CN115232184B - 呋喃核糖基吡啶衍生物及其药物组合物和用途 - Google Patents
呋喃核糖基吡啶衍生物及其药物组合物和用途Info
- Publication number
- CN115232184B CN115232184B CN202111478725.8A CN202111478725A CN115232184B CN 115232184 B CN115232184 B CN 115232184B CN 202111478725 A CN202111478725 A CN 202111478725A CN 115232184 B CN115232184 B CN 115232184B
- Authority
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- China
- Prior art keywords
- acid
- compound
- enyl
- alkyl
- alkenyl
- Prior art date
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Abstract
本发明属于药物领域,具体涉及呋喃核糖基吡啶衍生物及其药物组合物和用途。本发明提供一种如下式I所示的化合物,其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物或其前药,其具有非常优异的抗肿瘤活性,对于治疗肿瘤疾病具有重要意义。
Description
技术领域
本发明属于药物领域,具体涉及呋喃核糖基吡啶衍生物及其药物组合物和用途。
背景技术
烟酰胺核糖(NR)是维生素B3的一种衍生物,可以与磷酸、腺嘌呤形成烟酰腺嘌呤二核苷酸(NAD,也称辅酶I)和烟酰胺腺嘌呤二核苷酸磷酸(NADP,也称辅酶II),是一种主要辅酶NAD+的前体。烟酰胺腺嘌呤二核苷酸是一种传递质子的辅酶,它出现在细胞很多代谢反应中,参与蛋白质、碳水化合物和脂肪等化合物的分解,如:亮氨酸脱氢酶、甲酸氨脱氢酶、葡萄糖脱氢酶催化的手性还原都需要烟酰胺腺嘌呤二核苷酸的帮助来完成整个反应,氧化反应亦是如此,随着细胞的衰老或者病变,烟酰胺腺嘌呤二核苷酸的数量就会减少。
烟酰胺核糖及其衍生物的生物学功能是目前生物学和医学研究的热点之一,其在肥胖、听力损伤、老年性神经退行性病变如阿尔兹海默症、帕金森等疾病中有保护作用,可改善认知减退,并且烟酰胺核糖应用在制备治疗非酒精性脂肪肝炎的药物中,可以有效降低动物模型的肝脏脂质含量、肝脏炎症等。
发明内容
本发明提供一种如下式I所示的化合物,其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物或其前药:
其中,R1、R2、R3相同或不同,彼此独立地选自C1-22烷基或C2-22烯基,优选地,R1、R2、R3中至少一个为C7-22烷基或C7-22烯基,例如C7-12烷基、C20-22烷基、C7-12烯基或C20-22烯基;
A-选自药学上可接受的阴离子,例如R4COO-或卤素阴离子;
R4选自C1-22烷基或C2-22烯基,优选C7-22烷基或C7-22烯基,例如C7-12烷基、C20-22烷基、C7-12烯基或C20-22烯基。
根据本发明的实施方案,R1、R2、R3相同或不同,彼此独立地选自C7-22烷基;例如为C7-12烷基或C20-22烷基;优选地,R1、R2、R3中至少一个为C7-12烷基或C20-22烷基;A-选自R4COO-或卤素阴离子,其中R4选自C7-12烷基或C20-22烯基。
根据本发明的实施方案,R1、R2、R3相同或不同,彼此独立地选自C7-14烷基,例如庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基或十四烷基。
根据本发明优选的实施方案,R1、R2、R3中的至少一个,更优选两个或三个基团选自癸基。
根据本发明示例性的技术方案,A-选自R4COO-或Cl-;优选地,R4选自C7-14烷基,例如庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基或十四烷基。
根据本发明的实施方案,式I所示的化合物具有下式II所示的结构:
其中,R1、R2、R3、A-彼此独立地具有上文所述的定义。
根据本发明示例性的实施方案,式I所示的化合物具有下式III所示的结构:
本发明还提供式I所示化合物,其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物或其前药的制备方法,包括以下步骤:式a所示的化合物与R1-C(O)-Y、R2-C(O)-Y和/或R3-C(O)-Y反应得到式I所示的化合物;
其中,R1、R2、R3、A-彼此独立地具有上文所述的定义;
Y选自离去基团,例如为卤素。
根据本发明的实施方案,所述反应可以在有机碱的存在下进行;所述有机碱可以选自三乙胺、吡啶、DIPEA、DMAP、DBU中的至少一种。
本发明还提供一种药物组合物,其包含式I所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物或其前药化合物中的至少一种。
本发明还提供一种药物组合物,其包含治疗有效量的式I所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物或其前药化合物中的至少一种。
根据本发明的实施方案,所述药物组合物还包括至少一种药学上可接受的辅料。
可按药剂领域中熟知的方式制备这些药物组合物,可通过多种途径给予它们,这取决于是否需要局部或全身治疗和所治疗的区域。可局部(例如,透皮、皮肤、眼和粘膜包括鼻内、阴道和直肠递药)、肺(例如,通过吸入或吹入粉末或气雾剂,包括通过喷雾器;气管内、鼻内)、口服或肠胃外给药。肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注;或颅内例如鞘内或脑室内给药。可按单次大剂量形式肠胃外给药,或可通过例如连续灌注泵给药。局部给予的药用组合物和制剂可包括透皮贴剂、软膏、洗剂、霜剂、凝胶剂、滴剂、栓剂、喷雾剂、液体剂、粉末制剂和散剂。常规药物载体、水、粉末或油性基质、增稠剂等可能是必须的或需要的。
在制备本发明的药物组合物时,通常将活性成分与辅料混合,通过辅料稀释或装入例如胶囊、小药囊、纸或其它容器形式的这种载体内。当辅料用作稀释剂时,它可以是固体、半固体或液体物质,用作溶媒、载体或活性成分的介质。因此,所述药物组合物可以是以下形式:片剂、丸剂、散剂、锭剂、小药囊、扁囊剂、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂(固体或溶于液体溶媒);含例如高达10%重量活性化合物的软膏剂、软和硬明胶胶囊、栓剂、无菌注射溶液和无菌包装粉末。
适宜的辅料的某些实例包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。所述辅料还可选自:润滑剂例如滑石粉、硬脂酸钠、硬脂酸镁、油酸钠、苯甲酸钠、乙酸钠、氯化钠和矿物油;湿润剂;乳化剂和悬浮剂;防腐剂例如苯甲酸甲酯和苯甲酸羟基丙酯;甜味剂和矫味剂。可通过使用本领域中已知的方法配制本发明组合物,以便在给予患者后提供速释、缓释或延迟释放活性成分的作用。
可按单位剂型配制组合物,每一剂量含约5~1000mg,更通常约100~500mg活性成分。术语“单位剂型”是指物理上分离的适宜作为用于人患者和其它哺乳动物的单一剂量单位,各单位含有与适宜的药物赋形剂混合的经计算可产生所需疗效的预定量的活性物质。
活性化合物的有效剂量的范围可很大,通常按药用有效量给药。但是,可以理解实际给予的化合物的量通常由医师根据相关情况决定,它们包括所治疗的病症、所选择的给药途径、所给予的实际化合物;患者个体的年龄、重量和反应;患者症状的严重程度等。
对于制备固体组合物例如片剂,将主要的活性成分与药物赋形剂混合,形成含本发明化合物的均匀混合物的固体预制剂组合物。当称这些预制剂组合物为均匀时,是指活性成分通常均匀地分布在整个组合物中,致使该组合物可容易地划分为同等有效的单位剂型例如片剂、丸剂和胶囊剂。然后将该固体预制剂划分为上述类型的含例如约0.1~1000mg本发明活性成分的单位剂型。
可将本发明的片剂或丸剂包衣或复合,得到提供长效作用优点的剂型。例如,片剂或丸剂含内剂量和外剂量组分,后者是前者的被膜形式。可通过肠溶层将两种组分隔离,肠溶层用于在胃中阻止崩解,以使内组分完整通过十二指肠或延迟释放。多种物质可用于此类肠溶层或包衣剂,此类物质包括多种高分子酸和高分子酸与此类物质如虫胶、鲸蜡醇和醋酸纤维素的混合物。
其中可掺入本发明化合物和药物组合物,用于口服或注射给药的液体形式包括水溶液、适当矫味的糖浆剂、水或油混悬液;和用食用油例如棉子油、芝麻油、椰子油或花生油矫味的乳剂;以及酏剂和类似的药用溶媒。
用于吸入或吹入的药物组合物包括溶于药学上可接受的水或有机溶剂或其混合物的溶液剂和混悬液、散剂。液体或固体组合物可含有如上所述适宜的药学上可接受的赋形剂。在某些实施方案中,通过口服或鼻呼吸途径给予所述药物组合物,实现局部或全身作用。可通过使用呈惰性的气体,使组合物成雾化。可直接由雾化装置吸入雾化溶液,或雾化装置可与面罩帷或间歇正压呼吸机连接。可通过口服或由按适当方式递送制剂的装置通过鼻给予溶液、混悬液或粉末形式的药物组合物。
给予患者的化合物或药物组合物的量不固定,取决于给予的药物、给药的目的例如预防或治疗;患者的状态、给药的方式等。在治疗应用时,可给予已患疾病的患者足够治愈或至少部分抑制疾病及其并发症症状的量的组合物。有效剂量应取决于所治疗的疾病状态和主治临床医师的判断,该判断取决于例如疾病的严重程度、患者的年龄、体重和一般状况等因素。
给予患者的药物组合物可以是上述药用组合物形式。可通过常规灭菌技术或可过滤灭菌,将这些组合物灭菌。可将水溶液包装原样使用,或冻干,给药前,将冻干制剂与无菌水性载体混合。化合物制剂的pH通常为3~11,更优选5~9,最优选7~8。可以理解,使用某些前述赋形剂、载体或稳定剂会导致形成药物盐。
本发明化合物的治疗剂量可根据例如以下而定:治疗的具体用途、给予化合物的方式、患者的健康和状态,以及签处方医师的判断。本发明化合物在药用组合物中的比例或浓度可不固定,取决于多种因素,它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1~10%(w/v)该化合物的生理缓冲水溶液提供本发明化合物,用于肠胃外给药。某些典型剂量范围为约1μg/kg~约1g/kg体重/日。在某些实施方案中,剂量范围为约1mg/kg~约2000mg/kg体重/日,优选约50mg/kg~约500mg/kg体重/日。剂量很可能取决于此类变量,如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验系统导出的剂量-反应曲线外推,得到有效剂量。
本发明还提供式I所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物或其前药化合物在制备药物中的用途。
根据本发明的实施方案,所述药物用于预防和/或治疗肿瘤。
根据本发明的实施方案,所述肿瘤可以为癌,例如胶质瘤、乳腺癌、肝癌或肺癌,其实例可以选自胶质瘤细胞U87 MG、小细胞肺癌细胞NCI-H69、乳腺癌细胞MDA-MB-468、乳腺癌细胞MCF-7、肝癌细胞HuH7、三阴性乳腺癌细胞MM231。
本发明还提供式I所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物或其前药化合物,在治疗和/或预防肿瘤中的用途。
本发明还提供治疗和/或预防肿瘤疾病的方法,包括给予患者治疗或预防有效量的式I所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物或其前药化合物中的至少一种。
术语定义与说明
除非另有说明,本申请说明书和权利要求书中记载的基团和术语定义,包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等,可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当被理解为本申请说明书和/或权利要求书记载的范围内。
除非另有说明,本说明书和权利要求书记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如,数值范围“1-20”相当于记载了数值范围“1-20”中的每一个整数数值即1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20。
术语“卤素”表示氟、氯、溴和碘。
术语“C1-22烷基”应理解为表示具有1~20个碳原子的直链或支链饱和一价烃基,其也可称为“直链或支链的C1-22烷基”。例如,表示具有1、2、3、4、5、6、7、8、9、10、11、1、13、14、15、16、17、18、19、20、21或22个碳原子的直链和支链烷基。“C8-12烷基”表示具有8、9、10、11或12个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基、十九烷基、二十烷基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基壬基、1-甲基壬基、1-乙基辛基、1,2-二甲基辛基、新戊基、1,1-二甲基辛基、4-甲基壬基、3-甲基壬基、2-乙基辛基、3,3-二甲基辛基、2,2-二甲基辛基、2,3-二甲基辛基或1,3-二甲基辛基等或它们的异构体。
术语“C2-22烯基”应理解为优选表示直链或支链的一价烃基,其包含一个或多个双键并且具有2~22个碳原子,优选“C2-10烯基”。“C2-10烯基”应理解为优选表示直链或支链的一价烃基,其包含一个或多个双键并且具有2、3、4、5、6、7、8、9或10个碳原子,例如,具有2、3、4、5或6个碳原子(即,C2-6烯基),具有2或3个碳原子(即,C2-3烯基)。应理解,在所述烯基包含多于一个双键的情况下,所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
本发明的化合物可以溶剂合物(如水合物)的形式存在,其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂,特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
根据其分子结构,本发明的化合物可以是手性的,因此可能存在各种对映异构体形式。因而这些化合物可以以消旋体形式或光学活性形式存在。本发明的化合物涵盖了各手性碳为R或S构型的异构体或其混合物、消旋体。本发明的化合物或其中间体可以通过本领域技术人员公知的化学或物理方法分离为对映异构体化合物,或者以此形式用于合成。在外消旋的胺的情况中,通过与光学活性的拆分试剂反应,从混合物制得非对映异构体。适当的拆分试剂的示例是光学活性的酸,例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种光学活性的樟脑磺酸。借助光学活性的拆分试剂(例如固定在硅胶上的二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸酯聚合物),也可有利地进行色谱对映体拆分。用于此目的的适当的洗脱剂是含水或含醇的溶剂混合物,例如,己烷/异丙醇/乙腈。可以根据已知的方法,例如通过萃取、过滤或柱层析来分离相应的稳定异构体。
术语“药学上可接受的阴离子”包括其合适的酸根或阴离子,例如选自下列酸的酸根或阴离子:无机酸,如矿物酸,例如氢卤酸(如盐酸、氢溴酸和氢碘酸)、硫酸、磷酸硫酸盐、硫酸氢盐、半硫酸盐、硫氰酸盐、过硫酸盐和磺酸;有机羧酸,如具有取代(例如,被卤素取代)或未取代的1至22个碳原子的直链或支链烷基的羧酸,如乙酸、丙酸、丁酸、戊酸、己酸、辛酸、壬酸、癸酸、十一烷酸、十二烷酸、十三烷酸、十四烷酸或十五烷酸;具有取代(例如,被卤素取代)或未取代的2至22个碳原子的直链或支链烯基的羧酸,如丙烯酸、丁烯酸、戊烯酸、己烯酸、辛烯酸、壬烯酸、癸烯酸、十一烯酸、十二烯酸、十三烯酸、十四烯酸或十五烯酸;饱和或不饱和二羧酸,例如草酸、丙二酸、琥珀酸、马来酸、富马酸、邻苯二甲酸或四邻苯二甲酸;羟基羧酸,例如抗坏血酸、乙醇酸、乳酸、苹果酸、酒石酸或柠檬酸;用氨基酸,例如天冬氨酸或谷氨酸;苯甲酸;或有机磺酸,如取代(例如,通过卤素取代)或未取代的(C1-C4)-烷基-或芳基-磺酸,如甲烷-或对甲苯磺酸。
优选的酸根或阴离子可以选自下列酸的酸根或阴离子:例如乙酸、、丙酸、丁酸、戊酸、己酸、辛酸、壬酸、癸酸、十一烷酸、十二烷酸、十三烷酸、十四烷酸或十五烷酸、三氟乙酸、乳酸、葡萄糖酸、柠檬酸、酒石酸、马来酸、苹果酸、泛酸、己二酸、藻酸、天冬氨酸、苯甲酸、丁酸、二葡糖酸、环戊酸、葡庚糖酸、甘油磷酸、草酸、庚酸、己酸、富马酸、烟酸、棕榈酸酯、果胶酸、3-苯基丙酸、苦味酸、新戊酸、丙酸、酒石酸、乳糖酸、pivolate、樟脑酸和琥珀酸,有机磺酸如甲磺酸、乙磺酸、2-羟基乙烷磺酸、樟脑磺酸、2-萘磺酸、苯磺酸、对氯苯磺酸和对甲苯磺酸;和无机酸如酸、氢溴酸、氢碘酸、硫酸、硫酸氢、半硫酸、硫氰酸、过硫酸、磷酸和磺酸。
术语“同位素标记物”,表示本发明化合物中至少一个原子被同位素代替。所述同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素,如相应的2H、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F和36Cl。用同位素如氘(即2H)取代可以提供由更大的代谢稳定性,例如增加的体内半衰期或降低的剂量需求产生的某些治疗优势,因此在某些情况下可能是优选的。例如,本发明包括其中任一氢原子被氘原子代替的式I化合物。
术语“患者”是指包括哺乳动物在内的任何动物,优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物,最优选人。
术语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量,它包括以下一项或多项:(1)预防疾病:例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病:例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病:例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。治疗有效量最初可以由细胞培养测定来进行估计,也可以从体内数据估计初始剂量。使用这些初步指导,本领域普通技术人员可以确定人类的有效剂量。此外,也可以通过细胞培养物或实验动物中的标准药物程序来确定本文所述化合物的毒性和治疗功效,例如通过测定LD50和ED50。
有益效果
本发明化合物可用于治疗/预防肿瘤疾病,以及制备用于抗肿瘤的药物。所述化合物具有非常优异的抗肿瘤活性,对于治疗肿瘤疾病具有重要意义。
附图说明
图1实施例1中化合物NRTDA的1H NMR谱图。
图2实施例1中化合物NRTDA的MS谱图。
图3实施例1中化合物NRTDA的HPLC谱图。
图4实施例2中不同浓度的化合物NRTDA对不同癌细胞的抑制率图:(a)为对U87 MG的抑制率图;(b)为对NCI-H69的抑制率图;(c)为对MDA-MB-468的抑制率图;(d)为对MCF-7的抑制率图。
图5实施例2中不同浓度的化合物NR对不同癌细胞的抑制率图:(a)MDA-MB-468的抑制率图;(b)为对MCF-7的抑制率图。
图6实施例2中不同浓度的化合物NRTDA、NR和SD在不同作用时间内,分别对HuH7或MM231的OD 490nm处吸光值图(*P<0.05与对照组比较;**P<0.01与对照组比较;***P<0.001与对照组比较;****P<0.0001与对照组比较)。
图7实施例2中不同浓度的化合物NR和SD的组合对HuH7的OD 490nm处吸光值图(*P<0.05与单药组比较;**P<0.01与单药组比较;***P<0.001与单药组比较;****P<0.0001与单药组比较)。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
实施例1:1-((2R,3R,4S,5R)-3,4-二癸酰氧基-5-(癸酰氧甲基)四氢呋喃-2-基)-3-氨甲酰基吡啶-1-鎓氯化物(NRTDA)的制备
在10~15℃将癸酰氧(150g,786.54mmol,163.22mL,3.27eq)滴加到烟酰胺核糖氯化物(化合物NR,70g,240.80mmol,1eq)的吡啶(1L)溶液中。然后室温搅拌4小时,反应液直接过滤,减压浓缩。得到的残留物用快速硅胶柱层析法(洗脱剂:0-5%的甲醇/二氯甲烷)分离纯化,得到1-((2R,3R,4S,5R)-3,4-二癸酰氧基-5-(癸酰氧甲基)四氢呋喃-2-基)-3-氨甲酰基吡啶-1-鎓氯化物(化合物NRTDA,32g,41.52mmol,收率17.24%,纯度97.77%)呈橙黄的固体,表征谱图见图1-3。
MS m/z(ESI):717.7;
1H NMR:EB5107-1-P1A(400MHz,DMSO-d6)δ9.62(s,1H),9.18-9.37(m,2H),9.02(s,1H),8.37-8.49(m,1H),8.24(s,1H),6.69(d,J=3.38Hz,1H),5.67(dd,J=3.75,5.50Hz,1H),5.47(t,J=5.88Hz,1H),4.63-4.72(m,1H),4.39-4.57(m,2H),2.23-2.46(m,6H),1.49-1.58(m,6H),1.15-1.35(m,36H),0.80-0.91(m,9H)。
实施例2:细胞活性测试
测试不同化合物(NRTDA、NR和/或葵酸钠(SD))分别对胶质瘤细胞U87MG、小细胞肺癌细胞NCI-H69、乳腺癌细胞MDA-MB-468、乳腺癌细胞MCF-7、肝癌细胞HuH7、三阴性乳腺癌细胞MM231的抑制率。
(1)分别收集对数期胶质瘤细胞U87 MG、小细胞肺癌细胞NCI-H69、乳腺癌细胞MDA-MB-468、乳腺癌细胞MCF-7,调整细胞悬液浓度至5×104个/mL,每孔加入100ul,铺板使待测细胞调密度至5000个/孔,边缘孔用无菌PBS填充。
(2)5%CO2,37℃孵育,至细胞单层铺满孔底(96孔平底板),加入浓度梯度的药物,前一天下午铺板,次日上午加药。设置不同药物浓度梯度,每孔100ul,设4~6个复孔。同时设置调零孔(培养基、MTT、二甲基亚砜),对照孔(细胞、相同浓度的药物溶解介质、培养液、MTT、二甲基亚砜)。
NRTDA设置的浓度梯度为:5μM、10μM、20μM、40μM、80μM、160μM、320μM;NR+SD:NR设置的浓度梯度为:0、100μM、200μM、400μM和800μM,SD设置的浓度梯度为:0、300μM、600μM和1200μM。
(3)5%CO2,37℃孵育24小时,倒置显微镜下观察。
(4)每孔加入20ul MTT溶液(5mg/ml,即0.5%MTT),5%CO2,37℃培养箱继续培养4h。
(5)终止培养,小心吸去孔内培养液。
(6)每孔加入150ul二甲基亚砜,置摇床上低速振荡10min,使结晶物充分溶解。在酶联免疫检测仪OD 490nm处测量各孔的吸光值,计算得到抑制率。
测试组:化合物NRTDA分别对U87 MG、NCI-H69、MDA-MB-468、MCF-7的抑制率,结果如图4所示;
对照组:化合物NR分别对MDA-MB-468、MCF-7的抑制率,结果如图5所示;化合物NRTDA、NR和SD分别对HuH7或MM231的OD 490nm处吸光值图,结果如图6所示;化合物NR和SD的组合对HuH7的OD 490nm处吸光值,结果如图7所示。
以上结果表明,NRTDA在合适的浓度条件下,对多种肿瘤细胞具有明显的抑制作用;NR在100~800μM对肝癌细胞HuH7无毒性作用;SD在200~1200μM对肝癌细胞HuH7无毒性作用;NR与SD的组合对肝癌细胞HuH7无明显杀伤作用。因此,NRTDA具有非常明显的抗肿瘤活性,对于治疗肿瘤疾病具有重要意义。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (8)
1.下式II所示的化合物:
(II)
其中,R1、R2、R3为壬基;
A-选自药学上可接受的阴离子。
2.根据权利要求1所述的化合物,其特征在于,A-选自R4COO-或卤素阴离子;
R4选自C1-22烷基或C2-22烯基。
3.根据权利要求2所述的化合物,其特征在于,R4选自选自C7-22烷基或C7-22烯基。
4.根据权利要求2所述的化合物,其特征在于,R4选自选自C7-12烷基、C20-22烷基、C7-12烯基或C20-22烯基。
5.根据权利要求1所述的化合物,其特征在于,A-选自R4COO-或Cl-;R4选自庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基或十四烷基。
6.如权利要求1所述的化合物,其中式II所示的化合物具有下式III所示的结构:
7.药物组合物,其包含权利要求1-6任一项所述的式II所示的化合物中的至少一种。
8.权利要求1-6任一项所述的式II所示的化合物在制备药物中的用途;
所述药物用于预防和/或治疗胶质瘤、乳腺癌、肝癌或小细胞肺癌。
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