CN110372732A - 白坚木碱-喹啉型二聚吲哚生物碱化合物及其应用 - Google Patents
白坚木碱-喹啉型二聚吲哚生物碱化合物及其应用 Download PDFInfo
- Publication number
- CN110372732A CN110372732A CN201910748652.6A CN201910748652A CN110372732A CN 110372732 A CN110372732 A CN 110372732A CN 201910748652 A CN201910748652 A CN 201910748652A CN 110372732 A CN110372732 A CN 110372732A
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- China
- Prior art keywords
- aspidospermine
- compound
- quinoline type
- indole alkaloid
- dimeric indole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了如式Ⅰ所示的白坚木碱‑喹啉型二聚吲哚生物碱化合物:其中,R1选自氢、羟基、甲氧基、乙氧基、氨基、脂肪烃基、脂肪氨基、酰胺、卤素;R2选自氢、羟基、甲氧基、乙氧基、氨基、脂肪烃基、脂肪氨基、酰胺、卤素;R3选自氢、羟基、甲氧基、乙氧基、氨基、脂肪烃基、脂肪氨基、酰胺、卤素;本发明通过LPS诱导的RAW 264.7细胞炎症模型对白坚木碱‑喹啉型二聚吲哚生物碱化合物进行抗炎活性评价,实验结果证实白坚木碱‑喹啉型二聚吲哚生物碱化合物具有抗炎活性,且景东山橙植物原料易得,价格低廉,生物碱提取工艺简单;白坚木碱‑喹啉型二聚吲哚生物碱化合物在制备抗炎药物中拥有良好的开发应用前景。
Description
技术领域
本发明涉及一种白坚木碱-喹啉型二聚吲哚生物碱化合物及其在制备抗炎药物中的应用。
背景技术
炎症是一种威胁人类健康的常见多发病,主要表现为肿胀、红、热、痛以及功能障碍,这是血管系统的活体组织为了应对损伤因子产生的防御反应,物理、化学或生物等内源或外源刺激都可能导致炎症。很多疾病甚至癌症都有可能发生炎症反应,炎症反应的调控以及治疗对人类健康具有重要意义。体内炎症反应涉及多种细胞的参与,其中巨噬细胞是调控机体炎症反应最主要的细胞之一。在炎症反应过程中机体产生的NO、IL-6以及TNF-α等细胞因子主要来源于活化的巨噬细胞。当LPS刺激正常细胞诱导其产生炎症,细胞内即开始启动一系列的炎性反应,包括一些炎症相关细胞因子的转录与合成。
抗炎药是用于治疗组织受到损伤后所发生的反应炎症的药物。抗炎药有两大类:一类是甾体抗炎药,另一类是非甾体抗炎药即医疗实践中所指的解热镇痛抗炎药,这类药物包括阿司匹林、对乙酰氨基酚、吲哚美辛、萘普生、萘普酮、双氯芬酸、布洛芬、尼美舒利、罗非昔布、塞来昔布等。目前市场上的一些抗炎药物具有一定胃肠道以及肾脏副作用,如阿司匹林会对粘膜表面产生直接的损害,此外,有报道布洛芬导致无菌性脑膜炎和吲哚美辛导致头痛。
开发以炎症因子为靶点的抗炎类天然药物是控制慢性炎症的有效途径。天然产物中含有多种具有抗炎活性的化学分子,如黄酮类化合物和多糖。生物碱是天然产物的重要来源,结构骨架丰富,生物活性广泛。目前已报道的小檗碱以及益母草碱具有显著的抗炎活性。山橙属植物富含单萜吲哚生物碱,tabersonine以及衍生物是一类重要的特征成分,在炎症性疾病中具有较好的疗效。此外,其他化学成分的抗炎活性尚不清晰。因而,从山橙属植物中寻找具有抗炎作用的化合物,对于开发高效低毒的新型抗炎制剂具有很好的应用价值。本发明提供的白坚木碱-喹啉型二聚吲哚生物碱类化合物及其作为抗炎药物尚未见报道。
发明内容
本发明提供了一种新的白坚木碱-喹啉型二聚吲哚生物碱化合物,其分离自景东山橙,其化学结构式如式Ⅰ所示:
其中, R1选自氢、羟基、甲氧基、乙氧基、氨基、脂肪烃基、脂肪氨基、酰胺、卤素;R2选自氢、羟基、甲氧基、乙氧基、氨基、脂肪烃基、脂肪氨基、酰胺、卤素;R3选自氢、羟基、甲氧基、乙氧基、氨基、脂肪烃基、脂肪氨基、酰胺、卤素。
上述脂肪烃基、脂肪氨基是指饱和不饱和脂肪烃取代基,其中,饱和脂肪烃基是指直链或带有支链的烷基、环烷基,例或如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、环丙基环十二烷基等,而不饱和脂肪烃基是指链烯基、炔基或链二烯基,链烯基如烯丙基、异戊烯基、1-十二烯基,炔基如1-十八炔基、2-十八炔基,链二烯基如香叶基、1,3-十八烯基、9-十八烯基等。
当R1、R2和R3同时为氢时,白坚木碱-喹啉型二聚吲哚生物碱化合物结构式如式Ⅱ所示:
。
本发明另一目的是将上述白坚木碱-喹啉型二聚吲哚生物碱化合物应用在制备抗炎药物中,具体是应用在制备自身慢性炎症反应的治疗药物中。
本发明抗炎药物中还可以加入一种或多种药物上可接受的辅料,所述辅料包括药学领域常规的填充剂、稀释剂、粘合剂、赋形剂、吸收促进剂、填充剂、表面活性剂和稳定剂等,必要时还可加入香味剂、色素和甜味剂等。
本发明所述应用除制成胶囊外,还可以制成丸剂、粉剂、片剂、粒剂、口服液和注射液等多种形式。
本发明中用RAW 264.7炎症细胞用于试验;取对数生长期的RAW 264.7细胞经消化计数后,以1×104个/孔接种于96孔板中,在5% CO2,37℃条件下培养24h后加入不同浓度受试样品,继续培养2h后,加入1.0µg/mL的LPS,继续培养24h,收集培养基上清液待测;通过MTT法分别测定不同分组的吸光值,从而评价受试化合物对RAW 264.7细胞的毒性大小;实验结果表明本发明的白坚木碱-喹啉型二聚吲哚生物碱化合物,即化合物melokhanine K,对LPS刺激的RAW 264.7细胞具有很小的毒性作用;通过上清液测定LPS诱导RAW 264.7细胞产生NO的结果显示,化合物melokhanine K对LPS 诱导RAW 264.7细胞产生NO的含量有较为显著的抑制活性。
本发明优点和技术效果:本发明首次从景东山橙中获得白坚木碱-喹啉型二聚吲哚生物碱化合物,抗炎活性实验结果表明该化合物在浓度为30μM时具有一定的抗炎活性,本发明中的化合物为研制抗炎制剂提供了先导化合物,有利于植物药用资源的开发利用。
附图说明
图1为化合物melokhanine K对LPS诱导RAW264.7细胞产生NO的影响结果;
图2为化合物melokhanine K干预下LPS诱导RAW264.7细胞IL-6表达水平结果;
图3为化合物melokhanine K干预下LPS诱导RAW264.7细胞TNF-α表达水平结果。
具体实施方式
下面通过实施例对本发明作进一步详细说明,但本发明的内容并不局限于此,本实施例中方法如无特殊说明的均按常规方法操作,所用试剂如无特殊说明的采用常规市售试剂或按常规方法配置的试剂。
实施例1:化合物melokhanine K的提取分离
取景东山橙植物样品,经干燥、粉碎后,用体积浓度为80%的甲醇溶液回流提取3次,每次3h,过滤除去滤渣后合并提取液,减压浓缩,将不含有机试剂的样品(浸膏状)用酸水(体积浓度0.5% 的盐酸溶液)转移至大烧杯中,并调pH至2-3,用乙酸乙酯萃取3次,收集水层(生物碱部分)加氢氧化钠调pH至9-10,再用乙酸乙酯萃取3次,收集乙酸乙酯层,浓缩得到乙酸乙酯萃取物;将乙酸乙酯层萃取物用硅胶柱进行粗分,硅胶粒径为100-200目,用氯仿/丙酮溶液进行梯度(体积比依次为1:0、1:1、0:1)洗脱总共得到3个部分依次为Fr.A、Fr.B、Fr.C;Fr.B部分3g用C18中压柱10%、20%、40%、60%、70%甲醇水体系划段,取其Fr.B-1部分(中压70%甲醇水段)过硅胶柱(粒径为200-300目),以石油醚-丙酮(体积比为3:1)两相体系为洗脱液进行洗脱,收集洗脱液,浓缩干燥,即得化合物melokhanine K(2mg);
鉴定结果如下:
化合物melokhanine K:黄色油状;[α]20 D =+75 (c 0.4, MeOH); UV (MeOH) λmax(log ε): 211 (4.43), 256 (4.08), 362 (2.77) nm; IR (KBr) νmax 3444, 1637,1384, 1046 cm–1; HRESIMS m/z 655.3250 [M+H]+ (calcd. for C41H42N4O4, 655.3279). 1H (600 MHz) 和13C NMR (150 MHz) (CDCl3) NMR 数据见表1;以上数据结合2D NMR分析证实melokhanine K为白坚木碱-喹啉型二聚吲哚生物碱化合物;
以上所述的白坚木碱-喹啉型二聚吲哚生物碱化合物melokhanine K为新的天然有机化合物。
表1:化合物melokhanine K的1H NMR和13C NMR数据
NO. | <i>δ</i><sub>H</sub>(<i>J </i>in Hz) | <i>δ</i><sub>C</sub> | NO. | <i>δ</i><sub>H</sub>(<i>J </i>in Hz) | <i>δ</i><sub>C</sub> |
2 | 168.3 s | 2' | 59.2 s | ||
3a | 3.79, m | 47.0 t | 3'a | 3.39, m | 49.0 t |
3b | 3.36, m | 3'b | 3.28, d (7.3) | ||
5a | 3.28, d (7.3) | 54.9 t | 5'a | 3.24, d (10.7) | 52.9 t |
5b | 3.10, m | 5'b | 3.11, m | ||
6a | 2.33, dd (13.9, 7.0) | 38.6 t | 6'a | 2.52, dd (13.2, 3.4) | 36.0 t |
6b | 1.96, dd (9.2, 4.5) | 6'b | 1.90, m | ||
7 | 57.2 s | 7' | 51.2 s | ||
8 | 129.7 s | 8' | 123.6 s | ||
9 | 7.57, d (2.2) | 123.9 d | 9' | 7.23, d (7.8) | 125.8 d |
10 | 140.5 s | 10' | 6.70, t (7.8) | 116.7 d | |
11 | 7.55, d (2.2) | 127.1 d | 11' | 7.07, t (7.8) | 126.9 d |
12 | 6.84, d (7.8) | 115.4 d | 12' | 6.69, d (7.8) | 112.5 d |
13 | 135.7 s | 13' | 142.1 s | ||
14 | 5.90, d (10.6) | 125.6 d | 14' | 5.95, dd (10.4, 2.4) | 128.3 d |
15 | 5.86, dd (10.6, 1.2) | 129.7 d | 15' | 5.82, d (10.4) | 128.1 d |
16 | 67.9 s | 16' | 65.2 s | ||
17a | 2.28, dd (11.2, 8.0) | 40.42 t | 17'a | 2.30, d (11.8) | 41.4 t |
17b | 2.12, d (11.2) | 17'b | 2.05, m | ||
18 | 0.94, 3H, d (7.1) | 8.57 q | 18' | 0.72, 3H, d (7.1) | 9.9 q |
19 | 2.23, dd (14.1, 7.1) | 53.1 d | 19' | 2.85, m | 49.7 d |
20 | 45.4 s | 20' | 46.5 s | ||
21 | 3.59, d (12.1) | 61.2 d | 21' | 2.38, s | 73.2 d |
<i>C</i>O | 209.7 s | <i>C</i>'O<sub>2</sub>Me | 171.4 s | ||
C'O<sub>2</sub><i>Me</i> | 3.25, 3H, s | 51.3 q |
实施例2:化合物melokhanine K对LPS刺激巨噬细胞RAW 264.7产生NO的抑制
(1)实验方法
通过硝酸盐还原酶法检测培养基中亚硝酸钠的量来评估RAW 264.7细胞的释放(每孔2×104个细胞),让RAW 264.7细胞在96孔细胞培养板上生长,并在5%CO2的环境中于37℃培养24小时;然后加入不同浓度的试验样品,本试验受试化合物试验浓度分别设置为10μg/mL、20μg/mL、30μg/mL,采用地塞米松(10μg/mL)作为阳性对照,LPS作为阴性对照;继续培养2h,加入LPS(5μg/mL),在相同条件下继续培养24h,收集培养上清液进行检测;根据一氧化氮(NO)测定试剂盒(硝酸还原酶法)的说明书测定细胞中NO的含量,具体操作如下:
①加入样品和R1、R2混合试剂,37℃水浴60min;
②加入R3、R4,抽提室温静置40min,3500~4000转/分,离心10min;
③取上清0.5mL,加入显色剂,静置10min,用酶标仪测定吸光度值,测定波长为550nm。
(2)结果
SPSS 17.0统计软件分析,数值均以“平均数±标准差”表示,不同组间的变化用t检验验证其差异性;使用Origin 9.0绘图(*P<0.05则表示与阴性对照组存在显著性差异);
实验结果见表2和图1,从LPS诱导RAW 264.7细胞产生NO的结果可以看出:化合物melokhanine K对LPS诱导RAW 264.7细胞产生NO有较为显著的抑制活性;
表2:化合物melokhanine K在30μM下对LPS诱导RAW 264.7细胞产生NO的影响
组别 | 平均值 | SD |
空白对照组 | 2.03 | 0.08 |
阴性对照组 | 15.76 | 0.17 |
地塞米松 | 9.78 | 0.16 |
化合物melokhanine K | 9.31 | 0.07 |
实施例3:化合物melokhanine K对LPS 诱导的RAW264.7 巨噬细胞炎症因子的影响
(1)材料
DMEM培养液(美国Gibco公司)、胎牛血清(美国Gibco公司)、RPMI-1640培养液(美国Gibco公司)、磷酸盐缓冲液(上海beyotime公司)、双抗(美国HyClone公司)、DMSO(美国Sigma公司)、MTT(美国Sigma公司),本发明化合物及地塞米松均用DMSO配制。
(2)供试液的制备
称取1mg化合物melokhanine K,加入DMSO溶解,上样前用DMEM不完全培养液稀释至所需浓度,并使得上样后的DMSO终浓度不超过0.1%。
(3)方法
取每孔200µL的RAW264.7 细胞悬液(5×104个/mL)接种于96孔培养板,培养24h待其贴壁后加入受试化合物稀释液10μL至培养液中,化合物melokhanine K终浓度分别为10、20、30μmol/L,每个浓度均设3个复孔;设细胞空白对照组、阳性对照组(地塞米松)及样品组(浓度为10、20、30μmol/L,均含等浓度的DMSO),阴性对照为等体积DMEM完全培养基。
(4)培养
加药(地塞米松及样品)后继续置于37℃,5%CO2培养箱培养。
(5)MTT法测定细胞OD值
加药培养24h后,除去上清液,每孔加入150μL MTT(0.5mg/mL)溶液,置于37℃、5 % CO2培养箱内继续培养4h后,除去上清液,加入等体积的DMSO溶解甲臜,震荡均匀后于540nm处测定每孔的吸光值;通常情况下,甲臜生成量与活细胞数成正比,因此可以根据光密度OD值推测出活细胞的数目,并按下式计算细胞抑制率:
抑制率(%)=(OD值对照孔-OD值加样孔)/ OD值对照孔×100%。
(6)数据处理
实验数据OD值采用“平均数±标准差”来表示,数理统计及方差分析工作采用Origin软件完成。
(7)实验结果见表3,表中结果显示化合物melokhanine K在浓度为30μM时RAW264.7细胞的存活率为92.81%,效果与地塞米松相当;
表3:化合物melokhanine K对RAW 264.7细胞的存活率影响
30 μM | 平均值 | SD |
地塞米松 | 89.93 | 0.79 |
化合物melokhanine K | 92.81 | 5.22 |
;
图2 结果显示化合物melokhanine K干预下LPS诱导RAW 264.7细胞IL-6表达水平,IL-6是一种由淋巴、非淋巴细胞产生的多功能细胞因子,对免疫应答、急性期反应;造血和神经系统有多方面作用;IL-6含量升高表明机体内有组织损伤或者感染发生;IL-6表达水平的高低可以一定程度上反映炎症反应的强弱;通过对实验组RAW 264.7细胞分泌的IL-6含量的检测,可以看出,与LPS诱导的炎症模型组相比,化合物melokhanine K干预下对RAW264.7产生的IL-6表达量有抑制作用;
图3结果显示化合物melokhanine K干预下LPS诱导RAW 264.7细胞TNF-α表达水平,TNF-α是一种主要由单核细胞和巨噬细胞产生的单核因子,其生物学活性非常复杂,包括对造血、免疫和炎症的调节;对血管和凝血的影响和对多种器官都有作用。通过化合物对LPS诱导的RAW 264.7细胞分泌的TNF-α含量的检测可以发现,与LPS诱导的模型组相比,经化合物melokhanine K处理后,对RAW 264.7细胞产生的TNF-α有抑制效果。
Claims (3)
1.结构式如式Ⅰ所示的白坚木碱-喹啉型二聚吲哚生物碱化合物:
其中,R1选自氢、羟基、甲氧基、乙氧基、氨基、脂肪烃基、脂肪氨基、酰胺、卤素;R2选自氢、羟基、甲氧基、乙氧基、氨基、脂肪烃基、脂肪氨基、酰胺、卤素;R3选自氢、羟基、甲氧基、乙氧基、氨基、脂肪烃基、脂肪氨基、酰胺、卤素。
2.根据权利要求1所述的白坚木碱-喹啉型二聚吲哚生物碱化合物,其特征在于,当R1、R2和R3同时为氢时,白坚木碱-喹啉型二聚吲哚生物碱化合物结构式如式Ⅱ所示:
。
3.权利要求1或2所述的白坚木碱-喹啉型二聚吲哚生物碱化合物在制备抗炎药物中的应用。
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CN115073481A (zh) * | 2021-03-13 | 2022-09-20 | 中国科学院昆明植物研究所 | 一种呋喃白坚木碱二聚体或其药学上可接受的盐及其制备方法和应用、药物组合物 |
CN115677732A (zh) * | 2022-11-01 | 2023-02-03 | 北京中医药大学东直门医院 | 生物碱二聚体及应用 |
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CN115073481A (zh) * | 2021-03-13 | 2022-09-20 | 中国科学院昆明植物研究所 | 一种呋喃白坚木碱二聚体或其药学上可接受的盐及其制备方法和应用、药物组合物 |
CN115073481B (zh) * | 2021-03-13 | 2024-04-12 | 中国科学院昆明植物研究所 | 一种呋喃白坚木碱二聚体或其药学上可接受的盐及其制备方法和应用、药物组合物 |
CN115677732A (zh) * | 2022-11-01 | 2023-02-03 | 北京中医药大学东直门医院 | 生物碱二聚体及应用 |
CN115677732B (zh) * | 2022-11-01 | 2023-11-24 | 北京中医药大学东直门医院 | 生物碱二聚体及应用 |
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