CN104473928A - Pj147在制备血管生成抑制药物中的应用 - Google Patents
Pj147在制备血管生成抑制药物中的应用 Download PDFInfo
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Abstract
本发明属于医药技术领域，涉及PJ147-6在血管生成抑制方面的应用，具体涉及PJ147-6作为血管生成抑制剂在关节炎、银屑病、眼科疾病、动脉粥样硬化等新生血管依赖性和新生血管相关性疾病中的应用。PJ147-6的结构下所示。该类化合物属于环二肽类化合物，结构稳定，配以适当药用辅料可制成临床上可以接受的各种剂型。血管生成抑制试验结果表明，PJ147-6能够抑制血管内皮生长因子VEGF的表达，并具有很好的血管生成抑制活性。
Description
技术领域：
本发明涉及医药技术领域，具体涉及单体化合物PJ147-6在制备血管生成抑制药物中的应用
背景技术：
新生血管形成在生 理及病理条件下均有发生。生理性的血管形成主要发生在胚胎发育、妊娠以及女性的生理周期等过程中。病理性的新生血管形成是局部的，一些疾病如各种原因引起的肿瘤、眼部新血管形成、关节炎、皮肤疾患、动脉粥样硬化等，都在局部有大量的微血管生成。因此，发现新的血管生成抑制剂将对有血管新生而引起的各种疾病提供新的治疗药物。
发明内容：
1、本发明的目的是提供一种单体化合物PJ147-6在制备抑制血管生成药物中的应用。为实现上述目的，本发明采取的技术方案是：PJ147-6在制备抑制血管生成药物中的应用。
2、所述的PJ147-6作为单一成分或与其他药学上可接受的成分构成组合物以制备抑制血管生成的药物。
3、所述的抑制血管生成的药物剂型为胶囊剂、片剂、口服制剂、微囊制剂、注射剂、栓剂、喷雾剂或软膏剂。
4、所述的抑制血管生成药物为抑制银屑病病变组织血管新生的药物。
5、所述的抑制血管生成药物为抑制Paget’s疾病血管新生的药物。
6、所述的抑制血管生成药物为抑制良性血管增生疾病的血管新生的药物。
7、所述的抑制血管生成药物为抑制关节炎病变组织的血管新生的药物。
8、所述的抑制血管生成药物为抑制动脉粥样硬化病变处的血管新生的药物。
9、所述的抑制血管生成药物为抑制新生血管性眼病的血管生成的药物。
10、所述的新生血管性眼病为原发性或继发性新生血管性眼病。
附图说明：
图1为PJ147-6抑制血管内皮生长因子VEGF的表达。
本发明优点在于：
本发明提供了PJ147-6的用途，首次发现PJ147-6可有效抑制VEGF的生成，具有抗血管生成活性，可作为血管生成抑制剂使用。本发明首次发现PJ147-6抗血管生成作用，能够作为血管生成抑制剂应用于血管生成药物的制备以治疗关节炎、银屑病、眼科疾病、动脉粥样硬化等新生血管依赖性和新生血管相关性疾病。
实例1：
1、荷瘤小鼠模型的制备
小鼠自由饮水进食，12h循环光照，适应环境四天。抽取生长状态良好的昆明种小鼠体内传代（第8天）的U14肿瘤细胞(腹水) ,用无菌生理盐水稀释，调整细胞密度约为2.63×107 个/ml-1，混匀后于每只小鼠右前肢腋下注射0.2ml。
2、分组及给药
U14：小鼠于接瘤24h后，按体重均衡随机分为8组，每组11-12只。分组如下：受试样品PJ-147-6 分为45mg/kg、15mg/kg、5mg/kg组。市售环磷酰胺注射液25mg/kg组；模型对照组。所有给药组均每天灌胃给药一次，模型对照组每天灌胃等体积的蒸馏水，给药体积为10 ml/kg。
3、观测指标
观察记录各组小鼠的体重及生存状态（小鼠的一般活动情况，皮毛，尿液颜色及粪便等）。动物于最后一次给药后24小时后，称重、取血进行白细胞计数、记录在体肿瘤长度和宽度，处死，剥离瘤组织和相关脏器（计算公式如下：TIR =100%×（模型组平均瘤重-给药组平均瘤重）/模型组平均瘤重。
PJ-147-6对U14荷瘤小鼠肿瘤增长抑制作用，结果显示：与模型组相比， PJ-147-6各剂量组对肿瘤的抑制作用呈剂量依赖性，最高抑瘤率分别为67. 9%。肿瘤周围血管呈松散状态，且经westblot分析结果表明，PJ147-6能够抑制血管内皮生长因子VEGF的表达，结果如图1所示：
实例2：
选择 7天龄活胚蛋，随机分组，每组 12个，在照卵灯下寻找胚头中轴侧区域，划定 1cm×1cm圆形开窗部位，用体积分数为70%乙醇溶液消毒开窗部位，在鸡胚气室端钻2mm小孔并穿透壳膜。暴露出鸡胚尿囊膜，用微量进样器将各组药物滴加入甲基纤维素滤膜中，将滤膜放置于尿囊膜上血管部位，给药方式为: 对照为每个鸡胚生理盐水20μL。 给药组为100μg/个，加药完毕后用胶带密实封口。并继续放入 37℃的孵箱内孵育72小时。
提取物处理鸡胚 72小时后，实验结果显示，对照组微孔滤膜周围 CAM血管生长良好，呈树枝状、叶脉样平行生长; 药物组血管变细、侧枝减少、药物滤膜近端血管密度减少等现象。最终统计PJ147-6的血管生成抑制率为26%。
Claims (2)
1.PJ147-6作为血管生成抑制剂在制备血管生成药物中的应用，PJ147-6的结构如下所示：
。
2.PJ147-6作为血管生成抑制剂在关节炎、银屑病、眼科疾病、动脉粥样硬化等新生血管依赖性和新生血管相关性疾病中的应用。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101255139A (zh) * | 2008-03-18 | 2008-09-03 | 沈阳药科大学 | 抗肿瘤化合物二酮哌嗪pj147的合成方法 |
| CN101935306A (zh) * | 2010-07-22 | 2011-01-05 | 沈阳药科大学 | 新的二酮哌嗪类衍生物及其应用 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101255139A (zh) * | 2008-03-18 | 2008-09-03 | 沈阳药科大学 | 抗肿瘤化合物二酮哌嗪pj147的合成方法 |
| CN101935306A (zh) * | 2010-07-22 | 2011-01-05 | 沈阳药科大学 | 新的二酮哌嗪类衍生物及其应用 |
Non-Patent Citations (1)
| Title |
|---|
| XUE-ZHENG LI ET AL.: "Synthesis and bioactivity of diketopiperazine PJ147 and its derivatives", 《JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH》 * |
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