CN114948965B - 一种化合物在制备防治组织损伤药物中的应用 - Google Patents
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Abstract
本发明属于生物医药技术领域,具体涉及一种化合物在制备防治组织损伤药物中的应用。本发明提供一种化合物在制备防治组织损伤药物中的应用,所述化合物具有式I所示结构。本发明提供的具有式I所示结构的化合物能够抑制IRF1转录活性,对组织损伤具有防治作用,且能增强组织细胞损伤后的细胞增殖能力,修复受损组织。本发明提供的式I所示结构的化合物在制备防治组织损伤药物,尤其是在制备辐射和/或氧化造成的皮肤组织炎性损伤药物等方面上具有重要意义和应用价值。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种化合物在制备防治组织损伤药物中的应用。
背景技术
皮肤是人体最大的组织和器官,放射性皮肤损伤是肿瘤放射治疗和放射性事故中最常见的并发症,具有进展快、损伤重、难愈合等特点,目前暂无特效防治药物问世。研究表明,电离辐射、病毒感染、化疗药物等均可引起组织细胞焦亡、坏死等炎症性死亡发生,造成组织损伤,而机体在感受到电离辐射等刺激(损伤相关生物模式)和病毒等微生物感染(病原相关生物模式)时,引起免疫反应过度激活,形成“炎症风暴”,也会加重组织损伤。
干扰素调节因子1(Interferonregulatory factor,IRF1)既是一种转录因子,也是肿瘤抑制因子,其激活后可通过转录调控影响下游干扰素和干扰素诱导基因(ISGs)的表达,参与调控固有免疫、获得性免疫、机体对细菌病毒等应激反应、细胞增殖和凋亡、DNA损伤修复、抑制肿瘤生长和促进肿瘤免疫应答等重要功能。但外界刺激(如电离辐射、病毒感染等)引起IRF1过度激活也是引起组织剧烈炎症反应进而造成组织炎性损伤的重要原因。
发明内容
本发明的目的在于提供一种化合物在制备防治组织损伤药物中的应用化合物。本发明提供的式I所示结构的化合物对组织损伤具有防止作用,能够有效减轻组织损伤进展。
为了实现上述目的,本发明提供如下技术方案:
本发明提供了一种化合物在制备防治组织损伤药物中的应用,所述化合物具有式I所示结构:
优选的,所述组织损伤为由干扰素调节因子1激活引起过度炎症反应导致的组织损伤。
优选的,所述组织损伤为皮肤组织损伤。
优选的,所述皮肤组织损伤为放射性皮肤损伤。
优选的,所述放射性皮肤损伤为电离辐射所致皮肤损伤。
优选的,所述皮肤组织损伤为氧化性皮肤损伤。
优选的,所述皮肤组织损伤为病毒所致皮肤损伤。
优选的,所述组织损伤为电离辐射所致肺部组织损伤。
本发明提供了一种防治组织损伤药物,包括一种化合物和药物辅料,所述化合物具有式I所示结构:
优选的,所述防治组织损伤药物的剂型包括注射剂、膏剂或气雾剂。
一种化合物在制备防治组织损伤药物中的应用,所述化合物具有式I所示结构:
本发明提供的式I所示结构的化合物(命名为IRSKIN-1)能够抑制IRF1转录活性,对由干扰素调节因子1激活引起过度炎症反应导致的组织损伤具有防治作用,且能增强组织细胞炎性损伤后细胞增殖能力,修复受损组成。本发明提供的式I所示结构的化合物在制备防治组织损伤药物,尤其是在制备辐射和/或氧化造成的皮肤组织炎性损伤药物等方面上具有重要意义和应用价值。
附图说明
图1为IRF1敲除小鼠受照射后出现皮肤损伤的照片;其中,图1中:(a)和(c)为野生型小鼠,(a)为照射后19天,(c)为照射后41天;(b)、(d)为IRF1缺失型小鼠,(b)为照射后19天,(d)为照射后41天;
图2为IRF1野生型和缺失型小鼠的皮肤损伤的评分结果;
图3为IRF1敲除小鼠受照射后皮肤炎症因子芯片结果;
图4为基于双荧光素酶报告系统筛选出有效抑制IRF1转录活性药物研究的结果图;
图5为IRSKIN-1促进受照皮肤细胞增殖作用的研究结果;
图6为IRSKIN-1处理皮肤细胞后降低受辐照细胞死亡率的研究结果;
图7为IRSKIN-1处理降低受辐照小鼠原代皮肤细胞衰老率的研究结果;
图8为IRSKIN-1和DMSO分别处理对小鼠放射性皮肤损伤进展影响的结果;图8中:IRSKIN-1经DMSO溶解配置为50mM的溶液,按100μL/次,分别于照射前1天和前3天皮下注射一次,对照组给以等量DMSO溶液皮下注射,采集照后不同时间小鼠放射性皮肤损伤进展的照片;图8中:(a)、(c)为DMSO处理组小鼠,(a)为照射后15天,(c)为照射后30天;(b)、(d)为IRSKIN-1处理组小鼠,(b)为照射后15天,(d)为照射后30天;
图9为IRSKIN-1和DMSO处理对小鼠放射性皮肤损伤进展评分的影响图;
图10为IRSKIN-1和DMSO处理后受照小鼠炎症芯片结果图;
图11为IRSKIN-1抑制受照皮肤炎性死亡关键调控蛋白表达的作用测试结果图;
图12为本发明提供的式1所示结构的化合物的化学结构式。
具体实施方式
本发明提供了一种化合物在制备防治组织损伤药物中的应用,所述化合物具有式I所示结构:
在本发明中,式I所示结构的化合物采购自德国SPECS公司,网站为:
https://www.specs.net/index.php?page=startpage¬e=password%20for%20user%20-%20zshuaijun%20-%20correct。
在本发明中,式I所示结构的化合物的药物ID号为:AP-853/42423499。
在本发明中,式I所示结构的化合物的英文名称为:3-(4-oxo-3(4H)-quinazolinyl)-N-[4-(1-piperidinylsulfonyl)phenyl]propanamide。
在本发明中,式I所示结构的化合物的化学式为C22H24N4O4S。
在本发明中,式I所示结构的化合物的化学名称为:3-(4-氧代-3(4H)-喹唑啉基)-N-[4-(1-哌啶基磺酰基)苯基]丙胺。
在本发明中,所述组织损伤优选为由干扰素调节因子1激活引起过度炎症反应导致的组织损伤。
在本发明中,所述组织损伤优选为皮肤组织损伤。
在本发明中,所述皮肤组织损伤优选为放射性皮肤损伤。
在本发明中,所述放射性皮肤损伤优选为电离辐射所致皮肤损伤。
在本发明中,所述皮肤组织损伤优选为氧化性皮肤损伤。
在本发明中,所述皮肤组织损伤优选为病毒所致皮肤损伤。
在本发明中,所述组织损伤优选为电离辐射所致肺部组织损伤。
本发明提供了一种化合物在制备组织再生修复药物中的应用,所述化合物具有式I所示结构:
在本发明中,所述组织再生修复优选为在损伤组织部位含有相应组织的细胞增殖、分化、形成新的组织。
本发明提供了一种防治组织损伤药物,包括一种化合物和药物辅料,所述化合物具有式I所示结构:
在本发明中,所述药物辅料优选包括药学可接受的盐、赋形剂和载体中的一种或多种。
在本发明中,所述防治组织损伤药物的剂型优选包括注射剂、膏剂或气雾剂。
在本发明中,所述防治组织损伤药物中,式I所示结构的化合物的离体条件有效浓度优选为10~20μmol/L。
在本发明中,所述防治组织损伤药物中,式I所示结构的化合物的皮下注射有效剂量优选为100μg/次×2次。
在本发明中,本发明提供的化合物(命名为IRSKIN-1)、所用试剂、细胞株、动物、仪器等均为市售产品。
为了进一步说明本发明,下面结合附图和实施例对本发明提供的上述技术方案进行详细地描述,但不能将它们理解为对本发明保护范围的限定。
实施例1
IRF1敲除小鼠皮肤组织放射性损伤减轻实验
为明确IRF1在放射性皮肤损伤进展中的重要性,从美国Jackson实验室购置了IRF1敲除小鼠(stock number:002762)。该IRF1敲除小鼠与和野生型C57小鼠杂交后,经基因型鉴定得到第二代野生型和IRF1缺失型小鼠。按每只小鼠体重的1%给予1%水合氯醛腹腔注射进行麻醉后,对小鼠后肢皮肤进行脱毛,固定于木板上,以减少照射时意外产生的运动。
以美国瓦里安公司23EX型直线加速器产生的6MeV电子射线照射小鼠后肢皮肤,表面覆有1cm厚的组织补偿膜,非照射部位以铅板屏蔽,照射面积约为25mm×40mm,吸收剂量率为750cGy/min,剂量为35Gy。
观察皮肤损伤进展情况:参见图1,照射10天后,对照组小鼠(野生型),图1中的(a)和(c)出现皮肤湿性溃疡,而IRF1敲除组,图1中的(b)和(d)未见皮肤损伤。IRF1野生型和缺失小鼠的皮肤损伤的评分结果见图2(**P<0.01,*P<0.05)。炎症芯片结果如图3所示,结果显示IRF1缺失小鼠受照皮肤组织IL7、IL13、IL21和Fasl等炎症因子表达显著降低。
因此,实施例1的结果表明IRF1具有加重受照皮肤组织炎性损伤的作用;实施例1的结果也提示IRF1抑制剂可能具有增强皮肤组织的辐射防护作用。基于此,通过分子对接进行了化合物筛选,筛选到本发明的化合物IRSKIN-1可抑制IRF1与DNA的结合。
实施例2
IRSKIN-1抑制IRF1的转录活性实验
为明确化合物(IRSKIN-1)抑制IRF1转录活性的作用,依托汉恒生物科技(上海)有限公司构建h-IRF1 promoter-rluc腺病毒载体,该载体具有IRF1的四个结合位点,启动子下游是荧光素酶报告基因。该病毒基于双荧光素酶系统构建,可通过荧光素酶的酶活直接反应IRF1的转录活性,离体条件下按照100MOI滴度对人皮肤角质形成细胞(HaCaT细胞)进行感染,感染48小时后病毒感染效率即可满足实验需求,设置为0Gy未照射组;等量DMSO处理后照射组(X射线,20Gy,剂量率为1.7Gy/分钟)和IRSKIN-1处理后照射组(照前24h给以10μM IRSKIN-1处理,图4所示,**P<0.01)。
于照后1h采用Promega酶标仪及相应底物进行检测,结果如图4所示,电离辐射可引起HaCaT细胞转录活性提高,而IRSKIN-1预先处理组照后IRF1活性显著低于DMSO处理后照射组,表明该小分子化合物可有效抑制受照皮肤细胞IRF1转录活性。
实施例3
IRSKIN-1促进受照皮肤细胞增殖实验
为明确IRF1抑制剂IRSKIN-1促进受照皮肤细胞增殖的作用,分别于照射前给以细胞10μM IRSKIN-1或等量DMSO处理24小时,而后分别行单次2Gy或两次2GyX射线分割照射或单次4Gy Sr 90照射,而后通过克隆形成实验(六孔板每孔铺2500个细胞)评价IRSKIN-1对受照细胞增殖能力的影响。
实验结果如图5所示,给以IRSKIN-1预处理可以显著提高受X射线或Sr 90辐照皮肤细胞的克隆形成能力,表明IRSKIN-1具有促进受照细胞增殖的作用(**P<0.01)。
实施例4
IRSKIN-1处理降低受照细胞死亡率实验
为明确IRSKIN-1是否降低受照皮肤细胞死亡率的作用,分别于照射前给以细胞10μM IRSKIN-1或等量DMSO处理24小时,而后行单次20Gy X射线照射于照射后3天通过AV/PI染色法评价IRSKIN-1对受照细胞增殖能力的影响。
实验结果如图6所示,给以IRSKIN-1预处理可以降低X射线照射引起的细胞死亡率,表明IRSKIN-1具有降低受照细胞死亡率的作用(**P<0.01)。
实施例5
IRSKIN-1处理降低受照IRF1野生型小鼠原代皮肤细胞衰老率实验
为明确IRSKIN-1是否降低受照皮肤细胞衰老比率的作用,分离培养小鼠原代皮肤细胞,分别于照射前给以细胞10μM IRSKIN-1或等量DMSO处理24小时,而后行单次20Gy X射线照射于照射后3天通过β-半乳糖苷酶染色法评价IRSKIN-1对受照原代细胞衰老的影响。
实验结果如图7所示,给以IRSKIN-1预处理可以降低X射线照射引起的小鼠原代细胞β-半乳糖苷酶阳性比率(**P<0.01),表明IRSKIN-1具有抑制受照原代细胞衰老发生的作用。
实施例6
皮下注射IRSKIN-1有效减轻小鼠模型的放射性皮肤损伤进展实验
6~8周龄雄性C57 BL/6J小鼠购于江苏集萃药康生物科技有限公司,经适应性饲养后随机分为2组(每组6只),分别于照射前1天和前3天给予小鼠IRSKIN-1(DMSO溶解配置浓度为50mM的溶液,100μL/次)和等量DMSO溶液皮下注射一次;按每只小鼠体重的1%给予1%水合氯醛腹腔注射进行麻醉后,对小鼠后肢皮肤进行脱毛,固定于木板上,以减少照射时意外产生的运动。
以美国瓦里安公司23EX型直线加速器产生的6MeV电子射线照射大鼠臀部皮肤,表面覆有1cm厚的组织补偿膜,非照射部位以铅板屏蔽,照射面积约为30mm×40mm,吸收剂量率为750cGy/min,总剂量为45Gy,并且在照射用记号笔勾勒出照射区域范围。
观察皮肤损伤情况:结果表明IRSKIN-1皮下注射组小鼠放射性皮肤损伤进展较DMSO组更慢,溃疡创面面积更小。图8所示两组小鼠皮肤创面比较,IRSKIN-1处理组小鼠皮肤仅有很少区域出现湿性溃疡,表明在皮下注射IRSKIN-1具有减轻小鼠放射性皮肤损伤进展的作用。IRSKIN-1降低小鼠放射性皮肤损伤进展评分结果见图9。炎症芯片结果如图10所示,结果显示IRSKIN-1处理组小鼠皮肤组织G-CSF、TNF-RⅡ和MIP-1a表达升高,BLC表达降低。
实施例7
IRSKIN-1抑制受照皮肤炎性死亡关键调控蛋白表达的作用
为明确IRF1抑制剂IRSKIN-1抑制受照皮肤细胞炎性死亡的作用机制,分别于照射前给以细胞10μM IRSKIN-1或等量DMSO处理24小时,而后行单次20Gy X射线照射,而后通过免疫印迹检测细胞焦亡通路关键蛋白Caspase1和GSDMD及炎症因子IL1水解的改变,明确IRSKIN-1抑制受照皮肤细胞炎性死亡的作用及机制。
实验结果如图11所示,给以IRSKIN-1预处理可以抑制皮肤细胞Caspase1、GSDMD和IL1的水解,表明IRSKIN-1具有抑制受照细胞炎性死亡的作用。
上述结果表明该药物具有减轻辐射暴露后皮肤炎性损伤的作用。
尽管上述实施例对本发明做出了详尽的描述,但它仅仅是本发明一部分实施例,而不是全部实施例,还可以根据本实施例在不经创造性前提下获得其他实施例,这些实施例都属于本发明保护范围。
Claims (3)
1.一种化合物在制备防治组织损伤药物中的应用,所述化合物具有式I所示结构:
2.根据权利要求1所述的应用,其特征在于,所述组织损伤为皮肤组织损伤。
3.根据权利要求1所述的应用,其特征在于,所述组织损伤为电离辐射所致肺部组织损伤。
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