CN108785317B - 香加皮c21甾类化合物在制备ido抑制剂中的用途 - Google Patents
香加皮c21甾类化合物在制备ido抑制剂中的用途 Download PDFInfo
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- CN108785317B CN108785317B CN201710293310.0A CN201710293310A CN108785317B CN 108785317 B CN108785317 B CN 108785317B CN 201710293310 A CN201710293310 A CN 201710293310A CN 108785317 B CN108785317 B CN 108785317B
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- cortex periplocae
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (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)
- Steroid Compounds (AREA)
Abstract
本发明属于药品或保健品领域，具体涉及香加皮C21甾类化合物在制备IDO抑制剂中的用途。本发明通过研究发现，杠柳苷A、杠柳苷F、杠柳苷U和杠柳苷T对细胞内的IDO的抑制活性均优于阳性对照药1‑甲基色氨酸(1‑MT)对细胞内的IDO的抑制活性，具有显著的IDO的抑制活性，可以用于治疗癌症、阿尔茨海默病、自身免疫性疾病、强直性脊柱炎、细菌感染、白内障、心境障碍、抑郁症或焦虑症。
Description
技术领域
本发明属于药品或保健品领域，具体涉及香加皮C21甾类化合物在制备IDO抑制剂中的用途。
背景技术
IDO(indoleamine-2，3-dioxygenase)中文名为吲哚胺2，3-双加氧化酶，是肝脏以外唯一催化色氨酸沿犬尿氨酸途径(kynurenine pathway，KP)代谢的限速酶，可以将色氨酸分解为L-犬尿氨酸、吡啶甲酸和喹啉酸等多种代谢物。L-色氨酸作为人体内维持细胞活化和增殖所必需的氨基酸，也是构成蛋白质不可缺少的成分，它的缺乏会导致一些重要细胞的功能异常。自1967年被发现以来，IDO通过降解色氨酸抑制病原微生物增殖的机制、IDO与神经系统疾病之间的关系逐渐被阐明；并有研究证实，IDO还参与调节T细胞的反应，能够对T细胞的增殖和活化产生抑制作用，而这种抑制作用则介导了表达IDO肿瘤细胞的免疫逃逸现象。因此，IDO的表达或活性的异常增高，与多种疾病的发病机制密切相关，是导致多种疾病的重要因素，例如已被证实的肿瘤、阿尔茨海默病、抑郁症和老年性白内障、AIDS等病毒感染、莱姆病和链球菌感染等细菌感染等(可参考如下文献：IDO抑制剂的研究进展，孔令雷等，《中国药物化学杂志》，2009，19(2)：147-154；中国专利文献CN101429151A一种含(E)-4-(Β-溴乙烯基)苯氧酰基结构的IDO抑制剂及其制备方法，公开日期2009年5月13日)。因此，IDO抑制剂成为极具潜力的治疗药物，引起了众多学者的关注。
作为一种全新靶点，IDO成为极具潜力的癌症免疫治疗靶标。筛选高效、低毒的IDO抑制剂/抗体，并将其用于治疗上述疾病，成为了研究人员的共同诉求。1978年，有研究人员研究分离出了非选择性的竞争性IDO抑制剂，但其抑制效力微弱。20世纪90年代初，首次合成了色氨酸衍生物1-MT(即：indoximod)，其作为与底物色氨酸结构最接近的抑制剂，引起了人们对于IDO抑制剂更为广泛的关注和兴趣。IDO抑制剂的研发尚处于药物开发的初期，目前仅有2个化合物(epacadostat和indoximod)进入Ⅱ期临床，1个化合物(GDC-0919)进入Ⅰ期临床。
最初寻找IDO抑制剂的工作主要以化学合成为手段，以IDO的底物色氨酸为模板，在研究构效关系的基础上对其进行结构修饰，发表的文章和注册的专利几乎覆盖了所有能修饰的基团，但是收效甚微。从2006年起，国内外学者们尝试从天然产物中寻找具有新结构骨架的高活性的IDO抑制剂，如：Brastianos等从海绵Neopetrosiaexigua中提取了得到Exiguamine A(Ki值＝0.21μM)；Alban Pereir等从海水螅中提取得到Annulin C(Ki值＝0.14μM)；Caspari等发现商业可售的天然产物Brassinin(Ki值＝97.7μM)具有中等活性；中国专利文献CN101843618A公开了：小檗碱及其衍生物亦具有IDO抑制作用。
香加皮，别名为北五加皮、香五加，来源于萝藦科(Asclepiadaceae)杠柳属(Periploca)植物杠柳(Periploca sepium Bunge)的干燥根皮。香加皮，性温，味辛、苦，有毒，具有祛风湿、强筋骨的功效，临床上中用于风寒湿痹、腰膝酸软、心悸气短、下肢浮肿的治疗；该药材是治疗类风湿性关节炎的传统中药，药理研究表明该药材具有抗炎和免疫抑制作用。从1987年日本学者发现该药材具有抗肿瘤作用以来，对该药材抗肿瘤活性成分及其作用机制的研究报道也逐渐增多。香加皮C21甾类化合物是香加皮提取物中的成分。
目前，关于香加皮C21甾类化合物用于制备IDO抑制剂尚无报道。
发明内容
为此，本发明要解决的技术问题是现有技术中无香加皮C21甾类化合物用于制备IDO抑制剂的问题，从而提供香加皮C21甾类化合物在制备IDO抑制剂中的用途。
为解决上述技术问题，本发明是通过以下技术方案来实现的：
本发明提供香加皮C21甾类化合物及其药学上可接受的衍生物在制备IDO抑制剂中的用途；
所述IDO抑制剂用于治疗癌症、阿尔茨海默病、自身免疫性疾病、强直性脊柱炎、细菌感染、白内障、心境障碍、抑郁症或焦虑症；所述药学上可接受的衍生物选自盐、酯、前药或溶剂合物；
所述香加皮C21甾类化合物具有如下所示的结构：
R1为-H或-CHO，R2选自
及其乙酰化衍生物、
及其乙酰化衍生物、
及其乙酰化衍生物中的至少一种所形成的糖基残基。
本发明还提供香加皮C21甾类化合物及其药学上可接受的衍生物在制备治疗IDO介导的色氨酸代谢途径的病理学特征的疾病的药品中的用途，所述疾病为癌症、阿尔茨海默病、自身免疫性疾病、强直性脊柱炎、细菌感染、白内障、心境障碍、抑郁症或焦虑症；所述药学上可接受的衍生物选自盐、酯、前药或溶剂合物；
所述香加皮C21甾类化合物具有如下所示的结构：
R1为-H或-CHO，R2选自
及其乙酰化衍生物、
及其乙酰化衍生物、
及其乙酰化衍生物中的至少一种所形成的糖基残基。
其中，糖的乙酰化衍生物是指：糖分子中的游离羟基(-OH)被乙酰基(-Ac)所保护的糖衍生物。
所述药学上可接受的盐，例如，是与盐酸、硫酸、磷酸、硝酸等无机酸形成的盐，或是与柠檬酸、琥珀酸、酒石酸、甲磺酸等有机酸形成的盐。
根据文献(“Structural revision of periplocosides and periperoxides，natural immunosuppressive agents from the genus Periploca”，Luo-Yi Wang etal.，Phytochemistry，2011，72，2230-2236)的报道，本发明香加皮C21甾类化合物中，杠柳苷A(Periploside A)曾用名为杠柳毒苷E(Periplocoside E)。
优选地，上述用途中，R1为-H或-CHO，R2选自：
优选地，上述用途中，
R1为H且R2为
时，所述香加皮C21甾类化合物为杠柳苷A(Periploside A)；或者
R1为H且R2为
时，所述香加皮C21甾类化合物为杠柳苷F(Periploside F)；或者
R1为-CHO且R2为
时，所述香加皮C21甾类化合物为杠柳苷U(Periploside U)；或者
R1为H且R2为
时，所述香加皮C21甾类化合物为杠柳苷T(Periploside T)。
优选地，上述用途中，不包括以下技术方案：
杠柳苷A及其药学上可接受的衍生物在制备IDO抑制剂中的用途；所述IDO抑制剂用于治疗自身免疫性疾病。
优选地，上述用途中，不包括以下技术方案：
杠柳苷A及其药学上可接受的衍生物在制备治疗IDO介导的色氨酸代谢途径的病理学特征的疾病的药品中的用途，所述疾病为自身免疫性疾病。
优选地，上述用途中，所述香加皮C21甾类化合物按照常规工艺，加入常规辅料制成临床上可接受的片剂、胶囊剂、散剂、合剂、丸剂、颗粒剂、糖浆剂、贴膏剂、栓剂、气雾剂、软膏剂或注射剂。
所述常规辅料为：填充剂、崩解剂、润滑剂、助悬剂、粘合剂、甜味剂、矫味剂、防腐剂、基质等。填充剂包括：淀粉、预胶化淀粉、乳糖、甘露醇、甲壳素、微晶纤维素、蔗糖等；崩解剂包括：淀粉、预胶化淀粉、微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙纤维素、交联羧甲基纤维素纳等；润滑剂包括：硬脂酸镁、十二烷基硫酸钠、滑石粉、二氧化硅等；助悬剂包括：聚乙烯吡咯烷酮、微晶纤维素、蔗糖、琼脂、羟丙基甲基纤维素等；粘合剂包括，淀粉浆、聚乙烯吡咯烷酮、羟丙基甲基纤维素等；甜味剂包括：糖精钠、阿斯帕坦、蔗糖、甜蜜素、甘草次酸等；矫味剂包括：甜味剂及各种香精；防腐剂包括：尼泊金类、苯甲酸、苯甲酸钠、山梨酸及其盐类、苯扎溴铵、醋酸氯乙定、桉叶油等；基质包括：PEG6000、PEG4000、虫蜡等。
本发明的技术方案具有如下优点：
本发明通过研究发现，杠柳苷A、杠柳苷F、杠柳苷U和杠柳苷T对细胞内的IDO的抑制活性均优于阳性对照药1-甲基色氨酸(1-MT)对细胞内的IDO的抑制活性，具有显著的IDO的抑制活性，可以用于治疗癌症、阿尔茨海默病、自身免疫性疾病、强直性脊柱炎、细菌感染、白内障、心境障碍、抑郁症或焦虑症。
具体实施方式
本发明以下实施例和实验例中，杠柳苷A(Periploside A)、杠柳苷F(PeriplosideF)、杠柳苷U(Periploside U)和杠柳苷T(Periploside T)可以按照本发明实施例1的方法进行制备获得，也可以按照如下文献制备获得：
Studies on chemical constituents of antitumor fraction from Periplocasepium BGE.I.Chemical&Pharmaceutical Bulletin，1987，35(11)，4524-4529.
Studies on chemical constituents of antitumor fraction from Periplocasepium.II.Structures of new pregnane glycosides,periplocosides A,B andC.Chemical&Pharmaceutical Bulletin，1988，36(3)，982-987.
Studies on chemical constituents of antitumor fraction from Periplocasepium.IV.Structures of new pregnane glycosides,periplocosides D,E,L,andM.Chemical&Pharmaceutical Bulletin，1988，36(6)，2084-2089.
Studies on chemical constituents of antitumor fraction from Periplocasepium.V.Structures of new pregnane glycosides，periplocosides J,K,F andO.Chemical&Pharmaceutical Bulletin，1988，36(11)，4441-4446.
Immunosuppressive pregnane glycosides from Periploca sepium andPeriploca forrestii.Phytochemistry，2008，69(15)，2716-2723.
Structural revision of periplocosides and periperoxides，naturalimmunosuppressive agents from the genus Periploca.Phytochemistry，2011，72(17)，2230-2236.
Corrigendum to“Structural revision of periplocosides andperiperoxides，natural immunosuppressive agents from the genus Periploca”[Phytochemistry 72/17(2011)2230–2236].Phytochemistry，2013，95，445.
高效液相色谱法测定中药香加皮中7种孕甾烷糖苷类成分的含量，《世界科学技术-中医药现代化》，2015，17(1)，138-141.
实施例1香加皮C21甾类化合物的制备
取香加皮，粉碎，加入3倍重量的体积浓度为95％的乙醇水溶液加热回流提取3次，每次提取2小时，合并提取液，减压浓缩至无醇味，得香加皮浸膏；
将香加皮浸膏混悬于1倍重量的水中，然后以氯仿为萃取剂进行萃取2次，收集萃取液的有机相，然后进行减压浓缩，得香加皮氯仿萃取部位浸膏；
取香加皮氯仿萃取部位浸膏经AB-8大孔树脂柱层析纯化(大孔树脂柱的直径为8cm，柱体积为3.5L)，以水为流动相A、以乙醇为流动相B，按照如下程序进行梯度洗脱(梯度洗脱的流速为3BV/h)：先用A：B体积比为50％：50％的流动相洗脱5BV，再用A：B体积比为40％：60％的流动相洗脱5BV，再用A：B体积比为30％：70％的流动相洗脱5BV，再用A：B体积比为15％：85％的流动相洗脱5BV，再用A：B体积比为5％：95％的流动相洗脱5BV；收集流动相为A：B体积比为5％：95％的洗脱液，然后分别进行减压浓缩，得香加皮乙醇洗脱部位浸膏；
将香加皮乙醇洗脱部位浸膏经经Agilent SD-1的C18反相制备液相分离纯化，以水为流动相C、以甲醇为流动相D，按照如下程序进行梯度洗脱：先用C：D体积比为40％：60％的流动相洗脱，再用C：D体积比为25％：75％的流动相洗脱，再用C：D体积比为15％：85％的流动相洗脱，再用C：D体积比为5％：95％的流动相洗脱，通过TLC检测或HPLC-MS检测，分别收集各流动相的洗脱液，然后分别进行减压浓缩、干燥，分别得杠柳苷A、杠柳苷F、杠柳苷U和杠柳苷T(HPLC纯度≥95％)。
将上述制备得到的化合物分别通过1H-NMR、13C-NMR和HPLC-MS进行结构确认，通过与现有文献中的1H-NMR、13C-NMR和HPLC-MS分别进行比对，可知所制备得到的化合物分别为杠柳苷A(Periploside A)、杠柳苷F(Periploside F)、杠柳苷U(Periploside U)和杠柳苷T(Periploside T)。
实验例1本发明香加皮C21甾类化合物对IDO的抑制活性的研究
1、实验目的
利用质粒pcDNA3.1-IDO转染HEK293细胞，使其高表达IDO，然后测定本发明香加皮C21甾类化合物在细胞水平对IDO的抑制活性。
2、实验方法
将HEK 293细胞以2.5X104细胞/孔的密度接种于96孔板中，DMEM培养基培养(含10％胎牛血清、50U/mL青霉素和50mg/mL链霉素)，置于37℃、湿度95％、5％CO2的培养箱中培养。培养24h后，使用脂质体Lipofectamin 2000介导pcDNA3.1-hIDO质粒转染，分为阳性对照组和实验组1-9组。
阳性对照组以1-甲基色氨酸(1-MT)为供试品，实验组1-4组分别以实施例1制备的杠柳苷A、杠柳苷F、杠柳苷U和杠柳苷T为供试品。
转染24h后，各组分别加入对应的供试品进行孵育。孵育5h后，取140μL上清到另一96孔板中，加入10μL 30％(w/v)三氯乙酸，在65℃加热15min，然后12000rpm离心10min，取等体积2％(w/v)对-二甲氨基苯甲醛的乙酸溶液混合显色，最后采用酶标仪在492nm检测吸光值，活性测定结果用IC50值表示。
3、实验结果
各组对IDO的抑制活性的具体实验结果如表1所示。
表1各组对细胞水平IDO的抑制活性的具体实验结果
| 组别 | IC<sub>50</sub>(μM) |
| 阳性对照组 | 17.8 |
| 实验组1组 | 10.3 |
| 实验组2组 | 8.4 |
| 实验组3组 | 10.8 |
| 实验组4组 | 10.9 |
由表1可知：(1)实验组1-4组对细胞内的IDO的抑制活性均优于阳性对照组对细胞内的IDO的抑制活性，具有显著的IDO的抑制活性；
(2)实验组1-4组对细胞内的IDO的抑制活性相当，这表明香加皮C21甾类化合物的R1和R2取代基的不同对抑制活性无明显影响。
4、实验结论
杠柳苷A、杠柳苷F、杠柳苷U和杠柳苷T对细胞内的IDO的抑制活性均优于阳性对照药1-甲基色氨酸(1-MT)对细胞内的IDO的抑制活性，具有显著的IDO的抑制活性。
实验例2本发明香加皮C21甾类化合物对强直性脊柱炎的治疗效果
1、实验目的
采用蛋白聚糖免疫方法建立小鼠强直性脊柱炎模型，然后灌胃本发明香加皮C21甾类化合物，ELISA法检测炎性标志物血清TNF-α和NF-кB受体活化因子配体(RANKL)水平，并检测血清IDO活性(Kyn/Trp)，验证本发明香加皮C21甾类化合物对于强直性脊柱炎的疗效。
2、实验方法
2.1实验动物
健康雄性BALB/c小鼠32只，体重(18±2)g，鼠龄4～5周，均购自上海斯莱克。
2.2供试药物
以实施例1制备的杠柳苷A和杠柳苷F为供试药物。
2.3实验分组及造模
将小鼠适应性喂养1周后，取其中8只作为空白对照组。取剩余的24只采用蛋白聚糖免疫方法建立强直性脊柱炎模型，鼠腹腔注射蛋白聚糖乳剂0.15mL(75μg+弗氏佐剂)，首次免疫后7天可加强免疫，腹腔注射0.15mL乳剂，造模共21天；造模成功后，分为3组：实验组1-2组和模型对照组。实验组1-2组分别给予实施例1制备的杠柳苷A和杠柳苷F灌胃给药，每日1次，每次0.2g/10g。模型对照组和空白对照组均给予等量生理盐水灌胃。各组均给药60天，于第61天眼眶取血。
2.4炎症因子测定
采用ELISA检测动物外周血中血清TNF-α和RANKL水平，按照试剂盒说明书操作。
2.5IDO活性检测
利用高效液相色谱技术同时检测小鼠血清中Trp浓度与Kyn浓度。因为IDO能催化底物Trp代谢生成产物Kyn，故Kyn/Trp比值可以反映IDO活性。
血清在4℃下放置过夜，3000rpm离心15min。取上清血清，加入等体积的5％高氯酸溶液，于漩祸混匀器上混匀0.5-1min。室温静置10-15min，以充分沉淀血清中的蛋白，然后以12000rpm离心10min，取上清液加入1/2体积甲醇(色谱纯)，在漩祸仪上振荡5min，然后12000rpm离心10min，最后上清经过0.45μm过滤器过滤后进行上样，检测血清中犬尿氨酸/色氨酸(Kyn/Trp)比值，从而反映IDO活性的变化。色谱条件：C18柱(250mm×4.6mm，5μm)；流动相：15mmol/L乙酸钠-乙酸溶液(含体积分数为7％的乙腈，pH 3.5)；流速：1mL/min；检测波长：225nm；进样量：20μL；柱温25℃。
2.6统计学处理
采用SPSS22.0统计学软件进行分析，计量数据用均数±标准差
表示，行t检验；计数资料用百分比表示，行χ2检验；P＜0.05表示差异有统计学意义。
3、实验结果
各组小鼠的具体实验结果如表2所示。
表2各组小鼠血清TNF-α和RANKL水平以及对IDO活性的抑制作用
#与空白对照组比较P＜0.05，*与模型对照组比较P＜0.05
由表2可知，(1)模型对照组小鼠的血清TNF-α和RANKL水平明显升高，这表明强直性脊柱炎模型造模成功；(2)实验组1-2组小鼠的血清TNF-α和RANKL水平显著降低(P＜0.05)，且显著降低IDO活性(P＜0.05)；这表明，实施例1制备的杠柳苷A和杠柳苷F通过抑制IDO活性起到对强直性脊柱炎的治疗效果。
4、实验结论
本发明杠柳苷A和杠柳苷F可以显著降低强直性脊柱炎模型的血清TNF-α和RANKL水平，且对IDO活性具有显著的抑制作用；本发明杠柳苷A和杠柳苷F对强直性脊柱炎具有显著的治疗作用。
实验例3本发明香加皮C21甾类化合物对于链球菌感染的治疗作用
1、实验目的
通过对链球菌感染小鼠灌胃本发明香加皮C21甾类化合物，检测其对于链球菌感染小鼠的死亡抑制率，验证其对链球菌感染的治疗作用。
2、实验方法
2.1实验动物
健康雄性昆明小鼠40只，体重(18±2)g，鼠龄4～5周，均购自上海斯莱克。
2.2供试药物
以实施例1制备的杠柳苷A和杠柳苷F为供试药物。
2.3实验分组及造模
溶血性链球菌CMCC(B)32171标准菌株接种兔血琼脂平板，划线后培养得到有明显溶血环的单菌落。取单菌落接种于THY培养基(含5％小牛血清)扩增过夜，OD600nm＝0.6(约109CFU/ml)时，4℃保存备用。THY培养基(每升含胰蛋白胨20克，酵母浸出物3克，牛肉膏5克，氯化钠2克，葡萄糖4克，碳酸钠2.5克，磷酸氢二钠0.4克，调pH至7.4。固体培养基：再加入1.5％琼脂粉，高压蒸气灭菌30min，置于4℃保存)。
取10只小鼠，作为空白对照组。将其余30只小鼠均分为3组：实验组1-2组和模型对照组，每组10只小鼠。实验组1-2组分别给予杠柳苷A和杠柳苷F灌胃给药，每次80mg/kg。模型对照组和空白对照组均给予等量生理盐水灌胃。实验组1-2组和模型对照组灌胃1h后，均尾静脉注射OD600nm＝0.6化脓性链球菌322171PBS溶液，注射剂量：0.4ml菌液/10g小鼠，每隔24h给药1次，每隔6h观察1次，分别记录时间6h、12h、24h、48h的小鼠的死亡情况。
3、实验结果
各组不同时间对链球菌感染小鼠死亡的影响如表3所示。
表3各组对链球菌感染小鼠死亡的影响(n＝10)
由表3可知，(1)给药48小时后，实验组1-2组的小鼠存活率分别为70％和80％，而模型对照组小鼠的存活率仅为20％；这表明，实施例1制备的杠柳苷A和杠柳苷F能够显著提高链球菌感染小鼠的存活率，对链球菌感染有显著的治疗作用。
4、实验结论
本发明杠柳苷A和杠柳苷F对链球菌感染有显著的治疗作用。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (2)
1.香加皮C21甾类化合物或其药学上可接受的盐作为唯一活性成分在制备治疗溶血性链球菌的药品中的用途，
所述香加皮C21甾类化合物具有如下所示的结构：
其中，R1为H且R2为
，所述香加皮C21甾类化合物为杠柳苷A；或者
R1为H且R2为
，所述香加皮C21甾类化合物为杠柳苷 F。
2.根据权利要求1所述的用途，其特征在于，所述香加皮C21甾类化合物按照常规工艺，加入常规辅料制成临床上可接受的片剂、胶囊剂、散剂、合剂、丸剂、颗粒剂、糖浆剂、贴膏剂、栓剂、气雾剂、软膏剂或注射剂。
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