CN109890375B - 细胞的atp-依赖性反向转运蛋白抑制剂及其生产方法 - Google Patents
细胞的atp-依赖性反向转运蛋白抑制剂及其生产方法 Download PDFInfo
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Abstract
本发明涉及药物化合物化学，特别是寡聚醚多元醇结构的手性缀合物(旋光活性杂化分子)的组，它们是ATP‑依赖性反向细胞转运蛋白的抑制剂(OEP抑制剂)。OEP抑制剂是具有等摩尔比的旋光活性聚氧丙烯己醇和聚氧化丙二醇的缀合物。所要求保护的产生缀合物的方法提供了通过抑制细胞的多重耐药机制来获得增加药物作用有效性的制品的可能性。
Description
本发明涉及生理活性物质的开发领域，即寡聚醚多元醇性质 (OEP)的手性缀合物(旋光杂化分子)的组，其是ATP-依赖性细胞反向 转运蛋白的抑制剂，缩写为ABC-转运蛋白(ATP结合弹夹转运蛋白)。 本发明可用于生物学，药理学，药物学，医学，农业和生态学领域， 以显著提高生理活性物质包括药物抗肿瘤，心血管，抗过敏，抗炎 等的有效性，通过在要求保护的ABC-转运蛋白抑制剂的作用下抑制 细胞的多重耐药机制来进行。
现代药物疗法最紧迫的问题之一是异常细胞的多重耐药性-细胞 对药物的先天或获得性免疫，它们的作用机制和结构不同。病理细胞 耐药性出现的主要机制之一是能够利用ABC-转运蛋白家族的ATP-依 赖性泵重新捕获和释放渗入细胞的异生素分子[1]。
ABC-转运蛋白家族包括P-gp糖蛋白(P-糖蛋白)，多药耐药相关蛋 白(MRP)和乳腺癌抗药性蛋白质(BCRP)。这些ABC-转运蛋白的活性(其 在细胞中发生病理过程时表达显著增加)导致药物疗法的有效性显著 降低。有关大部分肿瘤化疗药物的实例方面已经详细显示和研究了这 类作用[2]，包括目标药物，而且在许多其他病理学中，ABC-转运蛋白 显著降低了药物的有效性。ABC-转运蛋白具有广泛的底物特异性，从 而可以从许多不同治疗组的药物中反向捕获和释放细胞。
作为实例(实际上并未穷尽)，ABC-转运蛋白底物为[3]：镇痛药 (阿西马多林，芬太尼，吗啡，喷他佐辛)；抗生素(氨苄西林，阿奇霉 素，头孢哌酮，头孢曲松，克拉霉素，多西环素，红霉素，短杆菌肽 A，短杆菌肽D，格帕沙星，伊曲康唑，酮康唑，左氧氟沙星，利福平，司帕沙星，四环素，缬氨霉素等)；抗病毒药物(地拉韦啶，洛匹那韦， 拉米夫定，奈非那韦，齐多夫定)；抗心律失常药(胺碘酮，地高辛， 利多卡因，普罗帕酮，奎尼丁，维拉帕米)；抗癌药物(5-氟尿嘧啶， 放线菌素D，必生群(bisantrin)，苯丁酸氮芥(chlorambuzyl)，秋水 仙碱，顺铂，citarabine，柔红霉素，多西他赛，多柔比星，表柔比 星，依托泊苷，hephytinib，伊立替康，甲氨蝶呤，丝裂霉素C，米 托蒽醌，紫杉醇(paklitaxel)，他莫昔芬，替尼泊苷，拓泊替康，长 春碱，长春新碱等)；抗组胺药(西咪替丁，非索非那定，雷尼替丁， 特非那定)；降血脂药(洛伐他汀，辛伐他汀，普伐他汀，瑞舒伐他汀)； 钙通道阻滞剂(azidopine，苄普地尔，地尔硫卓，非洛地平，硝苯地 平，nizoldipine，尼群地平，thiapamil，维拉帕米)；抗HIV药(安 普那韦，茚地那韦，洛匹那韦，奈非那韦，沙奎那韦，利托那韦)；免 疫抑制剂(环孢菌素A，西罗莫司，他克莫司)，抗抑郁药(氯丙嗪，吩 噻嗪)和许多其他天然，合成或半合成来源的药用化合物。
因此，产生有效且安全的细胞ATP-依赖性反向转运蛋白抑制剂是 提高包括药物在内的多种生理活性物质的有效性的有希望的方法。这 些药物的产生将显著降低活性物质的治疗剂量，并因此降低其副作用， 从而在药理学和医学上实现质的飞跃。
从研究的技术水平已知多种化合物，包括可以抑制ABC-转运蛋白 的批准药物。因此，开展了大规模的研究工作，以创造作为药物的ABC- 转运蛋白抑制剂，它们增加癌细胞对抗癌药物作用的敏感性[3]。特别 是作为P-gp抑制剂，具有活性并且研究了用于联合抗肿瘤化疗的阿托 伐他汀，氨氯地平，环孢菌素A，双硫仑，硝苯地平，维拉帕米，制 剂GF120918，LY475776，LY335979，MS-209，OC144-093，普卢兰尼 克L61，PSC-833，R101933，S9788，VX-710，XR-9576，V-104。作为 MRP2的抑制剂研究了阿奇霉素，环孢菌素A，呋塞米，格列本脲，丙 磺舒，MK-571。作为BCRP抑制剂研究了环孢菌素A，双嘧达莫， elakridar，fumitremorgin C，新生霉素，奥他赛，reserpin，利托 那韦，他立喹达，GF120918，VX-710，XR-9576。
从技术水平可知，三代ABC-转运蛋白抑制剂是有区别的：
第1代：环孢菌素A，维拉帕米(实例)。这些化合物是有效的反 向转运抑制剂，但它们本身具有高毒性。它们与化疗药一起使用并未 导致显著的临床效果。
第2代：PSC-833和VX-710(实例)。这些化合物也是有效的反向 转运抑制剂。然而，它们与化疗药一起使用也没有导致显著的临床效 果；此外，观察到与药物-药物相互作用相关的治疗的显著副作用。
第3代：GF120918、LY335979、R101933和XR9576(实例)。与第 1代和第2代抑制剂相比，这些化合物在体外模型中是更有效的反向 转运抑制剂。然而，由于安全性低(不期望的副作用)和治疗效能不 足，所以它们与化学治疗药一起使用不会导致显著的临床效果。
一般而言，本领域目前的研究状况的特点是体外水平的局部成功， 然而，向体内的转变，甚至更多的临床研究，通常未产生预期的效果， 主要是由于组合物存在不期望的副作用，非最佳药代动力学，以及缺 乏抑制作用的有效性[3]。同时，在所有现代研究中，都注意到在这个 方向上进一步搜索的前景。
基于此，显而易见的是，为了充分实现该方法的前景，需要更有 效和更安全的ABC-转运蛋白抑制剂。
未确定申请日期时所要求的匹配显著特征的技术解决方案的类似 方案或原型；但是，申请人确定了大量的手段来解决预期目的的任务。
所要求保护的技术方案使用创造性方法，其同时允许显著提高治 疗效能，增加安全性，以及显著降低活性药物物质的成本，改善获得 该物质的生产过程的性能。同时，所要求保护的技术解决方案提供了 用世界上预先未知的产品进入国际市场的机会。
要求保护的技术方案的目的是获得寡聚醚多元醇细胞的反向 ABC-转运蛋白抑制剂(OEP抑制剂)，其由分子量为300-500Da的聚氧 丙烯二醇和分子量为1000-1500Da的聚氧丙烯己醇组成。
所要求保护的技术方案的目的在于通过实施以下方案的化学方法 来实现：
其中：
1-山梨醇((2S,3R,4R,5R)-己-1,2,3,4,5,6-己醇)；
2-包含双官能氧的化合物，其中R＝-O-；[-OCH2CH(CH3)]k-O-, k＝1-7；
3-氧丙烯；
M(OH)x-金属氢氧化物，其M是碱金属或碱土金属，x＝1或2；
n＝2-6，主要是n＝4；
m＝5-9，主要是m＝7。
因此，所要求保护方法的技术方案每次在一个反应器中使用可用 试剂一步实施，所述试剂按比例提供期望的缀合物，其具有等摩尔比 的旋光化合物4和化合物5。
整个过程根据上述方案进行，如下所述。
将初始反应物1和2装入反应器-聚合反应器中，加入碱性催化剂， 开启搅拌，并将反应混合物维持在90-100℃的温度下在氮气氛中30 分钟，得到均匀物料。然后，计算量的化合物3以在聚合反应器中提 供不高于0.39MPa(4kgf/cm2)的压力和不高于115℃的温度的速率 进料。此后，将反应物料保持在不高于115℃的温度下1-1.5小时， 直到压降停止。
计算反应物1、2和M(OH)x的比例，使得它们与氧丙烯反应，得 到化合物4和5的等摩尔混合物。n＝4的化合物4和m＝7的化合 物5是在所述阴离子寡聚反应中形成的主要寡聚化成分。计算化合物 3的量，使得所得化合物4和5的等摩尔混合物具有215-240mg KOH/g的羟值。
丙二醇，双丙二醇，三丙二醇，四丙二醇，五丙二醇，六丙二醇， 七丙二醇或水，或它们的混合物可作为双官能含氧化合物2起作用。 当碱金属或碱土金属氢氧化物与含氧化合物或山梨醇相互作用时，释 放水，在计算所得目标产物4和5的等摩尔比时，还必须对其进行考 虑。
对于化合物4，最佳分子量为1200Da，同时它还显示1000-1500 Da的效能。对于化合物5，最佳分子量为400Da，而在300-500Da 范围内，它也是有效的。超出指定的分子量范围也是可能的，但伴随 着所得ABC-转运蛋白抑制剂活性的一定程度降低。
ABC-转运蛋白抑制剂可以通过替代方法获得，该方法由于其著名 性而不是由申请人提供，并由下列步骤组成：通过在碱催化条件下分 别使化合物1和2与氧丙烯3反应分别地单独获得化合物4和5，它 们以等摩尔量进一步机械混合。
通过以下内容示例本发明：
图1-OEP抑制剂粘度与温度的关系图。
图2-OEP抑制剂的HPLC-MS光谱。
图3-化合物对条件正常和肿瘤人细胞的半-最大生长抑制浓度 (CC50和IC50,μM)。
图4-根据HPLC-MS数据的分析的细胞裂解物中OEP抑制剂的含 量。
图5-加入效应物后细胞悬浮液中DPHT(1,6-二苯基-1,3,5-己三 烯)的荧光偏振：OEP抑制剂，多柔比星和OEP抑制剂的组合物，胆固 醇和Tritone X-100。(A)MCF-7细胞；(B)具有MDR MCF-7/Vin的细 胞。悬浮密度为2×106个细胞/ml，温度为25℃，浓度如下：OEP 抑制剂-8.7、87和870μg/ml，多柔比星-1μM，胆固醇-100μg/ml， Triton X-100-0.05％。
图6-多柔比星在极化CaCo-2细胞中的跨上皮转运的直方图。缩 写：顶端-基底外侧转运(A-B)，基底外侧-顶端转运(B-A)。
图7-用多柔比星、OEP抑制剂或它们的组合处理48小时后原始和 遗传修饰的MCF-7细胞的免疫印迹结果的照片。
图8-效应物对Sf9细胞的分离膜的人P-糖蛋白的ATP-酶活性的 作用(按蛋白质计为0.2mg/ml)。对照：在5mmol ATP和0.1mmol 长春碱存在下膜的基本活性。
图9-用OEP-抑制剂(87、430、2175μg/ml)、多柔比星(10μM) 和它们的组合物(OEP抑制剂87μg/ml+DOX10μM)处理的细胞 MCF-7(A)和MCF-7/Vin(B)的裂解物中的ATP含量。
此外，申请人提供了获得OEP抑制剂的方法的实施例。
实施例1.由山梨醇-水起始系统得到OEP抑制剂的方法
将27.3g(0.15mol)山梨醇装入配备机械搅拌器，冷却器，热 电偶，氧化物注入管的钢聚合反应器中，并加入0.6g(0.01mol)氢 氧化钾至2.51g(0.139mol)水。用氮气吹扫反应器三次。激活搅拌 并将其在90-100℃的氮气氛中保持30分钟以获得均匀的物料。将温度升至115℃并分批加入270g(4.65mol)氧丙烯，其加入速率使聚 合反应器中的压力不高于0.39mPa(4kgf/cm2)且温度不高于115℃。 在加入计算量的氧丙烯后，将反应物料维持在不高于120℃的温度下 1-1.5小时，直到压降停止。
将获得的OEP抑制剂用50％正磷酸水溶液中和至pH为6.5-7.5， 在80-90℃的温度下真空除去水，并通过胶带围绕(belting)用蒙脱土 过滤。在所有操作之后，获得270g浅黄色产物。粘度为645mPa*s， 密度为1.038g/cm3(20℃)。羟值为220mg KOH/g(GOST 25261-82cl.3.1)。
实施例2.由山梨醇-丙二醇的起始系统得到OEP抑制剂
将28.7g(0.157mol)山梨醇装入配备机械搅拌器，冷却器，热 电偶，氧化物注入管的钢聚合反应器中，并加入0.63g(0.01mol) 氢氧化钾至10.98g(0.145mol)丙二醇。用氮气吹扫反应器三次。 激活搅拌并将其在90-100℃的氮气氛中保持30分钟以获得均匀的物料。将温度升至115℃并分批加入274g(4.73mol)氧丙烯，其加入速 率使聚合反应器中的压力不高于0.39mPa(4kgf/cm2)且温度不高于 115℃。在加入计算量的氧丙烯后，将反应物料维持在不高于120℃的 温度下1-1.5小时，直到压降停止。
将获得的OEP抑制剂用50％正磷酸水溶液中和至pH为6.5-7.5， 在80-90℃的浴温下真空除去水，并通过胶带围绕用蒙脱土过滤。在 所有操作之后，获得285g浅黄色产物。粘度为618mPa*s，密度 为1.035g/cm3(20℃)。羟值为231mg KOH/g(GOST 25261-82cl. 3.1)。
实施例3.由山梨醇-双丙二醇的起始系统得到OEP抑制剂
根据实施例2中给出的方法进行反应。起始物质的量：山梨醇 -27.3g(0.15mol)，KOH-0.6g(0.011mol)，双丙二醇-18.5g(0.14 mol)。氧丙烯的量为255g(4.4mol)。中和及过滤后，得到308g浅黄 色产物。粘度为623mPa*s，密度为1.036g/cm3(20℃)。羟值为 227mgKOH/g(GOST 25261-82cl.3.1)。
实施例4.由山梨醇-三丙二醇的起始系统得到OEP抑制剂
根据实施例2中给出的方法进行反应。起始物质的量：山梨醇 -27.3g(0.15mol),KOH-0.61g(0.011mol)，三丙二醇-26.7g(0.14 mol)。氧丙烯的量为246g(4.24mol)。中和及过滤后，得到280g浅 黄色产物。粘度为629mPa*s，密度为1.036g/cm3(20℃)。羟值 为229mgKOH/g(GOST 25261-82cl.3.1)。
实施例5.由山梨醇-四丙二醇的起始系统得到OEP抑制剂
根据实施例2中给出的方法进行反应。起始物质的量：山梨糖醇 -27.29g(0.15mol)，KOH-0.6g(0.011mol)，四丙二醇-34.75g (0.14mol)。氧丙烯的量为246g(4.24mol)。中和及过滤后，得到 285g浅黄色产物。粘度为620mPa*s，密度为1.034g/cm3(20℃)。 羟值为233mg KOH/g(GOST 25261-82cl.3.1)。
通过在碱性催化条件下使丙二醇与氧丙烯反应获得五-，六-和七 丙二醇。测定每个样品的羟值。
实施例6.由山梨醇-五丙二醇的起始系统得到OEP抑制剂
根据实施例2中给出的方法进行反应。起始物质的量：山梨醇— 27.3g(0.15mol)，KOH-0.61g(0.011mol)，五丙二醇-42.8g(0.14 mol)。氧丙烯的量为230g(3.95mol)。中和及过滤后，得到285g 浅黄色产物。粘度为627mPa*s，密度为1.033g/cm3(20℃)。羟 值为231mgKOH/g(GOST 25261-82cl.3.1)。
实施例7.由山梨醇-六丙二醇的起始系统得到OEP抑制剂
根据实施例2中给出的方法进行反应。起始物质的量：山梨醇— 27.31g(0.15mol)，KOH-0.6g(0.011mol)，六丙二醇—50.87g (0.14mol)。氧丙烯的量为222g(3.83mol)。中和及过滤后，得到 283g浅黄色产物。粘度为615mPa*s，密度为1.037g/cm3(20℃)。 羟值为225mg KOH/g(GOST 25261-82cl.3.1)。
实施例8.由山梨醇-七丙二醇的起始系统得到OEP抑制剂
根据实施例2中给出的方法进行反应。起始物质的量：山梨醇— 27.3g(0.15mol)，KOH-0.61g(0.011mol)，七丙二醇—58.9g (0.14mol)。氧丙烯的量为214g(3.83mol)。中和及过滤后，得到 283g浅黄色产物。粘度为623mPa*s，密度为1.036g/cm3(20℃)。 羟值为224mg KOH/g(GOST 25261-82cl.3.1)。
得到的OEP抑制剂是无色或微黄色液体，室温下的粘度为575-715 MPa*s(图1显示了OEP抑制剂的粘度对温度的依赖性)，密度为 1.01-1.05g/cm3(20℃)。羟值为215-240mgKOH/g，10％溶液(乙 醇/水-70/30)的pH为5.5-7.5。
OEP抑制剂的特征在于在小质量(400-1200Da)和较重质量 (1500-2000Da)范围内的一组m/c峰(图2)，其反映了存在统计的一 组缩聚反应产物。使用Agilent ZORBAXExtend-C18色谱柱(色谱柱尺 寸为1×150mm，粒径为3.5μm)，在Agilent 1260二元系统色谱仪 (真空脱气机G1379B，二元梯度泵G1312B，柱恒温箱G1316A，自动进 样器G1367E，自动进样器G1330 B恒温器)上进行分析，所述色谱柱 带有Extend Guard前置柱(1×17mm，粒径为5μm)。检测器是具有 DuoSpray电离源的高分辨率AB Sciex 5600的四极杆飞行时间法(quadruped-time-of-flight)质谱仪。流动相：溶剂A是10mM甲酸 铵在水和甲醇(90:10％)的混合物中的溶液；溶剂B是0.1％甲酸的乙 腈溶液。OEP抑制剂的最强峰用于其在生物基质中的定量分析。
所要求保护的技术方案的技术效果是获得寡聚醚多元醇性质的手 性缀合物(旋光活性杂化分子)的方法，所述手性缀合物是细胞ATP-依 赖性反向转运蛋白的抑制剂(OEP抑制剂)，以显著增强生理活性物质 作用的有效性，所述生理活性物质选自抗癌，心血管，抗过敏，抗炎 和其他药物化合物。
此外，申请人提出了用于实现所要求保护的技术方案的名称和 缩写。
ABC(ATP结合弹夹)
APS-过硫酸铵
ATP(腺苷三磷酸)-腺苷3-磷酸
C-胞嘧啶
DOX-多柔比星
EGTA(乙二醇-双(2-氨基乙醚)-N,N,N’,N’-四乙酸)
FAM-6-羧基荧光素
G-鸟嘌呤
HRP(辣根过氧化物酶)
LC-MS-合并质谱法的液相色谱法
m/c—质荷比
P-gp-P-糖蛋白
pH-氢指数
Pi(无机磷酸盐)
T-胸腺嘧啶
U/μL-每微升单位
Vin-长春碱
A260-260nm处以埃计的波长值
A-腺嘌呤
DMSO-二甲亚砜
DNA-脱氧核糖核酸
DPHT-二苯己三烯
Drugs-药物产品
DF-剂型
Mkg-微克
ML-毫升
MDR-多重耐药性
MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物，黄 色四唑)-四唑鎓染料
RPM-每分钟转数
OEP-寡聚醚多元醇
RNA-核糖核酸
PSB-磷酸盐缓冲液
EDTA-乙二胺四乙酸
材料和方法
化学试剂和材料
多柔比星(DOX)盐酸盐，哇巴因(ouabain)八水合物，五乙二醇 98％，β-巯基乙醇，乙二醇四乙酸(EGTA)，硫酸铍四水合物，氟化钠， 钼酸铵购自Sigma-Aldrich(USA)。溴酚蓝，脱氧胆酸钠，三-盐酸盐 (三-(氧甲基)氨基甲烷(amomethane)盐酸盐)，过硫酸铵(APS)，十二 烷基硫酸钠(SDS)购自Amresco(USA)。MTT3-(4,5-二甲基噻唑-2- 基)-2,5-二苯基四唑鎓溴化物)购自Life technologies(USA)。L- 谷氨酰胺，不含Ca2+和Mg2+离子的达尔贝科(Dulbecco's)溶液，胰蛋 白酶-EDTA溶液，不含酚红的Hanks溶液，α-MEM和DMEM培养基购自 PanEco(Russia)。1,6-二苯基-1,3,5-己三烯(DPHT)，二硫苏糖醇 (1,4-双(硫烷基)丁-2,3-二醇)，抗坏血酸，胆固醇，
X-100， 硫酸长春碱，ATP二钠盐水合物，HEPES(4-(2-羟乙基)-1-哌嗪乙磺 酸)购自Acros Organics。十二烷基硫酸钠(SDS)和乙二胺四乙酸(EDTA) 购自Helicon。
细胞培养条件：
将细胞MCF-7、MCF-7/Vin、HSF、CaCo-2、HCT-15、HCT-116、 OVCAR-4、PC-3、A-498、NCI-H322M、M-14、SNB-19、SF细胞-539(表 1)在37℃下在5％CO2气氛中在α-MEM培养基中培养，该培养基中添 加了10％胎牛血清，L-谷氨酰胺和1％青霉素-链霉素，直至形成单层。为了获得细胞悬浮液，通过添加具有血清的α-MEM培养基来胰蛋白酶 消化单层细胞，随后灭活胰蛋白酶。通过排除锥虫蓝(trypan blue) 在Neubauer室中进行细胞计数。细胞以1：6的比例每周传代2次。
表1
使用的细胞系列表
实施例9.OEP抑制剂的体外细胞毒性作用探查
使用MTT试验在温育72小时期间研究OEP抑制剂对人肿瘤和条件 正常细胞的增殖潜力的影响。将1000个细胞加入到96-孔板的孔中的 90μl培养基中，并在CO2培养箱中温育24小时，以使细胞粘附在 基质上。接下来，以10μl/孔的体积加入制备的研究化合物溶液(OEP 抑制剂)的等分试样。该研究一式三份进行。代替分析的化合物，在板 的对照孔中导入相似体积的mQ。施用测试物质后，将细胞在CO2培养 箱中在标准条件下培养72小时。接下来，使用真空抽吸器从板中除去 含有测试物质的培养基，加入营养培养基和5mg/ml MTT试剂，并在 CO2培养箱中温育3-4小时。在温育时间过去后，用真空抽吸器除去 含有MTT试剂的培养基，加入100μl DMSO并温育5-10分钟。在Tecan 读板仪上在555nm处检测出现的紫色染色(参比波长为650nm)。绘制 剂量-响应曲线并测定半数最大细胞生长抑制浓度(IC50)。结果显示 在图3中。
因此，对该表的详细分析使我们能够得出明确可解释的结论，即 对于所研究的大多数IC50细胞，OEP抑制剂超过1.5mg/ml，这表明 所要求保护的缀合物的完全安全性。同时，能够确定OEP抑制剂对 SNB-19胶质母细胞瘤和SF-539神经胶质肉瘤细胞的特异性(IC50分别 为0.46±0.12mg/ml和0.46±0.12mg/ml)，这表明其一些对这些类 型的细胞具有微不足道的自身抗肿瘤作用。
实施例10.OEP抑制剂对MCF-7和MCF-7/Vin细胞质膜的微量 粘稠度的作用评价
影响其生理活性的细胞膜的关键物理化学特征是微量粘稠，其是 双层中脂质迁移率的量度，其在膜渗透性和膜蛋白的功能作用中起重 要作用。为了评估质膜微量粘稠度，基于使用二苯基己三烯(DPHT)的 亲脂性指示剂使用荧光方法，其荧光取决于细胞膜流动性。
将密度为2×106个细胞/ml的细胞悬浮液与终浓度为1μM 的DPHT一起温育30分钟。接下来，使用多通道分配器将OEP抑制剂 溶液的等分试样(10μl)加入到细胞悬浮液中至终浓度为8.7；87和 870μg/ml，以及浓度为1μM的多柔比星及其与OEP抑制剂的组合 物(DOX1μM+OEP抑制剂8.7μg/ml；DOX1μM+OEP抑制剂 87μg/ml)。测试终浓度为100μg/ml的胆固醇以及浓度为0.05％ 的亲脂性洗涤剂Triton X-100作为阳性对照，其显著改变细胞质膜的 微量粘稠度。在导入等分样品后立即检测DPHT的荧光偏振1小时，间 隔10分钟。
OEP抑制剂对MCF-7和MCF-7/Vin细胞质膜的微量粘稠度的影 响结果如图5所示。
因此，获得的数据表明OEP抑制剂浓度为8.7、87和870μg/ml， 以及多柔比星及其与OEP抑制剂的组合物没有显著改变MCF-7和 MCF-7/Vin细胞悬浮液中DPHT荧光的极化。由于荧光的极化与荧光 团微环境的粘度成正比[4]，因此，从中可以得出结论，研究中的OEP抑制剂不影响所研究细胞的质膜的微量粘稠度。具有比质膜磷脂更大 粘度的胆固醇显著增加了DPHT荧光的极化和膜的微量粘稠度。作为强 洗涤剂的Triton X-100逐渐溶解质膜，这可通过DPHT荧光的极化显 著降低来证明。研究中的OEP抑制剂对哺乳动物细胞的细胞质膜的微 量粘稠度没有显著影响，这表明其对肿瘤细胞的细胞质膜的脂双层的 惰性。
实施例11.OEP抑制剂在抗性肿瘤细胞中蓄积的评价
已知环氧乙烷和氧丙烯的一些疏水性嵌段共聚物具有穿透细胞质 膜屏障的能力，在细胞质中蓄积并对细胞内细胞器和酶发挥作用。特 别地，经证实普卢兰尼克P85具有改变线粒体膜的微量粘稠度和分离 氧化磷酸化的性质[5]，[6]。在这方面，有意义的是确定测试的OEP 抑制剂的胞内蓄积程度。使用液相色谱结合质谱(HPLC-MS)进行细胞裂 解物中抑制剂含量的鉴定和定量。
将MCF-7/RES细胞以每孔50,000个细胞的量分散在6-孔板中， 并在37℃和5％CO2下培养24小时。将抑制剂的等分试样加入细胞中， 其最终浓度为8.7、87和870μg/ml，并在37℃和5％CO2下培养96 小时。将相应体积的去离子水加入对照样品中。在温育时间过去后， 用抽吸器收集含有OEP抑制剂的培养基。通过用Hanks溶液悬浮将细 胞与平板表面隔离，并转移到15ml管中洗涤至少5次(400g，4分钟)。 将150μl含有内标的去离子水-浓度为10-5 M的五乙二醇加入到细 胞沉淀中。通过两个冷冻和解冻循环裂解细胞(在-75℃下4分钟，在 37℃的水浴中温育2分钟)，然后超声处理4分钟。取等份的裂解物用 于随后使用Life Technologies PierceTM BCA蛋白质测定试剂盒测 定样品中的蛋白质的量。向细胞裂解液中加入700μl冷却的甲醇， 在-20℃下温育15分钟，然后在17400g和0℃下离心20分钟。将上 清液转移到清洁的试管中并在冷冻干燥器中真空干燥。在进行分析之 前即刻将干燥的细胞裂解物溶于200μl补充有0.1％甲酸的1：1甲 醇/水混合物中。使用与AB Sciex 5600质谱仪(AB Sciex，USA)偶联 的Agilent 1260 Infinity色谱仪(Agilent Technologies，Inc.， USA)上的色谱系统进行所有HPLC-MS实验。
评价OEP抑制剂在抗性肿瘤细胞中蓄积的结果示于图4中的表3 中。
对OEP抑制剂的胞内蓄积的HPLC-MS分析显示，在与OEP抑制剂 一起培养的细胞的裂解物中存在毫微微摩尔(femto)和皮摩尔量的聚 合物(抑制剂浓度：8.7、87和870μg/ml，培养时间是96小时)。值 得注意的是，随着培养基中OEP抑制剂浓度从8.7增加到870μg/ml，未观察到胞内含量的增加。裂解物中不存在浓度依赖性和OEP抑制剂 的低含量启示，检测到的OEP抑制剂的痕量与其在质膜上的非特异性 吸附相关并且不是由于其渗透到细胞的细胞质中所导致的。因此，能 够得出结论，该缀合物是高度安全的。
实施例12.OEP抑制剂对多柔比星通过CaCo-2细胞质膜的跨上皮 运输的作用的评价
在极化的CaCo-2细胞中，反向P-gp转运蛋白位于胞质膜的顶侧， 并提供包括多柔比星在内的大量底物的反向转运(B-A)。
将Caco-2细胞以10,000个细胞/孔接种到Millicell96双成分 板中，并在37℃和5％CO2下温育21天。通过使用Millicell-ERS仪 器测量电阻(TEER)来检查单层的完整性，本实验以至少3KΩ/孔的 TEER值开始。为了确定多柔比星从顶端(A)到基底外侧(B)区域[A-B] 的转运速率，用过滤器将90μl多柔比星或多柔比星和OEP抑制剂 (0.087-870μg/ml)加入3个孔中，并且将250μl HBSS缓冲液加 入下部板的接受孔中。为了确定从基底外侧(B)到顶端(A)[B-A]区域的 转运速率，用过滤器在3个孔中加入90μl HBSS缓冲液与1％DMSO，并且在板的下部孔中加入250μl多柔比星或多柔比星和OEP抑制剂 (0.087-870μg/ml)。将组装的Millicell 96 CaCo-2系统在37℃ 下在振荡器上温育2小时，同时以300rpm搅拌。然后从插入物的每个 部分取出70μl等分试样，并使用QTRAP 5500系统(AppliedBiosystems)和Agilent Infinity 1290色谱仪(Agilent Technologies)进行HPLC-MS分析。
评价OEP抑制剂对多柔比星跨上皮转运的影响的结果在图6中显 示为多柔比星穿过CaCo-2细胞的质膜的渗透速率。
可以观察到，CaCo-2细胞从膜的基底外侧向顶端部分(B-A)输出 多柔比星。作用于位于膜顶端部分的P-gp的OEP抑制剂抑制多柔比星 的反向向转运，使其在A-B方向的含量增加：浓度为8.7μg/ml， 增加1.9倍；浓度为87μg/ml，增加3.5倍；浓度为870μg/ml， 增加3.8倍。实验数据由三次独立实验的平均值±标准差表示。对于 统计学处理，使用学生标准进行多重比较，其中引入Bonferroni校正， P≤0.05。因此，显然能够得出结论，反向ABC-转运蛋白的ATP-依赖 性抑制剂是高效的。
实施例13 OEP抑制剂对P-gp(ABCB1)表达的影响
OEP抑制剂能够消除活性糖基化同种型190kDa ABCB1，而无活性 高甘露糖同种型175kDa转运蛋白在细胞中蓄积。
将细胞中浓度为3x104个细胞/cm2的MCF-7、MCF-7-ABCC1-DsRed (具有MRP-1的超表达)、MCF-7-ABCC2-BFP(具有MRP-2的超表达)、 MCF-7-ABCB1-GFP(具有P-gp超表达)在完全DMEM营养培养基中将如 下所述之一一起在37℃、5％CO2气氛中48小时培养：加入至终浓度 为3μM的多柔比星；或OEP抑制剂至终浓度为261μg/ml；或多柔 比星-OEP抑制剂组合物至终浓度为3μM：261μg/ml。使用经过调整和 修改的ABCAM方案 (http://www.abcam.com/ps/pdf/protocols/wb-beginner.pdf)通过免疫 印迹(Western Blot)研究蛋白质。ABCB1的单克隆抗体(目录号 sc-13131，Santa Cruz)以1：200的稀释度使用。与HRP缀合的以1：10,000稀释的抗-小鼠抗体(目录号ab6728，Abcam)用作二抗。以1： 2000的稀释度使用针对β-肌动蛋白的单克隆抗体(目录号mAbcam 8226，Abcam)。在ChemiDoc XRS+系统(Bio-Rad)上显现分析结果。
OEP抑制剂对P-gp表达(ABCB1)的作用结果如图7所示。
ABCB1蛋白由2种同种型代表，分子量为190kDa和175kDa(图7，上部和下部条带)。同时，190kDa同种型是蛋白质的糖基化活性 形式，而175kDa条带是高甘露糖无活性蛋白质[7]。结果表明MCF-7 对照细胞含有等量的活性和非活性蛋白质。暴露于多柔比星会增加蛋白质的活性形式的量，而OEP抑制剂几乎完全消除了ABCB1的活性形 式。同时，转运蛋白的非活性形式蓄积在细胞中。暴露于组合药物的 细胞表达蛋白质的活性和高甘露糖形式。无活性形式的表达证明OEP 抑制剂能够部分逆转多柔比星介导的转运蛋白的活化。我们在超表达 ABCC1和ABCC2基因的细胞中看到了相似的图片。因此，能够得出结 论：OEP抑制剂能够抑制反向ABC-转运蛋白的ATP-依赖性抑制剂的活 性。
实施例14.OEP抑制剂对具有ABCB1超表达的膜ATP-酶活性的影响
使用根据方法[8]超表达人重组P-糖蛋白的分离的昆虫细胞膜草 地贪夜蛾(Spodoptera frugiperda)(Sf9品系)的商品制剂研究膜P- 糖蛋白的ATP-酶活性。在P-糖蛋白的催化活性期间的ATP水解伴随通 过分光光度反应检测的无机磷酸盐(Pi)的形成。经证实，OEP抑制剂 以直接浓度依赖性方式抑制ATP-酶活性-随着浓度的增加，抑制作 用增强。
将浓度为8.7-870μg/ml的测试的OEP抑制剂与重组膜和底物一 起在1.5ml微管中温育，所述重组膜超表达P-糖蛋白，一式三份。 在880nm处测量反应产物的光密度，其与反向转运蛋白的活性和酶的 ATP-酶活性成正比。使用非特异性酶活性抑制剂-氟化铍-作为对 照。
在对照抑制剂和测试化合物存在下，获得的Sf9细胞分离膜的人 P-糖蛋白的ATP-酶活性值在图8中以直方图表示。
已确定OEP抑制剂显著抑制P-糖蛋白的ATP-酶活性。OEP抑制剂 的抑制活性随着其浓度从8.7增加至87μg/ml而缓慢降低，但在870 μg/ml的浓度下显著增加。在文献中，流行的观点是环氧乙烷和氧丙 烯的两亲性嵌段共聚物抑制P-糖蛋白的ATP-酶活性，这是由于掺入类 脂膜和转运蛋白的脂质微环境的微量粘稠度改变导致[9]-[11]。研 究中的OEP抑制剂不会显著改变细胞膜的微量粘稠度，因此，其作用 机制不排除对P-糖蛋白产生直接抑制作用的可能性。因此，能够得出 结论，OEP抑制剂显著抑制P-gp的ATP依赖性反向ABC-转运蛋白的活 性。
实施例15.OEP抑制剂对MCF-7、MCF-7/Vin细胞中ATP水平的 影响
将密度为2×106个细胞/ml的细胞悬浮液(MCF-7或MCF-7/ Vin)在25℃下与OEP载体(终浓度87、430和2175μg/ml)，或多柔 比星(终浓度10μM)，或浓度为10μM和87μg/ml的多柔比星与 OEP抑制剂的组合物一起温育2小时。然后通过离心(300g，4分钟) 沉淀细胞，并在缓冲溶液中洗涤，该缓冲溶液激活细胞中的ATP产生。 缓冲液组成：NaCl(122mM),NaHCO3(25mM)，葡萄糖(10mM)，KCl (3mM)，MgSO4(1.2mM)，K2HPO4(0.4mM)，CaCl2(1.4mM)和HEPES(10mM)。在强烈搅拌下，将所得细胞沉淀在冷却的裂解缓冲液中裂解 5分钟。裂解缓冲液的组成：Tris-HCL(0.05M)，EDTA(2mM)， TritonX100(1％)，NaF(10mM)。立即冷冻细胞裂解物并储存在-74℃ 直至分析。在分析之前，即刻将细胞裂解物解冻并在20,000g下从细 胞碎片离心7分钟，收集上清液用于随后分析ATP含量。使用Lumtek 生产的高灵敏度ATP试剂，在涉及荧光素酶，D-荧光素和ATP的反应 中使用化学发光技术测定细胞裂解物中ATP的含量。使用Infinite 200PRO读板仪(TECAN)测定荧光素氧化反应中化学发光的强度，其与 样品中的ATP浓度成正比。
OEP抑制剂对MCF-7、MCF-7/Vin细胞中ATP水平的影响的结果 如图9所示。
已经确定，即使在高浓度下暴露2小时的OEP抑制剂也不会导致 MCF-7和MCF-7/Vin细胞中ATP含量的降低。从文献中已知，环氧 乙烷和氧丙烯的疏水性嵌段共聚物由于渗透到细胞质中而导致培养物 中的哺乳动物细胞中ATP含量降低并且影响线粒体膜的功能状态。特 别地，经证实普卢兰尼克P85改变线粒体膜的微量浓稠度并解耦氧化 磷酸化[12]，[6]。将获得的数据与文献数据进行比较，可以得出结论， 由于结构的性质，所研究的OEP抑制剂不会渗透到细胞的胞质溶胶中， 并且不会影响线粒体的功能。多柔比星与OEP抑制剂的组合(OEP抑制 剂87μg/ml+DOX10μM)应用也不抑制MCF-7和MCF-7/Vin细 胞中的ATP生物合成。因此，能够得出结论，反向ABC-转运蛋白的ATP 依赖性抑制剂不影响肿瘤细胞中的ATP生物合成过程。
实施例16.OEP抑制剂体内的毒性参数
通过静脉内和胃内导入方法对两种性别的CD-1系(6-8周)小鼠、 Sprague Dawley大鼠(6-8周)和两性苏联丝毛兔(2-2.5kg)进行了OEP 抑制剂的急性毒性研究。
对缺乏食物的动物(持续不少于8小时的时间)进行胃内施用，自 由饮水。基于在导入物质之前刚刚记录的体重，对每只动物单独计算 施用体积。导入后一小时更新为可以食用饲料。
表4中显示了使用不同施用途径的OEP抑制剂的急性毒性(LD50) 参数。
表4
使用不同施用途径的OEP抑制剂的LD50
*per os-胃内施用
i/a-静脉内施用
根据获得的结果，OEP抑制剂当胃内施用时，根据毒性程度属于 无毒物质，当静脉内施用时属于低毒物质。已知最活跃的普卢兰尼克 L-61是药物SP1049C的一部分，它处于临床研究的第3阶段，具有更 高的毒性[13]。因此，在小鼠中使用静脉内施用途径的普卢兰尼克 L-61的LD50相当于800mg/kg。因此，可以得出结论，根据毒性类别， 反向ABC-转运蛋白的ATP-依赖性抑制剂可以归入与普卢兰尼克L-61 相比更安全的低毒和无毒化合物类别。
申请人提供的上述信息得出结论，要求保护的细胞ATP-依赖性反 向转运蛋白抑制剂显著增加活细胞和组织对药物的吸收。同时，细胞 ATP-依赖性反向转运蛋白的抑制剂的特征在于高安全性和效能。
因此，作为实验的结果，实现了目标-得到了细胞ATP-依赖性反 向转运蛋白的新抑制剂。
所要求保护的技术方案的技术效果在于，作为所进行的研究的结 果，OEP抑制剂通过一种方法得到，该方法包括：制备起始系统，在 碱性催化剂存在下起始系统的丙氧基化，中和得到的产物，纯化以便 得到期望的OEP抑制剂，其特征在于计算起始系统中的山梨醇：碱金 属或碱土金属氢氧化物：双官能含氧化合物之比，使得作为它们与氧 丙烯反应的结果，得到聚氧化丙二醇和聚氧丙烯己醇的等摩尔混合 物。
要求保护的细胞ATP-依赖性反向转运蛋白抑制剂：
-与文献中描述的大多数ABC-转运蛋白抑制剂相比，对人细胞培 养物具有低细胞毒性；
-不影响具有获得性耐药性的MCF-7品系和MCF-7/RES细胞的肿瘤 细胞的细胞质膜的微量粘稠度；
-不穿透细胞质膜进入MCF-7的肿瘤细胞；
-在8.7-870μg/ml的浓度范围内，它引起P-gp介导的多柔比星 反向转运的特异性抑制，使其在受体孔中的浓度分别增加1.9-3.8倍；
-能够消除活性糖基化同种型190kDa ABCB1，而无活性高甘露糖 同种型175kDa转运蛋白蓄积在细胞中。
-抑制具有人P-糖蛋白超表达的Sf9细胞分离膜的ATP-酶活性；
-不改变胞内ATP水平；
-当胃内施用时，根据毒性程度属于无毒物质，当通过静脉内施用 时-属于低毒物质；
-特征在于易于生产，原料低廉，生产可以在化工行业的现有企业 进行。
-提供以世界上在先未知的产品进入国际市场的机会。
参考文献清单包括描述所要求保护的技术方案所涉及的现有技术 的一些出版物。
同时，应当注意，基于所要求保护的技术方案，可以在不超出专 利权利要求的范围的情况下进行各种变型和/或改变。
所要求保护的技术方案满足有关本发明的独立权利要求中给出的 特征集合方面适用于本发明的“新颖性”标准，因为这组特征未从申 请人研究的技术水平中得到确定。
所要求保护的技术方案满足适用于发明的“创造性”标准，因为 获得的细胞ATP-依赖性反向转运蛋白的抑制剂和获得它的方法提供 了解决先前无法解决的问题的可能性，即治疗效能的显著增加，显著 提高安全性，并且还显著降低成品剂型的成本。
所要求保护的技术方案满足适用于本发明的“工业实用性”标准， 因为它可以使用已知的材料、设备和技术在专业企业中用于生产。
使用的资料清单
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2.Tiwari A.K.Revisiting the ABCs of multidrug resistance in cancerchemotherapy/A.K.Tiwari,K.Sodani,C.L.Dai,C.R. Ashby Jr.,Z.S.Chen//Curr.Pharm.Biotechnol.12(2011),P. 570-594
3.Chen Z.,Mammalian drug efflux transporters of the ATP bindingcassette(ABC)family in multidrug resistance:A review of the past decade./Z.Chen,T.Shi,L.Zhang,P.Zhu,M.Deng, C.Huang,T.Hu等人//Cancer Letters,370(2016),P.153-164
4.C.Kantor Biophisicheskaya chimiya[Biophysical chemistry].第2卷.Metody issledovania struktury i funktsii biopolimerov/[Methods of study ofstructure and function of biopolymers]C.Kantor,P.Shimmel,-Moscow:MIR Publ.,1985.
5.Batrakova E.V.Mechanism of sensitization of MDR cancer cells byPluronic block copolymers:Selective energy depletion /E.V.Batrakova,S.Li,W.F.Elmquist等人//Br J Cancer.-2001. -V.85,N.12.-P.1987-1997.
6.Kabanov A.V.An essential relationship between ATP depletion andchemosensitizing activity of Pluronic block copolymers/A.V.Kabanov,E.V.Batrakova,V.Y.Alakhov//J Control Release.2003.-V.91,N.1-2.-P.7583.
7.Gautherot,J.Effects of Cellular,Chemical,and PharmacologicalChaperones on the Rescue of a Trafficking-defective Mutant of the ATP-bindingCassette Transporter Proteins ABCB1/ABCB4/J.Gautherot,A-M. Durand-Schneider,D.Delautier,J-L.Delaunay,A.Rada,J. Gabillet,C.Housset,M.Maurice,T.
-Slimane//HEJOURNAL OF BIOLOGICAL CHEMISTRY.-2012.-第287卷-第7期- P.5070-5078.
8.Takahashi,K.Purification and ATPase Activity of Human ABCA1/K.Takahashi,Y.Kimura,N.Kioka,M.Matsuo,K.Ueda //The Journal of biologicalchemistry.2006.第281卷,第16 期.P.10760-10768.
9.Batrakova,E.V.Effect of pluronic P85 on ATPase activity of drugefflux transporters/E.V.Batrakova,S.Li,Y.Li,V.Y. Alakhov,A.V.Kabanov//PharmRes.2004.V.21,N.12.P. 2226-2233.
10.Regev,R Membrane fluidization by ether,other anesthetics,andcertain agents abolishes P-glycoprotein ATPase activity and modulates effluxfrom multidrug-resistant cells/R.Regev,Y.G.Assaraf,G.D.Eytan//Eur J Biochem.1999.第259卷.pp.18-24.
11.Womack,M.D.Detergent effects on enzyme activity and solubilizationof lipid bilayer membranes/M.D.Womack,D.A. Kendall,R.C.MacDonald//Biochimicaet Biophysica Acta(BBA) -Biomembranes.-1983.-第733卷-第2期-P.210-215.
12.Batrakova,E.V.Mechanism of pluronic effect on P-glycoproteinefflux systemin blood-brain barrier: contr ibutions of energy depletion andmembrane fluidization/ E.V.Batrakova,S.Li,S.V.Vinogradov等人//J Pharmacol ExpTher.-2001.-第299卷-第2期-P.483-493.
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Claims (6)
1.ATP-依赖性反向细胞转运蛋白的抑制剂，属于寡聚醚多元醇性质的手性缀合物的组，其是如下两种化合物的混合物：式4的聚氧丙烯己醇
其中n＝2-6；
和式5的聚氧丙烯二醇
其中m＝5-9；
其中式4化合物与式5化合物的摩尔比为0.9-1.1,所述抑制剂具有215-240mg KOH/g的羟值，式4化合物具有1000-1500Da的分子量，式5化合物具有300-500Da的分子量。
2.权利要求1的抑制剂，其特征在于式4化合物具有1200Da的分子量，且式5化合物具有400Da的分子量。
3.权利要求1的抑制剂，其特征在于式4化合物与式5化合物的摩尔比为1:1。
4.权利要求1的抑制剂，其特征在于在式4化合物中n＝4。
5.权利要求1的抑制剂，其特征在于在式5化合物中m＝7。
6.用于生产根据权利要求1的ATP-依赖性反向细胞转运蛋白的抑制剂的方法，所述方法包括：制备山梨醇和含双官能氧的化合物H-R-H的混合物，其中R＝-O-；[-OCH2CH(CH3)]kO-，且k＝1-7，然后，在碱金属或碱土金属氢氧化物存在下，该混合物与氧丙烯进一步相互作用，用酸进一步中和所得产物，然后纯化得到的产物。
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