CN117327063B - 一种抗菌药物及其应用 - Google Patents
一种抗菌药物及其应用 Download PDFInfo
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- CN117327063B CN117327063B CN202311631274.6A CN202311631274A CN117327063B CN 117327063 B CN117327063 B CN 117327063B CN 202311631274 A CN202311631274 A CN 202311631274A CN 117327063 B CN117327063 B CN 117327063B
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Abstract
本发明涉及抗菌药物技术领域,尤其涉及一种抗菌药物及其应用。所述小檗碱衍生物具有通式结构(I)或(II)所示结构:(I);(II);本发明通过对小檗碱的多个结构片段进行了结构修饰和优化,使得优化后的小檗碱衍生物表现出较强的增敏临床抗生素的活性,其可作为潜在的抗菌增效剂,有望使多种耐药抗生素回归抗鲍曼治疗的一线,增加临床用药选择,具有广阔的应用前景。
Description
技术领域
本发明涉及抗菌药物技术领域,尤其涉及一种抗菌药物及其应用。
背景技术
鲍曼不动杆菌(Acinetobacter baumannii, Ab)是一种革兰氏阴性致病菌,广泛分布于自然界,可引起多种医院获得性和社区获得性感染,包括肺炎、尿路感染和手术部位感染等,常见于重症监护病房患者,医院鲍曼不动杆菌的检出率为85.1%至93.4%,病死率高达58.4%至79.8%,临床用药选择受到极大限制,且其对全球人民的生命健康造成巨大的威胁。鲍曼不动杆菌因其致病性强、耐药机制复杂以及具有多重耐药性被称为全球性“超级细菌”,多重耐药鲍曼不动杆菌(Multidrug-resistantAcinetobacter baumannii, MDR-Ab)占菌群总数的70–90%,其中,碳青霉烯类耐药鲍曼不动杆菌(Carbapenem-resistantAcinetobacter baumannii, CRAB)已被世界卫生组织(World Health Organization, WHO)列为对人类健康构成巨大威胁的关键优先病原体的首位。粘菌素类抗生素已经成为治疗鲍曼不动杆菌的“最后防线”,更为严重的是,已有粘菌素耐药的鲍曼不动杆菌出现,临床可能面临无药可用的困境。因此,为避免进入后抗生素时代,迫切需要开发全新的抗鲍曼候选物或抗菌佐剂。
目前全新化学骨架抗生素的研发周期漫长,临床需求与创新药物的研发之间的差距日渐增加,而联合用药治疗可延长临床抗菌药物的使用寿命,也可应对新抗菌药物研发困难的局势,是针对耐药、拓宽抗菌谱的有效策略。因此,研发增敏临床抗生素的全新佐剂有望解决临床鲍曼不动杆菌的严重耐药问题。
鲍曼不动杆菌产生抗生素耐药的主要机制包括:抗生素外排、产生降解或修饰抗生素的酶、与抗生素发生作用的位点产生突变及降低膜对于抗生素的渗透性,外排泵是能够调节细菌胞内的药物或毒性物质排出胞外的膜蛋白,外排泵抑制剂可以抑制耐药细菌对药物的外排,从而恢复其对抗生素的敏感性。近二十年里,外排泵抑制剂的发现和优化引起了人们的极大关注,然后由于安全性、药代性质等因素,目前针对抗生素耐药相关的外排泵抑制剂尚无药物上市,外排泵抑制剂的研究有待深入研究。其中,耐药结节化细胞分化家族(RND)中的外排泵AdeABC成为鲍曼不动杆菌耐药中的重要多药外排系统,在80%的临床分离的耐药鲍曼不动杆菌菌株中表达,介导对广谱抗菌药物的耐药性,包括β-内酰胺类、氟喹诺酮类、四环素、大环内酯和氯霉素等,AdeABC外排泵具有三组分结构,包括膜融合蛋白(AdeA)、外排蛋白(AdeB)及外膜通道蛋白(AdeC),AdeB捕获磷脂双分子层或细胞质内膜中的底物,之后通过AdeC运输底物。
氨曲南(ATM)是临床上唯一被FDA批准使用的单环β-内酰胺类抗生素,用于治疗革兰氏阴性菌感染。但是,β-内酰胺酶的产生和外排泵的过表达导致氨曲南对鲍曼不动杆菌的具有微弱的抗菌活性。因此,联合用药被认为是增强氨曲南抗鲍曼活性的有效途径,将为临床耐药菌感染提供更多的治疗选择。小檗碱(BBR)是一种来源于黄连、小檗、黄檀等植物异喹啉生物碱,具有较低的遗传毒性和致突变性,是治疗痢疾、肠炎等疾病的临床药物。研究证明,小檗碱与抗生素联合使用对多类细菌具有体外协同抑制活性,包括耐甲氧西林金黄色葡萄球菌、凝固酶阴性葡萄球菌及多药耐药肺炎克雷伯菌等,但目前小檗碱与抗生素联合的协同抗菌活性仍存在进一步改善空间。
鉴于此,特提出本发明。
发明内容
为了解决上述技术问题,本发明以小檗碱为先导物,以协同抗菌活性为导向,对小檗碱的多个结构片段进行了结构修饰和优化,优化后的小檗碱衍生物表现出较强的临床抗生素的增敏活性。
基于此,本发明的具体技术方案如下:
第一方面,本发明首先提供一种小檗碱衍生物,其具有通式结构(I)或(II)所示结构:
(I);/>(II);
其中,X代表氯或溴;Z代表O或NH;
R1选自-(CH2)n1C≡R、-CH2C≡CCH2CH3、-(CH2)n2CH=CH2、-CH2(CH2OCH2)n3C≡R或-CH3;
R2选自-(CH2)n4C≡R、-CH2C≡CCH2CH3、-(CH2)n2CH=CH2、-CH2(CH2OCH2)n3C≡R或-CH3;
R3、R4各自独立地选自-CH3或-(CH2)n1C≡R;
n1、n3各自独立地代表2~6的整数,n2代表3~6的整数,n4代表1~6的整数;R为C或N。
本发明发现,小檗碱中C环共轭结构及亚甲二氧基是其协同抗菌活性的必需基团,而在保留必需基团的同时对其通式结构中其他基团进行上述优化后,能够显著增强其协同抗菌的活性。
作为优选,所述小檗碱衍生物具有通式结构(II-1)~(II-3)任一所示结构:
(II-1);/>(II-2);
(II-3);
其中,其中,X代表氯或溴;
R1选自-(CH2)n1C≡R、-CH2C≡CCH2CH3、-(CH2)n2CH=CH2、-CH2(CH2OCH2)n3C≡R或-CH3;R2选自-(CH2)n4C≡R、-CH2C≡CCH2CH3、-(CH2)n2CH=CH2、-CH2(CH2OCH2)n3C≡R或-CH3;
n1、n3各自独立地代表2~6的整数,n2代表3~6的整数,n4代表1~6的整数;R为C或N。
作为优选,通式(II-3)中,R1为-(CH2)n1C≡R。
作为优选,所述小檗碱衍生物具有通式结构(II-4)、(II-5)以及(II-6)中任一所示结构:
(II-4);/>(II-5);
(II-6);
其中,n为5或6;R为C或N。
本发明进一步发现,所述小檗碱衍生物中R1与R2的碳链长度对其协同抗菌效果有一定影响,当将R1与R2的碳原子数为5或6时,能够进一步提升协同抗菌活性。
第二方面,本发明还提供上述小檗碱衍生物的制备方法,具体地,根据所述小檗碱衍生物种类的不同,其制备方法分为以下几种情况:
1)当所述小檗碱衍生物中R3、R4缩合成环(即具有通式结构(II)所示结构),而Z代表O,R2为CH3时,所述小檗碱衍生物的制备方法包括如下步骤:
将小檗碱盐酸盐在负压20~30 mmHg、195℃下反应30~50 min后得到深红色固体,而后用乙醇/浓盐酸进行酸化。真空浓缩有机相,残渣通过硅胶柱层析进一步分离纯化,以二氯甲烷和甲醇作为流动相,通过Flash快速柱色谱纯化,得到。将/>、无水乙腈、碳酸钾以及第一原料在65~80℃下反应,TLC监测反应进程,反应完全后,冷却至固体完全析出,抽滤,将滤液硅胶拌样,以二氯甲烷和甲醇作为流动相,通过Flash快速柱色谱纯化得到黄色固体。
根据产物的不同,所述第一原料对应性地包括4-溴-1-丁炔、7-溴庚炔、8-溴辛-1-炔、5-溴戊腈、6-溴己腈、7-溴庚腈、1-溴-2-戊炔、7-溴-1-庚烯、8-溴-1-辛烯、3-(2-(2-溴乙氧基)乙氧基)丙-1-炔、丙炔-三聚乙二醇-溴、1-溴-3,6,9,12-四氧杂十五碳-14-炔等。
相应地,本领域技术人员能够根据实际具体产物的不同选择第一原料制得所述小檗碱衍生物。
2)在通式结构(II)所示结构中,当Z代表NH时,所述小檗碱衍生物的制备方法包括如下步骤:
将小檗碱盐酸盐与第二原料在90~110℃下反应10~15h,反应结束后冷却至室温,有机相在真空下浓缩,用乙酸乙酯洗涤混合物,以二氯甲烷和甲醇作为流动相,通过Flash快速柱色谱纯化得到红色固体。
相应得,本领域技术人员能够根据实际具体产物的不同选择第二原料如6-氨基己腈等制得所述小檗碱衍生物。
3)在通式结构(II)所示结构中,Z代表O,R1为CH3时,所述小檗碱衍生物的制备方法包括如下步骤:
将唐松草分定、无水乙腈、碳酸钾以及第三原料在60~80℃下反应,TLC监测反应进程,反应完全后,冷却至固体完全析出,抽滤,将滤液硅胶拌样,以二氯甲烷和甲醇作为流动相,通过Flash快速柱色谱纯化得到黄色固体。
根据产物的不同,所述第三原料对应性地包括3-溴丙炔、4-溴-1-丁炔、8-溴辛-1-炔、5-溴戊腈、6-溴己腈、7-溴庚腈、1-溴-2-戊炔、7-溴-1-庚烯、8-溴-1-辛烯、3-(2-(2-溴乙氧基)乙氧基)丙-1-炔、丙炔-三聚乙二醇-溴、1-溴-3,6,9,12-四氧杂十五碳-14-炔等。
相应得,本领域技术人员能够根据实际具体产物的不同选择第三原料制得所述小檗碱衍生物。
4)当所述小檗碱衍生物中R3、R4开环且均为-CH3时,所述制备方法包括:将1)中所述小檗碱盐酸盐替换为巴马汀盐酸盐,先制得,而后与第四原料反应得到所述小檗碱衍生物。
相应得,本领域技术人员能够根据实际具体产物的不同选择第四原料如8-溴辛-1-炔、6-溴己腈等制得所述小檗碱衍生物。
5)当所述小檗碱衍生物中R3、R4开环,R3为-CH3,而对R4进行前述取代时,所述制备方法包括:
将非洲防己碱、无水乙腈、碳酸钾以及第五原料在60~80℃下反应,TLC监测反应进程,反应完全后,冷却至固体完全析出,抽滤,将滤液硅胶拌样,以二氯甲烷和甲醇作为流动相,通过Flash快速柱色谱纯化得到黄色固体。
相应得,本领域技术人员能够根据实际具体产物的不同选择第四原料如7-溴庚-1-炔、6-溴己腈等制得所述小檗碱衍生物。
6)当所述小檗碱衍生物中R3、R4开环,R4为-CH3,而对R3进行前述取代时,所述制备方法包括:将5)中的非洲防己碱替换为药根碱。
本发明中,所述制备方法以X为Cl为例,本领域技术人员可根据实际情况将X替换为Br。
第三方面,本发明进一步提供所述的小檗碱衍生物在抗鲍曼不动杆菌方面的应用。
第四方面,本发明还提供一种抗菌药物,其含有所述的小檗碱衍生物。
作为优选,所述的抗菌药物中包括所述小檗碱衍生物和抗生素。
作为优选,所述抗生素包括氨曲南、美罗培南、阿米卡星、环丙沙星、头孢吡肟和氯霉素中的一种或几种。
作为优选,所述氨曲南与小檗碱衍生物的质量比为(1~8):(1~8)。
作为优选,所述美罗培南、阿米卡星、环丙沙星、头孢吡肟和氯霉素中的任一种与所述小檗碱衍生物的质量比为1:(2~256)。
作为优选,所述的抗菌药物中包括所述小檗碱衍生物、抗生素和β-内酰胺酶抑制剂。
进一步地,所述β-内酰胺酶抑制剂包括阿维巴坦;所述的抗菌药物中包括所述小檗碱衍生物、氨曲南和阿维巴坦。
阿维巴坦属于二氮杂双环辛酮化合物,是目前最具有前景的β-内酰胺酶抑制剂,它能抑制几乎所有丝氨酸-β-内酰胺酶(serine β-lactamases, SBLs),但不能抑制金属β-内酰胺酶(metallo-β-lactamases, MBLs)。氨曲南不易被MBLs灭活,但作为单一制剂效力有限,当结合阿维巴坦抑制多种SBLs的能力时,可能能够成为产MBLs、SBLs及两者酶的碳青霉烯类耐药的肠杆菌的治疗方案。大量的体外药敏实验已证实了该策略的可行性,并且该组合获FDA合格传染病产品和快速通道资格。然而,该方法对鲍曼不动杆菌的抗菌活性较弱。本发明发现,所述小檗碱衍生物/氨曲南/阿维巴坦的三药组合对产ESBL鲍曼不动杆菌具有较佳的协同抗菌活性。
第五方面,本发明还提供所述的抗菌药物在抗鲍曼不动杆菌方面的应用。
第六方面,本发明还提供上述含有所述小檗碱衍生物、抗生素和β-内酰胺酶抑制剂的抗菌药物在抗产ESBL鲍曼不动杆菌方面的应用。
作为优选,在抗产ESBL鲍曼不动杆菌时,所述小檗碱衍生物、氨曲南和阿维巴坦的质量比为(1~8):(1~8):(0.5~4)。
基于上述技术方案,本发明的有益效果在于:
本发明通过对小檗碱的多个结构片段进行了结构修饰和优化,使得优化后的小檗碱衍生物表现出较强的增敏临床抗生素的活性,其可作为潜在的抗菌增效剂,有望使多种耐药抗生素回归抗鲍曼治疗的一线,增加临床用药选择,具有广阔的应用前景。
附图说明
为了更清楚地说明本发明或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作一简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为本发明提供的化合物2a~2l、化合物3a~3b以及化合物4的制备路线;
图2为本发明提供的化合物5a~5l、化合物6a~6b的制备路线;
图3为本发明提供的化合物8a~8b的制备路线;
图4为本发明提供的化合物9a~9d的制备路线;
图5、图6和图7分别为本发明提供的实施例2化合物2b的氢谱、碳谱以及高分辨质谱图;
图8、图9和图10分别为本发明提供的实施例5化合物2e的氢谱、碳谱以及高分辨质谱图;
图11为本发明提供的化合物2e/氨曲南/阿维巴坦对三株鲍曼不动杆菌临床株的棋盘法结果;
图12为本发明提供的化合物2e/氨曲南/阿维巴坦对发光鲍曼菌株UAlAb的棋盘法结果;
图13为本发明提供的化合物2e、氨曲南单药及两药联合的大蜡螟体内药敏实验;其中,A为大蜡螟幼虫感染模型的体内抗菌实验示意图;B为2e和氨曲南单独或联合治疗感染鲍曼不动杆菌ATCC 19606大蜡螟幼虫的存活率;C为2e和氨曲南单独或联合治疗感染可发光鲍曼菌株UAlAb大蜡螟的存活率;D为将可发光鲍曼菌株接种到大蜡螟幼虫体内,给予PBS 24 h后幼虫表面的荧光强度,E为给予氨曲南+阿维巴坦治疗组24 h后,检测感染了可发光鲍曼菌株后的大蜡螟幼虫表面的荧光强度,F为接种可发光鲍曼菌株的大蜡螟幼虫,在给予化合物2e/氨曲南/阿维巴坦治疗24 h后,幼虫表面的荧光强度;
图14为本发明提供的化合物2e与抗生素联用对鲍曼不动杆菌的协同作用结果;其中,A~C分别为化合物2e与美罗培南、阿米卡星、环丙沙星、头孢吡肟、氯霉素及舒巴坦联合用药对鲍曼不动杆菌标准株(ATCC 19606)的棋盘法结果(A)、FICI值(B)及使用synergyfinder平台计算的ZIP分数(C)。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面将结合本发明中的附图,对本发明中的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
若非特别说明,实施例中所用的各种原料均为市售常规原料,所用的技术手段为本领域技术人员所熟知的常规手段。
以下实施例中,熔点用MP90 熔点仪测定(Mettler toledo, Columbus, USA),未经校正;1H-NMR和13C-NMR 用 Bruker Avance III 600 核磁共振仪测定(Varian, SanFrancisco, USA),溶剂为 DMSO-d 6 (其中,化合物5g和z48的溶剂为DMSO-d 6 和CD3OH);ESIHR-MS 用Autospec Ultima-TOF 质谱测定仪测定(Micromass UK Ltd., Manchester,U.K.);Flash 柱分离纯化用 Combiflash Rf 200 快速制备液相(Teledyne, Nebraska,USA);紫外检测为上海宝山顾村电光仪器厂的 ZF-7A 手提紫外检测灯;所用试剂为毕得公司、伊诺凯公司、通广和 GENERAL REAGENT 等国产分析纯试剂。
实施例1 9-(丁-3-炔-1-氧基)小檗碱溴化物(2a)的合成
将小檗碱盐酸盐(2.78 g, 7.5 mmol)置于250 mL圆底烧瓶中,保持负压为20–30mmHg,加热至195°C反应45 min后得到深红色固体,用乙醇/浓盐酸(95 mL, 5.0 mL)进行酸化。有机相在真空下浓缩,残渣通过硅胶柱层析进一步分离纯化,以二氯甲烷和甲醇作为流动相,通过Flash快速柱色谱纯化,得到黄色产物1(2.22 g, 收率83%)。向化合物1(0.36 g,1.0 mmol)的无水乙腈中(10.0 mL),加入碳酸钾(0.41 g, 3.0 mmol),加热至71℃。向反应体系中加入4-溴-1-丁炔(0.40 g, 3.0 mmol),TLC监测反应进程,冷却至固体完全析出,抽滤,将滤液硅胶拌样,以二氯甲烷和甲醇作为流动相,通过Flash快速柱色谱纯化得到黄色固体2a(47%)。熔点:239–241℃;1H NMR (600 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 8.96 (s,1H), 8.20 (d,J= 9.1 Hz, 1H), 8.02 (d,J= 9.1 Hz, 1H), 7.80 (s, 1H), 7.10 (s,1H), 6.17 (s, 2H), 4.93 (t,J = 6.3 Hz, 2H), 4.38 (t,J= 6.7 Hz, 2H), 4.07 (s,3H), 3.22 (t,J= 6.3 Hz, 2H), 3.00 (t,J= 2.6 Hz, 1H), 2.85–2.79 (m, 2H);13C NMR(151 MHz, DMSO-d 6 ) δ 150.5, 149.8, 147.7, 145.3, 141.9, 137.4, 133.0, 130.6,126.6, 123.8, 121.6, 120.4, 120.2, 108.4, 105.4, 102.1, 81.4, 73.0, 71.6,57.0, 55.4, 26.3, 19.6; HRMS: calcd for C23H20NO4Br [M−Br]+: 374.1387, found:374.1378.
实施例2 9-(庚-6-炔-1-氧基)小檗碱溴化物(2b)的合成
参照实施例1操作,以化合物1和7-溴庚炔为原料,经相同的反应和后处理方法,得到黄色固体2b(收率57%)。熔点:223–225℃; 1H NMR (600 MHz, DMSO) δ 9.75 (s, 1H),8.95 (s, 1H), 8.19 (d,J= 9.1 Hz, 1H), 7.99 (d,J= 9.1 Hz, 1H), 7.80 (s, 1H),7.09 (s, 1H), 6.17 (s, 2H), 4.95 (t,J= 6.2 Hz, 2H), 4.28 (t,J= 6.6 Hz, 2H),4.06 (s, 3H), 3.21 (t,J= 6.2 Hz, 2H), 2.78 (t,J= 2.7 Hz, 1H), 2.28–2.19 (m,2H), 1.89 (t,J= 6.9 Hz, 2H), 1.58–1.56 (m, 4H);13C NMR (151 MHz, DMSO) δ150.41, 149.80, 147.67, 145.28, 142.82, 137.43, 133.01, 130.68, 126.66,123.31, 121.65, 120.45, 120.22, 108.40, 105.42, 102.07, 84.47, 74.10, 71.28,57.03, 55.30, 28.95, 27.73, 26.31, 24.48, 17.67; HRMS: calcd for C26H26NO4Br [M−Br]+: 416.1856, found: 416.1840.
实施例3 9-(辛-7-炔-1-氧基)小檗碱溴化物(2c)的合成
参照实施例1操作,以化合物1和8-溴辛-1-炔为原料,经相同的反应和后处理方法,得到黄色固体2c(收率38%)。熔点:231–233℃;1H NMR (600 MHz, DMSO-d 6 ) δ 9.75 (s,1H), 8.95 (s, 1H), 8.20 (d,J= 9.2 Hz, 1H), 7.99 (d,J= 9.0 Hz, 1H), 7.80 (s,1H), 7.09 (s, 1H), 6.17 (s, 2H), 4.95 (t,J= 6.4 Hz, 2H), 4.29 (t,J= 6.8 Hz,2H), 4.05 (s, 3H), 3.21 (t,J= 6.4 Hz, 2H), 2.76 (t,J= 2.7 Hz, 1H), 2.22–2.16(m, 2H), 1.94–1.82 (m, 2H), 1.56–1.42 (m, 6H);13C NMR (151 MHz, DMSO-d 6 ) δ150.4, 149.8, 147.7, 145.3, 142.8, 137.5, 133.0, 130.7, 126.7, 123.3, 121.6,120.5, 120.2, 108.4, 105.4, 102.1, 84.5, 74.1, 71.2, 57.0, 55.3, 29.3, 27.9(2), 26.3, 24.7, 17.6; HRMS: calcd for C27H28NO4Br [M−Br]+: 430.2013, found:430.1996.
实施例4 9-(丁-4-氰-1-氧基)小檗碱溴化物(2d)的合成
参照实施例1操作,以化合物1和5-溴戊腈为原料,经相同的反应和后处理方法,得到黄色固体2d(收率45%)。熔点:240–242℃;1H NMR (600 MHz, DMSO-d 6 ) δ 9.78 (s, 1H),8.95 (s, 1H), 8.20 (d,J= 9.1 Hz, 1H), 8.00 (d,J= 9.0 Hz, 1H), 7.80 (s, 1H),7.09 (s, 1H), 6.17 (s, 2H), 4.96 (t, J = 6.3 Hz, 2H), 4.31 (t,J = 6.3 Hz,2H), 4.06 (s, 3H), 3.21 (t,J= 6.4 Hz, 2H), 2.65 (t,J= 7.1 Hz, 2H), 2.05–1.94(m, 2H), 1.91–1.82 (m, 2H);13C NMR (151 MHz, DMSO-d 6 ) δ 150.4, 149.8, 147.7,145.3, 142.7, 137.5, 133.0, 130.7, 126.6, 123.5, 121.6, 120.7, 120.4, 120.2,108.4, 105.4, 102.1, 73.4, 57.1, 55.3, 28.5, 26.3, 21.6, 16.0; HRMS: calcdfor C24H23N2O4Br [M−Br]+: 403.1652, found: 403.1650.
实施例5 9-(戊-5-氰-1-氧基)小檗碱溴化物(2e)的合成
参照实施例1操作,以化合物1和6-溴己腈为原料,经相同的反应和后处理方法,得到黄色固体2e(收率57%)。熔点:230–232℃;1H NMR (600 MHz, DMSO-d 6 ) δ 9.76 (s, 1H),8.95 (s, 1H), 8.20 (d,J = 9.2 Hz, 1H), 8.00 (d,J= 9.0 Hz, 1H), 7.80 (s, 1H),7.09 (s, 1H), 6.17 (s, 2H), 4.96 (t,J= 6.3 Hz, 2H), 4.30 (t,J= 6.5 Hz, 2H),4.06 (s, 3H), 3.21 (t,J= 6.3 Hz, 2H), 2.56 (t,J= 6.9 Hz, 2H), 1.94–1.87 (m,2H), 1.72–1.53 (m, 4H);13C NMR (151 MHz, DMSO-d 6 ) δ 150.4, 149.8, 147.7,145.2, 142.8, 137.4, 133.0, 130.7, 126.7, 123.3, 121.6, 120.7, 120.4, 120.2,108.4, 105.4, 102.1, 73.9, 57.0, 55.3, 28.7, 26.3, 24.5 (2), 16.2; HRMS:calcd for C25H25N2O4Br [M−Br]+: 417.1809, found: 417.1807.
实施例6 9-(己-6-氰-1-氧基)小檗碱溴化物(2f)的合成
参照实施例1操作,以化合物1和7-溴庚腈为原料,经相同的反应和后处理方法,得到黄色固体2f(收率67%)。熔点:244–246℃;1H NMR (600 MHz, DMSO-d 6 ) δ 9.75 (s, 1H),8.95 (s, 1H), 8.20 (d,J= 9.1 Hz, 1H), 7.99 (d,J = 9.0 Hz, 1H), 7.80 (s, 1H),7.09 (s, 1H), 6.17 (s, 2H), 4.96 (t,J= 6.4 Hz, 2H), 4.29 (t,J= 6.7 Hz, 2H),4.06 (s, 3H), 3.21 (t,J= 6.4 Hz, 2H), 2.53 (t,J= 7.0 Hz, 2H), 1.92–1.86 (m,2H), 1.65–1.58 (m, 2H), 1.56–1.44 (m, 4H);13C NMR (151 MHz, DMSO-d 6 ) δ 150.4,149.8, 147.7, 145.3, 142.8, 137.4, 133.0, 130.7, 126.7, 123.3, 121.6, 120.7,120.4, 120.2, 108.4, 105.4, 102.1, 74.0, 57.0, 55.3, 29.2, 27.8, 26.3, 24.7,24.5, 16.1; HRMS: calcd for C26H27N2O4Br [M−Br]+: 431.1965, found: 431.1959.
实施例7 9-(戊-2-炔-1-氧基)小檗碱溴化物(2g)的合成
参照实施例1操作,以化合物1和1-溴-2-戊炔为原料,经相同的反应和后处理方法,得到黄色固体2g(收率41%)。熔点:180–182℃;1H NMR (600 MHz, DMSO-d 6 ) δ 9.86 (s,1H), 8.98 (s, 1H), 8.23 (d,J = 9.2 Hz, 1H), 8.05 (d,J= 9.1 Hz, 1H), 7.81 (s,1H), 7.10 (s, 1H), 6.18 (s, 2H), 5.02 (t,J= 2.3 Hz, 2H), 4.97 (t,J= 6.4 Hz,2H), 4.07 (s, 3H), 3.23–3.18 (m, 2H), 2.16–2.10 (m, 2H), 0.90 (t,J= 7.5 Hz,3H);13C NMR (151 MHz, DMSO-d 6 ) δ 150.9, 149.9, 147.7, 145.4, 141.0, 137.5,132.8, 130.7, 126.5, 124.2, 122.4, 120.4, 120.3, 108.4, 105.4, 102.1, 91.0,74.7, 61.6, 57.1, 55.3, 26.3, 13.4, 11.6; HRMS: calcd for C24H22NO4Br [M−Br]+:388.1543, found: 388.1531.
实施例8 9-(庚-6-烯-1-氧基)小檗碱溴化物(2h)的合成
参照实施例1操作,以化合物1和7-溴-1-庚烯为原料,经相同的反应和后处理方法,得到黄色固体2h(收率59%)。熔点:226–228℃;1H NMR (600 MHz, DMSO-d 6 ) δ 9.75 (s,1H), 8.95 (s, 1H), 8.19 (d,J= 9.0 Hz, 1H), 7.99 (d,J= 9.0 Hz, 1H), 7.80 (s,1H), 7.09 (s, 1H), 6.17 (s, 2H), 5.88–5.79 (m, 1H), 5.03 (d,J= 17.3 Hz, 1H),4.96 (d,J= 9.2 Hz, 3H), 4.28 (t,J= 6.7 Hz, 2H), 4.05 (s, 3H), 3.21 (t,J= 6.3Hz, 2H), 2.08 (q,J= 6.9 Hz, 2H), 1.93–1.84 (m, 2H), 1.54–1.41 (m, 4H);13C NMR(151 MHz, DMSO-d 6 ) δ 150.4, 149.8, 147.7, 145.3, 142.9, 138.7, 137.5, 133.0,130.7, 126.7, 123.3, 121.7, 120.4, 120.2, 114.8, 108.4, 105.4, 102.1, 74.2,57.0, 55.3, 33.1, 29.3, 28.0, 26.3, 24.8; HRMS: calcd for C26H28NO4Br [M−Br]+:418.2013, found: 418.2009.
实施例9 9-(辛-7-烯-1-氧基)小檗碱溴化物(2i)的合成
参照实施例1操作,以化合物1和8-溴-1-辛烯为原料,经相同的反应和后处理方法,得到黄色固体2i(收率67%)。熔点:222–224℃;1H NMR (600 MHz, DMSO-d 6 ) δ 9.75 (s,1H), 8.95 (d,J= 2.1 Hz, 1H), 8.19 (d,J= 9.2 Hz, 1H), 7.99 (d,J= 9.1 Hz, 1H),7.80 (d,J= 1.7 Hz, 1H), 7.09 (s, 1H), 6.17 (s, 2H), 5.87–5.76 (m, 1H), 5.04–4.98 (m, 1H), 4.98–4.90 (m, 3H), 4.28 (t,J = 6.8 Hz, 2H), 4.05 (s, 3H), 3.21(t,J= 6.4 Hz, 2H), 2.05 (q,J= 6.9 Hz, 2H), 1.90–1.85 (m, 2H), 1.53–1.35 (m,6H);13C NMR (151 MHz, DMSO-d 6 ) δ 150.4, 149.8, 147.7, 145.3, 142.9, 138.7,137.4, 133.0, 130.7, 126.7, 123.3, 121.6, 120.4, 120.2, 114.7, 108.4, 105.4,102.1, 74.2, 57.0, 55.3, 33.1, 29.4, 28.3, 28.2, 26.3, 25.1; HRMS: calcd forC27H30NO4Br [M−Br]+: 432.2169, found: 432.2169.
实施例10 9-(2-(2-(丙-2-炔-1-基氧基)乙氧基)乙氧基)小檗碱溴化物(2j)的合成
参照实施例1操作,以化合物1和3-(2-(2-溴乙氧基)乙氧基)丙-1-炔为原料,经相同的反应和后处理方法,得到黄色固体2j(收率51%)。熔点:199–201℃;1H NMR (600 MHz,DMSO-d 6 ) δ 9.75 (s, 1H), 8.94 (s, 1H), 8.19 (d,J= 9.1 Hz, 1H), 8.01 (d,J= 9.1Hz, 1H), 7.80 (s, 1H), 7.09 (s, 1H), 6.17 (s, 2H), 4.93 (t,J= 6.3 Hz, 2H),4.45–4.39 (m, 2H), 4.07 (d,J= 4.6 Hz, 5H), 3.83–3.78 (m, 2H), 3.63–3.59 (m,2H), 3.56–3.52 (m, 2H), 3.38 (t,J= 2.4 Hz, 1H), 3.22 (t,J= 6.3 Hz, 2H);13C NMR(151 MHz, DMSO-d 6 ) δ 150.5, 149.9, 147.7, 145.4, 142.6, 137.5, 133.0, 130.6,126.6, 123.6, 122.0, 120.5, 120.3, 108.5, 105.5, 102.1, 80.2, 77.2, 73.0,69.4, 69.3, 68.6, 57.5, 57.0, 55.5, 26.4; HRMS: calcd for C26H26NO6Br [M−Br]+:448.1755, found: 448.1755.
实施例11 9-(2-(2-(2-(丙-2-炔-1-基氧基)乙氧基)乙氧基)乙氧基)小檗碱溴化物(2k)的合成
参照实施例1操作,以化合物1和丙炔-三聚乙二醇-溴为原料,经相同的反应和后处理方法,得到黄色固体2k(收率47%)。熔点:164–166℃;1H NMR (600 MHz, DMSO-d 6 ) δ9.77 (s, 1H), 8.95 (s, 1H), 8.20 (d,J = 9.1 Hz, 1H), 8.01 (d,J= 9.1 Hz, 1H),7.80 (s, 1H), 7.09 (s, 1H), 6.17 (s, 2H), 4.93 (t,J= 6.4 Hz, 2H), 4.44–4.41(m, 2H), 4.08–4.04 (m, 5H), 3.84–3.79 (m, 2H), 3.62–3.58 (m, 2H), 3.53–3.51(m, 2H), 3.49 (s, 4H), 3.38 (t,J= 2.4 Hz, 1H), 3.22 (t,J= 6.4 Hz, 2H);13C NMR(151 MHz, DMSO-d 6 ) δ 151.0, 150.3, 148.2, 145.9, 143.0, 137.9, 133.4, 131.1,127.1, 124.1, 122.5, 120.9, 120.7, 108.9, 105.9, 102.6, 80.7, 77.6, 73.5,70.2, 70.0, 69.8 (2), 68.9, 57.9, 57.5, 55.9, 26.9; HRMS: calcd for C28H30NO7Br[M−Br]+: 492.2017, found: 492.2025.
实施例12 9-(2-(2-(2-(2-(丙-2-炔-1-基氧基)乙氧基)乙氧基)乙氧基)乙氧基)小檗碱溴化物(2l)的合成
参照实施例1操作,以化合物1和1-溴-3,6,9,12-四氧杂十五碳-14-炔为原料,经相同的反应和后处理方法,得到黄色固体2l(收率34%)。熔点:173–175℃;1H NMR (600MHz, DMSO-d 6 ) δ 9.77 (s, 1H), 8.96 (s, 1H), 8.20 (d,J= 9.1 Hz, 1H), 8.01 (d,J= 9.1 Hz, 1H), 7.81 (s, 1H), 7.10 (s, 1H), 6.18 (s, 2H), 4.94 (t,J= 6.3 Hz,2H), 4.46–4.39 (m, 2H), 4.07 (d,J= 4.2 Hz, 5H), 3.84–3.78 (m, 2H), 3.62–3.57(m, 2H), 3.55–3.50 (m, 2H), 3.50–3.43 (m, 8H), 3.39 (t, J = 2.4 Hz, 1H), 3.22(t,J = 6.4 Hz, 2H);13C NMR (151 MHz, DMSO-d 6 ) δ 150.5, 149.8, 147.7, 145.4,142.5, 137.4, 132.9, 130.6, 126.6, 123.6, 122.0, 120.4, 120.2, 108.4, 105.4,102.1, 80.2, 77.1, 73.0, 69.7, 69.6 (2), 69.5, 69.4, 69.3, 68.4, 57.4, 57.0,55.4, 26.4; HRMS: calcd for C30H34NO8Br [M−Br]+: 536.2279, found: 536.2288.
实施例13 9-(戊-5-氰-1-氨基)小檗碱氯化物(4)的合成
将小檗碱盐酸盐(0.37 g, 1.0 mmol)置于6-氨基己腈(1.1 g, 10.0 mmol)中,100℃下加热反应12 h。冷却至室温,有机相在真空下浓缩,用乙酸乙酯(10.0 mL)洗涤混合物,以二氯甲烷和甲醇作为流动相,通过Flash快速柱色谱纯化得到红色固体4(收率33%)。熔点:204–206℃;1H NMR (600 MHz, DMSO-d 6 ): δ 10.13 (s, 1H), 8.70 (s, 1H), 7.90(d,J= 8.7 Hz, 1H), 7.76 (s, 1H), 7.49 (d,J= 8.4 Hz, 1H), 7.07 (s, 1H), 6.44(s, 1H), 6.16 (s, 2H), 4.80 (t,J= 6.1 Hz, 2H), 3.97 (d,J= 1.0 Hz, 3H), 3.59(q,J= 6.7 Hz, 2H), 3.19 (t,J= 6.3 Hz, 2H), 2.49 (d,J= 7.3 Hz, 2H), 1.67–1.55(m, 4H), 1.48–1.41 (m, 2H);13C NMR (151 MHz, DMSO-d 6 )δ 149.5, 147.6, 146.7,146.4, 137.0, 135.6, 133.0, 130.2, 124.5, 120.7, 120.6, 119.7, 117.0, 116.1,108.4, 105.2, 102.0, 56.9, 54.8, 46.8, 29.5, 26.6, 25.4, 24.5, 16.1; HRMS:calcd for C25H26N3O3Br [M−Br]+: 416.1969, found: 416.1971.
实施例14 10-(丙-2-炔-1-氧基)小檗碱溴化物(5a)的合成
向唐松草分定(0.36 g, 1.0 mmol)的无水乙腈中(10.0 mL),加入碳酸钾(0.41g, 3.0 mmol),加热至71℃。向反应体系中加入3-溴丙炔(0.36 g, 3.0 mmol),TLC监测反应进程,冷却至固体完全析出,抽滤,将滤液硅胶拌样,以二氯甲烷和甲醇作为流动相,通过Flash快速柱色谱纯化得到黄色固体5a(收率35%)。熔点:188–190℃;1H NMR (600 MHz,DMSO-d 6 ): δ 9.91 (s, 1H), 8.96 (s, 1H), 8.21 (d,J= 9.1 Hz, 1H), 8.00 (d,J=9.1 Hz, 1H), 7.81 (s, 1H), 7.09 (s, 1H), 6.18 (s, 2H), 5.17 (d,J= 2.4 Hz,2H), 4.94 (t,J= 6.3 Hz, 2H), 4.12 (s, 3H), 3.71 (t,J= 2.4 Hz, 1H), 3.21 (t,J=6.4 Hz, 2H);13C NMR (151 MHz, DMSO-d 6 ) δ 149.9, 148.0, 147.7, 145.6, 144.7,138.1, 133.8, 130.8, 128.2, 123.1, 121.5, 120.4, 120.2, 108.4, 105.5, 102.1,79.4, 78.4, 62.2, 57.4, 55.2, 26.3; HRMS: calcd for C22H18NO4Br [M−Br]+:360.1230, found: 360.1221.
实施例15 10-(丁-3-炔-1-氧基)小檗碱溴化物(5b)的合成
参照实施例14操作,以唐松草分定和4-溴-1-丁炔为原料,经相同的反应和后处理方法,得到黄色固体5b(收率43%)。熔点:234–236℃;1H NMR (600 MHz, DMSO-d 6 ): δ 9.89(s, 1H), 8.93 (s, 1H), 8.19 (d,J= 9.1 Hz, 1H), 7.96 (d,J= 9.0 Hz, 1H), 7.79(s, 1H), 7.09 (s, 1H), 6.17 (s, 2H), 4.93 (t,J= 6.3 Hz, 2H), 4.39 (t,J= 6.3Hz, 2H), 4.16 (s, 3H), 3.21 (t,J= 6.4 Hz, 2H), 2.96 (t,J= 2.6 Hz, 1H), 2.81–2.75 (m, 2H);13C NMR (151 MHz, DMSO-d 6 ) δ 149.9, 149.1, 147.7, 145.5, 143.9,137.7, 133.3, 130.7, 127.7, 123.3, 121.4, 120.4, 120.1, 108.4, 105.4, 102.1,81.2, 72.7, 67.7, 62.0, 55.2, 26.3, 19.1; HRMS: calcd for C23H20NO4Br [M−Br]+:374.1387, found: 374.1376.
实施例16 10-(辛-7-炔-1-氧基)小檗碱溴化物(5c)的合成
参照实施例14操作,以唐松草分定和8-溴辛-1-炔为原料,经相同的反应和后处理方法,得到黄色固体5c(收率47%)。熔点:206–208℃;1H NMR (600 MHz, DMSO-d 6 ): δ 9.88(s, 1H), 8.94 (s, 1H), 8.19 (d,J= 9.1 Hz, 1H), 7.97 (d,J= 9.0 Hz, 1H), 7.79(s, 1H), 7.09 (s, 1H), 6.17 (s, 2H), 4.93 (t,J= 6.4 Hz, 2H), 4.29 (t,J= 6.4Hz, 2H), 4.12 (s, 3H), 3.21 (t,J= 6.4 Hz, 2H), 2.76 (t,J= 2.6 Hz, 1H), 2.21–2.15 (m, 2H), 1.87–1.80 (m, 2H), 1.54–1.43 (m, 6H);13C NMR (151 MHz, DMSO-d 6 )δ 149.8, 149.7, 147.7, 145.4, 143.8, 137.5, 133.0, 130.7, 127.6, 123.4,121.5, 120.5, 120.2, 108.4, 105.4, 102.1, 84.5, 71.2, 69.5, 61.9, 55.2, 28.6,27.9, 27.8, 26.3, 24.9, 17.6; HRMS: calcd for C27H28NO4Br [M−Br]+: 430.2013,found: 430.2012.
实施例17 10-(丁-4-氰-1-氧基) 小檗碱溴化物(5d)的合成
参照实施例14操作,以唐松草分定和5-溴戊腈为原料,经相同的反应和后处理方法,得到黄色固体5d(收率25%)。熔点:214–216℃;1H NMR (600 MHz, DMSO-d 6 ): δ 9.89(s, 1H), 8.95 (s, 1H), 8.19 (d,J= 9.1 Hz, 1H), 7.98 (d,J= 9.1 Hz, 1H), 7.80(s, 1H), 7.09 (s, 1H), 6.17 (s, 2H), 4.94 (t,J= 6.4 Hz, 2H), 4.34 (t,J= 6.2Hz, 2H), 4.12 (s, 3H), 3.21 (t,J= 6.3 Hz, 2H), 2.64 (t,J= 7.1 Hz, 2H), 1.99–1.90 (m, 2H), 1.85–1.77 (m, 2H);13C NMR (151 MHz, DMSO-d 6 ) δ 149.8, 149.6,147.7, 145.4, 143.8, 137.5, 133.1, 130.7, 127.5, 123.4, 121.5, 120.6, 120.4,120.2, 108.4, 105.4, 102.1, 68.7, 62.0, 55.2, 27.8, 26.3, 21.7, 16.0; HRMS:calcd for C24H23N2O4Br [M−Br]+: 403.1652, found: 403.1649.
实施例18 10-(戊-5-氰-1-氧基)小檗碱溴化物(5e)的合成
参照步骤实施例14操作,以唐松草分定和6-溴己腈为原料,经相同的反应和后处理方法,得到黄色固体5e(收率49%)。熔点:213–215℃;1H NMR (600 MHz, DMSO-d 6 ): δ9.89 (s, 1H), 8.94 (s, 1H), 8.20 (d,J= 9.1 Hz, 1H), 7.98 (d,J= 9.0 Hz, 1H),7.79 (s, 1H), 7.09 (s, 1H), 6.17 (s, 2H), 4.94 (t,J= 6.3 Hz, 2H), 4.31 (t,J=6.3 Hz, 2H), 4.12 (s, 3H), 3.21 (t,J= 6.3 Hz, 2H), 2.56 (t,J= 6.9 Hz, 2H),1.90–1.83 (m, 2H), 1.71–1.64 (m, 2H), 1.64–1.57 (m, 2H);13C NMR (151 MHz,DMSO-d 6 ) δ 149.8, 149.7, 147.7, 145.4, 143.8, 137.5, 133.0, 130.7, 127.6,123.4, 121.5, 120.7, 120.4, 120.2, 108.4, 105.4, 102.1, 69.3, 61.9, 55.2,28.0, 26.3, 24.7, 24.4, 16.1; HRMS: calcd for C25H25N2O4Br [M−Br]+: 417.1809,found: 417.1807.
实施例19 10-(己-6-氰-1-氧基)小檗碱溴化物(5f)的合成
参照步骤实施例14操作,以唐松草分定和7-溴庚腈为原料,经相同的反应和后处理方法,得到黄色固体5f(收率47%)。熔点:228–230℃;1H NMR (600 MHz, DMSO-d 6 ): δ9.88 (s, 1H), 8.94 (s, 1H), 8.19 (d,J = 9.1 Hz, 1H), 7.97 (d,J= 8.7 Hz, 1H),7.79 (s, 1H), 7.09 (s, 1H), 6.17 (s, 2H), 4.93 (t,J= 6.4 Hz, 2H), 4.30 (t,J =6.4 Hz, 2H), 4.12 (s, 3H), 3.21 (t,J= 6.4 Hz, 2H), 2.52 (d,J= 7.0 Hz, 2H),1.88–1.81 (m, 2H), 1.64–1.58 (m, 2H), 1.55–1.44 (m, 4H);13C NMR (151 MHz,DMSO-d 6 ) δ 149.8, 149.7, 147.7, 145.4, 143.8, 137.5, 133.0, 130.7, 127.6,123.4, 121.5, 120.7, 120.4, 120.1, 108.4, 105.4, 102.1, 69.5, 61.9, 55.2,28.5, 27.7, 26.3, 24.7, 24.6, 16.1; HRMS: calcd for C26H27N2O4Br [M−Br]+:431.1965, found: 431.1966.
实施例20 10-(戊-2-炔-1-氧基)小檗碱溴化物(5g)的合成
参照实施例14操作,以唐松草分定和1-溴-2-戊炔为原料,经相同的反应和后处理方法,得到黄色固体5g(收率31%)。熔点:246–248℃;1H NMR (600 MHz, DMSO-d 6 /CD3OD): δ9.82 (s, 1H), 8.82 (s, 1H), 8.17 (d,J= 9.0 Hz, 1H), 8.01 (d,J= 9.1 Hz, 1H),7.75 (s, 1H), 7.03 (s, 1H), 6.15 (s, 2H), 5.09 (t,J= 2.2 Hz, 2H), 4.93 (t,J=6.4 Hz, 2H), 4.18 (d,J= 2.5 Hz, 3H), 3.25 (d,J= 7.7 Hz, 2H), 2.25–2.19 (m,2H), 1.06 (t,J= 7.5 Hz, 3H);13C NMR (151 MHz, DMSO-d 6 /CD3OD) δ 151.1, 149.1,148.9, 146.1, 145.7, 139.1, 134.8, 131.5, 129.1, 123.7, 122.6, 121.2, 120.9,109.0, 106.2, 103.0, 91.2, 74.6, 62.5, 58.5, 56.3, 27.3, 13.7, 12.4; HRMS:calcd for C24H22NO4Br [M−Br]+: 388.1543, found: 388.1530.
实施例21 10-(庚-6-烯-1-氧基)小檗碱溴化物(5h)的合成
参照实施例14操作,以唐松草分定和7-溴-1-庚烯为原料,经相同的反应和后处理方法,得到黄色固体5h(收率41%)。熔点:210–212℃;1H NMR (600 MHz, DMSO-d 6 ): δ 9.88(s, 1H), 8.94 (s, 1H), 8.19 (d,J= 9.1 Hz, 1H), 7.97 (d,J= 9.0 Hz, 1H), 7.79(s, 1H), 7.09 (s, 1H), 6.17 (s, 2H), 5.87–5.77 (m, 1H), 5.03 (dq,J= 17.2, 1.7Hz, 1H), 4.98–4.92 (m, 3H), 4.29 (t,J= 6.4 Hz, 2H), 4.11 (s, 3H), 3.21 (t,J=6.4 Hz, 2H), 2.08 (q,J= 7.0 Hz, 2H), 1.87–1.81 (m, 2H), 1.54–1.42 (m, 4H);13CNMR (151 MHz, DMSO-d 6 ) δ 149.8, 149.7, 147.7, 145.4, 143.7, 138.6, 137.5,133.0, 130.7, 127.6, 123.4, 121.5, 120.4, 120.1, 114.8, 108.4, 105.4, 102.1,69.5, 61.8, 55.2, 33.1, 28.6, 27.9, 26.3, 24.9; HRMS: calcd for C26H28NO4Br [M−Br]+: 418.2013, found: 418.2009.
实施例22 10-(辛-7-烯-1-氧基)小檗碱溴化物(5i)的合成
参照实施例14操作,以唐松草分定和8-溴-1-辛烯为原料,经相同的反应和后处理方法,得到黄色固体5i(收率47%)。熔点:203–205℃;1H NMR (600 MHz, DMSO-d 6 ): δ 9.88(s, 1H), 8.94 (s, 1H), 8.19 (d,J= 9.1 Hz, 1H), 7.97 (d,J= 9.1 Hz, 1H), 7.79(s, 1H), 7.09 (s, 1H), 6.17 (s, 2H), 5.85–5.77 (m, 1H), 5.01 (dq,J= 17.2, 1.8Hz, 1H), 4.98–4.90 (m, 3H), 4.29 (t,J= 6.4 Hz, 2H), 4.11 (s, 3H), 3.21 (t,J=6.3 Hz, 2H), 2.05 (q,J= 6.8 Hz, 2H), 1.87–1.79 (m, 2H), 1.55–1.46 (m, 2H),1.44–1.35 (m, 4H);13C NMR (151 MHz, DMSO-d 6 ) δ 149.8, 149.7, 147.7, 145.4,143.8, 138.7, 137.5, 133.0, 130.7, 127.6, 123.4, 121.5, 120.4, 120.1, 114.7,108.4, 105.4, 102.1, 69.6, 61.8, 55.2, 33.1, 28.7, 28.2 (2), 26.3, 25.3;HRMS: calcd for C27H30NO4Br [M−Br]+: 432.2169, found: 432.2172.
实施例23 10-(2-(2-(丙-2-炔-1-基氧基)乙氧基)乙氧基)小檗碱溴化物(5j)的合成
参照实施例14操作,以唐松草分定和3-(2-(2-溴乙氧基)乙氧基)丙-1-炔为原料,经相同的反应和后处理方法,得到黄色固体5j(收率35%)。熔点:182–184℃;1H NMR (600MHz, DMSO-d 6 ): δ 9.88 (s, 1H), 8.93 (s, 1H), 8.20 (d,J= 9.1 Hz, 1H), 7.96 (d,J= 9.1 Hz, 1H), 7.80 (s, 1H), 7.09 (s, 1H), 6.17 (s, 2H), 4.93 (t,J= 6.4 Hz,2H), 4.45–4.42 (m, 2H), 4.16–4.11 (m, 5H), 3.87–3.83 (m, 2H), 3.67–3.64 (m,2H), 3.61–3.57 (m, 2H), 3.42 (t,J= 2.4 Hz, 1H), 3.20 (t,J= 6.4 Hz, 2H);13C NMR(151 MHz, DMSO-d 6 ) δ 149.8, 149.4, 147.7, 145.4, 144.0, 137.6, 133.2, 130.7,128.0, 123.1, 121.4, 120.4, 120.1, 108.4, 105.4, 102.1, 80.3, 77.1, 69.6,69.2, 68.9, 68.5, 61.8, 57.5, 55.1, 26.3; HRMS: calcd for C26H26NO6Br [M−Br]+:448.1755, found: 448.1763.
实施例24 10-(2-(2-(2-(丙-2-炔-1-基氧基)乙氧基)乙氧基)乙氧基)小檗碱溴化物(5k)的合成
参照实施例14操作,以唐松草分定和丙炔-三聚乙二醇-溴为原料,经相同的反应和后处理方法,得到黄色固体5k(收率34%)。熔点:172–174℃;1H NMR (600 MHz, DMSO-d 6 ):δ 9.88 (s, 1H), 8.94 (s, 1H), 8.19 (d,J= 9.1 Hz, 1H), 7.96 (d,J= 9.1 Hz, 1H),7.79 (s, 1H), 7.09 (s, 1H), 6.17 (s, 2H), 4.94 (t,J= 6.4 Hz, 2H), 4.48–4.39(m, 2H), 4.17–4.09 (m, 5H), 3.88–3.83 (m, 2H), 3.66–3.60 (m, 2H), 3.57–3.51(m, 6H), 3.41 (t,J= 2.4 Hz, 1H), 3.21 (t,J= 6.4 Hz, 2H);13C NMR (151 MHz,DMSO-d 6 ) δ 149.8, 149.4, 147.7, 145.4, 144.0, 137.6, 133.2, 130.7, 128.0,123.1, 121.4, 120.4, 120.1, 108.4, 105.4, 102.1, 80.3, 77.1, 69.9, 69.8,69.5, 69.2, 68.9, 68.5, 61.8, 57.5, 55.1, 26.3; HRMS: calcd for C28H30NO7Br [M−Br]+: 492.2017, found: 492.2026.
实施例25 10-(2-(2-(2-(2-(丙-2-炔-1-基氧基)乙氧基)乙氧基)乙氧基)乙氧基)小檗碱溴化物(5l)的合成
参照实施例14操作,以唐松草分定和1-溴-3,6,9,12-四氧杂十五碳-14-炔为原料,经相同的反应和后处理方法,得到黄色固体5l(收率29%)。熔点:158–160℃;1H NMR(600 MHz, DMSO-d 6 ): δ 9.88 (s, 1H), 8.93 (s, 1H), 8.20 (d,J= 9.1 Hz, 1H),7.96 (d,J= 9.1 Hz, 1H), 7.80 (s, 1H), 7.09 (s, 1H), 6.17 (s, 2H), 4.93 (t,J=6.4 Hz, 2H), 4.46–4.41 (m, 2H), 4.14 (s, 3H), 4.12 (d,J= 2.4 Hz, 2H), 3.87–3.85 (m, 2H), 3.65–3.62 (m, 2H), 3.56–3.48 (m, 10H), 3.41 (t,J= 2.4 Hz, 1H),3.21 (t,J= 6.4 Hz, 2H);13C NMR (151 MHz, DMSO-d 6 ) δ 149.8, 149.5, 147.7,145.4, 144.0, 137.6, 133.2, 130.7, 128.0, 123.2, 121.4, 120.4, 120.1, 108.4,105.4, 102.1, 80.3, 77.1, 69.9, 69.8, 69.7 (2), 69.5, 69.2, 68.9, 68.5, 61.8,57.5, 55.2, 26.3; HRMS: calcd for C30H34NO8Br [M−Br]+: 536.2279, found:536.2285.
实施例26 9-(辛-7-炔-1-氧基)巴马汀溴化物(8a)的合成
将巴马汀盐酸盐(2.9 g, 7.5 mmol)置于250 mL圆底烧瓶中,保持负压为20–30mmHg,加热至195°C反应45 min后得到深红色固体,用乙醇/浓盐酸(95 mL, 5.0 mL)进行酸化。有机相在真空下浓缩,残渣通过硅胶柱层析进一步分离纯化,以二氯甲烷和甲醇作为流动相,通过Flash快速柱色谱纯化,得到黄色产物7(2.1 g, 收率75%)。向化合物7(0.37 g,1.0 mmol)的无水乙腈中(10.0 mL),加入碳酸钾(0.41 g, 3.0 mmol),加热至71℃。向反应体系中加入8-溴辛-1-炔(0.57 g, 3.0 mmol),TLC监测反应进程,冷却至固体完全析出,抽滤,将滤液硅胶拌样,以二氯甲烷和甲醇作为流动相,通过Flash快速柱色谱纯化得到黄色固体8a(收率39%)。熔点:203–205℃;1H NMR (600 MHz, DMSO-d 6 ): δ 9.75 (s, 1H), 9.04(s, 1H), 8.20 (d,J= 9.1 Hz, 1H), 8.02 (d,J= 9.1 Hz, 1H), 7.72 (s, 1H), 7.10(s, 1H), 4.97 (t,J= 6.3 Hz, 2H), 4.29 (t,J= 6.8 Hz, 2H), 4.06 (s, 3H), 3.94(s, 3H), 3.87 (s, 3H), 3.23 (t,J= 6.4 Hz, 2H), 2.76 (t,J= 2.6 Hz, 1H), 2.20–2.16 (m, 2H), 1.89 (t,J= 7.2 Hz, 2H), 1.54–1.44 (m, 6H). 13C NMR (151 MHz,DMSO-d 6 ) δ 151.5, 150.3, 148.7, 145.3, 142.8, 137.7, 133.1, 128.7, 126.7,123.2, 121.6, 119.9, 118.9, 111.3, 108.8, 84.5, 74.1, 71.2, 57.0, 56.2, 55.9,55.5, 29.4, 27.9 (2), 26.0, 24.8, 17.6. HRMS: calcd for C28H32NO4Br [M−Br]+:446.2326, found: 446.2331.
实施例27 9-(戊-5-氰-1-氧基)巴马汀溴化物(8b)的合成
参照实施例26操作,以化合物7和6-溴己腈为原料,经相同的反应和后处理方法,得到黄色固体8b(收率45%)。熔点:221–223℃;1H NMR (600 MHz, DMSO-d 6 ): δ 9.76 (s,1H), 9.10 (t, J= 4.9 Hz, 1H), 8.22–8.18 (m, 1H), 8.05 (d, J= 9.0 Hz, 1H),7.72 (d, J= 1.7 Hz, 1H), 7.13–7.07 (m, 1H), 4.98 (d, J= 6.5 Hz, 2H), 4.34–4.28 (m, 2H), 4.06 (d, J= 1.4 Hz, 3H), 3.94 (s, 3H), 3.92–3.83 (m, 3H), 3.24(t, J= 6.4 Hz, 2H), 2.57 (t, J= 6.9 Hz, 2H), 1.95–1.88 (m, 2H), 1.72–1.57 (m,4H);13C NMR (151 MHz, DMSO-d 6 ) δ 151.5, 150.2, 148.7, 145.2, 142.7, 137.6,133.1, 128.6, 126.6, 123.2, 121.5, 120.7, 119.9, 118.9, 111.3, 108.8, 73.9,57.0, 56.2, 55.8, 55.5, 28.7, 25.9, 24.6, 24.5, 16.2; HRMS: calcd forC26H29N2O4Br [M−Br]+: 433.2122, found: 433.2123.
实施例28 9-(辛-7-炔-1-氧基)巴马汀溴化物(9a)的合成
向非洲防己碱(0.37 g, 1.0 mmol)的无水乙腈中(10.0 mL),加入碳酸钾(0.41g, 3.0 mmol),加热至71℃。向反应体系中加入7-溴庚-1-炔(0.53 g, 3.0 mmol),TLC监测反应进程,冷却至固体完全析出,抽滤,将滤液硅胶拌样,以二氯甲烷和甲醇作为流动相,通过Flash快速柱色谱纯化得到黄色固体9a(收率47%)。熔点:201–203℃;1H NMR (600 MHz,DMSO-d 6 ) δ 9.88 (s, 1H), 9.05 (d,J= 4.5 Hz, 1H), 8.20 (d,J= 8.7 Hz, 1H), 8.05(d,J= 9.0 Hz, 1H), 7.71 (s, 1H), 7.09 (s, 1H), 4.96 (t,J= 6.5 Hz, 2H), 4.14(t,J= 6.5 Hz, 2H), 4.10 (s, 3H), 4.07 (s, 3H), 3.87 (s, 3H), 3.23 (t,J= 6.4Hz, 2H), 2.77 (t,J= 2.6 Hz, 1H), 2.26 – 2.18 (m, 2H), 1.80 (t,J= 6.7 Hz, 2H),1.56 (t,J= 3.6 Hz, 4H);13C NMR (151 MHz, DMSO-d 6 ) δ 151.7, 150.2, 148.1,145.4, 143.6, 137.7, 133.1, 128.6, 126.7, 123.4, 121.3, 119.9, 118.9, 111.4,109.9, 84.4, 71.3, 68.8, 61.9, 57.0, 55.9, 55.4, 28.3, 27.7, 26.0, 24.8,17.7; HRMS: calcd for C27H30NO4Br [M−Br]+: 432.2169, found: 432.2165.
实施例29 9-(辛-7-炔-1-氧基)巴马汀溴化物(9b)的合成
参照实施例28操作,以非洲防己碱和6-溴己腈为原料,经相同的反应和后处理方法,得到黄色固体9b(收率61%)。熔点:213–215℃;1H NMR (600 MHz, DMSO-d 6 ) δ 9.89 (s,1H), 9.04 (s, 1H), 8.21 (d,J= 9.1 Hz, 1H), 8.05 (d,J= 9.0 Hz, 1H), 7.73 (s,1H), 7.10 (s, 1H), 4.95 (t,J= 6.4 Hz, 2H), 4.15 (t,J= 6.4 Hz, 2H), 4.09 (d,J=19.0 Hz, 6H), 3.88 (s, 3H), 3.23 (t,J= 6.4 Hz, 2H), 2.56 (t,J= 7.0 Hz, 2H),1.85–1.80 (m, 2H), 1.79–1.65 (m, 2H), 1.60–1.56 (m, 2H);13C NMR (151 MHz,DMSO-d 6 ) δ 151.7, 150.2, 148.0, 145.4, 143.6, 137.7, 133.1, 128.7, 126.8,123.4, 121.3, 120.7, 119.9, 118.9, 111.5, 110.0, 68.7, 61.9, 57.0, 55.9,55.4, 27.9, 26.0, 24.9, 24.5, 16.1; HRMS: calcd for C26H29N2O4Br [M−Br]+:433.2122, found: 433.2119.
实施例30 9-(辛-7-炔-1-氧基)巴马汀溴化物(9c)的合成
向药根碱(0.37 g, 1.0 mmol)的无水乙腈中(10.0 mL),加入碳酸钾(0.41 g,3.0 mmol),加热至71℃。向反应体系中加入7-溴庚-1-炔(0.53 g, 3.0 mmol),TLC监测反应进程,冷却至固体完全析出,抽滤,将滤液硅胶拌样,以二氯甲烷和甲醇作为流动相,通过Flash快速柱色谱纯化得到黄色固体9c(收率55%)。熔点:199–201℃;1H NMR (600 MHz,DMSO-d 6 ) δ 9.88 (s, 1H), 9.07 (d,J= 6.5 Hz, 1H), 8.20 (d,J= 9.0 Hz, 1H), 8.05(d,J= 9.1 Hz, 1H), 7.71 (s, 1H), 7.09 (s, 1H), 4.95 (t,J= 6.4 Hz, 2H), 4.10(s, 3H), 4.07 (s, 5H), 3.94 (s, 3H), 3.22 (t,J= 6.5 Hz, 2H), 2.77 (t,J= 2.6Hz, 1H), 2.21–2.19 (m, 2H), 1.78 (t,J= 6.8 Hz, 2H), 1.54–1.52 (m, 4H);13C NMR(151 MHz, DMSO-d 6 ) δ 150.9, 150.2, 148.8, 145.4, 143.6, 137.7, 133.1, 128.6,126.8, 123.4, 121.3, 119.8, 118.8, 112.2, 109.0, 84.4, 71.2, 68.4, 61.9,57.0, 56.3, 55.4, 28.0, 27.6, 25.9, 24.7, 17.6; HRMS: calcd for C27H30NO4Br [M−Br]+: 432.2169, found: 432.2169.
实施例31 9-(辛-7-炔-1-氧基)巴马汀溴化物(9d)的合成
参照实施例30操作,以药根碱和6-溴己腈为原料,经相同的反应和后处理方法,得到黄色固体9d(收率67%)。熔点:207–209℃;1H NMR (600 MHz, DMSO-d 6 ) δ 9.88 (s, 1H),9.06 (d,J= 3.3 Hz, 1H), 8.21 (d,J= 9.2 Hz, 1H), 8.05 (d,J= 9.1 Hz, 1H), 7.72(s, 1H), 7.10 (s, 1H), 4.95 (t,J= 6.4 Hz, 2H), 4.09 (d,J= 19.1 Hz, 8H), 3.94(s, 3H), 3.22 (t,J= 6.4 Hz, 2H), 2.55 (t,J= 7.1 Hz, 2H), 1.83–1.78 (m, 2H),1.68–1.63 (m, 2H), 1.56–1.51 (m, 2H);13C NMR (151 MHz, DMSO-d 6 ) δ 150.9,150.2, 148.8, 145.4, 143.6, 137.7, 133.1, 128.6, 126.8, 123.4, 121.3, 120.7,119.8, 118.9, 112.2, 109.0, 68.2, 61.9, 57.0, 56.2, 55.4, 27.7, 25.9, 24.8,24.4, 16.1; HRMS: calcd for C26H29N2O4Br [M−Br]+: 433.2122, found: 433.2121.
对比例1 9-(辛-7-炔-1-基氧基)四氢原小檗碱溴化物(3a)的合成
向化合物2c(0.51 g, 1.0 mmol)的无水甲醇(5.0 mL)溶液中,在0℃条件下缓慢加入硼氢化钠(0.11 g, 3.0 mmol),在常温下反应直至 TLC分析显示反应完成。抽滤,将滤液硅胶拌样,以石油醚和乙酸乙酯作为流动相,通过Flash快速柱色谱纯化得到白色固体3a(收率55%)。熔点:111–113℃;1H NMR (600 MHz, DMSO-d 6 ) δ 6.90 (s, 1H), 6.86 (d,J=8.4 Hz, 1H), 6.83 (d,J= 8.4 Hz, 1H), 6.66 (s, 1H), 5.94 (dd,J= 4.0, 1.1 Hz,2H), 4.05 (d,J= 15.7 Hz, 1H), 3.93–3.86 (m, 2H), 3.75 (s, 3H), 3.39–3.35 (m,2H), 3.29 (dd,J= 15.8, 3.7 Hz, 1H), 3.08–3.05 (m, 1H), 2.93–2.87 (m, 1H),2.74 (t,J= 2.6 Hz, 1H), 2.63–2.52 (m, 2H), 2.45 (td,J= 11.4, 3.4 Hz, 1H),2.17 (td,J= 6.9, 2.7 Hz, 2H), 1.67 (p,J= 6.7 Hz, 2H), 1.50–1.39 (m, 6H).13CNMR (151 MHz, DMSO-d 6 ) δ 149.8, 145.7, 145.4, 143.6, 130.9, 128.3, 127.6,127.5, 123.5, 111.2, 108.0, 105.7, 100.5, 84.5, 71.7, 71.1, 59.1, 55.7, 53.6,50.8, 35.8, 29.7, 29.0, 28.0, 27.9, 25.0, 17.7. HRMS: calcd for C27H31NO4[M+H]+: 434.2326, found: 434.2322.
对比例2 9-(戊-5-氰-1-氧基)四氢原小檗碱溴化物(3b)的合成
参照对比例1操作,以化合物2e为原料,经相同的反应和后处理方法,得到白色固体3b(收率69%)。熔点:107–109℃;1H NMR (600 MHz, DMSO-d 6 ) δ 6.91–6.82 (m, 3H),6.66 (s, 1H), 5.94 (dd,J= 4.1, 1.1 Hz, 2H), 4.06 (d,J = 15.7 Hz, 1H), 3.94–3.85 (m, 2H), 3.76 (s, 3H), 3.42–3.35 (m, 2H), 3.30 (dd,J= 15.7, 3.7 Hz, 1H),3.11–3.06 (m, 1H), 2.94–2.86 (m, 1H), 2.62–2.55 (m, 1H), 2.53 (t,J= 7.0 Hz,3H), 2.46 (td,J= 11.4, 3.4 Hz, 1H), 1.74–1.67 (m, 2H), 1.67–1.59 (m, 2H),1.58–1.51 (m, 2H).13C NMR (151 MHz, DMSO-d 6 ) δ 149.8, 145.7, 145.4, 143.5,130.9, 128.3, 127.6, 127.5, 123.5, 120.7, 111.2, 108.0, 105.7, 100.5, 71.5,59.0, 55.7, 53.5, 50.7, 35.7, 29.0 (2), 24.8, 24.5, 16.1; HRMS: calcd forC25H28N2O4[M+H]+: 421.2122, found: 421.2120.
对比例3 10-(辛-7-炔-1-氧基)四氢小檗碱溴化物(6a)的合成
向化合物5c(0.51 g, 1.0 mmol)的无水甲醇(5.0 mL)溶液中,在0℃条件下缓慢加入硼氢化钠(0.11 g,3.0 mmol),在常温下反应直至 TLC分析显示反应完成。抽滤,将滤液硅胶拌样,以石油醚和乙酸乙酯作为流动相,通过Flash快速柱色谱纯化得到白色固体6a(收率59%)。熔点:105–107℃;1H NMR (600 MHz, DMSO-d 6 ): δ 6.90 (s, 1H), 6.88–6.79(m, 2H), 6.66 (s, 1H), 5.94 (d,J= 4.3 Hz, 2H), 4.05 (d,J= 15.8 Hz, 1H), 3.95(t,J= 6.3 Hz, 2H), 3.75 (s, 3H), 3.41–3.34 (m, 2H), 3.29 (dd,J= 15.8, 3.7 Hz,1H), 3.13–3.06 (m, 1H), 2.93–2.87 (m, 1H), 2.74 (t,J= 2.6 Hz, 1H), 2.63–2.52(m, 2H), 2.45 (td,J= 11.5, 3.4 Hz, 1H), 2.16 (td,J= 6.8, 2.7 Hz, 2H), 1.72(p,J= 6.5 Hz, 2H), 1.40–1.50 (m, 6H).13C NMR (151 MHz, DMSO-d 6 ) δ 149.1,145.7, 145.4, 144.6, 130.9, 128.2, 127.5 (2), 123.6, 112.1, 108.1, 105.7,100.5, 84.5, 71.1, 68.0, 59.5, 59.0, 53.4, 50.7, 35.8, 29.0, 28.7, 27.9,27.8, 25.1, 17.6. HRMS: calcd for C27H31NO4[M+H]+: 434.2326, found: 434.2342.
对比例4 9-(戊-5-氰-1-氧基)四氢小檗碱溴化物(6b)的合成
参照对比例3操作,以化合物5e(1.0 mmol)为原料,经相同的反应和后处理方法,得到白色固体6b(收率71%)。熔点:129–131℃;1H NMR (600 MHz, DMSO-d 6 ): δ 6.90 (s,1H), 6.87 (d,J= 8.6 Hz, 1H), 6.82 (d,J= 8.4 Hz, 1H), 6.66 (s, 1H), 5.94 (d,J=4.3 Hz, 2H), 4.05 (d,J= 15.7 Hz, 1H), 3.96 (t,J= 6.3 Hz, 2H), 3.75 (s, 3H),3.41–3.26 (m, 4H), 3.12–3.06 (m, 1H), 2.90 (ddd,J= 16.4, 11.4, 5.2 Hz, 1H),2.60 (d,J= 15.8 Hz, 1H), 2.53 (d,J= 6.9 Hz, 2H), 2.48–2.41 (m, 1H), 1.76 (p,J= 6.6 Hz, 2H), 1.64 (p,J= 7.1 Hz, 2H), 1.54 (p,J= 7.5, 6.8 Hz, 2H).13C NMR(151 MHz, DMSO-d 6 ) δ 149.1, 145.7, 145.4, 144.6, 130.9, 128.3, 127.6, 127.5,123.6, 120.7, 112.2, 108.1, 105.7, 100.5, 67.9, 59.6, 59.0, 53.4, 50.7, 35.8,29.0, 28.1, 24.9, 24.5, 16.1. HRMS: calcd for C25H28N2O4[M+H]+: 421.2122,found: 421.2119.
对比例5 9-(丁-3-烯-1-氧基)小檗碱溴化物(2m)的合成
参照实施例1操作,以化合物1和4-溴-1-丁烯为原料,经相同的反应和后处理方法,得到黄色固体2m(收率41%)。熔点:233–235℃; 1H NMR (600 MHz, DMSO-d 6 ) δ 9.75(s, 1H), 8.94 (s, 1H), 8.20 (d,J= 9.1 Hz, 1H), 8.00 (d,J= 9.1 Hz, 1H), 7.80(s, 1H), 7.09 (s, 1H), 6.17 (s, 2H), 6.00–5.94 (m, 1H), 5.22 (dd,J= 17.4, 2.1Hz, 1H), 5.13 (d,J= 10.3 Hz, 1H), 4.94 (t,J= 6.3 Hz, 2H), 4.36 (t,J= 6.8 Hz,2H), 4.06 (s, 3H), 3.21 (t,J= 6.4 Hz, 2H), 2.65 (q,J= 6.7 Hz, 2H); 13C NMR(151 MHz, DMSO-d 6 ) δ 150.43, 149.84, 147.70, 145.32, 142.56, 137.47, 134.90,133.02, 130.69, 126.68, 123.46, 121.65, 120.45, 120.22, 117.34, 108.44,105.45, 102.10, 73.08, 57.07, 55.37, 33.98, 26.35. HRMS: calcd for C23H23NO4Br[M−Br]+: 376.1543, found: 376.1537.
上述实施例和对比例中小檗碱衍生物的反应路线见图1~图4。其中,图1为化合物2a~2l、化合物3a~3b以及化合物4的制备路线;图2为化合物5a~5l、化合物6a~6b的制备路线;图3为化合物8a~8b的制备路线;图4为化合物9a~9d的制备路线。上述实施例2中化合物2b和实施例5中化合物2e的氢谱、碳谱以及高分辨质谱图见图5~图10。其中,实施例2化合物2b的氢谱、碳谱以及高分辨质谱图分别为图5、图6和图7;实施例5化合物2e的氢谱、碳谱以及高分辨质谱图分别为图8、图9和图10。
试验例1
1、所述小檗碱衍生物协同抗鲍曼活性结果及构效关系研究
本发明对小檗碱衍生物协同抗鲍曼活性结果及构效关系进行了研究,实施例和对比例制得的小檗碱衍生物的活性结果见表1,以小檗碱为对照化合物,采用肉汤微量稀释法测定小檗碱衍生物的MIC值,并采用棋盘法评价了小檗碱衍生物与氨曲南联合使用对ATCC19606的抗菌活性。所有衍生物和氨曲南的协同抗菌活性通过计算得到的FICI值进行评价。当FICI≤ 0.5时,该组合被定义为协同效应,当 0.5<FICI<4 时定义为叠加效应,当 FICI≥ 4 时定义为拮抗效应。
表1
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2、所述小檗碱衍生物的体外药代稳定性评价
本发明以含有酯键的临床麻醉药物—丙美卡因(propantheline, Pro)作为阳性对照药,将化合物2e和丙美卡因分别与人血孵育,分别在0、10、30、60和120 min测定残余率,评价化合物2e的血浆稳定性。如表2所示,阳性对照药在1 h内在血液中快速水解,化合物2e在2 h内保持稳定,优于阳性对照药。结果表明,化合物2e在人血浆中具有高稳定性,具有较好的药代性质。本发明实施例中的其余化合物也均具有化合物2e相当的体外药代稳定性,篇幅限制,不一一展开论述。
表2 化合物2e的体外血浆稳定性
3、所述小檗碱衍生物的体外协同抗菌活性评价
3.1 化合物2e与氨曲南联用对鲍曼标准菌株及临床分离菌株的协同作用
为了考察化合物2e能否联合氨曲南增强抗多重耐药鲍曼不动杆菌的协同效应,本发明选取了一株标准菌株(ATCC 17978)和十株临床分离菌株(包括3株碳青霉烯类敏感菌株和7株碳青霉烯类耐药鲍曼不动杆菌菌株)进行棋盘法测试。如表3所示,氨曲南与化合物2e联合使用对ATCC 17978、21-22、21-24和20-6均表现协同效应(FICI<0.5),氨曲南的MIC值由8~16 µg/mL降低至2~4 µg/mL。此外,与ATCC 19606相比,碳青霉烯类耐药菌表现出更高的氨曲南抗性(MIC值在64~128 µg/mL),但化合物2e的加入可以显著增强碳青霉烯类耐药菌对氨曲南的敏感值(FICI值介于0.281~0.313之间),部分恢复此类菌的抗生素敏感性。
本发明进一步评估了化合物2e联合氨曲南对三株产超广谱β-内酰胺酶鲍曼不动杆菌(22-LP37、22-LP41和22-LP42)的协同效应,三株菌株的FICI值介于0.516~0.531之间,表明两药联用组对产ESBL菌株仅具有叠加效应。本发明发现,这可能是因为β-内酰胺酶水解氨曲南,导致氨曲南的浓度降低,从而无法产生协同效应。因此,本发明进一步引入β-内酰胺酶抑制剂,探索其是否能恢复该类菌对2e和氨曲南联用组的敏感性。
表3 化合物2e联合氨曲南对鲍曼不动杆菌标准株的抗菌活性
3.2 化合物2e联合氨曲南/阿维巴坦对产ESBL鲍曼不动杆菌的协同作用
阿维巴坦属于二氮杂双环辛酮化合物,是目前最具有前景的β-内酰胺酶抑制剂,它能抑制几乎所有丝氨酸-β-内酰胺酶(serine β-lactamases, SBLs),但不能抑制金属β-内酰胺酶(metallo-β-lactamases, MBLs)。氨曲南不易被MBLs灭活,但作为单一制剂效力有限,当结合阿维巴坦抑制多种SBLs的能力时,可能能够成为产MBLs、SBLs及两者酶的碳青霉烯类耐药的肠杆菌的治疗方案。大量的体外药敏实验已证实了该策略的可行性,并且该组合获FDA合格传染病产品和快速通道资格。然而,该方法对鲍曼不动杆菌的抗菌活性较弱。因此,本发明对所述化合物2e/氨曲南/阿维巴坦的三药组合对上述产ESBL鲍曼不动杆菌(22-LP37、22-LP41和22-LP42)的体外抗菌活性。如表4和表5所示,化合物2e(16~32 µg/mL)与氨曲南/阿维巴坦(剂量比为2:1)联合用药的抗菌活性远高于各单独抗菌活性,联用组合对3个菌株的FICI值分别为0.145、0.270和0.297(见图11)。可见,化合物2e/氨曲南/阿维巴坦三重联用组合对β-内酰胺酶稳定,该组合对产生β-内酰胺酶的鲍曼不动杆菌表现出较好的抗菌作用。
表4 化合物2e、氨曲南及阿维巴坦对三株联合氨曲南对产ESBL鲍曼菌株的抗菌活性
表5 化合物2e联合氨曲南/阿维巴坦对产ESBL鲍曼菌株的抗菌活性
为了能够动态监测抗菌药物的协同抗鲍曼活性,本发明采用由文献《One-stepengineering of a stable, selectable marker-free autoluminescent Acinetobacterbaumannii for rapid continuous assessment of drug activity》(Jiang H, Gao Y,Zeng S, et al. [J]. J. Microbiol. Biotechnol., 2019, 29(9): 1488−93.)中提供的产超广谱β-内酰胺酶的发光菌株UAlAb进行体内外抗菌活性评价。通过观察棋盘法结果中各孔的荧光强度,化合物2e(32 µg/mL)、氨曲南(4 µg/mL)及阿维巴坦(2 µg/mL)三药联用组对UAlAb菌株表现出显著的协同作用(见图12)。以上结果说明三药联用对产ESBL的鲍曼菌株表现出较好的协同抗菌活性。
本发明实施例中的其余化合物也相应能够提高上述体外协同抗菌活性,篇幅限制,不一一展开论述。
4、所述小檗碱衍生物的体内药效学评价
目前,研究人员多采用大蜡螟(Galleria mellonella)幼虫模型评价抗感染化合物的体内药效。因此,本发明采用感染ATCC 19606的大蜡螟幼虫模型,进一步进行化合物2e、氨曲南单药及两药联合的大蜡螟体内药敏实验(见图13A)。配制致死剂量菌液(1×106CFU)感染幼虫,并在感染后0.5 h单次注射10 µL的PBS,化合物2e单药组、氨曲南单药组和化合物2e/氨曲南联合组,其中化合物2e和氨曲南的剂量分别为8.3、66.7 mg/kg。如图13B所示,PBS组、化合物2e组或氨曲南组的大蜡螟幼虫在48 h内死亡,而化合物2e+氨曲南联合组显示大蜡螟幼虫的生存率增加,感染后96 h的大蜡螟幼虫的存活率为80%(4/5),联用组与单药组存活率差异有统计学意义(P<0.01)。体内大蜡螟感染模型试验进一步验证两药的协同效应,与单药治疗组以及对照组相比,化合物2e联合氨曲南治疗后的感染大蜡螟的存活率显著增加,说明两药联合对感染鲍曼不动杆菌的大蜡螟幼虫具有保护作用。
如图13C~F所示,在感染自发光菌株的大蜡螟幼虫感染模型中,菌株感染24 h时,对照组、两药联用组及三药联用组大蜡螟幼虫存活率分别为0%(0/5)、60%(3/5)及100%(5/5),对照组24 h发光最强,两药联用组表现出一定的保护作用,荧光强度较对照组减弱,但最终幼虫在72 h内全部死亡。同时,三药联用组表现最优的保护作用,在感染24 h后的存活率为80%(4/5)且荧光强度最弱。发光菌株UAlAb的可视化结果表明,化合物2e+氨曲南+阿维巴坦组在产ESBL鲍曼不动杆菌感染的大蜡螟幼虫模型中显示有协同作用,并且其与对照组或氨曲南+阿维巴坦组相比能够明显增加被感染的大蜡螟幼虫的生存率。
本发明实施例中的其余化合物与氨曲南(以及阿维巴坦)联用后也相应能够提高大蜡螟幼虫的生存率,篇幅限制,不一一展开论述。
5、所述小檗碱衍生物与不同抗生素联用对鲍曼不动杆菌的协同作用
为了进一步研究所述小檗碱衍生物与其他临床抗菌药物的协同作用,本研究选择了5种临床上用于治疗鲍曼不动杆菌的代表性抗生素,包括美罗培南(MEM,碳青霉烯类)、阿米卡星(AMI,氨基糖苷类)、环丙沙星(CIP,氟喹诺酮类)、头孢吡肟(CPM,β内酰胺类抗生素)和氯霉素(CAP,氯霉素类),通过棋盘法评价化合物2e与不同抗生素组合的协同抗鲍曼活性。此外,还选择了β-内酰胺酶抑制剂—舒巴坦,该药物已被证明对鲍曼不动杆菌具有临床疗效。棋盘法结果表明(图14A和图14B),化合物2e显著增加了鲍曼不动杆菌对6种抗菌药物的敏感性,所有组合的FICI值均小于0.5,化合物2e(64~128 μg/mL)使6种抗菌药物的MIC降低至原来的1/4(表6)。如图14C所示,为了进一步分析及可视化不同组合协同活性的强弱,本发明采用SynergyFinder平台对两药联用组合的协同活性进行打分,具体参考文献《SynergyFinder 2.0: visual analytics of multi-drug combination synergies》(Ianevski A, Giri AK, Aittokallio T. Nucleic Acids Res., 2020, 48(W1): W488−93.)。结果表明,美罗培南、阿米卡星、环丙沙星、头孢吡肟、氯霉素和舒巴坦与化合物2e联用的ZIP分数分别为20.011、15.605、10.143、13.891、12.343、8.496和12.602(ZIP分数>0表示两药联用具有一定的协同作用;ZIP分数>10表示两药联用具有强烈的协同作用)。上述结果说明化合物2e能增强鲍曼不动杆菌对结构类型丰富的多类抗生素的敏感性。
本发明实施例中的其余化合物与上述不同抗生素联用后也相应能够增强鲍曼不动杆菌对多类抗生素的敏感性,篇幅限制,不一一展开论述。
表6 化合物2e联合不同抗生素对ATCC 19606的抗菌活性
其中,关于上述实验例和对比例协同抗鲍曼不动杆菌衍生物的生物实验方法具体包括:
1、细菌菌株种类及培养条件
本研究中使用的鲍曼不动杆菌菌菌株来自中国医学科学院病原微生物收藏中心(CAMS-CCPM-A),包括ATCC标准菌株。本研究中的菌株包括两种标准菌株(A. baumanniiATCC 19606和A. baumannii ATCC 17978)以及13株临床分离菌株,其中包括7株CRAB菌株和3株ESBL菌株。所有菌株在37°C条件下,置于阳离子调节的MH肉汤培养基Ⅱ(cation-adjusted Mueller-Hinton broth, CAMHB)或MH肉汤培养基(Mueller-Hinton agar)中培养。
2、棋盘法测定药物协同抗菌活性试验
根据临床实验室标准化协会(CLSI)指南,采用微量稀释法分别测定小檗碱衍生物或氨曲南体外抑制细菌生长所需的最低浓度,为最小抑菌浓度(Minimal InhibitoryConcentration,MIC)。将起始浓度为1024 μg/mL的化合物加入到96孔微孔板中,并使用MH肉汤稀释成所需浓度。菌株在MH培养基上划线并过夜培养,取10 μL细菌悬液加于96孔板中使其最终浓度为5×105CFU/mL,将96孔板置37℃恒温培养20 h后观察细菌生长情况并读取化合物的MIC值。
采用微量稀释棋盘法评价氨曲南和小檗碱衍生物联合使用对标准菌株及临床分离菌株的协同抑制活性。将5×105CFU/mL的细菌悬液加入到含有两倍系列稀释的氨曲南和小檗碱衍生物的96孔板中(MH肉汤培养基Ⅱ)。棋盘滴定中使用氨曲南和小檗碱衍生物的范围分别为1~64 µg/mL和0.25~1024 µg/mL。置于37℃恒温培养20 h后,通过计算FICI来分析组合协同效应,其公式如下:FICI=(药物A联用的MIC/药物A单用的MIC)+(药物B联用的MIC/药物B单用的MIC)。同时,通过如下公式计算三药联合的FICI分析组合效应:FICI = (药物A联用的MIC/药物A单用的MIC) + (药物B联用的MIC/药物B单用的MIC) + (药物C联用的MIC/药物C单用的MIC)。当FICI ≤ 0.5时,定义为协同作用;当0.5<FICI<4时,定义为无关作用;当FICI ≥ 4时,定义为拮抗作用。
本研究使用SynergyFinder在线平台(https://synergyfinder.fimm.fi)对2e与不同抗生素组合的协同作用进行可视化,通过ZIP方法计算得到ZIP分数从而评价化合物组合的协同抗菌活性。ZIP分数>0表示具有协同作用,ZIP分数>10表示具有强烈的协同作用。
3、人血浆稳定性试验
选择溴丙胺太林作为对照化合物,在人血浆中测试代表性化合物的稳定性。使用DMSO溶液配置10 mmol/L的化合物2d母液,并稀释至终浓度为100 μmol/L,参考2d溶液的配置步骤,溴丙胺太林溶液使用水进行稀释。将化合物溶液(2 μL)与98 μL的血浆样品混合,在37℃的水浴中孵育0、10、30、60和120 min。孵育完毕时,每个样品中立即加入500 μL的反应中止液(200 ng/mL甲苯磺丁脲和200 ng/mL拉贝洛尔乙腈溶液)进行充分混合以沉淀蛋白质,并在4000 rpm和4℃条件下离心20 min,提取150 μL的上清液,密封摇动10 min后进行LC-MS/MS分析。
4、大蜡螟细菌感染模型
将幼虫放置于室温下24 h以适应环境,直至进行化合物的抗菌活性测试。选择重量在270~330 mg、长度约2 cm的幼虫为动物模型,将鲍曼不动杆菌ATCC 19606在MH琼脂培养基上培养过夜,使用PBS溶液调整菌液终浓度约为108CFU/mL,使用玻璃微量注射器将菌液注入幼虫的右后腿部位,注射量为10 µL。感染0.5h后,在不同幼虫组的左后腿部位分别给予化合物2d、氨曲南及2d/氨曲南联用组合。此外,10只幼虫注射10 µL的PBS作为阴性对照,将幼虫在35℃的黑暗条件中孵育,并在感染后96 h中每天观察一次,若幼虫对机械刺激无响应,则被视为死亡。使用GraphPad Prism 8软件绘制每组的生存曲线,通过IVIS成像系统(PerkinElmer Inc.)采集发光的鲍曼不动杆菌菌株UAlAb在96孔板和幼虫中的生物发光信号,并进行成像。
5、细菌RNA提取及转录组分析
鲍曼不动杆菌ATCC 19606的过夜培养物在MH肉汤培养基Ⅱ中以1:100稀释,并在37℃下生长至对数期(OD600 nm = 0.4)。然后将细菌细胞与化合物2d/氨曲南(4/4 μg/mL)或氨曲南(4 μg/mL)共孵育4 h,通过离心收集,并保存在80℃。使用RNAsimple总RNA提取试剂盒(TIANGEN,DP419),根据试剂盒说明书进行RNA提取,RNA数量测定和转录组分析由Allwegene Tech (中国北京)进行,然后在Illumina Hiseq平台上以配对末端模式进行测序。过滤RNA-Seq原始数据并使用Cutadapt软件组装细菌转录组,使用bowtie2软件对照鲍曼不动杆菌ATCC 19606的基因组绘制RNA-Seq读数。实验独立重复3次。
6、实时荧光定量PCR实验
总RNA提取的方法与转录组测序相同,使用HiScript® III All-in-one RTSuperMix(Vazyme Biotech Co. Ltd, R333)对每个样品500 ng的总RNA的等量样品进行cDNA合成。根据说明书使用Taq Pro Universal SYBR qPCR Master Mix(Vazyme BiotechCo. Ltd, Q712)在qTOWER®3实时荧光定量PCR系统(Analytik Jena)上,以adeA、adeB、emrA、emrB和16S rRNA(作为内部对照)的cDNA为模板进行实时荧光定量PCR实验。引物序列见表7,通过ΔΔCt法相对于16S rRNA的水平进行归一化,计算相对RNA表达水平,使用GraphPad Prism 8软件进行数据分析。
表7 RT-qPCR 实验所用引物
最后应说明的是:以上实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。
Claims (7)
1.一种小檗碱衍生物,其特征在于,其具有通式结构(II-4)、(II-5)以及(II-6)中任一所示结构:
(II-4);/>(II-5);
(II-6);
其中,n为5或6;R为C或N。
2.权利要求1所述的小檗碱衍生物在制备抗鲍曼不动杆菌药物方面的应用。
3.一种抗菌药物,其特征在于,其包括权利要求1所述的小檗碱衍生物和抗生素。
4.根据权利要求3所述的抗菌药物,其特征在于,所述抗生素包括氨曲南、美罗培南、阿米卡星、环丙沙星、头孢吡肟和氯霉素中的一种或几种。
5.根据权利要求4所述的抗菌药物,其特征在于,所述氨曲南与小檗碱衍生物的质量比为(1~8):(1~8);所述美罗培南、阿米卡星、环丙沙星、头孢吡肟和氯霉素中的任一种与所述小檗碱衍生物的质量比为1:(2~256)。
6.根据权利要求3所述的抗菌药物,其特征在于,其包括权利要求1所述的小檗碱衍生物、抗生素和β-内酰胺酶抑制剂;其中,所述β-内酰胺酶抑制剂包括阿维巴坦。
7.根据权利要求6所述的抗菌药物,其特征在于,所述的小檗碱衍生物、抗生素和β-内酰胺酶抑制剂的质量比为(1~8):(1~8):(0.5~4)。
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