CN114539292B - 一种新型鬼臼毒素拼接抗肿瘤活性分子化合物及其制备方法及应用 - Google Patents
一种新型鬼臼毒素拼接抗肿瘤活性分子化合物及其制备方法及应用 Download PDFInfo
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- C07D—HETEROCYCLIC COMPOUNDS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (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)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种新型鬼臼毒素拼接抗肿瘤活性分子化合物,本发明通过鬼臼毒素与丁二酸酐在有机溶剂之中,在催化剂有机碱性小分子的催化及缚酸剂作用下,发生反应生成中间体,然后将抗肿瘤活性分子分别与上述中间体置于有机溶剂之中,在催化剂有机碱性小分子的催化和缩合剂作用下,进行酯化反应得到新型鬼臼毒素拼接抗肿瘤活性分子化合物。对药物的筛选和制药行业具有重要的应用价值,且通过体外抗肿瘤活性筛选发现,该类化合物对人非小细胞肺癌细胞、人肺腺癌耐顺铂株具有非常好的抑制作用,对人肺腺癌耐顺铂株的细胞毒性是阳性对照药物依托泊苷的80多倍,很有可能进一步开发成为新的防治肿瘤的药物。
Description
技术领域
本发明涉及化学技术领域,尤其是一种新型鬼臼毒素拼接抗肿瘤活性分子化合物及其制备方法及应用。
背景技术
奎宁(Quinine)又名金鸡纳碱、金鸡纳霜,是茜草科植物金鸡纳树及其同属植物的树皮中的主要生物碱,不仅具有显著的抗疟作用,还具有显著的抗肿瘤活性,能促进肿瘤细胞凋亡;喜树碱(Camptothecin)是从珙桐科植物喜树中提取分离得到,具有显著的抗肿瘤活性,以喜树碱作为先导化合物进行结构改造得到一系列化合物,如伊立替康、拓扑替康、贝洛替康、BNP-1350、Gimatecan,现已经上市用于临床或处于临床试验研究之中;吲哚(Indole)是一类重要的活性骨架,存在于许多的天然活性化合物之中,其中最突出的生物活性是其抗肿瘤活性,通过大量的科学研究,现在已经得到很多具有抗肿瘤活性的先导化合物、正在临床实验研究或已上市的抗肿瘤药物,如Selumetinib、奥希替尼、Strychnofoline、Ganetespib等。
鬼臼毒素(Podophyllotoxin)是从小蘖科鬼臼属植物华鬼臼的根和茎中提取分离得到的芳基萘类木脂素,由于可抑制人乳头瘤病毒(HPV)感染所导致疣状增殖的上皮细胞的分裂和增生,临床上主要用于治疗生殖器尖锐湿疣。同时鬼臼毒素最为突出的生物活性为抗肿瘤活性,但是由于毒性大导致强烈的不良反应限制了其应用,因此对鬼臼毒素开展了大量结构修饰工作,得到一系列具有抗肿瘤活性的鬼臼毒素衍生物,如依托泊苷(Etoposide,VP-16)和替尼泊苷(Teniposide,VM-26)等己成为目前临床上广泛使用的抗癌药物,然而,临床应用发现依托泊苷和替尼泊苷具有抗瘤谱窄、水溶性差,易产生多药耐药和严重的胃肠道功能紊乱等缺点,需进一步结构修饰或与其他活性分子拼接解决以上问题。
因此我们采用药物的拼合原理,将鬼臼毒素分别和奎宁、喜树碱、3-羟甲基吲哚通过丁二酸酐作为linker进行拼接,得到新型鬼臼毒素拼接抗肿瘤活性分子化合物,具有非常好的抗肿瘤活性,并提高抗瘤谱,解决耐药性,可以被进一步开发研究,同时也可以为生物活性筛选提供化合物源,对药物的筛选和制药行业具有重要的应用价值。
发明内容
本发明的目的是:提供一种新型鬼臼毒素拼接抗肿瘤活性分子化合物及其制备方法与应用,它是一类重要的医药中间体类似物、药物分子类似物,为体外抗肿瘤活性、抗病毒、抗疟疾活性筛选提供化合物源,对药物的筛选和制药行业具有重要的应用价值,其合成方法具有收率高、非常经济简便、后处理简单等优点。
本发明还发现该类化合物在制备防治肿瘤疾病药物中的应用。
本发明是这样实现的:一种新型鬼臼毒素拼接抗肿瘤活性分子化合物,该类化合物具有如通式(Ⅰ)所示的结构:
式中,Drug为奎宁、1-Boc-3-羟甲基-2-甲基吲哚或喜树碱。
一种新型鬼臼毒素拼接抗肿瘤活性分子化合物及其制备方法:
将鬼臼毒素、丁二酸酐按摩尔比为1:2的比例在有机溶剂之中,在催化剂有机碱性小分子的催化及缚酸剂作用下,发生反应生成中间体,然后将抗肿瘤活性分子(奎宁;1-Boc-3-羟甲基-2-甲基吲哚;喜树碱)分别与上述中间体按摩尔比1:1.1的比例下置于有机溶剂之中,在催化剂有机碱性小分子的催化和缩合剂作用下,进行酯化反应得到新型鬼臼毒素拼接抗肿瘤活性分子化合物。
合成路线举例如下:
其中Drug=奎宁、1-Boc-3-羟甲基-2-甲基吲哚或喜树碱。
所述的有机小分子碱性催化剂为N,N,N、,N、-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲、4-二甲氨基吡啶或其它有机生物碱等,有机小分子碱性催化剂举例如下(但需强调的是本发明的有机小分子碱性催化剂不限于如下表示的内容):
缚酸剂为吡啶、三乙胺或其它有机生物碱等,缚酸剂举例如下(但需强调的是本发明的缚酸剂不限于如下表示的内容):
缩合剂为N,N'-二环己基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐或其它有机生物碱等,缩合剂举例如下(但需强调的是本发明的缩合剂不限于如下表示的内容):
所述的有机溶剂为N,N'-二甲基甲酰胺、二氯甲烷、甲苯、三氯甲烷、乙醚等。
鬼臼毒素与丁二酸酐、中间体与抗肿瘤活性分子(奎宁;1-Boc-3-羟甲基-2-甲基吲哚;喜树碱)在有机溶剂中反应温度为0-60℃,反应时间为0.5-12.0小时。
一种新型鬼臼毒素拼接抗肿瘤活性分子化合物在制备和防治肿瘤疾病药物中的应用。
通过采用上述技术方案,将鬼臼毒素、丁二酸酐按摩尔比为1:2的比例在有机溶剂之中,在催化剂有机碱性小分子的催化及缚酸剂作用下,发生反应生成中间体,然后将抗肿瘤活性分子(奎宁;1-Boc-3-羟甲基-2-甲基吲哚;喜树碱)分别与上述中间体按摩尔比1:1.1的比例下置于有机溶剂之中,在催化剂有机碱性小分子的催化和缩合剂作用下,进行酯化反应得到新型鬼臼毒素拼接抗肿瘤活性分子化合物。该类化合物分别同时包含鬼臼毒素和奎宁、吲哚、喜树碱骨架,不仅在抗肿瘤活性、抗病毒、抗疟疾活性等方面存在具有潜在的生物活性,还在多靶点药物的研究上具有重要意义,同时为生物活性筛选提供化合物源,对药物的筛选和制药行业具有重要的应用价值,且通过体外抗肿瘤活性筛选发现,该类化合物对人非小细胞肺癌细胞(A549)、人肺腺癌耐顺铂株(A549/DDP)具有非常好的抑制作用,优于阳性对照药依托泊苷和顺铂,很有可能进一步开发成为新的防治肿瘤的药物。本发明操作方法非常经济简便,产物收率较高,后处理简单,原料便宜易得,可进一步研究发掘其抗肿瘤机制及抗瘤谱。
附图说明
附图1为本发明的实施例1的化合物1a谱图数据;
附图2为本发明的实施例1的化合物2a谱图数据;
附图3为本发明的实施例1的化合物2b谱图数据;
具体实施方式
本发明的实施例:在反应管中依次加入414.41mg鬼臼毒素(1mmol),200.1mg丁二酸酐(2eq,2.0mmol),101.2mg缚酸剂三乙胺,122.1mg催化剂4-二甲氨基吡啶和5ml二氯甲烷溶液,室温反应2小时,TLC检测基本反应完全,旋干溶剂,上样经硅胶柱层析(洗脱剂:V(二氯甲烷):V(甲醇)=100:3)纯化得中间体化合物1a。白色固体,熔点:75.5–76.4℃;产率99.2%;核磁共振和高分辨质谱测试结果如下:1H NMR(CDCl3,400MHz)δ:6.78(s,1H),6.53(s,1H),6.39(s,2H),5.98(dd,J=6.2,1.3Hz,2H),5.93(d,J=9.1Hz,1H),4.60(d,J=4.4Hz,1H),4.36(dd,J=9.3,6.9Hz,1H),4.17(t,J=9.8Hz,1H),3.81(s,3H),3.76(s,6H),2.97–2.78(m,2H),2.75–2.68(m,2H).13C NMR(CDCl3,100MHz)δ:176.90,173.88,172.76,152.65,148.20,147.64,137.18,134.91,132.38,128.16,109.76,108.21,107.03,101.65,74.00,71.40,60.80,56.24,45.55,43.74,38.62,29.05,28.77.;HRMS(ESI-T OF)m/z:Calcd.for C26H26NaO11[M+Na]+:537.1373;Found:537.1378.
再取64.9mg奎宁(0.2mmol),上述中间体1a 113.1mg(0.22mmol),4.88mg催化剂4-二甲氨基吡啶(0.04mmol),76.5mg缩合剂1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,5ml二氯甲烷溶液于反应管之中,真空下反应12小时,TLC检测基本反应完全,加入20ml二氯甲烷稀释,然后加入1M盐酸溶液洗涤,取二氯甲烷层,用饱和食盐水洗涤,无水硫酸钠干燥,旋干二氯甲烷层上样经硅胶柱层析(洗脱剂:V(二氯甲烷):V(甲醇)=15:1至10:1)纯化得最终产物2a,白色固体,熔点:180.1-180.9℃;产率95.1%;核磁共振和高分辨质谱测试结果如下:1H NMR(CDCl3,400MHz)δ:8.75(d,J=4.5Hz,1H),8.04(d,J=9.2Hz,1H),7.42(dd,J=9.2,2.6Hz,1H),7.35(d,J=4.5Hz,1H),7.29(s,3H),6.77(s,1H),6.53(s,1H),6.38(s,2H),5.98(s,2H),5.87(d,J=9.2Hz,1H),5.76(s,1H),5.13 5.06(m,2H),4.60(d,J=4.4Hz,1H),4.09(s,3H),4.00(t,J=9.9Hz,1H),3.82(s,3H),3.76(s,6H),3.67(s,1H),3.47(s,1H),2.92 2.73(m,6H),2.02 1.72(m,8H),1.28(s,1H).13C NMR(CDCl3,100MHz)δ:173.65,172.87,152.65,148.22,147.64,144.79,137.17,134.85,132.31,131.89,127.99,109.72,108.12,107.12,101.64,101.14,74.22,71.11,70.60,60.80,58.76,56.21,45.53,43.71,42.89,38.60,29.16,28.89,27.28.;HRMS(ESI-TOF)m/z:Calcd.for C46H48N2NaO12[M+Na]+:843.3105;Found:843.3101.
化合物2b至2c的制备方法同化合物2a,投料比与化合物2a相同,可得到化合物2b和2c,反应产率见表1,但需强调的是本发明的化合物不限于表1所表示的内容。
表1为一种新型鬼臼毒素拼接抗肿瘤活性分子化合物的化学结构
本实施例制备化合物2b:白色固体,熔点:115.4-116.4℃;产率:99.3%;核磁共振和高分辨质谱测试结果如下:1H NMR(CDCl3,400MHz)δ:8.07(d,J=8.2Hz,1H),7.52(dd,J=7.5,1.6Hz,1H),7.23(td,J=7.2,1.6Hz,2H),6.76(s,1H),6.53(s,1H),6.38(s,2H),6.00–5.94(m,2H),5.80(d,J=8.9Hz,1H),5.31(d,J=3.5Hz,2H),4.60(d,J=4.3Hz,1H),4.34(dd,J=9.3,6.7Hz,1H),4.14(t,J=9.7Hz,1H),3.81(s,3H),3.75(s,6H),2.92–2.78(m,2H),2.74–2.66(m,4H),2.63(s,3H),1.68(s,9H).13C NMR(CDCl3,100MHz)δ:173.79,172.87,172.25,152.68,150.53,148.17,147.62,137.48,137.16,135.70,134.91,132.32,128.93,128.27,123.91,122.90,118.03,115.54,112.90,109.71,108.09,107.10,101.63,84.20,73.97,71.42,60.81,57.61,56.18,45.59,43.77,38.65,29.29,29.13,28.28,14.04.;HRMS(ESI-TOF)m/z:Calcd.for C41H43NNaO13[M+Na]+:780.2632;Found:780.2634.
本实施例制备化合物2c:褐色固体,熔点:195.5~196.5℃;产率:86.2%;;核磁共振和高分辨质谱测试结果如下:1H NMR(CDCl3,400MHz)δ:8.34(s,1H),8.11(d,J=8.5Hz,1H),7.87(dd,J=8.3,1.4Hz,1H),7.75–7.71(m,1H),7.61–7.57(m,1H),7.24(s,1H),6.67(s,1H),6.39(s,1H),6.20(s,2H),5.88(s,2H),5.71(d,J=9.3Hz,1H),5.60(d,J=17.2Hz,1H),5.30(d,J=17.3Hz,1H),4.36(d,J=4.5Hz,1H),3.80(dd,J=9.3,7.0H z,1H),3.74–3.69(m,5H),3.64(s,6H),3.60–3.55(m,1H),2.65–2.53(m,4H),2.23–1.94(m,4H),0.94(t,J=7.5Hz,3H).13C NMR(CDCl3,100MHz)δ:173.4,172.9,171.5,167.5,162.6,157.3,152.6,152.4,148.8,148.1,147.6,146.2,145.9,137.1,134.7,132.2,131.3,130.7,129.5,128.8,128.4,128.3,128.1,128.0,119.9,109.7,108.0,106.9,101.6,96.2,74.1,71.0,67.0,60.8,56.1,50.1,45.2,43.7,38.3,36.5,31.7,31.5,28.9,28.8,7.6.;HRMS(ESI-TOF)m/z:Calcd.For C46H40N2NaO14[M+Na]+:867.2377;Found:867.2374.
本发明的式(I)化合物具有重要的生物活性,通过MTT法体外对人非小细胞肺癌细胞(A549)、人肺腺癌耐顺铂株(A549/DDP)的细胞毒性试验表明:此类式(I)所示的结构的一种新型鬼臼毒素拼接抗肿瘤活性分子化合物对肿瘤细胞生长具有非常好的抑制作用,均明显优于阳性对照药物依托泊苷和顺铂,其中化合物2a对人肺腺癌耐顺铂株(A549/DDP)的细胞毒性是阳性对照药物依托泊苷的80多倍,同时化合物2a表现出较好的抗耐药性,经过一系列机制的研究,很有可能进一步开发成为新的防治肿瘤的药物。但需强调的是本发明的化合物不限于人非小细胞肺癌细胞(A549)、人肺腺癌耐顺铂株(A549/DDP)表示的细胞毒性。
药理实施例:化合物2a-2c对人非小细胞肺癌细胞(A549)、人肺腺癌耐顺铂株(A549/DDP)的体外抗肿瘤活性测试,采用改良MTT法,以A549/DDP细胞株为例。
取处于对数生长期,生长状态良好的A549/DDP细胞,用含10%小牛血清的培养基配成细胞悬液,以2×103个/孔接种在96孔板,同时设空白组,37℃培养过夜;分别将新配的化合物2a-2c的二甲基亚砜溶液以浓度梯度加入到各孔中,使孔中化合物最终浓度分别为0.01μmol/L,0.1μmol/L,1μmol/L,10μmol/L和100μmol/L,每组设3复孔;细胞培养72h后,每孔加入10μL MTT的磷酸盐缓冲液,再37℃下培养4h,离心5分钟除去未转化的MTT,每孔中加入150μL二甲基亚砜,以溶解还原的MTT晶体甲臜(formazan),用酶标仪在568nm波长测定各孔吸光值OD。细胞增殖抑制率=1-(实验组OD-空白组OD值)/(对照组OD值-空白组OD值),A549/DDP细胞半抑制浓度IC50由spss软件分析得到。
化合物2a-2c的体外抗肿瘤活性测试如表2所示,其中化合物2a对A549/DDP的细胞毒性(IC50=0.988±0.016μmol/L)是阳性对照药物依托泊苷(IC50=84.386±2.692μmol/L)的80多倍,同时化合物2a表现出较好的抗耐药性,对非耐药株A549的细胞毒性(IC50=0.085±0.003μmol/L)。化合物2c对A549的细胞毒性(IC50=0.068±0.003μmol/L)是阳性对照药物顺铂(IC50=39.137±2.873μmol/L)的500多倍。
表2化合物2a-2c的体外抗肿瘤活性测试结果
aData were expressed as mean IC50±SD(μM),n=3
bRF was computed as IC50(A549/DDP)/IC50(A549)
实验结论:非小细胞肺癌细胞(A549)、人肺腺癌耐顺铂株(A549/DDP)是测试化合物体外对肿瘤细胞细胞毒性的有效工具和评价指标,同时作为评价化合物对耐药肿瘤细胞的细胞毒性重要指标。本实验表明此类式(I)所示的一种新型鬼臼毒素拼接抗肿瘤活性分子化合物对人非小细胞肺癌细胞(A549)、人肺腺癌耐顺铂株(A549/DDP)具有非常强的细胞毒性,均明显优于阳性对照药物依托泊苷和顺铂,其中化合物2a对人肺腺癌耐顺铂株(A549/DDP)的细胞毒性是阳性对照药物依托泊苷的80多倍,同时化合物2a表现出较好的抗耐药性,对耐药株和非耐药株的活性一致,经过后期一系列机制研究,很有可能进一步开发成为新的防治肿瘤的药物。由此可见以上化合物具有开发成为抗肿瘤药物的潜力,且具有一定的经济和临床价值,值得我们继续深入研究下去。
Claims (5)
1.一种鬼臼毒素拼接抗肿瘤活性分子化合物,其特征在于:该化合物具有如式(Ⅰ)所示的结构:
2.一种如权利要求1所述的一种鬼臼毒素拼接抗肿瘤活性分子化合物的制备方法,其特征在于:将鬼臼毒素、丁二酸酐按摩尔比为1:2的比例在有机溶剂之中,在催化剂的催化和缚酸剂作用下,发生反应生成中间体,然后将上述中间体与1-Boc-3-羟甲基-2-甲基吲哚按摩尔比1:1.1的比例下置于有机溶剂之中,在催化剂的催化和缩合剂作用下,进行酯化反应得到新型鬼臼毒素拼接抗肿瘤活性分子化合物,所述合成路线如下:
3.根据权利要求2所述的一种鬼臼毒素拼接抗肿瘤活性分子化合物的制备方法,其特征在于:所述的有机溶剂为二氯甲烷、N,N'-二甲基甲酰胺、甲苯、三氯甲烷或乙醚。
4.根据权利要求2所述的一种鬼臼毒素拼接抗肿瘤活性分子化合物的制备方法,其特征在于:反应时间为0.5-12.0小时,所述的反应温度为0-60℃。
5.一种如权利要求1所述的一种鬼臼毒素拼接抗肿瘤活性分子化合物在制备防治肿瘤疾病药物中的应用,其特征在于:所述的肿瘤疾病为肺癌细胞A549或人肺腺癌耐顺铂株A549/DDP导致的肿瘤。
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