氟喹诺酮C-3三唑硫醚醇衍生物的合成与抗肿瘤活性研究
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摘要
近年来，全球肿瘤发病率逐年增高，肿瘤疾病已成为阻碍人类健康的第一杀手，抗肿瘤药物也随之得到迅猛发展。目前，在临床上使用的化学抗肿瘤药因选择性差、毒副作用大以及肿瘤细胞产生耐药性而导致化疗指数低，因此，寻找新的抗肿瘤先导化合物已成为药物化学亟待要解决的问题。喹诺酮类药物是以1,4-二氢-4-氧代-3-喹啉羧酸为骨架全合成的，具有广谱抗菌活性且抗菌活性强的，在临床上被广泛应用的抗感染类药物。细菌拓扑异构酶II (DNA旋转酶)是喹诺酮类抗菌药抑制细菌生长的主要靶酶，这与抗肿瘤药物杀死肿瘤细胞的机理极其相似[1]。根据此原理，目前已经合成了大量喹诺酮类候选抗肿瘤化合物，但均存在毒性与活性不相平衡、体内溶解度差导致生物利用度低或体内易被代谢失活等问题而未进入临床深入研究。这些化合物对喹诺酮的修饰主要集中在C-1和C-7位，对C-3羧基的修饰却很少见，而根据现有研究表明，C-3羧基并非为抗肿瘤作用的必须基团。因此，本文设想对C-3羧基进行结构改造，探讨其结构修饰对抗肿瘤活性的影响，意图寻找一种新型的喹诺酮类抗肿瘤先导化合物。
1、目标化合物的设计与合成
本文以诺氟沙星、环丙沙星和左氧氟沙星为原料，利用生物电子等排及活性拼接设计原理，用三唑硫醚醇替代喹啉环C-3羧基，得到相应的喹诺酮类的三唑硫醚醇目标化合物，经过MS，~1HNMR，IR光谱数据对所得化合物结构进行表征，都为目标化合物。
2、体外活性评价
采用MTT实验方法，评价了新目标化合物对人肺癌细胞A549、人肝癌细胞Bel-7402、人结肠癌细胞HCT-8的体外生长抑制情况。结果表明，所得的氟喹诺酮C-3三唑硫醚醇类化合物对三种癌细胞均有不同程度的抑制活性。
3、结论
本文设计合成21个化合物，MS、~1H-NMR、IR光谱数据与其结构特征相一致，为预期目标化合物。体外抗肿瘤活性测试结果显示，目标化合物对三种癌细胞均有不同程度的抑制活性，在浓度为5μg/ml情况下，对人结肠癌细胞HCT-8，三种化合物的结构改造都比对照品显示了较强的活性，其中14f、20b、20d和20f的的抑制率都在50%以上。因此，表明了对氟喹诺酮C-3羧基结构改造后对其抗肿瘤活性显示了积极的意义，具有开发新型喹诺酮类抗肿瘤药物的潜力。
In recent years, the incidence of tumors increased year by year in the world. Tumor disease hasbecame to the first killer obstacles to the human health, and anti-cancer drugs is then rapid development. Atpresent, anticancer drugs used in clinical has many toxic side effects, because there poor selectivity and thehigh tumor cell drug resistance, and the resistance of tumor cells. So, looking for the new anti-cancer leadcompounds has become to a urgent problem for the pharmaceutical chemistry. Quinolones are1,4-2hydrogen-4-oxygen-3-quinoline carboxylic acid as the backbone synthesis, with the strong fearures of thebroad-spectrum antimicrobial activity in clinical widely used anti-infective drugs. Bacterial topoisomeraseII cald DNA gyrase is the main target enzyme for quinolones kills bacteria. This is pretty similar to themechanism of anticancer drugs to kill cancer cells. According to this principle, a large number of thequinolones candidate for anti-tumor compounds have been synthesized. But they have toxicitis and activityimbalances, and the poor solubility in the body would lead the low bioavailability or inactivation becauseof easily be metabolized in the body. Thus, they didn’t come to clinical. The modification of thesecompounds on the quinolone is mainly concentrated in the C-1and C-7, but there are very rare on themodification of the carboxyl in the C-3. According to the existing research, the carboxyl in C-3is notessential groups for the anti-tumor effect. Therefore, this paper conceived structural transformation of thecarboxyl in C-3, and trying to find a new quinolone anti-cancer lead compounds.
1. Design and synthesis of target compounds
In this paper, we use norfloxacin, ciprofloxacin and levofloxacin as the raw materials, and the designis also take the advantage of bioisostere and activity stack principles. We take triazole sulfide saturatedalcohol instead of the quinoline C-3carboxyl, and get hold of triazole sulfide saturated alcohol targetcompounds to quinolones. After the spectroscopic data of MS,~1HNMR and IR, they are proved to be thetarget compound.
2. Activity evaluation in vitro
Use the method of MTT, we evaluated the inhibition in vitro growth for the new target compounds inthree kinds of cancer cells. They are human lung cancer cell A549, human hepatoma cell Bel-7402andhuman colon cancer cell HCT-8. The result shows that, the income compounds of fluoroquinolone C-3triazole sulfide saturated alcohols have vary inhibitory activity of three kinds of cancer cells.
3. Conclusion
This paper design and synthesized21compounds, and the spectroscopic data of MS,~1HNMR and IRshew that they were the target compounds. Antitumor activity in vitro test results indicate that the targetcompounds on the three kinds of cancer cell have different levels of inhibitory activity. In the concentrationof5μg/ml situation, atructural change of the three kinds of compounds show stronger activity than thereference substance, especially on the human colon cancer cells HCT-8. Where the14f,20b,20d and20fof the inhibition ratio is more than50%. Therefore, the structural transformation of the fluoroquinolone C-3carboxyl and its anti-tumor activity shows positive significance, and it has the potential to develop a newquinolone antineoplastic agents.
1、目标化合物的设计与合成
本文以诺氟沙星、环丙沙星和左氧氟沙星为原料，利用生物电子等排及活性拼接设计原理，用三唑硫醚醇替代喹啉环C-3羧基，得到相应的喹诺酮类的三唑硫醚醇目标化合物，经过MS，~1HNMR，IR光谱数据对所得化合物结构进行表征，都为目标化合物。
2、体外活性评价
采用MTT实验方法，评价了新目标化合物对人肺癌细胞A549、人肝癌细胞Bel-7402、人结肠癌细胞HCT-8的体外生长抑制情况。结果表明，所得的氟喹诺酮C-3三唑硫醚醇类化合物对三种癌细胞均有不同程度的抑制活性。
3、结论
本文设计合成21个化合物，MS、~1H-NMR、IR光谱数据与其结构特征相一致，为预期目标化合物。体外抗肿瘤活性测试结果显示，目标化合物对三种癌细胞均有不同程度的抑制活性，在浓度为5μg/ml情况下，对人结肠癌细胞HCT-8，三种化合物的结构改造都比对照品显示了较强的活性，其中14f、20b、20d和20f的的抑制率都在50%以上。因此，表明了对氟喹诺酮C-3羧基结构改造后对其抗肿瘤活性显示了积极的意义，具有开发新型喹诺酮类抗肿瘤药物的潜力。
In recent years, the incidence of tumors increased year by year in the world. Tumor disease hasbecame to the first killer obstacles to the human health, and anti-cancer drugs is then rapid development. Atpresent, anticancer drugs used in clinical has many toxic side effects, because there poor selectivity and thehigh tumor cell drug resistance, and the resistance of tumor cells. So, looking for the new anti-cancer leadcompounds has become to a urgent problem for the pharmaceutical chemistry. Quinolones are1,4-2hydrogen-4-oxygen-3-quinoline carboxylic acid as the backbone synthesis, with the strong fearures of thebroad-spectrum antimicrobial activity in clinical widely used anti-infective drugs. Bacterial topoisomeraseII cald DNA gyrase is the main target enzyme for quinolones kills bacteria. This is pretty similar to themechanism of anticancer drugs to kill cancer cells. According to this principle, a large number of thequinolones candidate for anti-tumor compounds have been synthesized. But they have toxicitis and activityimbalances, and the poor solubility in the body would lead the low bioavailability or inactivation becauseof easily be metabolized in the body. Thus, they didn’t come to clinical. The modification of thesecompounds on the quinolone is mainly concentrated in the C-1and C-7, but there are very rare on themodification of the carboxyl in the C-3. According to the existing research, the carboxyl in C-3is notessential groups for the anti-tumor effect. Therefore, this paper conceived structural transformation of thecarboxyl in C-3, and trying to find a new quinolone anti-cancer lead compounds.
1. Design and synthesis of target compounds
In this paper, we use norfloxacin, ciprofloxacin and levofloxacin as the raw materials, and the designis also take the advantage of bioisostere and activity stack principles. We take triazole sulfide saturatedalcohol instead of the quinoline C-3carboxyl, and get hold of triazole sulfide saturated alcohol targetcompounds to quinolones. After the spectroscopic data of MS,~1HNMR and IR, they are proved to be thetarget compound.
2. Activity evaluation in vitro
Use the method of MTT, we evaluated the inhibition in vitro growth for the new target compounds inthree kinds of cancer cells. They are human lung cancer cell A549, human hepatoma cell Bel-7402andhuman colon cancer cell HCT-8. The result shows that, the income compounds of fluoroquinolone C-3triazole sulfide saturated alcohols have vary inhibitory activity of three kinds of cancer cells.
3. Conclusion
This paper design and synthesized21compounds, and the spectroscopic data of MS,~1HNMR and IRshew that they were the target compounds. Antitumor activity in vitro test results indicate that the targetcompounds on the three kinds of cancer cell have different levels of inhibitory activity. In the concentrationof5μg/ml situation, atructural change of the three kinds of compounds show stronger activity than thereference substance, especially on the human colon cancer cells HCT-8. Where the14f,20b,20d and20fof the inhibition ratio is more than50%. Therefore, the structural transformation of the fluoroquinolone C-3carboxyl and its anti-tumor activity shows positive significance, and it has the potential to develop a newquinolone antineoplastic agents.
引文
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[3]蔡丽秋.2006年-2008年我院抗肿瘤药的应用分析[J].海峡药学,2010,22(1):146-148.
[4] Demetri GD, Chawla SP, von Mehren M, et al. Efficacyand safety of trabectedin in patients withadvanced or metastaticliposarcoma or leiomyosarcoma after failure of prioranthracyclines andifosfamide: results of a randomized phase Ⅱ study of two different schedules[J]. J Clin Oncol,2009,27(25):4188.
[5]林能明.全球抗肿瘤药研究新进展[J].中国药房,2010,21(14):1249-1253.
[6] Thompson CA. FDA approves pralatrexate for treatment ofrare lymphoma[J]. Am J Health SystPharm,2009,66(21):1890.
[7] Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacyand safety of degarelix: a12-month,comparative, randomized, open-label, parallel-group phase Ⅲstudy in patients with prostate cancer[J].BJU Int,2008,102(11):1531.
[8] Chawla SP, Chua VS, Fernandez L, et al. Advanced phaseⅠ/Ⅱ studies of targeted gene delivery invivo: intravenous Rexin-G for gemcitabine-resistant metastatic pancreatic cancer [J]. Mol Ther,2010,18(2):435.
[9] Schneider-Merck T, Lammerts van Bueren JJ, Berger S, et al. Human IgG2antibodies againstepidermal growth factor receptor effectively trigger antibody-dependent cellularcyto toxicity but, incontrast to IgG1, only by cells of myeloid lineage[J]. J Immunol,2010,184(1):512.
[10] McKeage MJ, Reck M, Jameson MB, et al. Phase Ⅱ study of ASA404(vadimezan,5,6-dimethylxanthenone-4-aceticacid/DMXAA)1800mg/m(2) combined with carboplatinandpaclitaxel in previously untreated advancednon-small cell lung cancer[J]. Lung Cancer,65(2):192.
[11] Janet E, Stout, Kelly Sens, et al. Comparative activity of quinolones, macrolides and ketolides againstLegionella species using in vitrobroth dilution and intracellular susceptibility testing[J]. InternationalJournal of Antimicrobial Agents,2005,25:302-307.
[12]王明贵,林东防.喹诺酮类抗菌药物的研究进展[J].继续医学教育,2007,21(27):26-29.
[13] Kim OK, Ohemeng K, Barrett JF. Advances in DNA gyrase inhibitors[J]. Expert Opin InvestingDrugs,2001,10(2):199-212.
[14] Kishii R, Takei M, Fukuda H, Contribution of the8-methoxy group to the activity of gatifloxacinagainst type II topoisomerases of strep to coccus pnenmoniae[J]. Antimicrobial Agents andChe-motherapy,2003,47(1):77-81.
[15]冯连顺,刘明亮.喹诺酮类药物的结构修饰及“非经典”生物活性研究进展[J].2010,37[2],139-143.
[16]屈凌波,刘艳,郭宗儒.氟喹诺酮类药物构效关系的研究进展[J].中国药物化学杂志,2001,11(4):241-244.
[17] Domagala JM. Structure activity and structure side effect relationship for the quinoloneantibacterials[J]. J Antimicrob chemother,1994,33(4):685-706.
[18] Stein GE. The4-quinolone antibiotics: past,present and future[J]. Pharmacothe,1988,8(6):301-314.
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