CN108191898B - 一种苯并硼唑7位查尔酮衍生物及其制备与应用 - Google Patents
一种苯并硼唑7位查尔酮衍生物及其制备与应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及药物化学技术领域,具体涉及一种苯并硼唑7位查尔酮衍生物及其制备与应用。
背景技术
近十年来,苯并硼唑类化合物在药物化学领域中的应用得到了飞速的发展,有望成为一类新型抗感染药物。目前已有抗真菌药物5-氟苯并硼唑(tavaborole)于2014年被美国食品药品监督管理局(FDA)批准上市,用于治疗甲癣;另外,磷酸二酯酶-4抑制剂crisaborole于2016年被美国食品药品监督管理局(FDA)批准上市,用于治疗过敏性皮炎(http://www.fda.gov/)。
尽管苯并硼唑类化合物被广泛应用于抗真菌,抗细菌,抗寄生虫,抗病毒和抗炎等领域(Chem.Rev.2015,115,5224-5247.;Sci.China Chem.2013,56,1372-1381.),但目前其在抗肿瘤领域的相关研究较少。
发明内容
本发明的目的就是为了克服上述现有技术存在的缺陷而提供一种低毒性的苯并硼唑7位查尔酮衍生物及其制备与应用。
本发明的目的可以通过以下技术方案来实现:一种苯并硼唑7位查尔酮衍生物,该衍生物的分子式为:
优选的,所述的稠环基包括萘基,所述杂环基及杂环取代基中的杂环包括呋喃、噻吩或吡咯中的一种,所述取代苯基、取代杂环基中的取代物包括卤素、羟基、甲氧基、甲硫基、烷基、硝基或三氟甲基中的一种。
最优选的,所述的R为对位三氟甲基取代的苯基或3’,4’-二氯取代的苯基。
一种如上所述苯并硼唑7位查尔酮衍生物的制备方法,包括以下步骤:
所述的混合溶液为甲醇或乙醇与水的混合溶液,甲醇或乙醇和水的体积比为(0.5~10):1。
所述的反应时间为0.5~72h,所述盐酸调节pH至1~7。
一种如上所述苯并硼唑7位查尔酮衍生物的应用,该衍生物具有抗肿瘤活性,具有抑制肿瘤组织生长的活性,所以可以用于合成预防和治疗肿瘤的药物,所述肿瘤包括卵巢癌SKOV3,乳腺癌MDA-MB231,结肠癌HCT116等肿瘤细胞系。另外,该类化合物对正常细胞系毒性较低。其中正常细胞系包括但不限于MCF-10A和WI-38等人正常细胞系。
与现有技术相比,本发明的有益效果体现在以下几方面:
(1)该类化合物具有较好的抑制肿瘤细胞增殖的活性,可以有效地抑制卵巢癌,乳腺癌,结肠癌等常见肿瘤细胞的增殖,并且该类化合物对人正常细胞系的毒性较低;
(2)合成简单,没有涉及非常繁琐的步骤,合成成本低。
附图说明
图1为实施例9所得衍生物在体内肿瘤增殖抑制活性测试中肿瘤体积随治疗时间的变化示意图;
图2为实施例9所得衍生物在体内肿瘤增殖抑制活性测试中小鼠体重随治疗时间的变化示意图;
图3为实施例9所得衍生物在体内肿瘤增殖抑制活性测试中肿瘤质量与空白组肿瘤质量的比对图。
具体实施方式
下面对本发明的实施例作详细说明,本实施例在以本发明技术方案为前提下进行实施,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。
实施例1
(E)-1-苯基-3-(1-羟基-1,3-二氢-苯并[c][1,2]硼唑-7-基)-2-丙烯酮(1)
在乙醇(8mL)和水(2mL)的混合溶剂中加入苯乙酮(223mg,1.85mmol)和氢氧化钠(245mg,6.15mmol)。室温搅拌10分钟后,加入化合物1-羟基-7-甲酰基-1,3-二氢-苯并[c][1,2]硼唑(200mg,1.23mmol)并室温搅拌过夜。用1M盐酸调节反应液pH值至3后过滤。滤饼用硅胶柱层析(二氯甲烷/甲醇=250/1)纯化,所得产物再用正己烷/乙酸乙酯=3/1打浆得到化合物1(90.0mg,27.6%)。1H NMR(400MHz,DMSO-d6):δ9.38(s,1H),8.22(d,J=16.0Hz,1H),8.15(d,J=7.8Hz,2H),8.10(d,J=16.0Hz,1H),8.04(d,J=7.6Hz,1H),7.69(t,J=7.6Hz,1H),7.58(t,J=7.8Hz,3H).7.47(d,J=7.6Hz,1H),5.04(s,2H)ppm;13C NMR(100MHz,DMSO-d6):δ189.4,154.6,142.7,137.9,137.6,133.0,131.1,128.7,128.4,125.6,123.1,69.7ppm;HRMS(ESI):[M+Na]+C16H13BO3Na calcd 287.0855,found 287.0858;mp:135-138℃;HPLC:purity 95.7%,retention time 18.3min。
实施例2
(E)-1-(萘-1-基)-3-(1-羟基-1,3-二氢-苯并[c][1,2]硼唑-7-基)-2-丙烯酮(2)
合成方法类似实施例1,不同之处在于:
(3)反应时间为72h,反应后用盐酸调节pH至1,打浆最终得到化合物2(72.5mg,62.3%)。1H NMR(400MHz,DMSO-d6):δ9.23(s,1H),8.36-8.34(m,1H),8.16(d,J=8.2Hz,1H),8.12(d,J=16.0Hz,1H),8.06-8.03(m,1H),8.01(dd,J=7.2,1.0Hz,1H),7.96(d,J=7.6Hz,1H),7.75(d,J=16.0Hz,1H),7.67-7.60(m,3H),7.56(t,J=7.6Hz,1H),7.47(d,J=7.6Hz,1H),5.03(s,2H)ppm;13C NMR(100MHz,DMSO-d6):δ154.6,143.6,137.6,136.2,133.3,131.7,131.1,129.8,128.4,127.8,127.5,127.4,126.3,125.3,125.1,124.7,123.2,69.6ppm;HRMS(ESI):[M+H]+C20H16BO3calcd 315.1192,found 315.1196;mp:178-181℃;HPLC:purity 97.3%,retention time 19.6min。
实施例3
(E)-1-(呋喃-2-基)-3-(1-羟基-1,3-二氢-苯并[c][1,2]硼唑-7-基)-2-丙烯酮(3)
合成方法类似实施例1,不同之处在于:
(3)反应时间为0.5h,反应后用盐酸调节pH至6.9,打浆最终得到化合物3(43.0mg,45.7%)。1H NMR(400MHz,DMSO-d6):δ9.36(s,1H),8.21(d,J=16.0Hz,1H),8.07(d,J=1.6Hz,1H),8.01(d,J=7.6Hz,1H),7.86(d,J=16.0Hz,1H),7.78(d,J=3.6Hz,1H),7.57(t,J=7.6Hz,1H),7.47(d,J=7.6Hz,1H),6.80(dd,J=3.6,1.6Hz,1H),5.04(s,2H)ppm;13CNMR(100MHz,DMSO-d6):δ176.8,154.5,152.9,148.2,141.3,137.6,131.0,125.1,123.0,122.9,119.2,112.5,69.6ppm;HRMS(ESI):[M+H]+C14H12BO4calcd 255.0829,found255.0833;mp:126-129℃;HPLC:purity 99.3%,retention time 15.3min。
实施例4
(E)-1-(4-羟基苯基)-3-(1-羟基-1,3-二氢-苯并[c][1,2]硼唑-7-基)-2-丙烯酮(4)
合成方法类似实施例1(30.0mg,10.7%)。1H NMR(400MHz,DMSO-d6):δ10.4(s,1H),9.34(s,1H),8.14(d,J=16.0Hz,1H),8.07(d,J=16.0Hz,1H),8.06(d,J=8.8Hz,2H),8.00(d,J=7.6Hz,1H),7.56(t,J=7.6Hz,1H),7.45(d,J=7.6Hz,1H),6.90(d,J=8.8Hz,2H),5.04(s,2H)ppm;13C NMR(100MHz,CD3OD):δ191.3,164.0,156.3,144.2,140.0,132.5,132.4,131.1,127.4,124.8,123.8,116.5,72.0ppm;HRMS(ESI):[M+H]+C16H16BO4calcd281.0985,found 281.0985;mp:198-200℃;HPLC:purity 97.1%,retention time16.2min。
实施例5
(E)-1-(4-甲巯基苯基)-3-(1-羟基-1,3-二氢-苯并[c][1,2]硼唑-7-基)-2-丙烯酮(5)
合成方法类似实施例1(40.0mg,12.9%)。1H NMR(400MHz,DMSO-d6):δ9.36(s,1H),8.20(d,J=16.0Hz,1H),8.09(d,J=8.6Hz,2H),8.08(d,J=16.0Hz,1H),8.04(d,J=7.6Hz,1H),7.57(t,J=7.6Hz,1H),7.47(d,J=7.6Hz,1H),7.40(d,J=8.6Hz,2H),5.04(s,2H),2.57(s,3H)ppm;13C NMR(100MHz,DMSO-d6):δ188.1,154.6,145.4,142.3,138.0,133.8,131.1,128.9,125.5,124.9,123.0,122.9,69.7,13.8ppm;HRMS(ESI):[M+Na]+C17H17BO3SNa calcd 333.0733,found 333.0731;mp:166-169℃;HPLC:purity 96.2%,retention time 19.5min。
实施例6
合成方法类似实施例1(90.0mg,23.5%)。1H NMR(400MHz,DMSO-d6):δ9.45(s,1H),8.20(d,J=16.0Hz,1H),8.13(d,J=16.0Hz,1H),8.00(d,J=7.6Hz,1H),7.58(t,J=7.6Hz,1H),7.48(d,J=7.6Hz,1H),7.42(s,2H),5.05(s,2H)3.90(s,6H),3.77(s,3H)ppm;13C NMR(100MHz,DMSO-d6):δ188.2,154.8,152.8,142.8,141.8,138.1,133.0,131.0,126.7,123.4,123.0,105.9,69.7,60.1,56.1ppm;HRMS(ESI):[M+H]+C19H20BO3Na calcd355.1353,found 355.1352;mp:178-181℃;HPLC:purity 97.5%,retention time18.1min。
实施例7
(E)-1-(4-乙基苯基)-3-(1-羟基-1,3-二氢-苯并[c][1,2]硼唑-7-基)-2-丙烯酮(7)
合成方法类似实施例1(89.8mg,30.5%)。1H NMR(400MHz,DMSO-d6):δ9.38(s,1H),8.20(d,J=16.0Hz,1H),8.10(d,J=16.0Hz,1H),8.07(d,J=7.6Hz,2H),8.03(d,J=7.6,1H),7.56(t,J=7.6Hz,1H),7.46(d,J=7.6Hz,1H),7.40(d,J=7.6Hz,2H),5.04(s,2H),2.70(q,J=7.6Hz,2H),1.21(t,J=7.6Hz,3H)ppm;13C NMR(100MHz,DMSO-d6):δ188.9,154.6,149.5,142.3,138.0,135.4,131.1,128.6,128.1,125.6,123.2,123.0,69.7,28.1,15.1ppm;HRMS(ESI):[M+H]+C18H18BO3 calcd 293.1349,found 293.1346;mp:140-142℃;HPLC:purity 95.4%,retention time 20.5min。
实施例8
合成方法类似实施例1(124.8mg,37.4%)。1H NMR(400MHz,DMSO-d6):δ9.38(s,1H),8.32(d,J=8.0Hz,2H),8.27(d,J=16.0Hz,1H),8.10(d,J=16.0Hz,1H),8.08(d,J=7.6Hz,1H),7.95(d,J=8.0Hz,2H),7.59(t,J=7.6Hz,1H).7.50(d,J=7.6Hz,1H),5.05(s,2H)ppm;13C NMR(100MHz,DMSO-d6):δ188.9,154.6,143.7,140.8,137.6,131.1,129.2,123.4,122.8,69.7ppm;HRMS(ESI):[M+Na]+C17H12BF3O3Na calcd 355.0729,found355.0725;mp:185-188℃;HPLC:purity 96.5%,retention time 20.3min。
实施例9
(E)-1-(3,4-二氯苯基)-3-(1-羟基-1,3-二氢-苯并[c][1,2]硼唑-7-基)-2-丙烯酮(9)
合成方法类似实施例1(234.4mg,67.9%)。1H NMR(400MHz,DMSO-d6):δ9.38(s,1H),8.39(d,J=1.8Hz,1H),8.27(d,J=16.0Hz,1H),8.13-8.08(m,3H),7.86(d,J=8.4Hz,1H),7.59(t,J=7.6Hz,1H),7.50(d,J=7.6Hz,1H),5.05(s,2H)ppm;13C NMR(100MHz,DMSO-d6):δ187.1,154.5,143.7,137.6,137.5,135.8,131.8,131.0,130.2,128.3,125.6,123.3,122.2,69.6ppm;HRMS(ESI):[M+H]+C16H12BCl2O3Na calcd 333.0257,found 333.0262;mp:205-207℃;HPLC:purity 95.5%,retention time 21.7min。
实施例10
(E)-1-(3-硝基苯基)-3-(1-羟基-1,3-二氢-苯并[c][1,2]硼唑-7-基)-2-丙烯酮(10)
合成方法类似实施例1(30.0 mg,13.1%)。1H NMR(400 MHz,DMSO-d6):δ9.40(s,1H),8.83(s,1H),8.59(d,J=7.6 Hz,1H),8.51(dd,J=8.0,1.2 Hz,1H),8.30(d,J=16.0Hz,1H),8.17(d,J=16.0 Hz,1H),8.12(d,J=7.6 Hz,1H).7.89(t,J=8.0 Hz,1H),7.60(t,J=7.6 Hz,1H),7.51(d,J=7.6 Hz,1H),5.05(s,2H)ppm;13C NMR(100MHz,DMSO-d6):δ187.7,154.6,148.1,144.1,138.7,137.5,134.5,131.0,130.5,127.2,125.8,123.5,122.7,122.3,69.7 ppm;HRMS(ESI):[M+H]+C16H12BNO5 calcd 310.0887,found 310.0891;mp:197-199℃;HPLC:purity 96.2%,retention time 18.0min。
将上述10个实施例制备得到的衍生物进行生物活性测试,具体操作如下:
1、细胞增殖抑制测试
(1)细胞培养。所有肿瘤细胞系(MDA-MB231,SKOV3和HCT116)和人正常细胞系(MCF-10A和WI-38)均购于ATCC(美国菌种保藏中心)。肿瘤细胞系在DMEM完全培养基(高糖DMEM培养基,加入10%胎牛血清,100 units/mL青霉素,100 mg/mL链霉素)中培养。MCF-10A在DMEM完全培养基(高糖DMEM培养基,加入10%胎牛血清)中培养。WI-38在MEM完全培养基(MEM培养基,加入10%胎牛血清和1%非必需氨基酸(NEAA))中培养。细胞在CO2细胞培养箱中37℃培养。当细胞复苏后传代三次以上,长至80%满时且状态良好时可用于活性测试。
(2)具体操作。用四氮唑(MTT)法测试化合物对细胞的增殖抑制活性。简言之,细胞种于96孔板中,加入不同浓度的化合物孵育48h。然后在每孔中加入20μL MTT(5mg/mL)并孵育4h。吸去上清,每孔加入150μL DMSO并震摇20min。酶标仪(Thermo Varioskan Flash)读取550nm下各孔的光密度值(OD)。每个化合物在每个浓度下设三个复孔。
(3)按下式计算药物对细胞系的增殖抑制率:细胞增殖抑制率=(OD阴性对照试-OD试验)/(OD阴性对照-OD空白)×100%。以同一样品的不同浓度对细胞增殖抑制率作图可得到剂量反应曲线,用软件GraphPad Prism 5分析,从中求出样品的半数抑制浓度IC50。
表1部分化合物对细胞增殖抑制的IC50
从表1中可以看出,本发明提供的化合物部分具有较好的抑制细胞增殖的活性。
2、体内肿瘤增殖抑制活性测试
六周龄雌性裸鼠购自上海灵畅实验动物有限公司。收集对数期生长状况良好的SKOV3细胞,用PBS调节浓度至2×107cells/mL。裸鼠皮下种植肿瘤,每个肿瘤种植2×106个细胞,待瘤块长至约50mm3,随机将裸鼠分成两组,每组五只,分别腹腔注射空白溶剂(5%乙醇,30%PEG400和65%ddH2O)和实施例9得到的衍生物。给药剂量为35mg/kg,每天一次,每周五次,持续5周。肿瘤体积和小鼠体重每三天测量一次,肿瘤体积用公式(a×b2)/2计算,a为瘤块最大直径,b为瘤块最小直径。实验结束后,断颈法处死裸鼠,取出瘤块并称量瘤重,实验结果如图1、图2和图3所示,本实验得到上海交通大学药学院动物伦理委员会批准。
从图1,图3中可以看出,化合物9可以显著地抑制肿瘤的增长。通过比较小鼠体重的变化可以看出(图2)化合物9组平均体重相对于空白组没有明显的降低。
Claims (4)
2.根据权利要求1所述的一种苯并硼唑7位查尔酮衍生物用于制备预防和治疗肿瘤的药物中的应用,其特征在于,所述的R为对位三氟甲基取代的苯基或3’,4’-二氯取代的苯基。
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