CN101506186A - 取代的n-酰基高丝氨酸内酯 - Google Patents
取代的n-酰基高丝氨酸内酯 Download PDFInfo
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- CN101506186A CN101506186A CNA2007800279728A CN200780027972A CN101506186A CN 101506186 A CN101506186 A CN 101506186A CN A2007800279728 A CNA2007800279728 A CN A2007800279728A CN 200780027972 A CN200780027972 A CN 200780027972A CN 101506186 A CN101506186 A CN 101506186A
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- General Chemical & Material Sciences (AREA)
- Transplantation (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
取代的N-酰基高丝氨酸内酯具有式(I)及其任何对映异构体,其中R是含有5-14个碳原子的饱和或不饱和的直链或支链脂肪烃基;R2是H或1-4C烷基;R3是H或F。与已知的N-酰基高丝氨酸内酯相比,这些化合物表现免疫抑制剂活性同时还表现减少的生物传感体(自诱导物)活性。
Description
本发明涉及取代的N-酰基高丝氨酸内酯。更具体地说,其涉及某些表现免疫抑制剂活性同时还表现生物传感体(biosensor)(自诱导物)活性减少的取代N-酰基高丝氨酸内酯。本发明还涉及包含此取代的N-酰基高丝氨酸内酯作为有效成分的药物组合物。
免疫抑制剂化合物诱导免疫应答系统的抑制。已知的表现免疫抑制剂活性的化合物包括真菌代谢物环孢霉素A和被称为FK506的大环内酯类抗生素(产自筑波链霉菌(Streptomyces tsukabaensis)的代谢物)。在移植和许多疾病的治疗中,这两种药物在临床上和实验上已被用于抑制免疫系统。
自身免疫性疾病是主体“自身”与“非自身”的辨别受到破坏和个体的免疫系统(获得性的和先天的组分)攻击自身组织的疾病。这些疾病范围从常见的实体例如类风湿性关节炎、甲状腺自身免疫性疾病和1型糖尿病至较少见的实体例如多发性硬化以及至更罕见的病症例如重症肌无力。基础生物医学科学尤其免疫学的研究进展已显示:造成诱导和持续大多数自身免疫性疾病的主要和基本的损害存在于自身反应增殖的T淋巴细胞中。事实上,大多数自身免疫性疾病与T细胞稳态的损失有关。健康免疫系统的均衡的平衡明显由T辅助性1(Th1)和T辅助性2(Th2)淋巴细胞亚群的细胞因子的反抑制产物维持。在自身免疫中,Th1细胞因子起主导作用;在变态反应中,Th2细胞因子取而代之。细胞因子与偏向Th1的应答的发展密切相关,因此,自身免疫性疾病是TNF-α。
环孢霉素A和FK506已被临床应用在自身免疫性疾病的治疗中并具振奋人心的结果。
目前可用的免疫抑制剂药物具有狭窄的治疗指数(即毒性对临床疗效)的缺点。这些化合物已知具有肾毒性、神经毒性和潜在的致糖尿病性,而这已限制它们在以上提及的领域中的应用。问题还与这些化合物的给药、其生物利用率及其在临床上和实验室中水平的监控并存。
N-酰基高丝氨酸内酯是已知的。WO 92/18614公开具有下式的化合物
其中n是2或3;Y是O、S或NH;X是O、S或NH,而R是任选的取代的C1-C12烷基或酰基。在此文献的这些化合物公开作为自诱导物和控制基因表达的药剂。天然的自诱导物是微生物在代谢中产生的化合物,其随后起提高微生物基因表达的作用。在WO92/18614公开的同一系列的化合物在Journal of Bacteriology,第175卷,第12期,1993年6月,第3856-3862页也被提及,但也未曾教导它们可能在微生物以外具有的任何效果。
G.Papaccio,Diabetes Res.Clin.Pract.,第13卷,第1期,1991,第95-102页,公开了N-乙酰基高半胱氨酸硫代内酯作为超氧化物歧化酶的增强子用于尝试提高对抗化学诱导的糖尿病的保护作用。
使用N-乙酰基高半胱氨酸硫代内酯修饰IgE分子是由J.Ljaljevic等在Od.Med.Nauka,第24卷,1971,第137-143页和ChemicalAbstracts,第78卷,第7期,1973年2月,摘要No.41213a中教导。然而,在这篇论文中没有免疫抑制的建议。
US-A-5,591,872公开了化合物N-(3-氧代十二酰)高丝氨酸内酯作为绿脓杆菌(Pseudomonas aeruginosa)的自诱导物分子。在“Infectionand Immunity”,第66卷,第1期,1998年1月中,作者报道了N-(3-氧代十二酰)高丝氨酸内酯(OdDHL)在抑制伴刀豆球蛋白A促细胞分裂原(concavalin A mitogen)刺激的鼠脾细胞的增殖和LPS刺激粘附鼠腹腔巨噬细胞的TNF-α产生的作用。
在WO 95/01175中,与先前在WO 92/18614中公开的化合物相关的一类化合物被描述为表现抗变态反应活性和抑制组胺释放。
WO 01/74801公开了免疫抑制剂N-酰基高丝氨酸内酯的新亚类。可用下式表示的这些化合物和其任何对映异构体被报道在有生命的动物体内能够调节免疫应答,
其中R是下式的酰基
其中R1和R2之一是H而另一个选自OR4、SR4和NHR4,其中R4是H或1-6C烷基,或R1和R2与它们所连接的碳原子一起形成酮基,而R3是含有8-11个碳原子的直链或支链、饱和或不饱和的脂肪烃基并任选被一个或多个选自卤素、1-6C烷氧基、羧基、1-6C烷氧羰基、在N原子由1-6C烷基任选单取代或双取代的氨基甲酰和NR5R6的取代基取代,其中各R5和R6选自H和1-6C烷基或R5和R6与N原子一起形成吗啉代基或哌嗪1基。特别地,它们对人类淋巴细胞增殖具有抑制作用并下调单核细胞/巨噬细胞的TNF-α分泌,由此激活人类Th1淋巴细胞。在现有技术公开的所有这些N-酰基高丝氨酸内酯具有生物传感体活性,该活性是同时具有抗增殖活性的化合物的缺点。寻找与OdDHL有关的、具有相容的免疫调节特性却具有表现生物传感体活性降低的优点的化合物已成为该领域研究人员的目标。发明者相信目前已经发现此类化合物。
因此,本发明在第一方面提供式I化合物及其任何对映体
其中R1是含有5-14个碳原子的饱和或不饱和、直链或支链脂肪烃基;R2是H或1-4C烷基;R3是H或F。
上式I中基团R1是含有5-14C碳原子的饱和或不饱和的、直链或支链脂肪族烃基。例如,R1可以是直链或支链的5-14C烷基或直链或支链的5-14C链烯基或5-14C链炔基。优选地,R1是含有5-14个碳原子的直链烷基。此烷基的具体实例包括戊基、己基、庚基、辛基、壬基和癸基。根据本发明特别优选的实施方案,基团R1是正辛基。
上式I中基团R2选自包含H和1-4C烷基的基团。可由上式I的R2表示的1-4C烷基的实例包括甲基、乙基、丙基、异丙基正丁基和异丁基。优选本发明的R2是H或者是甲基。
上式I中基团R3选自H和氟。显然当式I的R3是氟基时,在氟基所连接的碳原子处将存在附加的手性中心。本发明涉及所述化合物的单独对映异构体结构形式和外消旋混合物。
本发明优选的化合物具有上式I,其中基团R1是正辛基,基团R2是H或甲基而基团R3是H或氟。本发明优选化合物的具体实例是N-(4-氮杂-3-氧代十二酰)-L-高丝氨酸内酯、N-(4-甲基-4-氮杂-3-氧代十二酰)-L-高丝氨酸内酯和N-(4-氮杂-2-氟-3-氧代十二酰)-L-高丝氨酸内酯。
一般而言,本发明的化合物可以通过将具有式R1R2NC(O)CHR3C(O)OH的取代羧酸(其中R1、R2和R3在以上定义)与N,N’-羰基二咪唑反应然后将N-酰基咪唑中间体与L-高丝氨酸内酯(通常作为盐酸盐)反应来制备。
在上述制备中描述为原料的羧酸,其自身可通过将胺R1R2NH与任选取代的丙二酸的乙酯的反应获得,以形成随后可被水解为羧酸的所需取代羧酸的乙酯。例如,我们已发现上式的取代羧酸,其中R3是H,可通过将胺R1R2NH与氯甲酰乙酸乙酯应然后将所得的乙酯水解成酸来简单制备。在其中基团R3是氟基的例子中,我们已发现通过胺R1R2NH和2-氟丙二酸二甲酯之间的反应我们可高产获得所需的取代羧酸的乙酯。
本发明的化合物已作为药物有效成分用在患有与免疫抑制剂活性相关的疾病或紊乱的个体治疗中。与OdDHL相比,本发明的化合物在抑制淋巴细胞增殖和TNF-α产生的同时,并表现自诱导物活性减少。因此,这些化合物可用来调节个体的免疫系统,例如用于治疗自身免疫性疾病。可通过施用有效剂量的本发明化合物来治疗的自身免疫性疾病具体实例包括:牛皮癣、多发性硬化和类风湿性关节炎。当然,对需要治疗的个体所施用的剂量会取决于所用的实际有效化合物、给药的方式、所需的治疗类型以及个体的身重。有效化合物可以以其自身或以合适的药物组合物的形式给药,所述药物组合物含有:例如合适的药用载体、赋形剂或稀释剂。其他的物质也可用于所述的药物组合物,例如抗氧化剂和稳定剂,其用途为本领域技术人员所熟知。
实施例
实施例1
N-(4-氮杂-3-氧代十二酰)-L-高丝氨酸内酯(4-氮杂-OdDHL)的合成步骤1.4-氮杂-3-氧代十二酸乙酯
在15分钟内逐滴地将氯甲酰乙酸乙酯(50.77mmol,6.5ml)加入冰冷搅拌的正辛胺(101.54mmol,13.12g)的无水二氯甲烷溶液(75ml)中,并进一步搅拌1小时。随后用饱和碳酸氢钠(3×20ml)、2M HCl(3×20ml)和饱和的氯化钠溶液(1×20ml)洗涤溶液。用MgSO4干燥并旋转蒸发有机溶剂,获得为白色固体的4-氮杂-3-氧代十二酸乙酯(8.5g,69%)。
TLC Rf 0.43,乙酸乙酯-正己烷(1:1)
1H NMR(250MHz,CDCl3)δ 0.93(3H,t,J6.0Hz,(CH3(CH2)7),1.07-1.77(13H,m,CH3(CH2)5和OCH2CH3),1.48(2H,m,CH3(CH2)5CH2),3.23(2H,t,J7.5Hz,CH3(CH2)6CH2),3.30(2H,s,COCH2COO),4.23(2H,q,J7.5Hz,OCH2CH3),7.71(1H,br s,NH).
步骤2.4-氮杂-3-氧代十二酸
将NaOH(8.75mmol,350mg)的水溶液(50ml)加入搅拌的4-氮杂-3-氧代十二酸乙酯(7.5mmol,1.81g)的乙醇(50ml)溶液中,并在室温下继续搅拌16小时。旋转蒸发此混合物去除乙醇。将残留物再溶解于水中并用乙酸乙酯洗涤。然后用2M HCl(pH1)酸化。产物4-氮杂-3-氧代十二酸用二氯甲烷(4×15ml)萃取。用MgSO4干燥并旋转蒸发二氯甲烷后,获得为白色固体的4-氮杂-3-氧代十二酸(1.35g,84.3%)。
1H NMR(250MHz,CDCl3)δ 0.9(3H,t,J6.15Hz,CH3(CH2)7),1.3(10H,m,CH3(CH2)5),1.54(2H,m,CH3(CH2)5CH2-),3.3(2H,J 6.4,CH3(CH2)6CH2),3.37(2H,s,COCH2CO),7.19(1H,s,NH),10.64(1H,s,COOH).
步骤3.N-(4-氮杂-3-氧代十二酰)-L-高丝氨酸内酯(4-氮杂-OdDHL)
先后将N,N’-羰基二咪唑(5.02mmol,943mg)、三乙胺(5.74mmol,0.8ml)和L-高丝氨酸内酯盐酸盐加入搅拌的4-氮杂-3-氧代十二酸(5.74mmol,1.23g)的无水二氯甲烷溶液(40ml)。将混合物在室温下搅拌过夜,然后进行溶剂旋转蒸发。将残留物再溶解于乙酸乙酯(40ml)并用饱和的碳酸氢钠(2×25ml)、2M HCl(3×25ml)和盐水(1×25ml)洗涤溶液。用MgSO4干燥并真空除去溶剂后,通过PLC使用正乙烷-乙酸乙酯(1:4)溶剂体系纯化所分离的产物4-氮杂-OdDHL(676mg,39.5%)。
TLC Rf 0.23,乙酸乙酯-正乙烷(4:1)
IR(KBr)3293(NH),1771(环C=O),1685(3-酰胺C=O),1645(1-酰胺C=O)cm-1
1H NMR(250MHz,CDCl3)δ 0.9(3H,t,J 6.5Hz,CH3(CH2)7),1.27(10H,m,CH3(CH2)5),1.5(2H,br,CH3(CH2)5CH2)2.34(1H,dd,J 9.9和1.5Hz,环,4α-H),2.66(1H,ddd,J 2.0,3.8和6.8Hz,环,4β-H),3.22(2H,t,J6.6Hz,CH3(CH2)6CH2),3.28(2H,s,COCH2CO),4.23(1H,ddd,J 3.0,4.4和6.3Hz,环,3H),4.49(1H,dd,J 7.65和1.3Hz,环,5α-H),4.6(1H,ddd,J 2.3,4.9和8.7Hz,环,5β-H),7.14(1H,br t,4-NH),8.2(1H,d,J 6.8Hz,NH-HSL).
ES-MSm/z 299.13(M+H,C15H26N2O4需要m/z 298),321.11(M+Na).
实施例2
N-(4-氮杂-4-甲基-3-氧代十二酰)-L-高丝氨酸内酯(4-氮杂-4-甲基-OdDHL)的合成
步骤1.4-氮杂-4-甲基--3-氧代十二酸乙酯
重复在以上实施例1的步骤1中描述的方法,除了使用N-甲基正辛胺代替正辛胺。经过二乙醚重结晶获得为半固体的标题产物(97%)。
TLC Rf 0.5,乙酸乙酯-正乙烷(1:1)
1H NMR(250MHz,CDCl3)δ 0.87(3H,t,J 6.7Hz,(CH3(CH2)7),1.26-1.32(13H,m,CH3(CH2)5和OCH2CH3),1.55(2H,s(宽的),CH3(CH2)5CH2),2.94,2.98(3H,2 x s,NCH3),3.24(1H,dd,J 1.9和7.6Hz,CH3(CH2)6CH(H)),3.39(1H,ddd,J 1.9,5.6和7.6Hz,CH3(CH2)6CH(H)),3.44(2H,s,COCH2COO),4.2(2H,两q(重叠),OCH2CH3).
步骤2.4-氮杂-4-甲基-3-氧代十二酸
根据在以上实施例1步骤2中描述的用于4-氮杂-3-氧代十二酸乙酯的方法,用NaOH(5.7mmol,226mg)溶液皂化4-氮杂-4-甲基-3-氧代十二酸乙酯(4.85mmol,1.246g)。获得为白色固体的产物4-氮杂-4-甲基-3-氧代十二酸(1.03g,93%)。
1H NMR(250MHz,CDCl3)δ 0.89(3H,t,J 6.0Hz,(CH3(CH2)7),1.3(10H,m,CH3(CH2)5),1.58(2H,br s,CH3(CH2)5CH2),3.03(3H,s,NCH3),3.24(2H,J7.6Hz,CH3(CH2)6CH2),3.42(2H,s,COCH2COO),10.15(1H,s,COOH).
步骤3.N-(4-氮杂-4-甲基-3-氧代十二酰)-L-高丝氨酸内酯(4-氮杂-4-甲基-OdDHL)
根据在实施例1步骤3中描述的方法,将4-氮杂-4-甲基-3-十二酸(3.9mmol,896mg)与盐酸L-高丝氨酸内酯(4.0mmol,550mg)连接。通过PLC在正乙烷-乙酸乙酯(1:4)中纯化标题产物4-氮杂-4-甲基-OdDHL(237mg,19.5%)。
TLC Rf-0.19,乙酸乙酯-正乙烷(4:1)
IR(KBr)3299(NH),1776(环C=O),1683(3-酰胺C=O),1654(1-酰胺C=O)cm-1
1H NMR(250MHz,CDCl3)0.88(3H,t,J 5.6Hz,(CH3(CH2)7),1.27(10H,m,CH3(CH2)5),1.53(2H,br s,CH3(CH2)5CH2),2.29(1H,dd,J 10.1和1.47Hz,环,4α-H),2.66(1H,dd,J 2.0和5.6Hz,环,4β-H),3.0(3H,2×s,NCH3),3.3(2H,t,J 7.72Hz,CH3(CH2)6CH2),3.38(2H s,COCH2CO),4.28(1H,dddd,1.49,3.19,4.05和6.1Hz,环,3H),4.48(1H,t,J 9.1Hz,环,5α-H),4.6(1H,dddd,J 1.5,2.6,4.5和7.2Hz,环,5β-H),8.84(1H,d,J 7.4Hz,NH-HSL).
ES-MS m/z 313.14(M+H,C16H28N2O4需要m/z 312),335.12(M+Na).
实施例3
4-氮杂-2-氟-3-氧代十二酰-L-高丝氨酸内酯(4-氮杂-2-F-OdDHL)
步骤1.4-氮杂-2-氟-3-氧代十二酸甲酯
室温下在1小时内将正辛胺(1mmol,166μl)的甲醇溶液(5ml)逐滴加入搅拌的2-氟丙二酸二甲酯(1mmol,150.11mg)的无水甲醇溶液(10ml)。然后在室温下进一步搅拌2小时。旋转蒸发溶液并用乙酸乙酯再溶解残留物。随后用2M HCl(2×10ml)和饱和的氯化钠(1×15ml)溶液洗涤乙酸乙酯溶液。用MgSO4干燥并旋转蒸发有机溶剂,获得双酰胺和4-氮杂-2-氟-3-氧代十二酸乙酯的混合物的白色固体。通过PLC在40-60石油醚-二乙醚(3:2)中纯化为白色固体的所需产物,(117mg,47%)。
TLC Rf 0.23,石油醚-二乙醚(3:2)
1H NMR(400MHz,CDCl3)δ 0.88(3H,t,J 6.4Hz,(CH3(CH2)7),1.29(10H,m,CH3(CH2)5),1.54(2H,br s,CH3(CH2)5CH2),3.32(2H,m,J 6.6Hz,CH3(CH2)6CH2),3.9(3H,s,OCH3),5.28(1H,d,J 49.2,C(H)F),6.42(1H,s,NH).
步骤2.4-氮杂-2-氟-3-氧代十二酸
将NaOH(0.28mmol,11.2mg)的水溶液(5ml)加入搅拌的4-氮杂-2-氟-3-氧代十二酸甲酯(0.28mmol,70mg)的甲醇(15ml)溶液中,并在室温下进一步搅拌2小时。旋转蒸发此混合物去除甲醇。将残留物再溶解于水(25ml)并用乙酸乙酯洗涤水溶液。然后用2M HCl(pH1)酸化。在乙酸乙酯(3×15ml)中萃取产物4-氮杂-2-氟-3-氧代十二酸。用MgSO4干燥并旋转蒸发乙酸乙酯,获得为白色固体的4-氮杂-2-氟-3-氧代十二酸(64mg,99%)。
1H NMR(400MHz,CDCl3)δ 0.9(3H,t,J 6.6Hz,(CH3(CH2)7),1.31(10H,m,CH3(CH2)5),1.60(2H,m,CH3(CH2)5CH2),3.4(2H,J 6.8Hz,CH3(CH2)6CH2),5.3(1H,d,J 47.2Hz,C(H)F),6.7(1H,s,NH),7.3(1H,br s,COOH)
步骤3.4-氮杂-2-氟-3-氧代十二酰-L-高丝氨酸内酯(4-氮杂-2-F-OdDHL)
先后将1,1’-羰基二咪唑(0.3mmol,49mg)、三乙胺(0.3mmol,42μl)和盐酸L-高丝氨酸内酯(0.3mmol,42mg)加入搅拌的4-氮杂-2-氟-3-氧代十二酸(0.28mmol,64mg)的无水二氯甲烷溶液(20ml)。将此混合物在室温下搅拌过夜,然后进行溶剂旋转蒸发。将残留物再溶解于乙酸乙酯(30ml)中。用饱和的碳酸氢钠(2×20ml)、1M KHSO4(2×20ml)和盐水(1×20ml)洗涤乙酸乙酯溶液。用MgSO4对其进行干燥并旋转蒸发溶剂。通过PLC在乙酸乙酯中纯化产物4-氮杂-2-甲基-OdDHL(8.2mg,10.4%)。
TLC Rf 0.32,乙酸乙酯
IR(KBr)3298(NH),1772(环C=O),1683(3-酰胺C=O),1653(1-酰胺C=O)cm-1
1H NMR(400MHz,CDCl3)0.89(3H,t,J 6.9Hz,(CH3(CH2)7),1.3(10H,m,CH3(CH2)5),1.56(2H,m,CH3(CH2)5CH2),2.27(1H,dd,J 8.97和2.3Hz,环,4α-H),2.80(1H,ddd,J 1.4,2.54和5.34Hz,环,4β-H),3.33(2H,m,CH3(CH2)6CH2),4.28(1H,dd,J 1.4和4.5Hz,环,3H),4.53(1H,m,环,5α-H),4.64(1H,ddd,J 2.64,2.94和4.14Hz,环,5β-H),5.3(1H,dd,J10.2和38.0Hz,CF(H)),6.63(1H,s,4-NH),7.5(1H,dd,J 13.3,6.4Hz,NH-HSL).
ES-MS m/z 317.12(M+H,C15H25FN2O4获得m/z 316),339.09(M+Na).
高丝氨酸内酯化合物的免疫调节活性
材料与方法
1.ConA促细胞分裂原刺激的鼠脾细胞增殖
用伴刀豆球蛋白A(Con A)细胞增殖测定来评价试验的高丝氨酸内酯(HSL)化合物对T细胞活化和增殖的效果。通过将[3H]-胸腺嘧啶脱氧核苷掺入DNA来评价增殖。从Harlan(Bicester,Oxon,UK)获得八周龄的雌性BALB/c小鼠并提供自由食物和水。通过切除脾并放置至RPMI 1640培养基中来制备脾细胞悬浮液。使用5ml注射器的柱塞迫使脾通过70μm孔径大小的金属丝网来制备单细胞悬浮液。离心沉淀细胞,并用0.017M Tris、0.144M氯化铵缓冲液pH7.2溶解红细胞。用含有2%(vol/vol)胎牛血清(FCS)的RPMI 1640培养基洗涤白细胞两次,并在由包含5% FCS、2mM L-谷氨酰胺和5 x 10-5M 2-巯基乙醇的RPMI 1640培养基组成的完全细胞培养基(CTCM)中再悬浮。将HSL化合物以1mM-0.1μM的范围在终体积为200μl的二倍递减CTCM稀释液中进行检测,所述CTCM稀释液含有1μg/ml Con A(Sigma,Poole,UK)和100,000个脾细胞。在37℃5%CO2-空气孵育48h后,加入补足在RPMI 1640培养基中的10μl 0.25μCi[3H]-胸腺嘧啶脱氧核苷(Amersham))并进一步孵育细胞24h。用Packardfiltermate收集器将细胞收集在玻璃纤维滤器上。向每个孔加入25μlMicroScint-O(Packard)后,用Packard TopCount闪烁计数器对滤器进行计数。
促细胞分裂原(伴刀豆球蛋白A)诱导的鼠脾细胞增殖是通过将氚标记的胸腺嘧啶脱氧核苷掺入DNA来指示,根据使用闪烁计数器的每分钟计数来显示。被试验的HSL化合物对细胞增殖的抑制效果通过每分钟计数的减少量来显示。
图1显示每分钟计数(CPM)对现有技术的化合物OdDHL和化合物N-(4-氮杂-3-氧代十二酰)-L-高丝氨酸内酯(4-氮杂-OdDHL)的浓度(微摩尔)所作的图。从此图可以看出,4-氮杂-OdDHL与OdDHL一样,抑制了脾细胞增殖。图2显示类似图1所作的图,不同之处在于,于此作出了获自OdDHL的图与获自化合物N-(4-甲基-4-氮杂-3-氧代十二酰)-L-高丝氨酸内酯(4-甲基-4-氮杂-OdDHL)的图的比较。如图2所示,化合物4-甲基-4-氮杂-OdDHL抑制了脾细胞增殖。图1和图2还显示了HSL化合物的自诱导物活性对HSL浓度(微摩尔)所作的图。
检测了4-氮杂-OdDHL、4-甲基-4-氮杂-OdDHL和化合物N-(2-氟-4-氮杂-3-氧代十二酰)-L-高丝氨酸内酯(2-氟-4-氮杂-OdDHL)的IC50值,即抑制50%鼠脾细胞群增殖所需的化合物剂量(微摩尔)。
还根据测量每种这些化合物在特别设计的细菌的生物报告体体系(bioreporter system)中诱导光产生的能力,测定了它们的自诱导物活性。自体诱导物(A.I.)活性通过受试的N-酰基高丝氨酸内酯化合物(AHL)在含有基于lux的生物发光报告质粒的大肠杆菌(E.coli)中诱导生物发光的能力来测量。使用含有(habour)报告质粒pSB1075的大肠杆菌(E.coli)JM109检测长链AHL,例如OdDHL。0此报告体含有绿脓杆菌(P.aeruginosa)的las R基因和并合至(fuse)来自发光假单胞菌(P.luminescens)的luxCDABE的lasl启动子,并优先地应答具有长为10-14碳的酰基链的AHL。
生物测定在96孔微量滴定板中进行。简而言之,将10μl待评价的化合物置于微滴定孔板中,并用LB培养基系列稀释以产生100μM-100fM范围的浓度。对合成的OdDHL进行相同的稀释并作为阳性对照使用。向每个孔加入100微升过夜的生物传感体菌株,于37℃下孵育4小时后测定光发射。在经校准以测量生物发光的Perkin Elmer TopCount仪器上根据每秒计数评价光的产生。数值表示为将生物报告体在37℃下暴露于OdDHL4小时后测定的生物发光的百分比。对合成OdDHL的稀释液的范围的对数回归分析通常返回0.96以上的可决系数值。
获得于试验化合物和OdDHL的IC50(μM)和A.I.活性(10μM)值如下表所示。
名称 | 结构 | IC50 *(μM) | AI活性**(10μM) |
4-氮杂-OdDHL | 17.1 | 2.8% | |
2-氟-4-氮杂-OdDHL | 21.8 | 19.9% | |
4-甲基-4-氮杂-OdDHL | 14.6 | 23.2% | |
OdDHL | 12.7 | 100.0% |
*IC50=抑制50%鼠脾细胞群增殖所需的化合物剂量。使用作为增殖标记的[3H]-胸腺嘧啶脱氧胸苷掺入测量并通过非线性回归分析确定。所有可决系数值都超过0.98。
**自诱导物活性是化合物在特别设计的细菌生物报告体体系中诱导光产生的能力的度量。数值表示为在细菌于37℃下暴露在OdDHL中4小时后所测量的生物发光的百分比。
Claims (9)
2.权利要求1的化合物,其中R1是含有5-14个碳原子的直链烷基。
3.权利要求2的化合物,其中R1是正辛基。
4.权利要求1-3中任一项化合物,其中基团R2选自H或甲基。
5.权利要求1的化合物,所述化合物是N-(4-氮杂-3-氧代十二酰)-L-高丝氨酸内酯。
6.权利要求1的化合物,所述化合物是N-(4-甲基-4-氮杂-3-氧代十二酰)-L-高丝氨酸内酯。
7.权利要求1的化合物,所述化合物是N-(4-氮杂-2-氟-3-氧代十二酰)-L-高丝氨酸内酯。
8.药物组合物,其包括作为有效成分的权利要求1-7中任一项的化合物和一种或多种可药用载体、赋形剂或稀释剂。
9.制备式I化合物及其任何对映异构体的方法,
其中R1是含有5-14个碳原子的饱和或不饱和的直链或支链脂肪烃基;R2是H或1-4C烷基;R3是H或F,所述的方法包括:将具有式R1R2NC(O)CHR3C(O)OH的取代羧酸与N,N’-羰基二咪唑反应,然后将N-酰基咪唑中间体与L-高丝氨酸内酯反应,其中R1、R2和R3为如上所定义。
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CN103980233A (zh) * | 2013-02-08 | 2014-08-13 | 中国人民解放军军事医学科学院毒物药物研究所 | 一种高丝氨酸内酯类衍生物、其制备方法和用途 |
CN104529802A (zh) * | 2014-12-13 | 2015-04-22 | 西安近代化学研究所 | 一种合成n,n′-双取代氟代丙二酰胺化合物的方法 |
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CN104496737B (zh) * | 2014-12-13 | 2017-12-22 | 西安近代化学研究所 | 一种合成α‑胺甲酰基氟乙酸酯化合物的方法 |
WO2017058757A1 (en) | 2015-10-01 | 2017-04-06 | The University Of Toledo | Use of acyl-homoserine lactone derivatives as anti-thrombotic agents |
CN110003148B (zh) * | 2019-04-29 | 2023-03-24 | 安徽安力肽生物科技有限公司 | 一种高丝氨酸内酯盐酸盐的制备方法 |
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CN102757437B (zh) * | 2012-06-12 | 2014-10-15 | 中国科学院化学研究所 | 酞菁纳米棒阵列薄膜及其制备方法与应用 |
CN103980233A (zh) * | 2013-02-08 | 2014-08-13 | 中国人民解放军军事医学科学院毒物药物研究所 | 一种高丝氨酸内酯类衍生物、其制备方法和用途 |
CN103980233B (zh) * | 2013-02-08 | 2017-07-04 | 中国人民解放军军事医学科学院毒物药物研究所 | 一种高丝氨酸内酯类衍生物、其制备方法和用途 |
CN104529802A (zh) * | 2014-12-13 | 2015-04-22 | 西安近代化学研究所 | 一种合成n,n′-双取代氟代丙二酰胺化合物的方法 |
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