CN114376998A - 酚酰胺类化合物或其植物提取物的药物应用 - Google Patents
酚酰胺类化合物或其植物提取物的药物应用 Download PDFInfo
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- CN114376998A CN114376998A CN202111480035.6A CN202111480035A CN114376998A CN 114376998 A CN114376998 A CN 114376998A CN 202111480035 A CN202111480035 A CN 202111480035A CN 114376998 A CN114376998 A CN 114376998A
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- spermine
- feruloyl
- hydroxyferuloyl
- coumaroyl
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Abstract
本发明涉及已知化合物或其植物提取物的新药物应用，具体涉及酚酰胺类化合物或其植物提取物的药物应用。本发明所述酚酰胺类化合物或其植物提取物在制备抑制前列腺特异性抗原PSA分泌的药物组合物、或者在制备抗前列腺增生、前列腺炎或抗前列腺瘤的药物组合物中的应用；所述酚酰胺类化合物为在精胺或腐胺单体的N基位点上修饰咖啡酸、p‑香豆酸或阿魏酸基团的一类化合物。本发明所述应用开拓了该类化合物新的应用领域，同时也为上述领域的病症的预防和治疗提供了新的途径。
Description
技术领域
本发明涉及已知化合物或其植物提取物的新药物应用，具体涉及酚酰胺类化合物或其植物提取物的药物应用。
背景技术
前列腺增生是老年男性常见慢性疾病，是一种特殊的组织病理性疾病。随着年龄增长前列腺增生的发病率不断提升高，症状随年龄加剧。据流行病学统计，50岁时发病率达40％，80岁以上的老年男性90％患有前列腺增生。值得注意的是，25％的患者发生尿路梗阻而需要药物和手术治疗，前列腺增生引起的一系列疾病已经成为危害老年男性健康的主要疾病之一。主要临床表现为夜尿次数增多，尿频，尿急、尿线变细、尿不尽感及不能憋尿等症状，并常会伴有其他并发症如前列腺炎、膀光结石甚至引起前列腺癌等。前列腺增生是腺体内细胞不受控制的非恶性增殖，这些增殖细胞常常发生在围绕尿道周围组织，随着增生的不断加重，腺体会挤压尿道，并会梗阻尿路，致使膀胱不会完全排空，进而会造成非细菌型前列腺炎。
目前抗前列腺增生方法主要是5α-还原酶抑制剂和α受体阻滞剂联合应用。5α-还原酶抑制剂可以降低前列腺体积和血液中PSA水平，从而缓解前列腺增生症状；α-还原酶抑制剂能够通过阻滞分布在前列腺和膀胱颈部平滑肌表面的α-肾上腺能受体，发挥缓解尿路梗阻的作用。但是5α-还原酶抑制剂会造成雄激素减少，从而给身体带来相关副作用。此外，该方法的不良反应和费用也相对较高；并且前列腺增生属于慢性疾病需要长期服药，上述治疗的毒副作用也给患者造成烦恼，并且这两种药物的作用靶点太过单一，对前列腺增生造成的其他疾病无治疗作用，如前列腺炎、前列腺癌等。这种情况造成了人们对天然产物制剂治疗前列腺增生等相关疾病的关注。
近年来，利用天然产物制剂治疗前列腺疾病已受到越来越多的人们的重视。目前公认的治疗该疾病的植物制剂为油菜蜂花粉。相关油菜蜂花粉植物制剂“前列康”或“普乐安”在治疗前列腺疾病方面具有良好的效果，多年来“前列康”片或“普乐安”片在临床上得到了广泛的应用，总有效率均在77％以上。然而，此类药物均是以完整油菜蜂花粉为主要成分，用药剂量较大。归其原因是对其中发挥作用的化合物不明确。此外，对花粉过敏者来说，完整油菜蜂花粉制剂也容易引起过敏反应，甚至对机体造成其他危害。
发明内容
本发明提供了酚酰胺类化合物或其植物提取物的新药物应用。
具体来讲，本发明提供酚酰胺类化合物或其植物提取物在制备抑制前列腺特异性抗原PSA分泌的药物组合物、或者在制备抗前列腺增生、前列腺炎或抗前列腺瘤的药物组合物中的应用。
所述的酚酰胺类化合物为在精胺或腐胺单体的N基位点上修饰咖啡酸、p-香豆酸、阿魏酸等基团的一类化合物，其具体结构式如下：
精胺单体：
腐胺单体：
其中：R1、R2、R3、R4、R5、R6可由以下RX中结构任意取代，且在RX中的7’和8’链接成的烯键可为顺式或反式；
RX：
本发明研究发现，上述酚酰胺类化合物在前列腺特异性抗原PSA分泌方面表现出非常好的活性，因此可利用这一活性治疗前列腺疾病。
同时本发明还发现，上述结构式所示的酚酰胺类化合物在抗前列腺增生、前列腺炎或抗前列腺瘤方面具有显著的效果。
因此，本发明提供酚酰胺类化合物或其植物提取物在制备抑制前列腺特异性抗原PSA分泌的药物、或者在制备抗前列腺增生、前列腺炎或抗前列腺瘤的药物组合物中的应用。
本发明所述酚酰胺类化合物包括腐胺基酚酰胺类化合物、精胺基酚酰胺类化合物。
其中，所述腐胺基酚酰胺类化合物包括：香豆酰腐胺、咖啡酰腐胺、阿魏酰腐胺、羟基阿魏酰腐胺、二-香豆酰腐胺、二-咖啡酰腐胺、二-阿魏酰腐胺、二-羟基阿魏酰腐胺、香豆酰-咖啡酰腐胺、香豆酰-阿魏酰腐胺、香豆酰-羟基阿魏酰腐胺、阿魏酰-羟基阿魏酰腐胺、咖啡酰-羟基阿魏酰腐胺、咖啡酰-阿魏酰腐胺。
所述精胺基酚酰胺类化合物包括：香豆酰精胺、阿魏酰精胺、咖啡酰精胺、羟基阿魏酰精胺、二-香豆酰精胺、二-阿魏酰精胺、二-咖啡酰精胺、二-羟基阿魏酰精胺、香豆酰-阿魏酰精胺、香豆酰-咖啡酰精胺、香豆酰-羟基阿魏酰精胺、阿魏酰-咖啡酰精胺、阿魏酰-羟基阿魏酰精胺、咖啡酰-羟基阿魏酰精胺、二-香豆酰-咖啡酰精胺、二-香豆酰-阿魏酰精胺、二-香豆酰-羟基阿魏酰精胺、二-咖啡酰-香豆酰精胺、二-咖啡酰-阿魏酰精胺、二-咖啡酰-羟基阿魏酰精胺、二-阿魏酰-香豆酰精胺、二-阿魏酰-咖啡酰精胺、二-阿魏酰-羟基阿魏酰精胺、二-羟基阿魏酰-香豆酰精胺、二-羟基阿魏酰-咖啡酰精胺、二-羟基阿魏酰-阿魏酰精胺、二-香豆酰-二咖啡酰精胺、二-香豆酰-二-阿魏酰精胺、二-香豆酰-二-羟基阿魏酰精胺、二-咖啡酰-二阿魏酰精胺、二-咖啡酰-二-羟基阿魏酰精胺、二-阿魏酰-二-羟基阿魏酰精胺、三-香豆酰-咖啡酰精胺、三-香豆酰-阿魏酰精胺、三-香豆酰-羟基阿魏酰精胺、三-咖啡酰-香豆酰精胺、三-咖啡酰-阿魏酰精胺、三咖啡酰-羟基阿魏酰精胺、三-阿魏酰-香豆酰精胺、三-阿魏酰-咖啡酰精胺、三-阿魏酰-羟基阿魏酰精胺、三-羟基阿魏酰-香豆酰精胺、三-羟基阿魏酰-咖啡酰精胺、四-香豆酰精胺、四-咖啡酰精胺、四-阿魏酰精胺、四-羟基阿魏酰精胺。
本发明所述的酚酰胺类化合物包括上述列举的化合物的顺反异构。
本发明所述的植物为植物花粉，优选为蜂花粉。
本发明所述药物组合物的活性成分的用药剂量为1-3mg/Kg体重/每天。
本发明中，按常规的药物制备方法，添加常规的赋形剂或药学上可接受的载体，可制得各种剂型的药物组合物。
其中，所述剂型可为片剂、胶囊、液体制剂、颗粒剂、丸剂、煎膏剂、悬浮剂、分散剂、糖浆剂、栓剂、注射剂。
所述赋形剂包括粘合剂、如聚乙烯比咯烷酮、羟丙基纤维素等；崩解剂，如羧甲基纤维素钠、低取代羟丙纤维素等；稀释剂，如淀粉、糖粉、糊精、微晶纤维素、甘露醇、乳糖、大豆油等；润滑剂，如硬脂酸镁、滑石粉等；甜味剂，如蔗糖、果糖、天冬甜素等；稳定剂，如羧甲基纤维素钠、环糊精等；防腐剂，如对羟基苯甲酸乙酯、苯甲酸钠等。
本发明涉及的原料和试剂均可市售得到。
本发明的有益效果如下：
所述酚酰胺类化合物或其植物提取物在制备抑制前列腺特异性抗原PSA分泌的药物、或者在制备抗前列腺增生、前列腺炎或抗前列腺瘤的药物组合物中的应用。
本发明所述应用开拓了该类化合物新的应用领域，同时也为上述领域的病症的预防和治疗提供了新的途径。
附图说明
图1为效果实施例2的激光共聚焦免疫荧光成像蛋白表达分析。
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范围。
本发明所述的精胺酚胺类化合物和腐胺酚胺类化合物均为已知化合物，且均可通过市售购买得到，或通过常规合成方法制备得到。
效果实施例1抑制前列腺特异性抗原PSA分泌活性测试
人前列腺癌LNCaP、C42B细胞接种于含10％热灭活胎牛血清，加入100U/mL青链霉素的RPMI-1640培养基中，培养温度为37℃，5％CO2培养箱中培养。待细胞生长良好，接种于96孔板，每孔细胞数为10000个，培养过夜。
将47个精胺酚胺类化合物、14个腐胺酚胺类化合物分别用DMSO溶解，分别设置浓度低(50μg/mL)、中(100μg/mL)、高(200μg/mL)和空白组，给药。给药后培养24小时，用化学发光法测定细胞上清中PSA含量。与空白组对比，计算出抑制率。
表1 14个腐胺酚胺类化合物对LNCaP细胞PSA抑制率
| 编号 | 50μg/mL | 100μg/mL | 200μg/mL |
| A1 | 19.44 | 34.10 | 55.91 |
| A2 | 23.19 | 40.24 | 64.38 |
| A3 | 20.16 | 31.09 | 59.11 |
| A4 | 14.92 | 34.54 | 70.48 |
| A5 | 19.10 | 50.33 | 69.14 |
| A6 | 24.53 | 44.72 | 55.32 |
| A7 | 14.19 | 30.41 | 48.46 |
| A8 | 22.55 | 47.26 | 70.03 |
| A9 | 26.83 | 51.12 | 71.38 |
| A10 | 17.48 | 29.41 | 59.90 |
| A11 | 16.66 | 36.12 | 56.42 |
| A12 | 12.42 | 29.38 | 50.13 |
| A13 | 19.78 | 30.22 | 49.22 |
| A14 | 11.09 | 29.94 | 51.39 |
表2 14个腐胺酚胺类化合物对C42B细胞PSA抑制率
| 编号 | 50μg/mL | 100μg/mL | 200μg/mL |
| A1 | 19.44 | 34.10 | 59.18 |
| A2 | 23.19 | 40.24 | 64.33 |
| A3 | 20.16 | 31.09 | 70.02 |
| A4 | 14.92 | 34.54 | 66.89 |
| A5 | 19.10 | 50.33 | 69.01 |
| A6 | 24.53 | 44.72 | 68.32 |
| A7 | 14.19 | 30.41 | 57.93 |
| A8 | 22.55 | 47.26 | 69.22 |
| A9 | 26.83 | 51.12 | 73.55 |
| A10 | 17.48 | 29.41 | 59.30 |
| A11 | 16.66 | 36.12 | 62.71 |
| A12 | 12.42 | 29.38 | 60.22 |
| A13 | 19.78 | 30.22 | 59.38 |
| A14 | 11.09 | 29.94 | 69.68 |
表3 47个精胺酚胺类化合物用药量200ug/mL抑制率
结果表明，随着浓度升高，酚胺类化合物抑制LNCaP、C42B细胞PSA抑制率逐渐升高。
给药浓度200μg/mL时，47个精胺酚胺类化合物对LNCaP细胞PSA的抑制率在67.8-90.73％，其中四羟基阿魏酰精胺抑制率最高；对C42B细胞PSA抑制率在62.19-89.43％，其中四羟基阿魏酰精胺抑制率最高。
给药浓度200μg/mL时，14个腐胺酚胺类化合物对LNCaP细胞PSA的抑制率在49.22-71.38％，对C42B细胞PSA抑制率在55.02-73.55％，其中阿魏酰-羟基阿魏酰腐胺的抑制率最高。
效果实施例2-3抗前列腺增生测试及抗前列腺炎测试
选用雄性SD大鼠36只，体重190-220g，在25±2℃、相对湿度55±5％的控制条件下喂养。将其随机分为3组，分别为7.1mg/kg剂量组和空白对照组和模型组。用λ-角叉菜胶诱导前列腺炎。临用前用生理盐水根据每组对应的用量配制成对应的混悬液进行灌胃给药。每天记录每只动物的食物摄入量、体重。第15天全部处死大鼠，取前列腺观察，并检测炎症因子。
前列腺湿重结果和前列腺指数结果显示，模型组与给药组存在显著性差异(P<0.01)，给药改变了前列腺器质性的改变。
HE染色结果显示，模型组大鼠的前列腺腺体大量减少，腺体间隙增宽，腺体间及小叶间大量炎性细胞浸润，还可见多处坏死灶，呈嗜酸性丝网状，少量腺体周围结缔组织增生，腺上皮细胞扁平化。
试验结果说明，精胺酚胺类化合物和腐胺酚胺类化合物的使用可以改善大鼠前列腺的组织改变，也能够显著降低大鼠血清和前列腺组织中的IL-6、IL-8、IL-1β和TNF-α的表达水平。
图1为效果实施例2的激光共聚焦免疫荧光成像蛋白表达分析。
效果实施例4植物提取物的毒性研究
选用健康清洁级体重为190-220g的大鼠20只，雌雄各半，随机分为2组，分别为35.5g/kg剂量组，相当于60kg体重成人临床日用剂量600倍，生理盐水空白对照组。灌胃给药3次，每日1次，观察给药有小鼠毒性反应、行为、体重、粪便及死亡情况，连续观察2周。观察结束后处死所有小鼠，进行解剖，观察主要脏器病变情况。
结果显示，在此剂量下，连续灌胃3天，灌胃后2周内各组小鼠均未死亡，观察状态良好，行为、体重、粪便无异常。处死后小鼠主要脏器为发生异常变化。通过极性毒性试验表明，酚酰胺类植物提取物的最大耐受量为35.5g，说明在此剂量下灌胃给药是安全的。
Claims (10)
1.酚酰胺类化合物在制备抑制前列腺特异性抗原PSA分泌的药物组合物、或者在制备抗前列腺增生、前列腺炎或抗前列腺瘤的药物组合物中的应用；
所述酚酰胺类化合物为在精胺或腐胺单体的N基位点上修饰咖啡酸、p-香豆酸或阿魏酸基团的一类化合物。
2.根据权利要求1所述的应用，其特征在于，所述酚酰胺类化合物包括腐胺基酚酰胺类化合物、精胺基酚酰胺类化合物。
3.根据权利要求2所述的应用，其特征在于，所述腐胺基酚酰胺类化合物包括：香豆酰腐胺、咖啡酰腐胺、阿魏酰腐胺、羟基阿魏酰腐胺、二-香豆酰腐胺、二-咖啡酰腐胺、二-阿魏酰腐胺、二-羟基阿魏酰腐胺、香豆酰-咖啡酰腐胺、香豆酰-阿魏酰腐胺、香豆酰-羟基阿魏酰腐胺、阿魏酰-羟基阿魏酰腐胺、咖啡酰-羟基阿魏酰腐胺、咖啡酰-阿魏酰腐胺。
4.根据权利要求2所述的应用，其特征在于，所述精胺基酚酰胺类化合物包括：香豆酰精胺、阿魏酰精胺、咖啡酰精胺、羟基阿魏酰精胺、二-香豆酰精胺、二-阿魏酰精胺、二-咖啡酰精胺、二-羟基阿魏酰精胺、香豆酰-阿魏酰精胺、香豆酰-咖啡酰精胺、香豆酰-羟基阿魏酰精胺、阿魏酰-咖啡酰精胺、阿魏酰-羟基阿魏酰精胺、咖啡酰-羟基阿魏酰精胺、二-香豆酰-咖啡酰精胺、二-香豆酰-阿魏酰精胺、二-香豆酰-羟基阿魏酰精胺、二-咖啡酰-香豆酰精胺、二-咖啡酰-阿魏酰精胺、二-咖啡酰-羟基阿魏酰精胺、二-阿魏酰-香豆酰精胺、二-阿魏酰-咖啡酰精胺、二-阿魏酰-羟基阿魏酰精胺、二-羟基阿魏酰-香豆酰精胺、二-羟基阿魏酰-咖啡酰精胺、二-羟基阿魏酰-阿魏酰精胺、二-香豆酰-二咖啡酰精胺、二-香豆酰-二-阿魏酰精胺、二-香豆酰-二-羟基阿魏酰精胺、二-咖啡酰-二阿魏酰精胺、二-咖啡酰-二-羟基阿魏酰精胺、二-阿魏酰-二-羟基阿魏酰精胺、三-香豆酰-咖啡酰精胺、三-香豆酰-阿魏酰精胺、三-香豆酰-羟基阿魏酰精胺、三-咖啡酰-香豆酰精胺、三-咖啡酰-阿魏酰精胺、三咖啡酰-羟基阿魏酰精胺、三-阿魏酰-香豆酰精胺、三-阿魏酰-咖啡酰精胺、三-阿魏酰-羟基阿魏酰精胺、三-羟基阿魏酰-香豆酰精胺、三-羟基阿魏酰-咖啡酰精胺、四-香豆酰精胺、四-咖啡酰精胺、四-阿魏酰精胺、四-羟基阿魏酰精胺。
5.根据权利要求2-4任一项所述的应用，其特征在于，所述酚酰胺类化合物包括顺、反异构体。
6.根据权利要求1-5任一项所述的应用，其特征在于，所述的药物组合物的活性成分为用药剂量的1-3mg/Kg体重/每天。
7.一种含酚酰胺类化合物的植物提取物在制备抑制前列腺特异性抗原PSA分泌的药物组合物、或者在制备抗前列腺增生、前列腺炎或抗前列腺瘤的药物组合物中的应用；
所述酚酰胺类化合物如权1-6任一项所定义。
8.根据权利要求7所述的应用，其特征在于，所述植物为植物花粉。
9.根据权利要求8所述的应用，其特征在于，所述植物花粉为蜂花粉。
10.根据权利要求7-9任一项所述的应用，其特征在于，所述的药物组合物的活性成分为用药剂量的1-3mg/Kg体重/每天。
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Non-Patent Citations (1)
| Title |
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| 韩明勇，等主编: "《肿瘤分子靶向治疗学》", vol. 2008, 上海科学技术出版社, pages: 294 * |
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