CN101611017A - 新化合物、包含该化合物的药物组合物以及该化合物的使用方法 - Google Patents
新化合物、包含该化合物的药物组合物以及该化合物的使用方法 Download PDFInfo
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Abstract
具有通式I的化合物,包含该化合物的药物组合物和使用该组合物治疗癌症、肥胖和微生物感染的方法:其中:R1=H、C1-C20烷基、环烷基、烯基、芳基、芳烷基或烷芳基、氰甲基、-OCH3、OC(O)CH3或OC(O)CF3,R2=-OCH2C(O)NHNH-R5,其中R5是(a)苯基,任选被一个或多个卤素、任选被卤素、-OH、-OR6取代的C1-C8烷基取代,其中R6是任选被卤素取代的C1-C8烷基或(b)2-,3-或4-吡啶基,任选被卤素、-OH、-OR6取代,其中R6是任选被卤素取代的C1-C8烷基,或(c)选自咪唑、噻唑、苯并咪唑、苯并噁唑、苯并噻唑、四唑、三唑和氨基噻唑的杂环;或(d)-C(O)R7,其中R7是C1-C20烷基、环烷基、烯基、芳基、芳烷基或烷芳基,或选自吡啶基、咪唑、噻唑、苯并咪唑、苯并噁唑、苯并噻唑、四唑、三唑和氨基噻唑的杂环;并且R3和R4彼此相同或不同,是C1-C20烷基、环烷基、烯基、芳基、芳烷基或烷芳基。
Description
发明背景
脂肪酸合酶
在细胞的生理学中,脂肪酸具有三个主要作用。首先,它们是生物膜的构件。其次,脂肪酸衍生物起激素和胞内信使的作用。第三,对本发明特别重要的,脂肪酸是燃料分子,其可以作为三酰甘油酯储存在脂肪组织中,三酰甘油亦称为中性脂肪。
在脂肪酸合成路径中涉及四种主要酶,它们是脂肪酸合酶(FAS)、乙酰基CoA羧化酶(ACC)、苹果酸酶和柠檬酸裂解酶。首要的酶,FAS,催化前体丙二酰基-CoA和乙酰基-CoA的NADPH-依赖性缩合,生成脂肪酸。NADPH是一种还原剂,在FAS反应周期中的两处通常起必要的电子供体的作用。其它三种酶(即,ACC、苹果酸酶和柠檬酸裂解酶)产生必要的前体。其它酶,例如产生NADPH的酶,也涉及脂肪酸的合成。
FAS具有一个酶学专门委员会(E.C.)号码2.3.1.85,又名作为脂肪酸合酶、脂肪酸连接酶,以及它的系统名酰基-CoA:丙二酰基-CoAC-酰基转移酶(脱羧基、氧酰基-和烯酰基-还原和硫代酸酯-水解)。在FAS催化合成脂肪酸中,存在7种不同的酶或不同的催化域:乙酰基转酰酶、丙二酰转酰酶、β-酮脂酰合成酶(缩合酶)、β-酮脂酰还原酶、β-羟酰脱水酶、烯酰还原酶和硫酯酶(Wakil,S.J.,Biochemistry,28:4523-4530,1989)。所有这7种酶共同形成FAS。
虽然FAS催化合成脂肪酸在低等生物体例如与在高等生物体例如人中相似,但是还是存在一些重要的区别。在细菌中,七种酶反应是通过七种单独的非相关联的多肽进行的。将此分类为II型FAS。相反,在分枝杆菌、酵母和人中的酶反应通过多功能多肽进行。例如,酵母具有由两种单独的多肽组成的复合物,而在分枝杆菌和人中,所有七种反应都是通过单一的多肽进行。将此分类为I型FAS。
FAS抑制剂
已经表明,许多化合物抑制脂肪酸合酶(FAS)。FAS抑制剂可以通过化合物抑制纯化的FAS的酶活性的能力进行确认。通过测定结合到脂肪酸中的放射性标记前体(即,乙酰基CoA或丙二酰基-CoA),或者通过分光光度法测定NADPH的氧化,可以测定FAS活性。(Dils等人,Methods Enzymol.,35:74-83)。
表1,在下阐述,列出若干FAS抑制剂。
在脂肪酸合成路径的四种酶当中,FAS是优选的抑制靶标,因为FAS唯一在脂肪酸合成路径内起作用,而其它三种酶涉及到其它细胞功能。因此,抑制其它三种酶中的一种更可能影响正常细胞。在由FAS进行的7种酶催化步骤当中,由缩合酶(即,β-酮脂酰合成酶)和烯酰还原酶催化的步骤是减少或停止脂肪酸合成的抑制剂的最常见的候选步骤。依据结构和功能很好地对FAS复合物的缩合酶进行表征。缩合酶的活性位点包含一种关键的半胱氨酸硫醇,其是抗血脂药例如抑制剂浅蓝菌素的靶标。
缩合酶的优选抑制剂包括各种化学化合物,包括烷化剂、氧化剂和能够进行二硫化物交换的试剂。酶的结合袋优选长链,E,E,二烯。
首要的是,含侧链二烯和一种对硫醇盐阴离子表现出反应的基团的试剂可能是一种好的缩合酶抑制剂。浅蓝菌素[(2S,3R)-2,3-环氧-4-氧代-7,10十二二烯酰基酰胺]是一个例子:
浅蓝菌素与脂肪酸合酶的缩合酶的活性部位中关键的半胱氨酸硫醇基团共价结合,使这种关键酶催化步骤失活(Funabashi等人J.Biochem.105:751-755,1989)。虽然已经指明浅蓝菌素具有其它活性,但是这些或者存在于微生物中,这些微生物可能不是人细胞的相关模型(例如,真菌中胆固醇合成的抑制(inhibition ofcholesterol synthesis in fungi),Omura(1976),Bacteriol.Rev.,40:681-697;或病毒中减少的RNA合成(diminished RNA synthesisin viruses),Perez等人(1991),FEBS,280:129-133),在基本上更高的药物浓度下出现(在5mg/ml时抑制病毒性HIV蛋白酶(inhibition of viral HIV protease at 5mg/ml),Moelling等人(1990),FEBS,261:373-377)或可以是抑制内源性脂肪酸合成的直接结果(B淋巴细胞和巨噬细胞中的抗原加工的抑制(inhibition ofantigen processing in B lymphocytes and macrophases),Falo等人(1987),J.Immunol.,139:3918-3923)。某些数据表明:浅蓝菌素没有特定抑制蛋白质的肉豆蔻酰化(Simon等人J.Biol.Chem.,267:3922-3931,1992)。
更多FAS抑制剂公开在美国专利号5,614,551中,其内容在此引入作为参考。包括脂肪酸合酶、柠檬酸裂解酶、乙酰基CoA羧化酶和苹果酸酶的抑制剂。
Tomoda及同事(Tomoda等人Biochim.Biophys.Act 921:595-598 1987;Omura等人J.Antibiotics 39:1211-1218 1986)描述了三氮菌素C(triacsin C)(有时称为WS-1228A),一种天然存在的酰基辅酶A合成酶抑制剂,其是链霉菌属放线菌(Streptomyces sp.)SK-1894的一种产物。三氮菌素C的化学结构是1-羟基-3-(E,E,E-2’,4’,7’-十一碳三亚烯基(undecatrienylidine))三氮烯。在8.7μM时,三氮菌素C引起大鼠肝酰基辅酶A合成酶50%的抑制;一种有关的化合物,三氮菌素A,通过一种与长链脂肪酸竞争的机理抑制酰辅酶A合成酶。酰基辅酶A合成酶的抑制对动物细胞来说是毒性的。Tomoda等人(Tomoda等人,J.Biol.Chem.266:4214-4219,1991)教导了:在1.0μM时,三氮菌素C引起Raji细胞中的生长抑制,此外还表明:三氮菌素C抑制Vero和Hela细胞的生长。此外,Tomoda等人教导了酰基辅酶A合成酶在动物细胞中是重要的,抑制该酶具有致死作用。
在美国专利号5,981,575(其内容在此引入作为参考)中所示的一族化合物(γ-取代的-α-亚甲基-β-羧基-γ-丁内酯)抑制脂肪酸的合成,抑制肿瘤细胞的生长以及引起体重减轻。在治疗应用上,与天然产物浅蓝菌素相比,′575专利中公开的化合物具有一些优点:[1]它们不含有浅蓝菌素的高反应性环氧基团,[2]它们在水溶液中是稳定的并且是可溶的,[3]它们可以通过两步合成反应制备,因此可以容易地大量制备,以及[4]它们容易被氚化成高比活性,以便进行生化分析和药理学分析。作为脂肪酸合酶抑制剂的该族化合物的合成,在′575专利中进行了描述,也描述了它们用作治疗表达FAS的肿瘤细胞的手段,以及它们用作减少体重的手段。′575专利还公开了任何脂肪酸合酶抑制剂全身地减少脂肪细胞物质(脂肪细胞数量或大小)的应用,作为减少体重的方法。
在小鼠和人中,脂肪酸合成的主要部位是肝脏(参见Roncari,Can.J.Biochem.,52:221-230,1974;Triscari等人,1985,Metabolism,34:580-7;Barakat等人,1991,Metabolism,40:280-5),泌乳的乳腺(参见Thomp son等人,Pediatr.Res.,19:139-143,1985)和脂肪组织(Goldrick等人,1974,Clin.Sci.Mol.Med.,46:469-79)。
脂肪酸合成的抑制剂作为抗微生物剂
最初从Cephalosporium caerulens的培养肉汤中分离得到的浅蓝菌素作为潜在的抗真菌抗生素。浅蓝菌素的结构特征在于(2R,3S)-环氧-4-氧代-7,10-反,反-十二烷酸酰胺。现已证明,它的作用机理是通过不可逆结合,抑制β-酮脂酰基-ACP合酶,该合酶是脂肪酸的生物合成所需的缩合酶。现已将浅蓝菌素分类为抗真菌剂,主要是抗念珠菌属(Candida)和酒精酵母(Saccharomyces sp)。此外,表明其抗某些细菌、放线菌和分枝杆菌的一些体外活性,但是还没有发现抗结核分枝杆菌活性。没有对脂肪酸合成抑制剂和特别是浅蓝菌素抗原生动物例如鼠弓形体(Toxoplasma gondii)或其它感染性真核病原体例如卡氏肺孢子虫(Pneumocystis carinii)、兰伯贾弟虫(Giardialamblia)、疟原虫(Plasmodium sp.)、阴道毛滴虫(Trichomonasvaginalis)、隐孢子虫属(Cryptosporidium)、锥虫属(Trypanosoma)、利氏曼虫属(Leishmania)和血吸虫属(Schistosoma)的活性进行评价。
对治疗特别敏感的感染性疾病是在感染动物的可及外表面造成损伤的疾病。可及外表面包括可以通过非侵入性方法(没有割破或穿透皮肤)达到的所有表面,包括皮肤表面本身、粘膜例如覆盖鼻腔、口腔、胃肠道或尿道表面的那些,以及肺表面例如肺泡囊。易感疾病包括:(1)皮肤真菌病或癣,尤其是由小孢子菌属(Microsporum)、发癣菌属(Trichophyton)、表皮癣菌属(Epidermophyton)或粘膜皮肤念珠菌(Mucocutaneous candidiasis)引起的;(2)真菌(mucotic)角膜炎,尤其是由曲霉菌属(Aspergilus)、镰刀菌属(Fusarium)或念珠菌属引起的;(3)阿米巴角膜炎,尤其是由棘阿米巴属(Acanthamoeba)引起的;(4)胃肠道疾病,尤其是由兰伯贾第虫、内阿米巴属(Entamoeba)、隐孢子虫属、小孢子菌属或念珠菌属(在免疫妥协的动物中最常见):(5)泌尿生殖器感染,尤其是由白色念珠菌(Candidaalbicans)或阴道毛滴虫引起的;以及(6)肺病,尤其是由结核分枝杆菌、曲霉菌属或卡氏肺囊虫引起的。对用脂肪酸合成抑制剂治疗敏感的感染生物体包括结核分枝杆菌,尤其是多种药物耐药的菌株,以及原生动物例如弓形体属(Toxoplasma)。
抑制脂肪酸合成的任何化合物可以用于抑制微生物细胞生长。但是,施用于患者的化合物必须是对患者和目标微生物细胞具有不同的毒性。因此,选择这样的抑制剂是有益的,其仅仅或主要影响靶标微生物细胞。
依赖于它们自己内源性合成脂肪酸的真核微生物细胞将表达I型FAS。这可以通过以下两个事实证明:即FAS抑制剂是生长抑制性的,以及外部加入脂肪酸可以保护正常的患者细胞而不是这些微生物细胞免受FAS抑制剂作用。因此,通过细胞防止合成脂肪酸的药剂可以用来治疗感染。在真核生物中,使用底物乙酰基CoA、丙二酰CoA和NADPH,由I型FAS合成脂肪酸。因此,可以将底物送入这种途径的其它酶也可以对脂肪酸合成的速率产生影响,因此在依赖内源性合成脂肪酸的微生物中是重要的。抑制任何这些酶的表达或活性将影响依赖于内源性合成脂肪酸的微生物细胞的生长。
在各种生物体中,I型FAS的产物不同。例如,在真菌酿酒酵母(S.cerevisiae)中,产物主要是与辅酶-A酯化的棕榈酸酯和硬脂酸酯。在耻垢分枝杆菌(Mycobacterium smegmatis)中,产物是碳长度在16到24之间的饱和脂肪酸辅酶A酯。这些脂质往往被进一步加工,以满足细胞对各种脂质组分的需要。
预期对下游中脂肪酸加工或使用的关键步骤的抑制可以抑制细胞功能,不管是依赖内源性脂肪酸的细胞还是使用由外部供给脂肪酸的细胞,因此,这些下游步骤的抑制剂对依赖内源性脂肪酸的微生物细胞可以并不具有足够地选择性。但是,现已发现,当施用这些微生物I型脂肪酸合成抑制剂时,可以使它们对通过下游脂肪酸加工和/或使用的抑制剂的抑制更敏感。由于这种协同作用,脂肪酸合成抑制剂与在脂质生物合成和/或使用中的下游步骤的一种或多种抑制剂一起给药,将选择性地对那些依赖内源性合成脂肪酸的微生物细胞产生影响。优选的组合包括FAS抑制剂和乙酰基CoA羧化酶,或者FAS和MAS抑制剂。
当确定哺乳动物被表达I型FAS的生物体的细胞感染时,或者如果在患者的生物体液中发现FAS,那么所述的哺乳动物或患者可以通过施用一种脂肪酸合成抑制剂进行治疗(专利号5,614,551)。
在美国专利5,759,837中描述了FAS抑制剂抑制癌细胞生长的应用,将其内容通过参考引入本文。但那篇申请没有描述或公开本文所述的任何化合物。
在WO 2004/005277中描述了可以作为FAS抑制剂发挥作用的一类化合物,将其内容通过参考引入本文。但那篇申请没有描述或公开本文所要求保护的任何化合物。
发明简述
现已发现新类型的化合物,其具有各种在治疗上有价值的性质,例如FAS-抑制,以及抗癌和抗微生物性质。
本发明的一个目的是提供一种引起动物和人中重量减轻的方法,其通过施用一种含药物稀释剂和式I的化合物的药物组合物进行。
本发明的另一目的是提供一种在人或动物中抑制脂肪酸合酶活性的方法,其通过施用一种含药物稀释剂和式I的化合物的药物组合物进行。
本发明的另一目的是提供一种在动物和人中治疗癌症的方法,其通过施用一种含药物稀释剂和式I的化合物的药物组合物进行。
本发明的又一个另外目的是提供一种在动物和人中预防癌细胞生长的方法,其通过施用一种含药物稀释剂和式I的化合物的药物组合物进行。
本发明的另一目的是提供一种抑制侵入性微生物细胞生长的方法,其通过施用一种含药物稀释剂和式I的化合物的药物组合物进行。
附图简述
附图1显示的是制备与本发明有关的化合物和中间体的合成路线图。
附图2显示的是制备在本发明下的化合物的合成路线图。
发明详述
本发明的化合物可以通过常规方法进行制备。在实施例中描述了多种化合物的合成。该化合物可用于治疗肥胖症、癌症或基于微生物的感染。
本发明的一个实施方案是具有以下通式的化合物:
其中:
R1=H、C1-C20烷基、环烷基、烯基、芳基、芳烷基或烷芳基、氰甲基、-OCH3、-OC(O)CH3或-OC(O)CF3,
R2=-OCH2C(O)NHNH-R5,其中R5是
(a)苯基,任选被一个或多个卤素、任选被卤素、-OH、-OR6取代的C1-C8烷基取代,其中R6是任选被卤素取代的C1-C8烷基,或
(b)2-,3-或4-吡啶基,任选被卤素、-OH、-OR6取代,其中R6是任选被卤素取代的C1-C8烷基,或
(c)选自咪唑、噻唑、苯并咪唑、苯并噁唑、苯并噻唑、四唑、三唑和氨基噻唑的杂环;或
(d)-C(O)R7,其中R7是C1-C20烷基、环烷基、烯基、芳基、芳烷基或烷芳基,或选自吡啶基、咪唑、噻唑、苯并咪唑、苯并噁唑、苯并噻唑、四唑、三唑和氨基噻唑的杂环;和
R3和R4彼此相同或不同,是C1-C20烷基、环烷基、烯基、芳基、芳烷基或烷芳基;
应当理解的是,当可用时,上述化合物的酮-互变异构形式也包括在式I中。
在一个优选的实施方案中,R1是H。
在另一个优选的实施方案中R5是C1-C10烷基、环烷基、烯基、芳基、芳烷基或烷芳基。
在另一个优选的实施方案中,R3是-H或-CH3。
在另一个优选的实施方案中,R4是正-C6-C8烷基。
在另一个优选的实施方案中,R6是C1-C10烷基。
本发明的另一个实施方案是一种药物组合物,包含药物稀释剂和式I的化合物。
本发明的组合物可以以单位剂型的形式施用于人和其它动物,例如片剂、胶囊、丸剂、粉剂、颗粒剂、无菌肠胃外溶液或悬浮液、口服溶液或悬浮液、含合适量所述化合物的水包油和油包水乳剂、栓剂以及流体悬浮液或溶液。当在本说明书中使用时,术语“药物稀释剂”和“药物载体”具有相同的含义。对于口服给药,可以制备固体或液体单位剂型。对于固体组合物例如片剂的制备,该化合物可以与常规组分例如滑石、硬脂酸镁、磷酸二钙、硅酸铝镁、硫酸钙、淀粉、乳糖、阿拉伯胶、甲基纤维素和作为药物稀释剂或载体的功能相似的物质混合。如下制备胶囊:该化合物与惰性药物稀释剂混合,接着将该混合物填充到适当大小的硬明胶胶囊中。如下制备软明胶胶囊:用机器将该化合物与可接受的植物油、轻质液状矿脂或其它惰性油的浆液进行包囊。
可以制备液体单位剂型或口服给药剂型例如糖浆剂、酏剂和悬浮液。该剂型可与糖或其他甜味剂、芳香调味剂和防腐剂一起溶于含水赋形剂形成糖浆剂。借助于悬浮剂例如阿拉伯胶、黄蓍胶、甲基纤维素等等,可以用一种含水载体制备悬浮液。
可以使用该化合物和无菌载体制备用于肠胃外给药的液体单位剂型。在制备溶液时,可以将该化合物溶于注射用水中,过滤灭菌,然后填充到合适的小瓶或安瓿中并密封。佐剂例如局部麻醉剂、防腐剂和缓冲剂可以溶于载体中。将其填充到小瓶中后,可以将组合物冷冻并真空除去水。然后,可以将冷冻干燥粉末在瓶中标重,在使用前重新构建。
预见的本发明化合物临床治疗适应症包括:(1)由侵入性微生物例如葡萄球菌属和肠道球菌属引起的感染;(2)在细胞过度表达脂肪酸合酶的许多组织中出现的癌症,以及(3)由于摄入过量热量引起的肥胖症。治疗的剂量和持续时间取决于各种因素,包括(1)患者的年龄、体重和器官功能(例如肝脏和肾功能);(2)所治疗疾病过程的性质和程度,以及任何现有显著的并发症和同时服用的药物,以及(3)与药物有关的参数例如产生治愈效果所需的给药途径、给药频率和持续时间、以及药物的治疗指数。通常,为了达到在靶标位置约1μg/m至10μg/ml的有效浓度的目的,选择剂量以使血清水平达到1ng/ml至100ng/ml。
实施例
本发明将通过下列实施例进行说明,但是本发明并不受这些实施例的限制:
如下所述合成本发明的一系列化合物。如下测定某些化合物的生物学活性:测定化合物的至少一些下列指标:[1]纯化的人FAS的抑制,[2]完整细胞中脂肪酸合成活性的抑制以及[3]对培养的MCF-7人乳腺癌细胞的细胞毒性,已知该细胞具有高水平的FAS和脂肪酸合成活性,使用结晶紫和XTT试验。选择低细胞毒性水平的化合物,然后在Balb/C小鼠中进行体重减轻测试。还测试了一些化合物抗革兰氏阳性和/或阴性菌的活性。
化合物的化学合成
含有O-乙酸肼的TLM衍生物的合成
三氟甲磺酸辛酯(1)。向冷却至-40℃的在CH2Cl2(212mL)中的辛醇(4.6g,35.3mmo)中加入吡啶(从CaH2新鲜蒸馏的,3.28mL,40.6mmol)和三氟甲磺酸酐(6.41mL,38.1mmol),将该溶液在-40℃下搅拌20分钟。然后缓慢搅拌该反应混合物,使其预热至室温3小时。然后通过硅藻土过滤该白色固体,用戊烷(2×70mL)洗涤。蒸发掉大多数溶剂,剩余约5-10mL的溶剂和所存在的白色沉淀。加入热戊烷(70mL),过滤该混合物,除去剩余的所有吡啶盐。再蒸发滤液,得到澄清淡橘色的油1(通过TLC,定量,rf=0.64 10% EtOAc/Hex),其可以立即使用。
2,2,4-三甲基-[1,3]氧硫杂环戊-5-酮(2)。用加入漏斗向冷却至0℃的硫代乙酸(14.0g,132.0mmol)中滴加2-甲氧基丙烯(50.5mL,528mmol)。溶液加热至室温,然后加热回流48小时。在冷却至室温后,加入Et2O(200mL),用Na2CO3(1N,3×150mL)萃取该混合物并用盐水(2×100mL)洗涤。干燥(MgSO4)合并的有机物,过滤并蒸发,得到粗的黄色油,将其在80-95℃下蒸馏(H2O抽气压,25-35 torr),得到纯的2(9.9g,52%)。1H NMR(300MHz,CDCl3)δ1.56(d,J=6.9Hz,3H),1.72(s,3H),1.74(s,3H),4.10(q,J=6.9Hz,1H);13C NMR(75MHz,CDCl3)δ17.9,30.8,31.4,42.5,86.2,175.0。
2,2,4-三甲基-4-辛基-[1,3]-氧硫杂环戊-5-酮(3)。在-78℃下,通过插管向LiHMDS(31.7mL,31.7mmol,1M在THF中)在THF(47mL)中的混合物中滴加2(4.3g,29.4mmol)在THF(47mL)中的溶液,将所得到的黄色溶液在-78℃下搅拌30分钟。然后,通过插管在室温下将在戊烷(8mL)中的三氟甲磺酸辛酯1(9.0g,35mmol)缓慢加入到该-78℃的烯醇化物的溶液中。在-78℃下搅拌2小时后,加入1N HCl(200mL),用Et2O(3×75mL)萃取该溶液。干燥(MgSO4)合并的有机物,过滤并蒸发。快速色谱法(2%EtOAc/己烷)得到了纯的3(5.45g,72%)。1H NMR(300MHz,CDCl3)δ0.86(bs,3H),1.25(m,10H),1.63(s,3H),1.73(s,3H),1.80(s,3H),1.5-1.81(m,4H);13C NMR(75MHz,CDCl3)δ14.0,22.6,25.5,29.0,29.1,29.3,29.4,31.8,32.5,33.5,41.4,58.1,84.7,177.7。
2-乙酰基硫烷基-2-甲基-癸酸乙酯(4)。向在EtOH(无水,14.6mL)中的3(5.33g,20.6mmol)中加入NaOEt(2.1M,12.7mL,26.9mmol)[由Na金属(1.24g,54mmol)在EtOH(24mL)中新鲜制备],该溶液在室温下搅拌。在30分钟后,将该溶液倒入NH4Cl(Sat)/1N HCl(100mL,3∶2)中,并用Et2O(3×75mL)萃取,然后用H2O彻底洗涤合并的有机物,干燥(MgSO4),过滤,蒸发并再溶于CH2Cl2(129mL)。向该预冷却的溶液(0℃)中加入NEt3(4.3mL,30.9mmol)和乙酰氯(3.2mL,41.2mmol)。在40分钟后,在0℃下,加入NH4Cl(Sat)(200mL),用CH2Cl2(3×70mL)萃取该溶液。干燥(MgSO4)合并的有机物,过滤并蒸发。快速色谱法(5%EtOAc/己烷)得到纯的4(3.1g,54%)。1H NMR(300MHz,CDCl3)δ0.87(t,J=6.9Hz,3H),1.22-1.27(m,15H),1.61(s,3H),1.75-1.84(m,2H),2.26(s,3H),4.18(q,J=7.1Hz,2H);13C NMR(75MHz,CDCl3)δ13.9,14.1,22.6,23.4,24.4,29.1,29.2,29.6,30.3,31.8,38.3,55.8,61.5,173.1,195.8。IR(NaCl)3430,1868,1693,1644cm-1;分析值(C15H28O3S)C,62.5;H,9.78;测定值:C,62.6;H,9.83。
4-羟基-5-甲基-5-辛基-5-H-噻吩-2-酮(5)。在-78℃下向在THF(155mL)中的4(3.11g,10.8mmol)中加入LiHMDS(13.4mL,13.4mmol,1.0M,在THF中),将溶液缓慢加热2小时至-5℃,然后在-5℃下再保持20分钟。然后将该溶液倒入1N HCl(200mL)中并用Et2O(3×100mL)萃取。干燥(MgSO4)合并的有机物,过滤并蒸发快速色谱法(20%EtOAc/2%CH3CO2H/己烷)得到5(1.2g,46%)。1H NMR(300MHz,CDCl3)(酮-互变异构体)δ0.86(t,J=6.7Hz,3H),1.19-1.24(m,10H),1.48-1.53(m,2H),1.65(s,3H),1.77-1.85(m,1H),1.94-2.01(m,1H),3.36(s,2H);1H NMR(300MHz,MeOD)(烯醇互变异构体)0.87-0.89(m,3H),1.29(m,10H),3.29(s,3H),1.81-1.87(m,2H);13C NMR(75MHz,MeOD)(烯醇互变异构体)δ14.7,23.8,26.4,27.1,30.5,30.6,30.8,33.2,39.8,61.3,103.1(m),189.8,197.8.IR(NaCl)3422,1593cm-1;分析值(C13H22O2S),C,64.4;H,9.15;测定值:C,64.3;H,9.10。
5-甲基-5-辛基-2-氧代-噻吩-4-基氧基)-乙酸叔丁酯(7)。向冷却至-40℃的在DMF(23mL)中的5(1.4g,5.8mmo l)中加入NaH(326mg,8.15mmol,60%,在矿物油中),将该溶液加热并在0℃下搅拌30分钟。然后直接加入溴乙酸叔丁酯6(1.29mL,8.73mmol),将该混合物加热,并在室温下搅拌3小时。加入NH4Cl(Sat)/1N HCl(6∶1,100mL)并用Et2O(3×70mL)萃取该溶液。用H2O洗涤合并的有机物,干燥(MgSO4),过滤并蒸发。快速色谱法(15%EtOAc/己烷)得到纯的7(1.7g,82%)。1H NMR(300MHz,CDCl3)δ0.86(t,J=6.9Hz,3H),1.24(s,12H),1.49(s,9H),1.68(s,3H),1.83-1.86(m,2H),4.43(s,2H),5.19(s,1H);13C NMR(75MHz,CDCl3)δ14.0,22.6,25.2,26.3,28.1,29.2,29.3,29.5,31.8,38.9,59.7,68.5,83.4,102.1,165.2,185.5,193.4。分析值C19H32O4S)C,64.0;H,9.05;测定值:C,64.1,H,9.08。
(5-甲基-5-辛基-2-氧代-噻吩-4-基氧基)-乙酸(8)。向溶于CH2Cl2(32mL)的7(1.7g,4.7mmol)中加入三氟乙酸(TFA)(9.1mL),将该溶液在室温下搅拌4-5小时。蒸发溶剂,粗物质进行色谱法处理(40%EtOAc/2%CH3CO2H/己烷),得到纯的8(1.1,77%)。1H NMR(300MHz,CDCl3)δ0.86(t,J=6.9Hz,3H),1.24(s,11H),1.47-1.48(m,1H),1.68(s,3H),1.84-1.88(m,2H),4.62(s,2H),5.31(s,1H);13C NMR(75MHz,CDCl3)δ14.1,22.6,25.1,26.1,29.2,29.3,29.5,31.8,38.9,60.1,67.7,102.4,169.8,185.8,195.4。IR(NaCl)3442,1645cm-1;分析值Cl5H24O4S)C,59.9;H,8.05;测定值:C,60.0;H,8.09。
(5-甲基-5-辛基-2-氧代-噻吩-4-基氧基)-乙酸-N′-(4-氯苯基)-酰肼(9)。向8(1.1g,3.67mmol)在CH2Cl2(17.3mL)中的冷却溶液(0℃)中加入盐酸1-[3-(二甲基氨基)丙基]-3-乙基碳二亚胺(EDC)(1.4g,7.3mmol),盐酸4-氯苯基肼(854mg,4.77mmol),NEt3(0.51mL,3.67mmol)和DMAP(67mg,0.55mmol)。将该混合物在0℃下搅拌30分钟,然后加热至室温并搅拌12小时。将该溶液倒入NH4Cl(Sat):HCl(1N)(4∶1,100ml)并用CH2Cl2(3×30ml)萃取。干燥(MgSO4)合并的有机物,过滤并蒸发,得到纯的9。快速色谱法[30%EtOAc/Hex(除去副产物)-然后35%EtOAc/Hex(500mL)-40%EtOAc/Hex(300mL)]得到纯的9(1.2g,77%)。1H NMR(300MHz,CDCl3)δ0.86(t,J=6Hz,3H),1.24(m,11H),1.46-1.54(m,1H),1.71(s,3H),1.82-1.90(m,2H),4.57(s,2H),5.39(s,1H),6.75(d,J=8.8Hz,2H),7.18(d,J=8.8Hz,2H),7.38(s,1H),8.09(s,1H);13C NMR(100MHz,CDCl3)δ14.1,22.6,25.3,26.1,29.2,29.3,29.5,31.8,38.8,59.7,69.7,103.2,114.7,126.4,145.8,129.2,165.9,184.3,193.5。IR(NaCl)2957,1695,1658,1609cm-1。
一般方法A:
向8(0.05mmol,1.0当量)在CH2Cl2(1.0mL)中的冷却溶液(0℃)中加入盐酸1-[3-(二甲基氨基)丙基]-3-乙基碳二亚胺(EDC)(0.1mmol,2.0当量)、肼衍生物(0.065mmol,1.3当量)和DMAP(0.0075mmol,0.15当量)和三乙胺(1.0倍当量),如果该反应中使用的是盐酸盐的话。将混合物在0℃下搅拌30分钟,然后加热至室温并搅拌12小时。将反应混合物转移到用CH2Cl2填装的硅胶柱上。快速色谱法(20%醚/CH2Cl2)得到纯的产物。
(5-甲基-5-辛基-2-氧代-噻吩-4-基氧基)-乙酸-N′-苯基酰肼(10)。
使用8(15.0mg,0.05mmol)和苯基肼(6.4μL,0.065mmol),根据一般方法A获得呈油状的化合物10(15.0mg,77%)(顺式:反式的比-27∶73)。1H NMR(400MHz,CDCl3)δ0.80(t,J=8.0Hz,3H),1.10-1.24(m,11H),1.41-1.51(m,1H),1.66(s,3H),1.78-1.84(m,2H),4.50(s,2H),5.33(s,1H),6.75(dd,J=1.2,8.0Hz,2H),6.90(dd,J=8.0,16.0Hz,1H),7.20(dd,J=8.0,16.0Hz,2H),8.03(s,1H);顺式化合物的代表性峰:1.62(s,3H),4.75(s,2H),5.13(s,1H);13C NMR(100MHz,CDCl3)δ14.1,22.6,25.4,26.3,29.2,29.3,29.5,31.8,39.0,59.4,70.0,103.5,113.6,122.0,129.4,147.0,165.6,183.9,193.0。
(5-甲基-5-辛基-2-氧代-噻吩-4-基氧基)-乙酸-N′-(3-甲基苯基)-酰肼(11)。
使用8(15.0mg,0.05mmol)和盐酸1-(3-甲基苯基)肼(10.2mg,0.065mmol),根据一般方法A获得呈油状的化合物11(7.0mg,35%)(顺式:反式的比-29∶71)。1H NMR(400MHz,CDCl3)δ0.87(t,J=8.0Hz,3H),1.19-1.29(m,11H),1.51-1.57(m,1H),1.74(s,3H),1.85-1.91(m,2H),2.30(s,3H),4.59(s,2H),5.14(s,1H),6.62-6.65(m,2H),6.77(d,J=8.0Hz,1H),7.07-7.19(m,1H),7.93(s,1H);顺式化合物的代表性峰:1.69(s,3H),2.33(s,3H),4.82(s,2H),5.23(s,1H);13C NMR(100MHz,CDCl3)δ14.1,21.5,22.6,25.0,26.4,29.2,29.4,29.6,31.8,38.5,59.0,70.0,103.0,110.5,114.0,122.5,129.0,139.0,147.0,165.0,184.0,193.0。
(5-甲基-5-辛基-2-氧代-噻吩-4-基氧基)-乙酸-N′-(4-三氟甲基苯基)-酰肼(12)。
使用8(15.0mg,0.05mmol)和盐酸1-[4-(三氟甲基)-苯基]肼(14.0mg,0.065mmol),根据一般方法A获得呈油状的化合物12(12.0mgs 53%)(顺式:反式的比-17∶83)。1H NMR(400MHz,CDCl3)δ0.80(t,J=8.0Hz,3H),1.10-1.25(m,11H),1.45-1.51(m,1H),1.68(s,3H),1.78-1.85(m,2H),4.56(s,2H),5.36(s,1H),6.29(s,1H),6.81(d,J=8.0Hz,2H),7.43(d,J=8.0Hz,2H),7.94(s,1H);顺式化合物的代表性峰:1.62(s,3H),4.74(s,2H),5.18(s,1H)。
(5-甲基-5-辛基-2-氧代-噻吩-4-基氧基)-乙酸-N′-(4-甲氧基苯基)-酰肼(13)。
使用8(15.0mg,0.05mmol)和盐酸1-(4-甲氧基苯基)肼(11.3mg,0.065mmol),根据一般方法A获得呈油状的化合物13(7.0mg,33%)(顺式:反式的比-25∶75)。1H NMR(400MHz,CDCl3)δ0.80(t,J=8.0Hz,3H),1.08-1.24(m,11H),1.41-1.51(m,1H),1.66(s,3H),1.80-1.84(m,2H),3.69(s,3H),4.50(s,2H),5.33(s,1H),6.76(s s,4H),7.90(s,1H);顺式化合物的代表性峰:1.63(s,3H),3.71(s,3H),4.76(s,2H),5.15(s,1H);13C NMR(75MHz,CDCl3)14.1,22.6,25.4,26.4,29.2,29.4,29.5,31.8,39.0,55.6,59.4,69.9,103.5,114.3,114.7,139.7,155.3,165.5,183.8,192.9。
(5-甲基-5-辛基-2-氧代-噻吩-4-基氧基)-乙酸-N′-(2,4-二氯苯基)-酰肼(14)。
使用8(19.0mg,0.063mmol)和盐酸1-(2,4-二氯苯基)肼(17.5mg,0.082mmol),根据一般方法A获得呈固体状的化合物14(17.0mg,59%)(顺式:反式的比-20∶80)。1H NMR(400MHz,CDCl3)δ0.86(t,J=7.2Hz,3H),1.15-1.31(m,11H),1.42-1.51(m,1H),1.72(s,3H),1.82-1.90(m,2H),4.77(s,2H),5.41(s,1H),6.38(s,1H),6.76(d,J=8.4Hz,1H),7.14(dd,J=2.0,8.4Hz,1H),7.32(d,J=2.0Hz,1H),8.11(s,1H);顺式化合物的代表性峰:1.65(s,3H),4.75(s,2H),5.20(s,1H);13C NMR(100MHz,CDCl3)δ14.1,22.6,25.4,26.3,29.2,29.4,29.5,31.8,39.0,59.5,69.8,103.5,114.4,120.5,126.5,127.8,129.4,141.9,165.5,183.9,193.0。
(5-甲基-5-辛基-2-氧代-噻吩-4-基氧基)-乙酸-N′-(3,4-二氯苯基)-酰肼(15)。
使用8(19.0mg,0.063mmol)和1-(3,4-二氯苯基)肼盐酸(17.5mg,0.082mmol),根据一般方法A获得呈半固体状的化合物15(12.0mg,42%)(顺式:反式的比-17∶83)。1HNMR(400MHz,CDCl3)δ0.80(t,J=6.8Hz,3H),1.09-1.23(m,11H),1.36-1.53(m,1H),1.67(s,3H),1.77-1.84(m,2H),4.54(s,2H),5.35(s,1H),6.21(s,1H),6.60(dd,J=2.4,8.8Hz,1H),6.84(d,J=2.4Hz,1H),7.21(d,J=8.8Hz,1H),8.0(s,1H);顺式化合物的代表性峰:1.65(s,3H),4.73(s,2H),5.18(s,1H);13C NMR(75MHz,CDCl3)δ14.1,22.6,25.4,26.3,29.2,29.4,29.5,31.8,39.0,59.5,69.8,103.5,113.2,115.2,124.8,130.9,133.2,146.7,165.9,184.0,193.2。
(5-甲基-5-辛基-2-氧代-噻吩-4-基氧基)-乙酸-N′-[2-氯-5-(三氟甲基)苯基]-酰肼(16)。
使用8(15.0mg,0.05mmol)和1-[2-氯-5-(三氟甲基)苯基]肼(13.6mg,0.065mmol),根据一般方法A获得呈油状的化合物16(10.4mg,42%)(顺式:反式的比-14∶86)。1HNMR(300MHz,CDCl3)δ0.80(t,J=6.6Hz,3H),1.06-1.24(m,11H),1.41-1.50(m,1H),1.67(s,3H),1.76-1.89(m,2H),4.58(s,2H),5.37(s,1H),6.53(d,J=3.3Hz,1H),6.98(d,J=1.5Hz,1H),7.07(dd,J=1.8,8.4Hz,1H),7.37(d,J=8.1Hz,1H),8.03(s,1H);顺式化合物的代表性峰:1.60(s,3H),4.77(s,2H),5.28(s,1H)。
(5-甲基-5-辛基-2-氧代-噻吩-4-基氧基)-乙酸-N′-(2-苯并噻唑)-酰肼(17)。
使用8(22.0mg,0.07mmol)和2-肼基苯并噻唑(14.6mg,0.09mmol),根据一般方法A获得呈固体状的化合物17(14.0mg,45%)(单个异构体)。1H NMR(400MHz,CDCl3)δ0.88(t,J=6.4Hz,3H),1.26-1.83(m,11H),1.52(m,1H),1.75(s,3H),1.86-1.99(m,2H),4.86(s,2H),5.22(s,2H),5.32(s,1H),7.36(t,J=7.2Hz,1H),7.48(t,J=7.2Hz,1H),7.81(d,J=8.0Hz,1H),7.85(d,J=8.0Hz,1H);m.p.151-152℃。
(5-甲基-5-辛基-2-氧代-噻吩-4-基氧基)-乙酸-N′-[6-甲基-4-(三氟甲基)-2-吡啶基]-酰肼(18)。
使用8(15.0mg,0.05mmol)和1-[6-甲基-4-(三氟甲基)-2-吡啶基]肼(12.5mg,0.065mmol),根据一般方法A获得呈油状的化合物18(12.5mg,53%)(顺式:反式的比-10∶90)。1H NMR(300MHz,CDCl3)δ0.79(t,J=8.4Hz,3H),1.10-1.29(m,11H),1.44-1.52(m,1H),1.70(s,3H),1.82-1.89(m,2H),2.41(s,3H),4.57(s,2H),5.37(s,1H),6.59(s,1H),6.81(s,1H),7.31(bs,1H),8.70(bs,1H);顺式化合物的代表性峰:1.62(s,3H),4.74(s,2H),5.29(s,1H)。
(5-甲基-5-辛基-2-氧代-噻吩-4-基氧基)-乙酸-N′-(2-氯苯基)-酰肼(19)。
使用8(98.0mg,0.33mmol)和盐酸2-氯苯基肼(77.0mg,0.43mmol),根据一般方法A获得化合物19(91.0mg,60%)。1H NMR(300MHz,CDCl3)δ0.85(t,J=7.0Hz,3H),1.23(m,11H),1.48-1.51(m,1H),1.69(s,3H),1.81-1.89(m,2H),4.56(s,2H),5.37(s,1H),6.49-6.51(m,1H),6.84-6.94(m,2H),7.12-7.35(m,2H),8.31(d,J=3.1Hz,1H)。13C NMR(100MHz,CDCl3)δ14.0,22.5,25.3,26.2,29.2,29.3,29.5,31.7,38.9,59.5,69.7,103.3,113.5,119.8,122.0,122.7,129.6,142.9,165.5,184.1,193.3。
(5-甲基-5-辛基-2-氧代-噻吩-4-基氧基)-乙酸-N′-(4-吡啶基)-酰肼(20)。
使用8(100.0mg,0.33mmol)和异烟肼(59.0mg,0.42mmol),根据一般方法A,在快速色谱法(5%MeOH/CHCl3)后获得化合物20(118.0mg,86%)。1H NMR(300MHz,CDCl3)δ0.85(t,J=7.0Hz,3H),1.23(m,11H),1.44-1.45(m,1H),1.68(s,3H),1.82-1.88(m,2H),4.69(s,2H),5.42(s,1H),7.64(d,J=5.3Hz,2H),8.67(m,2H)。13C NMR(100MHz,CDCl3)δ14.0,22.5,253,26.2,29.2,29.3,29.5,31.7,38.9,59.5,69.7,103.3,113.5,119.8,122.0,122.7,129.6,142.9,165.5,184.1,193.3。
(5-甲基-5-己基-2-氧代-噻吩-4-基氧基)-乙酸-N′-(4-氯苯基)-酰肼(21)。
如附图2所示的合成路线图制备该化合物。使用26(83.0mg,0.29mmol)和盐酸4-氯苯基肼(68.0mg,0.38mmol),根据一般方法A获得化合物21(34.0mg,30%)。1H NMR(300MHz,CDCl3)δ0.86(m,3H),1.26(m,7H),1.45-1.50(m,1H),1.71(s,3H),1.85-1.90(m,2H),4.57(s,2H),5.39(s,1H),6.74(d,J=8.8Hz,2H),7.20(d,J=8.8Hz,2H),7.59(s,1H),8.21(s,1H)。
生物学和生化学方法
从ZR-75-1人乳腺癌细胞中提纯FAS
人FAS从培养的ZR-75-1人乳腺癌细胞中提纯,该细胞从美国典型培养物保藏中心(American Type Culture Collection)获得。该方法改编自Linn等人1981和Kuhajda等人1994的方法,使用低渗性裂解、连续性聚乙二醇(PEG)沉淀以及阴离子交换色谱。ZR-75-1细胞在37℃下用5%的CO2在含10%胎牛血清、青霉素和链霉素的RPMI培养基中进行培养。
将10个T150瓶的汇合细胞用1.5ml裂解缓冲液(20mMTris-HCl,pH 7.5,1mM EDTA,0.1mM苯基甲磺酰氟(PMSF),0.1%Igepal CA-630)溶解,在冰上dounce匀浆20次。在4℃下,将裂解产物在JA-20旋转机(Beckman)中以20,000rpm离心30分钟,上清液用裂解缓冲液加至42ml。将50%的PEG 8000在裂解缓冲液中的溶液缓慢地加入到上清液上,使其最终浓度为7.5%。在4℃摇动60分钟后,溶液在4℃下在JA-20旋转机(Beckman)中以15,000rpm离心30分钟。然后,将固体PEG 8000加入到上清液中,使其最终浓度为15%。重复如上所述的摇动和离心后,粒状沉淀在4℃下在10ml缓冲液A(20mM K2HPO4,pH 7.4)中重悬浮过夜。0.45μM过滤后,将蛋白质溶液应用于Mono Q5/5阴离子交换柱(Pharmacia)。柱子用缓冲液A以1ml/分钟洗脱15分钟,接着结合材料以在60分钟内升至1M KCl的线性60-ml梯度溶液洗脱。FAS(MW~270kD)通常在0.25MKCl洗脱在三个已鉴定的0.5ml级份中,这些级份使用4-15%的带有考马斯G250着色剂的SDS-PAGE(Bio-Rad)进行确定。FAS蛋白浓度使用考马斯加蛋白测定试剂(Pierce)根据厂商的说明书使用BSA作为标准进行测定。此方法根据Coomassie-染色凝胶进行判断制得基本上纯的FAS(>95%)的制备物。
FAS酶活性的测定以及化合物IC50的测定
通过在OD340处,在96孔板中,使用分光光度法监测NADPH的丙二酰基-CoA依赖性氧化(Dils等人和Arslanian等人,1975),来测定FAS活性。每个孔中含有2μg纯化FAS、100mM K2HPO4,pH 6.5、1mM二硫苏糖醇(Sigma)和187.5 β-NADPH(Sigma)。以2、1和0.5mg/ml在DMSO中制备抑制剂的母液,当每孔中加入1μL母液时,最终浓度为20、10和5μg/ml。对于每一个实验,使用浅蓝菌素(Sigma)作为阳性对照,以及DMSO对照、抑制剂和空白(没有FAS酶)所有都是一式两份。
在Molecular Devices SpectraMax Plus分光光度计上进行测定。将含FAS、缓冲液、抑制剂和对照物的平板放在加热至37℃的分光光度计中。使用动力学方案,使含100μL 100mM的K2HPO4,pH 6.5的孔为空白,一式两份,平板在OD340处以10秒间隔读数5分钟,以测定任何NADPH的丙二酰基-CoA非依赖性氧化。将平板从分光光度计上移去,除空白外,每个孔中加入丙二酰基-CoA(67.4μM,每孔的最终浓度)和炔基-CoA(61.8μM,每孔的最终浓度)。使用动力学方案,如同上述对平板进行再次读数,以测定丙二酰基-CoA依赖性NADPH氧化。丙二酰基-CoA依赖性NADPH氧化和非丙二酰基-CoA依赖性NADPH氧化之间的ΔOD340的差异是特定的FAS活性。由于FAS制剂的纯度,非丙二酰基-CoA依赖性NADPH氧化是可忽视的。
化合物抗FAS的IC50通过对每个所测抑制剂浓度的ΔOD340进行绘图,进行线性回归并计算最佳拟合线,r2值和95%的置信区间来测定。化合物产生50%FAS抑制的浓度是IC50。对于每一化合物浓度,由SOFTmax PRO软件(Molecular Devices),描绘ΔOD340对时间图。使用Prism 3.0版(Graph Pad软件)计算线性回归、最佳拟合线,r2和95%置信区间。
结晶紫细胞生长试验
结晶紫试验测定细胞生长而不是细胞毒性。此试验使用在96孔板中的结晶紫染色的固定细胞,随后进行溶解并在分光光度计上测定OD490。OD490应所测的每单位时间的细胞生长。细胞用目的化合物或载体对照进行处理,计算每个化合物的IC50。
为了测定特定化合物抗癌细胞的细胞毒性,将每孔5×104MCF-7人乳腺癌细胞(从美国典型培养物保藏中心获得)平铺在24孔板中,每个孔中含带有10%胎牛血清、青霉素和链霉素的DMEM培养基。在37℃和5%CO2下过夜培养后,将溶于DMSO中的受试化合物以50,40,30,20和10μg/ml的浓度一式三份加入到孔中,加入量为1μl。如果需要的话,测试其它的浓度。将作为载体对照的1μl DMSO加入到一式三份孔中。使用C75以10和5μg/ml一式三份作为阳性对照。
孵育72小时后,每个孔中的细胞用0.5ml结晶紫染色剂(0.5%,在25%甲醇中)染色。10分钟后,冲洗孔,风干,然后振动下用0.5ml 10%的十二烷基硫酸钠溶解2小时。从每个孔中转移100μl到96孔板后,平板在OD490处在Molecular Devices SpectraMax Plus分光光度计上进行读数,使用SOFTmax Pro软件(Molecular Devices)计算平均OD490值,使用Prism 3.02版(Graph Pad软件,San Diego)通过线性回归分析确定IC50值。
XTT细胞毒性试验
XTT试验是[51Cr]释放细胞毒性试验的非放射性替代法。XTT是一种四唑盐,其唯一由代谢活性的活细胞还原成甲`染料。XTT的还原通过分光光度法以OD490-OD650进行测定。
为了测定特定化合物抗癌细胞的细胞毒性,将每孔9×103MCF-7人乳腺癌细胞(从美国典型培养物保藏中心获得),平铺在96孔板中,每个孔中含带有10%胎牛血清、胰岛素、青霉素和链霉素的DMEM培养基。在37℃和5%CO2下过夜培养后,将1μl体积溶于DMSO中的受试化合物以下列浓度加入到孔中:80、40、20、10、5、2.5、1.25和0.625μg/ml,一式三份。如果需要的话,测试其它浓度。将作为载体对照的1μl DMSO加入到一式三份孔中。使用C75以40、20、10、15、12.5、10和5μg/ml一式三份作为阳性对照。
孵育72小时后,按照每个厂商的说明书(细胞增殖试剂盒II(XTT)Roche),将细胞与XTI试剂一起培养4小时。在OD490和OD650处在Molecular Devices SpectraMax Plus分光光度计上对平板读数。三个含XTT试剂而没有细胞的孔用作板空白。XTT数据报告为OD490-OD650。使用SOFTmax Pro软件(Molecular Dynamics)计算平均值和平均值的标准误差。
化合物的IC50被定义为:与对照相比,引起OD490-OD65050%减少的药物浓度。对于每一化合物浓度,由SOFTmax PRO软件(MolecularDevices)计算OD490-OD650。将以对照百分比表示的FAS活性对药物浓度绘图,通过线性回归计算IC50。使用Prism 3.0版(Graph Pad软件)测定线性回归、最佳拟合线、r2和95%置信区间。
掺入到总脂质中的[14C]乙酸的测定和化合物IC50的测定
本试验测定[14C]乙酸向总脂质中的掺入,并且是体外脂肪酸合成路径活性的尺度。用它来测量体外脂肪酸合成的抑制。
将如上所述培养的MCF-7人乳腺癌细胞,以每孔5×104细胞平铺在24孔板中。过夜孵育后,将溶解在DMSO中的受试化合物以5、10和20μg/ml一式三份加入,如有必要使用更低的测试浓度。对于载体对照,将DMSO加入到一式三份孔中。使用C75以5和10μg/ml一式三份作为阳性对照。孵育4小时后,每个孔中加入0.25μCi的[14C]乙酸(10μl体积)。
再孵育2小时后,从孔中吸出培养基,向每个孔中加入800μl的氯仿∶甲醇(2∶1)和700μl的4mM的MgCl2。将每个孔中的内含物转到1.5Eppendorf管中,在高速Eppendorf微量离心机5415D中全速旋转2分钟。除去含水层(上部)后,向每个管中加入另外700μ的氯仿∶甲醇(2∶1)和500μl的4mM的MgCl2,然后如上所述离心1分钟。用巴斯德吸管除去水层并弃去。向每个管中再加入另外400μl的氯仿∶甲醇(2∶1)和200μl的4mM的MgCl2,然后,离心,弃去水层。将底层(有机)相转移到闪烁瓶中,在40℃和N2气下干燥。一旦干燥,加入3ml的闪烁剂(APB#NBC5104),对瓶进行14C计数。贝克曼闪烁计数器计算一式三份的平均cpm值。
化合物的IC50被定义为:与对照相比,引起掺入到脂质中的[14C]乙酸50%减少的药物浓度。通过对每个受试抑制剂浓度的平均cpm绘图,进行线性回归并计算最佳拟合线、r2值和95%的置信区间,来测定该值。对于每个化合物浓度,通过贝克曼闪烁计数器(型号LS 6500)计算平均cpm值。使用Prism 3.0版(Graph Pad软件)计算线性回归、最佳拟合线r2和95%置信区间的计算结果。
新FAS抑制剂的体重减轻筛选
使用Balb/C小鼠(Jackson实验室)进行初始体重减轻筛选。将动物养在温度和12小时白天/黑夜循环的房间中,小鼠自由摄取食物和水。每个受试化合物和载体对照使用三只小鼠,每个实验一式三份。在实验中,将用于每个测试化合物的小鼠分开饲养,三只小鼠共用一个笼。将化合物以10mg/ml的浓度稀释在DMSO中,小鼠以60mg/kg通过腹膜内注射给予约100μl DMSO或者仅仅给予载体。每日观察小鼠,并对小鼠进行称重;用Excel(微软公司)计算平均重量和标准误差。继续实验,直到所治疗的动物的体重达到治疗前的体重。
抗微生物性质
使用肉汤微稀释试验来评价化合物的抗微生物活性。化合物以二倍系列稀释进行测定,抑制可见生长的浓度(在对照的10%OD600)被定义为MIC。测试的微生物包括金黄色葡萄球菌(ATCC # 29213)、粪肠球菌(ATCC # 29212)、绿脓杆菌(ATCC # 27853)和大肠杆菌(ATCC# 25922)。试验在两种生长培养基中进行,培养基分别为米勒海顿肉汤和胰酶解酪蛋白大豆肉汤。
血液(Tsoy/5%的绵羊血)琼脂平板从维持在含10%甘油的T大豆肉汤中的冰冻贮备液中接种,然后在37℃孵育过夜。将菌落悬浮在灭菌肉汤中,以便浊度与0.5麦克法兰(McFarlard)标准的浊度相当。将接种物以1∶10稀释在灭菌肉汤中(米勒海顿或胰酶解酪蛋白大豆),在96孔板的每个孔中分配195μl。向孔中加入5μl体积下列浓度的溶于DMSO中的受试化合物:25、12.5、6.25、3.125、1.56和0.78μg/ml一式两份。如果需要的话,测试其它浓度。加入一式两份孔的5μl DMSO是载体对照。在每次测试中包括阳性对照化合物-万古霉素(粪肠杆菌和金黄色葡萄球菌)和妥布霉素(大肠杆菌和绿脓杆菌)的系列稀释。
在37℃孵育24小时后,平板在OD600处在Molecular DevicesSpectraMax Plus分光光度计上进行读数。使用SOFTmax Pro软件(Molecular Devices)计算平均OD600值,使用Prism 3.02版(GraphPad软件,San Diego)通过线性回归分析确定MIC值。MIC被定义为产生相当于10%的载体对照读数的OD600所需要的化合物浓度。
生物学试验的结果
Claims (25)
1.下式的化合物:
其中:
R1=H、C1-C20烷基、环烷基、烯基、芳基、芳烷基或烷芳基、-OCH3、-OC(O)CH3或-OC(O)CF3,
R2=-OCH2C(O)NHNH-R5,其中R5是
(a)苯基,任选被一个或多个卤素、任选被卤素、-OH、-OR6取代的C1-C8烷基取代,其中R6是任选被卤素取代的C1-C8烷基,或
(b)2-,3-或4-吡啶基,任选被卤素、-OH、-OR6取代,其中R6是任选被卤素取代的C1-C8烷基,或
(c)选自咪唑、噻唑、苯并咪唑、苯并噁唑、苯并噻唑、四唑、三唑和氨基噻唑的杂环;或
(d)-C(O)R7,其中R7是C1-C20烷基、环烷基、烯基、芳基、芳烷基或烷芳基,或选自吡啶基、咪唑、噻唑、苯并咪唑、苯并噁唑、苯并噻唑、四唑、三唑和氨基噻唑的杂环;和
R3和R4彼此相同或不同,是C1-C20烷基、环烷基、烯基、芳基、芳烷基或烷芳基;
2.权利要求1的化合物,其中R1是H。
3.权利要求1的化合物,其中R5是C1-C10烷基、环烷基、烯基、芳基、芳烷基或烷芳基。
4.权利要求1的化合物,其中R3是-H或-CH3。
5.权利要求1的化合物,其中R4是正-C6-C8烷基。
7.一种药物组合物,包含药物稀释剂和根据权利要求1的化合物。
8.根据权利要求7的药物组合物,其中R1是H。
9.根据权利要求7的药物组合物,其中R5是C1-C10烷基、环烷基、烯基、芳基、芳烷基、或烷芳基。
10.根据权利要求7的药物组合物,其中R3是-H或-CH3。
11.根据权利要求7的药物组合物,其中R4是正-C6-C8烷基。
13.一种在动物或人受试者内治疗癌症的方法,包括给所述受试者施用有效量的根据权利要求7的药物组合物。
14.权利要求13的方法,其中该受试者是人。
15.权利要求13的方法,其中该受试者是动物。
16.权利要求14的方法,其中该药物组合物包括选自下列的化合物:
18.一种在动物或人受试者内抑制脂肪酸合酶活性的方法,包括给所述受试者施用有效量的根据权利要求7的药物组合物。
19.权利要求18的方法,其中该受试者是人。
20.权利要求18的方法,其中该受试者是动物。
21.一种在动物或人受试者内抑制侵入性微生物细胞生长的方法,包括给所述受试者施用有效量的根据权利要求7的药物组合物。
22.权利要求21的方法,其中该受试者是人。
23.权利要求21的方法,其中该受试者是动物。
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