CN1298321C - 光损伤调控物在制备用于抑制由紫外线引起的光损伤的药物中的用途 - Google Patents
光损伤调控物在制备用于抑制由紫外线引起的光损伤的药物中的用途 Download PDFInfo
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- CN1298321C CN1298321C CNB038087766A CN03808776A CN1298321C CN 1298321 C CN1298321 C CN 1298321C CN B038087766 A CNB038087766 A CN B038087766A CN 03808776 A CN03808776 A CN 03808776A CN 1298321 C CN1298321 C CN 1298321C
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Abstract
本发明提供一种脯氨酸、4-羟基脯氨酸、或其烷基酯在制备用于抑制由紫外线引起的光损伤的药物中的用途。
Description
相关申请
本申请要求2002年4月19日提交的临时申请60/374,033的优先权。将该申请的完整公开在本文引用作为参考
技术领域
本发明涉及可以用作皮肤细胞光毒性调控物的分子和组合物。具体而言,“调控物”在用于本文时指能够加速或延迟因暴露于光照而引起的对细胞诸如皮肤细胞的损伤的物质。
背景技术
众所周知,光,特别是UVA光,伤害皮肤细胞。光毒性细胞损伤是通过光与某些皮肤内源化合物的反应发生的。光损伤发生的机制已经完全清楚了,可以简述如下。所涉及的分子(可以称为皮肤损伤的敏化剂或甚至加速剂)在存在氧气时与光发生反应,导致“活性氧”或“ROS”的形成。正是这些分子即ROS分子参与了导致细胞损伤的途径,包括致癌作用和光老化,但是又不限于这些现象。可以在Wondrak等人,J.Invest.Dermatol.,119:489-498,2002(完整引入本文作为参考)中找到这种现象的更多细节。
内源(例如皮肤)分子参与光毒性加速的事实提出了靶向疗法。详细地说,如果化合物在没有光照时基本上是惰性的,但是在接触光照后参与细胞破坏,那么这些化合物就可以用于需要靶向细胞死亡的情况。这些情况包括但不限于牛皮癣、痤疮、恶化前和恶性过度增殖性疾病诸如光化性角化病、以及本领域众所周知的其它状况。
相反,光活化分子的存在提出存在能够淬灭或抑制光照对细胞作用的分子。这些淬灭剂或抑制剂可用于需要逆转和/或抑制有害光照作用的情况。这些淬灭剂或抑制剂可用于预防和治疗目的。
因此,正如将在下文公开书中看到的,对细胞光毒性的调控是本文所述发明的焦点。调控物在用于本文时指可以由皮肤成分特别是胶原衍生的分子。
本发明涉及光损伤调控物在制备用于抑制由紫外线引起的光损伤的药物中的用途,其中所述光损伤调控物是脯氨酸、4-羟基脯氨酸、或其烷基酯,其中所述烷基酯包含1-24个碳原子的烷基部分。
附图说明
图1描绘了实施例中所采用的各种分子的结构。
图2描绘的结果显示了具有3-羟基吡啶中心结构的分子在暴露于光照后有效激发对细胞增殖的抑制。
图3比较了在存在光照时使用图1的3-羟基吡啶化合物在HaCaT细胞即角质细胞上获得的结果。
图4描绘了使用本文所述N-乙基衍生物在恶性黑素瘤上获得的结果。
图5与图4平行,但是所使用的细胞是乳癌细胞。
图6通过FACS(流式细胞计数)分析展示了N-乙基衍生物推动细胞凋亡的证据。
图7图示了BSA-B6复合物的合成方法。
图8显示了图7的复合物有效抑制细胞增殖。
图9是通过能量转移(图中的“ET”)淬灭光激活分子的提议机制。“S*”指完全激发的敏化剂,而“S”指敏化剂。
图10描绘了作为淬灭剂测试的脯氨酸衍生物的结果。
图11描绘了设计用于显示脯氨酸衍生物淬灭光敏化DNA损伤的功效的测定法的结果。
图12显示了如何确定本文所述化合物是否淬灭单体氧。
图13显示了抑制皮肤细胞光损伤的各种淬灭剂分子的保护作用。
优选实施方案的详述
实施例1
认为内源皮肤成分胶原最有可能是光毒性损伤和/或其抑制的起因。因此研究了这些分子。
吡啶啉(pyridinoline)是涉及交联胶原分子的氨基酸,并且研究了它在光毒性中的作用。吡啶啉的结构是众所周知的,以及本文所述其它分子的结构,描绘于图1中。
在HaCaT角质细胞和人CF3成纤维细胞上进行了一系列实验。在这些实验中,使细胞样品接触500μM吡啶啉、500μM锁链素(具有吡啶啉相关结构的弹性蛋白组分)、或500μM维生素B6(吡哆素)。对照不接受额外化合物。在一组实验中,细胞不接受外部光源。在另一组实验中,它们接受UVA光照,强度是3.3J/cm2。CF3成纤维细胞接受模拟日光或“SSL”,即2.3J/cm2UVA光照与0.12J/cm2UVB光照的组合。结果显示于图2中,即相对于对照(不添加化合物,无光照)的细胞增殖百分比。测量在激发后3天进行。
结果指示吡啶啉具有抗增殖效果,但是只在进行光照时。维生素B6显示明显更有效的抑制细胞增殖。
添加400U/ml过氧化氢酶(过氧化物清除剂)进行第二组实验。过氧化氢酶对维生素B6敏化绝对没有影响,说明该分子涉及过氧化物形成以外的机制。
根据这些结果,比较化合物的结构以确定能否鉴定分子的共有结构特征或“药效团”。注意到维生素B6和吡啶啉共享3-羟基吡啶中心结构,继而提出了下一个实验系列。
实施例2
在与上文所述平行的实验中研究了一组羟基吡啶衍生物。简而言之,测试了2、3、和4-羟基吡啶,还有N-乙基-3-羟基吡啶。所有结构描绘于图1中。
在增殖抑制测定法中测试了上文所述HaCaT细胞。细胞样品接受等量的上文所列4种化合物之一,并接触或不接受上文所述模拟日光(“SSL”)或单独接触同样上文所述UVA光照。
结果描绘于图3中。
与对照相比,3-羟基吡啶具有抑制效果,而N-乙基衍生物具有杀伤效果。N-乙基衍生物在存在UVA和UVB两种光照时也发挥功能,而3-羟基吡啶在存在UVB光照时发挥细胞增殖抑制剂的功能。
实施例3
继续上文所述实验,使用恶性黑素瘤细胞(G-361细胞)和恶性乳癌细胞(MCF-7)进行额外实验。在这些实验中,如上所述,在不同浓度和9.9J/cm2的UVA光照测试上文所述N-乙基衍生物。测量处理后2天的存活率。作为对照,只使用N-乙基衍生物和只进行UVA光照来进行实验。
图4(G-361细胞)和图5(MCF-7细胞)所示结果显示了该组合产生显著的细胞毒性。
在通过FACS分析G-361细胞时,数据显示细胞被推入程序化细胞死亡即凋亡。这在图6中可以看到,其中凋亡标记膜联蛋白V和碘丙锭的染色显示在使用N-乙基衍生物时染色细胞急剧增加,尤其是UVA浓度为3.3J/cm2时。
实施例4
本发明的有效物质是小分子。尽管小分子是有用的,然而有时希望将这些分子与较大分子复合,诸如蛋白质。例如,如果将小分子与对细胞上特定标记特异的抗体、特定受体的配体、核相关蛋白质、等等复合,那么这将有助于引导小分子。
为了测试这种方法的可行性,将维生素B6分子与牛血清清蛋白偶联。简而言之,将350mg牛血清清蛋白(BSA)分子与64mg维生素B6即吡哆醛一起反应,从而共价修饰牛血清清蛋白的赖氨酸侧链而形成Schiff碱。继而在1.5ml 0.25M磷酸盐缓冲液(pH7.4)中于37℃用58mg NaCNBH3还原Schiff碱过夜,并充分透析(48小时,4℃)。通过质谱和荧光光谱鉴定由此生成的BSA-B6加合物。然后将蛋白质冻干,并用于下面的实施例。图7描绘了合成方法。光谱实验指示每个BSA分子平均复合了5-6个吡哆醛分子。
实施例5
不加任何物质(对照)或者添加BSA或BSA-B6复合物,并用SSL处理HaCaT角质细胞样品或不进行处理,由此测试了实施例4中所述复合物的抗增殖效果。BSA和BSA-B6的浓度是10mg/ml,而SSL指2.3J/cm2UVA加0.12J/cm2UVB。处理后3天,使用Coulter计数器和标准方法测量增殖情况。
在图8所示结果中可以看到,BSA-B6复合物非常有效的抑制角质细胞增殖。
实施例6
上文实施例1-5中所列资料研究的是增强细胞破坏的分子。然而并非总是希望这样,而且在这个实施例和下面的实施例中,所述实验描述了抑制这个过程的分子。这些分子将称为光激发态淬灭剂或下文中的“QPES”。这些化合物的特征是能够灭活分子的光激发态,然后激发上文所述那类细胞死亡。
这些分子发挥功能的提议机制描绘于图9中,但是注意申请人不希望受到这种提议机制的约束。简而言之,对分子进行UV照射而发生电子激发(激发态,图中的“S*”),以及激发单体的形成,并在系统间过渡(ISC)后形成三体状态。这些是细胞光损伤中的关键中间体。QPES化合物通过能量转移(“ET”)接受与光损伤有关的化合物的激发能,中和光毒性中间体使之松弛回到基态,通过无害振动能或发热消散能量,从而消除这种作用。QPES化合物自身在此过程中不衰竭,并中和多个光损伤分子。
实施例7
众所周知ΦX174质粒只能由模拟日光的照射与作为UV敏化剂的AGE色素富集蛋白的组合作用进行切割。AGE-BSA(经过“高级glycation末端产物”修饰的牛血清清蛋白)是用于积累上文所述那类内源皮肤敏化剂的模型。可以在Wondrak等人,Photochem.Photobiol.Sci.,1:355-363,2002(完整引入本文作为参考)中找到显示这种特性的测定法的细节。这个实施例使用了这种测定法。
通过将样品在1%琼脂糖凝胶上进行电泳来显现质粒切割,并通过光密度分析法将损伤定量,即由闭环形式(未受损)形成松弛的开环形式,从而能够评估化合物的保护作用。
AGE切割在缺氧时进行,而且不能由抗氧化剂完全抑制。因此,如果化合物抑制质粒切割,那么不能简单的认为它是抗氧化剂。相反,必须假设上文所述经由淬灭激发态的抑制。
结果展示于下面的表中。已知是光激发态淬灭剂的细胞毒性NaN3是有效的,还有硫醇化合物,包括谷胱甘肽(“GSH”)、D-青霉胺、和N-乙酰-L-半胱氨酸(“NAC”)。
此测定法检验了实施例7中讨论的原理。
表1:对AGE敏化DNA切割的抑制
化合物 | %抑制(±SD) |
过氧化氢酶[400U/ml]SOD[300U/ml]甘露醇[20mM]L-组氨酸[20mM]NaN3[20mM]DAB CO[20mM]DFO[1mM]D-青霉胺[20mM]NAC[20mM]GSH[20mM] | 57.5±4.748.0±1.147.5±2.543.7±0.494.0±0.532.9±1.151.3±1.095.7±0.799.4±0.9100.0±0.0 |
使用这种测定法测试了一系列脯氨酸相关化合物和脯氨酸。化合物的结构描绘于图10中。图11列出了这些实验的结果。加入100mM待测化合物,并使质粒接触UVA光照(2.3J/cm2)和AGE-BSA(10mg/ml)之一、二者、或二者皆不。
L-Pro-OCH3是最有效的淬灭剂,但是测试的所有化合物都是有效的。
实施例8
如上所述,光激发氧即单体氧或“1O2”是基态三体氧或“3O2”的旋转配对同系物,也是已知涉及光毒性的最重要激发态分子。已经证明单体氧参与对细胞DNA、膜脂、以及结构蛋白像角蛋白和胶原蛋白等的光氧化损伤。开发了用于测定化合物诸如上文所述脯氨酸衍生物在淬灭单体氧中的功效的测定法。参阅Lion等人,Nature,263:442-443,1976(完整引入本文作为参考)。
众所周知,甲苯胺蓝(“TB”)在照射后生成1O2。在一种已知方法中,使用2,2,6,6-四甲基哌啶或“TEMP”捕捉1O2。形成稳定的自由基即2,2,6,6-四甲基哌啶-1-氧基或“TEMPO”,然后可以对它进行测量作为对1O2生成的测定。这种测定法的关键是以下事实,即其它活性氧不与TEMP发生反应而生成TEMPO,从而确保了该测定法对1O2形成是特异的。
将TEMP、TB、和上文所述分子之一组合,并用可见光照射5分钟,接受的总剂量是36J/cm2。详细地说,将100μM TB、7mM TEMP、与20mM待测化合物在磷酸盐缓冲液中在100μl体积的石英毛细管(1.5×90mm)中组合,使用商品化装置通过电子顺磁共振测量TEMPO自由基信号。同样测量对照,以测定不含待测化合物但进行光照时的信号以及标准TEMPO共振信号。
展示于图12板块A-G中的结果提供了下列资料。图A显示了完整的单体氧生成系统以及TEMPO信号生成。图B显示了商品化TEMPO参照物的旋转信号。图C证明了在图D-G中观察到的效果不是由待测化合物与TEMPO的直接反应引起的。图D和G证明了脯氨酸衍生物对单体氧的淬灭,并证明了脯氨酸羧基衍生物或4-羟基化不影响淬灭活性。另外,它还显示所有化合物都是有效的淬灭剂。
为了证明淬灭分子是物理淬灭剂而且在反应中不消耗,使用用于氨基酸分析的标准反相HPLC法,在长时间暴露于可见光(36J/cm2)之前和之后测量PBS中TB与L-脯氨酸混合物的氨基酸含量。在峰值、保持时间、或AUC值中都没有观察到变化,指示对1O2的化学惰性,从而提供了物理淬灭而非反应物消耗的证据。
实施例9
这些实验设计用于确定已经证明是淬灭剂的化合物是否有效保护皮肤细胞。
将培养的皮肤成纤维细胞(CF3细胞)暴露于来自通过染料敏化而原位形成的1O2的光氧化压力。
简而言之,在35mm培养皿中接种50,000个成纤维细胞,一天后在含有或不含TB(3.3μM,溶于Hanks缓冲盐溶液)时用可见光(暴露90秒钟,提供10.8J/cm2)进行处理。处理5分钟后,用磷酸盐缓冲液清洗细胞。照射过程中培养液中含有或不含待测化合物(10mM)。培养3天后,通过胰蛋白酶消化收获细胞,并使用Coulter计数器进行计数。
结果指示细胞增殖受到TB与光照组合的高度抑制(70%),但是二者单独使用都不能如此。化合物L-Pro-OCH3和4-OH-L-Pro-OCH3显示很清楚的保护效果,正如图13所示并在下表中定量:
表2:针对敏化光损伤的细胞保护[%±SD,n=3]
QPES-化合物: | L-ProL-Pro-OCH34-OH-L-Pro4-OH-L-Pro-OCH3 | 6.2±5.483.8±10.97.3±2.571.0±13.4 |
保护作用是通过下面的公式测定的:
在这些实验中较活泼的化合物是酯类化合物。如图10所示,在使用本领域众所周知的方法测定这些化合物的logP值时,酯类的logP值显著大于非酯化化合物。因为较大的logP值指示较大的亲脂性,所以可能的情况是它们的卓越功效要归于在皮肤中维持较长的停留时间并与细胞膜相互作用。预计具有大约-1.00至大约+8.00的logP值的脯氨酸酯衍生物特别有用。
实施例10
认为上文所述化合物4-羟基-L-脯氨酸甲酯是新的化合物,是新的一组化合物的代表。现在陈述该化合物的合成方法以及该家族其它成员的合成方针。
将4-羟基-L-脯氨酸与二碳酸二叔丁基酯在1N NaOH中于5℃反应30分钟,随后于室温搅动3.5小时。
然后将由此生成的受保护4-羟基脯氨酸与二甲基甲酰胺、碳酸钾、和甲基碘于0℃反应30分钟,随后于室温搅动1小时以生成甲酯。
然后使用三氟乙酸和标准方法对二碳酸叔丁基酯进行去保护。
这个反应中的关键成分是甲基碘。通过改变卤代烷,可以获得包含1-30个、优选1-26个碳原子的烷基的酯。
上述实施例陈述了本发明的各个方面,它涉及通过对受试者施用至少一种调控紫外线作用的物质来调控光损伤的方法。“调控”在用于本文时通常指提高光损伤速度(可用于需要抑制细胞增殖的情况)或降低损伤速度的能力。前一类的实例包括例如牛皮癣、痤疮、恶化前和恶性过度增殖性疾病诸如光化性角化病、黑素瘤、非黑素瘤皮肤癌、乳癌、和其它癌症、以及本领域技术人员知道的需要降低细胞增殖的其它状况。
优选的是,导致细胞增殖降低的光损伤增加是通过使用至少一种具有3-羟基吡啶环作为其“药效团”结构且由皮肤成分诸如胶原衍生的化合物实现的。这些化合物的实例是3-羟基吡啶自身、维生素B6、和最优选的N-烷基-3-羟基吡啶衍生物诸如盐类,其中衍生物的烷基链包含至少2个且可多达20个碳原子,优选直链,但是任选支链,可以进行或不进行取代。更优选的是,烷基在直链中包含2-10个碳原子,且最优选2-5个碳原子。正如上文所述资料所示,尤其优选N-乙基衍生物。增强化合物在皮肤中的停留时间长度的较长的N-烷基衍生物在特定情况中可能是优选的,诸如但不限于需要局部递送化合物的情况。
这些分子可以组合例如标准制药学成分和载体,诸如乳剂、洗剂、洗发剂、喷雾剂、贴片、或将治疗剂施用于皮肤的任何已知药学传递系统中所采用的那些成分和载体。
在特别期望靶向疗法时,可以将活性成分附着于第二种分子(可以是较大的)以改进靶向传递。这些较大分子包括例如抗体、受体的配体、激素、以及靶向细胞和/或由细胞选择性摄取的其它分子。
本发明的另一个特色是光损伤的淬灭特性。如上所述,脯氨酸及其衍生物是光损伤的有效淬灭剂。特别有效的是脯氨酸的烷基酯,诸如L-Pro-OCH3和4-OH-L-脯氨酸;然而,其它化合物也是有用的,正如已经显示的。应用模式正如上文关于讨论的增强剂所述。
本发明的其它特色对本领域普通技术人员而言是清楚的,因而无需本文赘述。
Claims (4)
1.光损伤调控物在制备用于抑制由紫外线引起的光损伤的药物中的用途,其中所述光损伤调控物是脯氨酸、4-羟基脯氨酸、或其烷基酯,其中所述烷基酯包含1-24个碳原子的烷基部分。
2.权利要求1的用途,其中所述脯氨酸烷基酯是L-Pro-OCH3。
3.权利要求1的用途,其中所述4-羟基脯氨酸烷基酯是4-OH-L-Pro-OCH3。
4.权利要求1的用途,其中所述药物为乳剂、洗剂、洗发剂、喷雾剂、或贴片的形式。
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