CN102838610B - 双吲哚二氧杂双环辛二酮 - Google Patents
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Abstract
本发明涉及式(I)所示的双吲哚基二氧杂双环[3.3.0]辛二酮类化合物,其合成方法和抗肿瘤活性,用于制备抗肿瘤药物。
Description
技术领域
本发明涉及有机化合物合成及医药应用领域,尤其涉及一种双吲哚取代的二氧杂双环辛二酮类化合物的合成方法及其应用。
背景技术
由未经治疗的晚期肿瘤患者代谢物中分离得到的一种纯化合物,用现代化学分析方法剖析其化学结构,证明其化学结构为:
用所得到的化合物对数种人类肿瘤细胞的传外抑制活性测试证明其有良好的抗肿瘤活性。
设计化学合成方法制备了与上述结构相同的化合物。
发明内容
本发明涉及一种新的化合物,即双吲哚基二氧杂双环二酮类化合物的发现,这类化合物的制备方法。本发明所涉及的化合物具有抑制或杀灭肿瘤细胞,具有抗肿瘤活性,可以用作制备抗肿瘤药物。
本发明是通过以下技术方案实现的:
第一方面,本发明涉及一种新有机化合物(式Ⅱ)的结构全鉴定,其各项分析数据如下:
外观:棕色粉末。熔点:~225℃(分群)。旋光值:[α]D 200(0.1,甲醇)。
分子量和分子式:分子量372.11,分子式:C22H16N2O4。
高分辨质谱(HRMS)测定值:m/z373.11883(M++1);理论计算值(C22H16N2O4):m/z372.11033(M+)。
紫外光谱(UV):(MECH,λMax,logε),273.8(0.10),199.2(2.94)。
红外光谱(IR):(√cm-1,强度):3427(s),3282(m),3100-2800(m),1652,1608(s),1575(s),1418(s),1282(s),1238(s),1106(m),740(s),597(m)。
核磁共振氢谱('H-NMR)(DMSO-d6,500MH2,√ppm):11.9,(1H,NM),8.27(1H,C4'-H),7.86(2H,C2',C7'-H),7.45(1H,C5'-H),7.18(2H,C2,C6'-H),6.30(1H,C1-H)。
核磁共振13C谱:(DMSO-d6,125MH2,√ppm):168.6(C4,C8),138.5(C7'a),137.3(C3'a),131.2(C2'),125.0(C6'),122.4(C4'),120.8(C5'),119.7(C7'),112.3(C3'),112.2(C2或C6)。111.7(C1或C5)。
由于化合物分子结构的对称性,在其1H-NMR谱中质子数和13C-NMR中碳原子数均为实 际数目的一半。但从质量分析判断为双吲哚取代的双内酯桥环结构。
第二方面,本发明还涉及这种化合物的制备方法,包括如下方法:
方法一,在多聚磷酸中,加入3-(吲哚-3'-基)丙烯酸,加热50-100℃反应1-4小时,冷却的反应混合物倒入水中,再用有机溶剂提取,并经核色谱分离得产物。
方法二,在有机溶剂(如甲醇)中,以高级金属盐(如三氯化铁)催化,溶入了3-(吲哚-3'-基)丙烯酸,通入氧气或空气反应,过滤沉淀之产物,在重结晶得纯化合物。
第三方面,本发明还涉及一种双吲哚基二氧杂双环[3.3.0]辛二酮类化合物在抗肿瘤药物中的应用。
所述的肿瘤为白血病、卵巢癌和乳腺癌。
具体实施方式
以下通过具体的实施例对本发明的技术方案作详细说明,本方案实施例在发明技术方案的前提下进行实施,给出了详细的实施方式和具体的操作过程,但本发明的保护范围不限于下述的实施例。
以下实施例制备的化合物为:
合成的路线为:
[实施例1]
3-(吲哚-3'-基)丙烯酸1.87克(10毫克分子)分次加入热至90-95℃的多聚磷酸中,同时用搅拌棒剧烈搅拌使加料分散均匀。加完后继续搅拌反应物1-4小时。
冷却至室温,将反应混合物倾入1升水中,将此水液用普通有机溶剂(乙酸乙醇,二氯甲烷,三氯甲烷)提取。提取液经MgSo4干燥。所得未见产物经核色谱(硅胶C,200-400 目)分离,甲醇/二氯甲烷洗脱,得产物0.21g(产率~11.3%)。
[实施例2]
200毫升甲醇中加入20克三氯化铁(化合物),搅拌下通入氧气。1小时后,缓慢加入1.87克(10毫克分子)3-(吲哚-3'-基)丙烯酸。反应液温度升高,必要时克加外部冷却以不使甲醇逸出。加完后,继续搅拌并通氧反应4-10小时。
反应完成后,产物过滤,滤物用水洗三次,压干后空气干燥,得粗产物1.43克。将粗产物溶于甲醇,加热至完全溶解后再加入少量甲烷至略现浑浊。置冰箱中,次日滤出沉淀物,干燥得纯化合物1.02克(产率~55%)。
[
实施例3]
抗肿瘤活性测试
1.材料与仪器
细胞株
人卵巢细胞株OVCa2780,人乳腺细胞株MCF,人髓样红白血病细胞株K562,小鼠淋巴白血病细胞株P388.
试剂
RPM1.1640培养液(吉诺生物医药技术有限公司),DNEM高糖培养液(吉诺生物医药技术有限公司),胎牛血清(FBS)(杭州四季青工程公司),青-链霉素溶液(100x)(Bowest子公司),磷酸盐缓冲溶液(PBS)(北京Solarbio技术有限公司)。0.25%胰酶溶液+0.02%乙二胺四乙酸(EDTA)(吉诺生物医药技术有限公司),磺酰罗丹明B(SRB)(Sigma公司),二甲基亚砜(DMSO)(上海钰森生物技术有限公司),三氯乙酸(TCA)(国药集团化学制剂有限公司),Tris碱(Sigma公司),冰醋酸(国药集团化学制剂有限公司)。
对照品
顺铂(国药集团北京第二制药厂)。
试剂配制
以冰醋酸与双蒸馏水配成1%醋酸溶液,以1%醋酸溶液与SRB配制成0.4%SRB溶液,于4℃避光保存。以TCA与双蒸馏水配制成50%TCA溶液,并以Tris碱与双蒸馏水配制成10mmol/L的Tris碱溶液,用氢氧化钠溶液调节pH=10.0;以被测样品(实施例1或例2所述化合物),对照品(顺铂)分别与DMSO配制成2mg1mL的原始溶液保存,实验时用配养基配制成所需浓度。
主要仪器
CO2培养箱(Thermo Forma SeriesⅡ),净化工作台(上海新苗医药器械制造有限公司),酶联免疫检测仪(Thermo MK3),倒置微生物显微镜(飞鸽TDL80-23)。
方法与结果
细胞培养
细胞接种于含FBS、1%青-链霉素溶液的配养基中,置于37℃,5%CO2培养箱中,每2-3天传代一次,试验时取对数生长期细胞。
SBR法测定IC50值
取对数生长期细胞,以配制好的新鲜培养基调节细胞悬液至5×104个/1ml,接种到96孔板中,每孔190μL,设药物处理组、平行对照组、空白对照组。在37℃5%CO2培养箱中配养12小时后,加入10μL不同浓度的被测试样品溶液和对照溶液,实验设置双复孔。平行对照组培养30min,药物处理组培养48h后,加入S0%TCA50μL固定细胞,静置5min后将96孔板置于4℃下30min。弃去固定液,水洗5次,空气干燥。每孔中加入0.4SRB溶液100μL,室温下置1h。弃去SRB溶液,用1%醋酸溶液洗涤5次后空气干燥。每孔中加入200μL10mmol/L的Tris碱溶液(pH=10),在570nm波长下用酶联免疫检测仪测定光密度(OD)值,用非线性回归分析计算IC50值。(表1)
表1双吲哚基-二氧杂双环[3.3.0]辛二酮的抗肿瘤活性
Claims (7)
1.一种化合物或其盐,其化学式为:
其化学式名称是:2.6-双(吲哚-3’-基)-3.7-二氧杂双环[3.3.0]辛烷-4.8-二酮。
2.用于制备权利要求1所述的化合物的方法,其特征在于:
(1)用三氯化铁作催化剂,由3-(吲哚-3’-基)丙烯酸在甲醇中通入氧气的制法;或
(2)用多聚磷酸作反应介质,3-(吲哚-3’-基)丙烯酸在50-100℃加热条件下用氧气或空气氧化的制备方法。
3.一种根据权利要求1所述的2.6-双(吲哚-3’-基)-3.7-二氧杂双环[3.3.0]辛烷-4.8-二酮类化合物的用途,其特征在于,该用途是在制备抗白血病,卵巢癌,乳腺癌药物中的用途。
4.根据权利要求1所述的2.6-双(吲哚-3’-基)-3.7-二氧杂双环-[3.3.0]辛烷-4.8-二酮化合物的盐,其特征是,该盐类是由所述的化合物与无机酸或有机酸合成的在药学上可接受的盐。
5.根据权利要求4所述的盐,其特征是,所述的有机酸为甲酸,乙酸,丙酸,草酸,丙二酸,丁二酸,戊二酸,己二酸,乳酸,富马酸,苹果酸,酒石酸,苯甲酸,二乙基乙酸,琥珀酸,氨基磺酸,氨基酸,桂皮酸,水杨酸,甲磺酸,对甲基磺酸,苯丙酸,烟酸,异烟酸或柠檬酸。
6.根据权利要求4所述的盐,其特征是,所述的无机酸为盐酸,硫酸,氢溴酸,磷酸或硝酸。
7.根据权利要求5所述的盐的用途,其特征在于,该用途为在制备抗白血病、卵巢癌和乳腺癌药物中的用途。
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