 1.77 (m, 2H), 1.45– 1.54 (m, 4H)。MS(ESI):C23H24O5,Calcd for [M+H]+ 381.1697; Found: 381.1。
实施例8:化合物Y8的制备
将柚皮素(100 mg, 0.37 mmol, 1.0 eq.)溶于1 mL DMF中,加入K2CO3(61 mg,0.44 mmol, 1.2 eq.) 室温下搅拌15 min, 加入hept-6-yn-1-yl ethanesulfonate (76mg, 0.37mmol, 1.0 eq.). 50°C下搅拌过夜,TLC和LCMS监控反应。加水淬灭,EA萃取三遍,合并有机相,饱和食盐水洗,干燥,过滤,旋干, 过flash(反相)(H2O/0.05%FA)/MeCN:20%-75%, 20 min)得到黄色固体12.2 mg,收率9.1%。化合物结构数据表征:1H NMR (500 MHz,DMSO-d6) δ 12.03 (s, 1H), 9.53 (s, 1H), 7.24 – 7.32 (m, 2H), 6.69 – 6.79 (m,2H), 6.00 (dt, J = 12.3, 2.2 Hz, 2H), 5.41 (dt, J = 12.7, 2.3 Hz, 1H), 3.95(t, J = 6.5 Hz, 2H), 3.28 (s, 1H), 3.22 (s, 1H), 2.65 – 2.68 (m, 1H), 2.053 –2.13 (m, 2H), 1.57 – 1.66 (m, 2H), 1.35 – 1.49 (m, 4H)。MS(ESI):C22H22O5,Calcdfor [M+H]+ 367.1540; Found: 367.1。
实施例9:化合物Y9的制备
将柚皮素(20 mg,0.07 mmol,1.0 eq.)用N,N-二甲基甲酰胺(0.30ml)溶解,室温下加入碳酸钾(15 mg,0.11 mmol,1.5 eq.)和溴丙炔(11 mg,0.08 mmol,1.2 eq.),室温反应过夜。TLC监控反应结束后,反应液用EA萃取3次,合并有机相后用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,酸碱反萃,过flash(反相)(0.05%FA水/ACN,30%-95%,20min),得到黄色固体化合物9。化合物结构数据表征:1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H),9.70 (s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 6.06 – 6.17(m, 2H), 5.50 (d, J = 11.7 Hz, 1H), 4.86 (d, J = 2.4 Hz, 2H), 3.66 (s, 1H),3.39 (s, 1H), 2.67 – 2.76 (m, 1H)。MS(ESI): C18H14O5,Calcd for [M+H]+ 311.0841;Found:311.1。
实施例10:化合物Y10的制备
将柚皮素(500 mg,1.83mmol,1.0 eq.)用N,N-二甲基甲酰胺(2.00ml)溶解,室温下加入碳酸钾(380 mg,2.75mmol,1.5 eq.)、二氟氯乙酸钠(425 mg,2.75mmol,1.5 eq.)室温反应过夜。TLC监控反应结束后,反应液用EA萃取3次,合并有机相后用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,酸碱反萃,过flash(反相)(0.05%FA水/ACN,30%-95%,20min),得到化合物10。化合物结构数据表征:1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 9.65(s, 1H), 7.42 (s, 1H), 7.33 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H),6.32 (d, J = 6.1 Hz, 2H), 5.54 – 5.59 (m, 1H), 3.42 (d, J = 4.3 Hz, 1H), 2.76– 2.81 (m, 1H)。MS(ESI):C16H12F2O5,Calcd for [M+H]+ 323.0653;Found:323.0。
实施例11:化合物Y11的制备
将柚皮素(20 mg,0.07 mmol,1.0 eq.)用N,N-二甲基甲酰胺(0.3 ml)溶解,室温下加入碳酸钾(15 mg,0.11 mmol,1.5 eq.)、1-溴-4,4,4-三氟丁烷(17 mg,0.08 mmol,1.2eq.)室温反应过夜。TLC监控反应结束后,反应液用EA萃取3次,合并有机相,用饱和食盐水洗2次,有机相无水硫酸钠干燥,过滤,浓缩,酸碱反萃,flash(反相)(0.05%FA水/ACN,30%-95%,20min),得到黄色固体2.5mg,收率9%。化合物结构数据表征:1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 9.61 (s, 1H), 7.32 (d, J = 8.5 Hz, 2H), 6.77 – 6.81 (m,2H), 6.06 – 6.13 (m, 2H), 5.46 – 5.52 (m, 1H), 4.06 – 4.11 (m, 2H), 2.67 –2.77 (m, 1H), 2.33 – 2.44 (m, 2H), 1.84 – 1.96 (m, 2H), 1.23 (s, 1H)。MS(ESI):C19H17F3O5,Calcd for [M+H]+ 383.1028;Found: 383.1。
实施例12:化合物Y12的制备
将柚皮素(20 mg,0.07 mmol,1.0 eq.)用N,N-二甲基甲酰胺(0.3 ml)溶解,室温下加入氟化钾(9 mg,0.15 mmol,2.0 eq.)、1-氟-2-碘乙烷(13 mg,0.07 mmol,1.0 eq.),80度反应过夜。TLC监控反应结束后,反应液用EA萃取3次,合并有机相,用饱和食盐水洗2次,有机相无水硫酸钠干燥,过滤,浓缩,flash(反相)(0.05%FA水/ACN,30%-95%,20min),得到白色固体10.4mg,收率44%。化合物结构数据表征:1H NMR (500 MHz, DMSO-d6) δ 12.10(s, 1H), 9.63 (s, 1H), 7.30 – 7.36 (m, 2H), 6.76 – 6.81 (m, 2H), 6.09 – 6.16(m, 2H), 5.48 – 5.52 (m, 1H), 4.75 – 4.79 (m, 1H), 4.65 – 4.69 (m, 1H), 4.31– 4.35 (m, 1H), 4.27 (s, 1H), 3.24 (s, 1H), 2.70 – 2.76 (m, 1H). MS(ESI):C17H15FO5,Calcd for [M+H]+ 318.0904;Found: 318.1。
实施例13:化合物Y13的制备
将柚皮素(500 mg,1.83mmol,1.0 eq.)用N,N-二甲基甲酰胺(2.0ml)溶解,室温下加入碳酸钾(380 mg,2.75mmol,1.5 eq.)、二氟氯乙酸钠(425 mg,2.75mmol,1.5 eq.)室温反应过夜。TLC监控反应结束后,反应液用EA萃取3次,合并有机相后用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,酸碱反萃,过flash(反相)(0.05%FA水/ACN,30%-95%,20min),得到黄色固体化合物13。化合物结构数据表征:1H NMR (400 MHz, DMSO-d6) δ 7.59 (s,0.5H), 7.46 (s, 1H), 7.40 (s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.28(s, 1H),7.22 (s, 0.5H), 7.08 (d, J = 16.3 Hz, 3H), 6.51 – 6.66 (m, 1H), 6.46 (d, J =8.6 Hz, 2H)。MS(ESI): C18H12F6O5,Calcd for[M+H]+423.0662;Found:423.0。
实施例14:化合物Y14的制备
将柚皮素(100 mg,0.36mmol,1.0 eq.)用N,N-二甲基甲酰胺(1.0ml)溶解,室温下加入碳酸钾(43 mg,0.73mmol,1.5 eq.)、3-氟-1-碘代丙烷(69 mg,0.36mmol,1.0 eq.)80度反应过夜。TLC监控反应结束后,反应液用EA萃取3次,合并有机相后用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,过flash(反相)(0.05%FA水/ACN,30%-95%,20min),得到黄色固体37.9 mg,收率31%。化合物结构数据表征:1H NMR (400 MHz, DMSO-d6) δ 12.12 (s,1H), 9.66 (s, 1H), 7.35 (d, J = 8.3 Hz, 2H), 6.81 (d, J = 8.4Hz, 2H), 6.09 –6.16 (m, 2H), 5.47 – 5.55 (m, 1H), 4.61 – 4.68 (m, 1H), 4.49 – 4.57 (m, 1H),4.11 – 4.18(m, 2H), 3.31 (s, 1H), 2.70 – 2.79 (m, 1H), 2.01 – 2.18 (m, 2H)。MS(ESI):C18H17FO5,Calcd for[M+H]+ 333.1133;Found:333.1。
实施例15:化合物Y15的制备
将柚皮素(20 mg,0.07mmol,1.0 eq.)用N,N-二甲基甲酰胺(0.3ml)溶解,室温下加入氟化钾(9 mg,0.15mmol,2.0 eq.)、1-溴-4-氟-丁烷(12 mg,0.07mmol,1.0 eq.)80度反应过夜。TLC监控反应结束后,反应液用EA萃取3次,合并有机相后用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,过flash(反相)(0.05%FA水/ACN,30%-95%,20min),冻干得到14.0mg白色固体,收率57%。化合物结构数据表征:1H NMR (500 MHz, DMSO-d6) δ 12.10 (s,1H), 9.62 (s, 1H), 7.30 – 7.36 (m, 2H), 6.77 – 6.82 (m, 2H),6.05 – 6.12 (m,2H), 5.45 – 5.52 (m, 1H), 4.53 (s, 1H), 4.41 – 4.47 (m, 1H), 4.03 – 4.09 (m,2H), 3.31 –3.31 (m, 1H), 2.68 – 2.76 (m, 1H), 1.71 – 1.80 (m, 4H)。MS(ESI):C19H19FO5,Calcd for[M+H]+ 347.1289;Found:347.1。
实施例16:化合物Y16的制备
将柚皮素(100 mg,0.37mmol,1.0 eq.)加1 ml N,N-二甲基甲酰胺溶解,室温下,依次加入氟化钾(43 mg,0.73mmol,2.0 eq.)和2-溴乙基甲基醚(153 mg,1.10mmol,3.0eq.) 反应过夜。TLC监控反应结束后,反应液用EA萃取3次,合并有机相后用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,过flash(反相)(0.05%FA水/ACN,30%-95%,20min),冻干得到淡黄色固体化合物Y16。化合物结构数据表征:1H NMR (400 MHz, DMSO-d6) δ 12.11 (s,1H), 9.63 (s, 1H), 7.30 – 7.36 (m, 2H), 6.77 – 6.83 (m, 2H),6.06 – 6.13 (m,2H), 5.45 – 5.53 (m, 1H), 4.12 – 4.17 (m, 2H), 3.60 – 3.65 (m, 2H), 3.29 (s,4H), 2.67 – 2.77 (m, 1H)。MS(ESI): C18H18O6,Calcd for[M+H]+ 331.1176;Found:331.1。
具体实施例三
上述具体实施例一种柚皮素衍生物对化疗痛的治疗作用
1、实验方法
1.1 实验动物与药物处理
雄性CD-1小鼠(约20 g),随机对照组(Ctrl组)和模型组(PTX)。按照参考文献(Sparreboom, A., et al Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL. Cancer Research. 1996.56(9):2112-5)配置PTX溶剂(5%无水乙醇,5%聚氧乙烯蓖麻油和90%生理盐水的混合溶液),PTX组小鼠腹腔注射PTX溶液(PTX:10 mg/kg;每10克体重注射0.1 ml溶液), Ctrl组腹腔注射等量溶剂。
1.2 实验动物鞘内注射柚皮素或柚皮素衍生物
模型组小鼠腹腔注射PTX后鞘内注射柚皮素(NAR)或柚皮素衍生物溶液(Y1、Y2、Y3、Y5、Y7或Y8,溶解于1% DMSO溶液);对照组(Ctrl)小鼠鞘内注射等量溶剂(1% DMSO溶液)具体操作步骤如下:腹腔注射5%水合氯醛麻醉(0.1ml/10g),背部剃毛,使用碘伏消毒。左手戴纱布手套,掌心压住鼠身,拇指中指按压骶骨两侧固定,食指按在双骶骨前缘连线正中点皮肤上(可触知棘突)指示进针位点,于L4—L5位置棘突间隙进针,以鼠尾出现突然侧向运动为成功标志;缓慢注射10 µl药物或溶剂,注射完毕后慢慢拔出针头。
1.3 动物行为学
在给药前和给药后第24和48小时测定机械痛阈。具体步骤如下:小鼠放入带有网格底板的玻璃盒子中适应1h后,采用up and down方法,用von frey纤毛(Stoelting, USA)测定小鼠单足脚掌的机械痛阈。
1.4 脊髓免疫荧光实验
行为学实验结束后,小鼠麻醉处死,用4%多聚甲醛心脏灌流固定,取出L4-L6的脊髓组织并置于4%多聚甲醛中进行24小时后固定,随后使用10%和30%的蔗糖溶液梯度脱水处理,待脊髓组织沉底后,使用OCT液冰冻包埋,使用冰冻切片机(Leica,Germany)包埋块切成厚度15µm的组织切片。切片封闭后,使用Iba-1一抗(1:500; abcam, USA)或GFAP一抗(1:250; CST, USA)4℃过夜,随后室温孵育Alexa Fluor 488荧光二抗 (1:200; abcam, USA)2h,最后DAPI染色封片,使用共聚焦荧光显微镜(Leica,Germany)拍摄成像,定量检测蛋白荧光强度, 以Ctrl + DMSO的荧光强度为标准,比较各组相对荧光强度之间的差异。
1.5 统计方法
采用GraphPad Prism 8.0 进行统计学分析,数据以均值±标准误绘图,组间比较采用双因素方差分析 (two-way ANOVA)。P < 0.05表示差异有统计学意义。
2、实验数据:
根据图1的实验结果显示,在PTX诱发的化疗痛小鼠模型中,多个柚皮素衍生物在较低剂量下(0.1-0.4 mg/ml,10 µl;即为1-4 µg)在给药后48小时内对PTX诱发的疼痛均有显著作用(图1)。鞘内注射4 µg剂量的 Y1(图1A)或Y2(图1B)可在给药后24小时和48小时有显著镇痛作用;鞘内注射1 µg剂量Y3(图1C), Y5(图1D),Y7(图1F)或Y8(图1G)在给药后24小时和48小时有显著镇痛作用;鞘内注射1 µg剂量Y6(图1E)在给药后24小时有显著镇痛作用。采用双因素方差分析 (two-way ANOVA)和Turkey’s multiple comparision tests(Post-hoc)进行统计分析。 Ctrl:正常对照;PTX:紫杉醇;Y1-8:柚皮素衍生物。*,** VS.Ctrl +DMSO 组;#,##,### VS. PTX +DMSO;*,# P < 0.05;##,** P < 0.01;### P < 0.005。
图2的实验结果显示,单次鞘内注射柚皮素10 mg/ml(共计100 µg )有镇痛效果,但注射柚皮素2 mg/ml(共计20 µg )在48小时内无显著镇痛作用,Ctrl:正常对照;PTX:紫杉醇;NAR:柚皮素。*,** VS. Ctrl +DMSO 组;#,## VS. PTX +DMSO;*,# P < 0.05;##,** P <0.01。
基础研究发现,脊髓星型胶质细胞和小胶质细胞的过度激活是多种病理性疼痛的重要发病机制之一。我们通过免疫荧光实验技术验证了PTX小鼠脊髓星型胶质细胞(图3A)和小胶质细胞(图3B)的激活标记物表达上调,鞘内注射柚皮素衍生物Y3(1 µg)显著抑制PTX诱发的脊髓星形胶质细胞(图3A)和小胶质细胞的激活(图3B)。采用双因素方差分析(two-way ANOVA)和Turkey’s multiple comparision tests (Post-hoc)进行统计分析。Ctrl:正常对照;PTX:紫杉醇;Y3:柚皮素衍生物。*,** VS. Ctrl +DMSO 组;#,## VS. PTX +DMSO; ##,** P < 0.01;*** P < 0.005。
以上结果提示多种柚皮素衍生物的镇痛效果显著优于柚皮素,其镇痛机制可能与抑制神经胶质细胞过度激活相关。
上述说明并非对本发明的限制,本发明也并不限于上述举例。本技术领域的普通技术人员在本发明的实质范围内,做出的变化、改型、添加或替换,也应属于本发明的保护范围。
Claims (3)
1.柚皮素衍生物在制备治疗化疗痛药物方面的用途,其特征在于柚皮素衍生物为至少一种具有以下结构式的化合物:
2.权利要求1所述的柚皮素衍生物在在制备治疗化疗痛药物方面的用途,其特征在于:所述的柚皮素衍生物Y3在制备化疗痛诱发的脊髓胶质细胞激活抑制剂方面的用途。
3.权利要求1所述的柚皮素衍生物在在制备治疗化疗痛药物方面的用途,其特征在于:所述的柚皮素衍生物在制备减轻炎性疼痛和神经病理性疼痛药物方面的用途。
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