【目的】将噻唑环构建至异长叶烷酮分子中,得到具有新型生物活性化合物,拓展松节油的应用领域,提高松节油的利用价值。【方法】异长叶烷酮与氨基硫脲缩合,生成异长叶烷酮缩氨基硫脲; 异长叶烷酮缩氨基硫脲再与α-溴代苯乙酮衍生物发生环化反应,得到11种异长叶烷基噻唑类化合物2a—2k。采用FT-IR、1H NMR、13C NMR、HPLC-MS等手段,对合成产物的结构进行了表征。采用最低抑制浓度(MIC)法和MTT法分别研究了异长叶烷基噻唑类化合物的抑菌活性和抗肿瘤活性。【结果】化合物4-(4-氯苯基)-2-(2-(1,1,5,5)-四甲基四氢-1H-2,4α-桥亚甲基萘-8(2H,5H,8αH)-亚基)肼基)噻唑(2b)和4-(2-萘基)-2-(2-(1,1,5,5)-四甲基四氢-1H-2,4α-桥亚甲基萘-8(2H,5H,8αH)-亚基)肼基)噻唑(2j)对枯草芽孢杆菌与荧光假单胞菌抑制效果较好,其最低抑制浓度(MIC)为7.5 μg/mL,化合物2b对真菌(白色念球菌与热带假丝酵母菌)的抑制效果优于其他化合物,其MIC值均为15.6 μg/mL; 异长叶烷酮缩氨基硫脲对人体肝癌细胞HepG2 的半抑制浓度(IC50)为(34.5±0.8)μg/mL,表明其对HepG2具有较好的抗癌活性。【结论】异长叶烷酮缩氨基硫脲可作为潜在的抗肿瘤药物。
Abstract
【Objective】This research is to construct the thiazole ring into the molecular skeleton of isolongifolanone for obtaining some new types of compounds with biological activity, developing the new application field and improving the utilization value of gum turpentine.【Method】Eleven novel isolongifolanyl thiazole derivatives(2a-2k)were synthesized by condensation and cyclization from isolongifolanone. Isolongifolanone was condensed with thiosemicarbazide to get the intermediate isolongifolanyl thiosemicarbazones, which was further cyclized with SymbolaA@-bromoacetophenone derivatives to obtain the compound 2a-2k. The structures of compound 2a-2k were characterized with FT-IR,1H NMR, 13C NMR, and HPLC-MS. The antimicrobial and antitumor activities of 2a-2k were investigated with minimum inhibitory concentrations assay(MIC)and MTT assay, respectively.【Result】The antibacterial activities of 4-(4-chlorophenyl)-2-(2-(1,1,5,5-tetramethyltetrahydro-1H-2,4SymbolaA@-methanonaphthalen-8-(2H,5H,8αH)-ylidene)hydrazinyl)thiazole(2b)and 4-(naphthalen-2-yl)-2-(2-(1,1,5,5-tetramethyl-tetrahydro-1H-2,4SymbolaA@-methanonaphthalen-8(2H,5H,8αH)-ylidene)hydrazinyl)thiazole(2j)were better than that of others against Bacillus subtilis and Pseudomonas fluorescens, and their MIC were 7.5 μg/mL. The antibacterial activity of compound 2b was better than that of others against fungus, and its MIC values against Candida albicans and Candida tropicalis was 15.6 μg/mL. It was also found that the antitumor activities of isolongifolanyl thiosemicarbazide against HepG2 was the best than that of its cyclized derivatives, and its IC50 was(34.5±0.8)μg/mL which was at the same level with that of the standard sample etoposide.【Conclusion】Isolongifolanyl thiosemicarbazide has the potential to be a new drug against HepG2 and deserves further research.
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参考文献
[1] BONDOCK S, KHALIFA W, FADDA A A. Synthesis and antimicrobial evaluation of some new thiazole, thiazolidinone and thiazoline derivatives starting from 1-chloro-3,4-dihydronaphthalene-2-carboxaldehyde[J]. Eur J Med Chem, 2007, 42(7): 948-954. DOI:10.1016/j.ejmech.2006.12.025.
[2] 张静, 康卓, 李淼. 具有生物活性的异噻唑类化合物研究进展[J]. 农药, 2011, 50(3): 157-164. ZHANG J, KANG Z, LI M. The research progress of isothiazole compounds with bioactivities [J]. Agrochemicals, 2011, 50(3): 157-164.
[3] BHARTI S K, NATH G, TILAK R, et al. Synthesis, anti-bacterial and anti-fungal activities of some novel Schiff bases containing 2,4-disubstituted thiazole ring[J]. Eur J Med Chem, 2010, 45(2): 651-660. DOI:10.1016/j.ejmech.2009.11.008.
[4] MORE P G, KARALE N N, LAWAND A S, et al. Synthesis and anti-biofilm activity of thiazole Schiff bases[J].Medicinal Chemistry Research, 2013, 23(2): 790-799. DOI:10.1007/s00044-013-0672-7.
[5] GHATOLE A M, LANJEWAR K R, GAIDHANE M K, et al. Evaluation of substituted methyl cyclohexanone hybrids for anti-tubercular, anti-bacterial and anti-fungal activity: facile syntheses under catalysis by ionic liquids[J].Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2015, 151: 515-524. DOI:10.1016/j.saa.2015.06.035.
[6] AMBRUS R, KOCBEK P, KRISTL J, et al. Investigation of preparation parameters to improve the dissolution of poorly water-soluble meloxicam[J]. Int J Pharm, 2009, 381(2): 153-159. DOI:10.1016/j.ijpharm.2009.07.009.
[7] HEINRICH A, DUFFIELD T F, LISSEMORE K D, et al. The effect of meloxicam on behavior and pain sensitivity of dairy calves following cautery dehorning with a local anesthetic[J]. J Dairy Sci, 2010, 93(6): 2450-2457. DOI:10.3168/jds.2009-2813.
[8] OBACH R S, KALGUTKAR A S, RYDER T F, et al. In vitro metabolism and covalent binding of enol-carboxamide derivatives and anti-inflammatory agents sudoxicam and meloxicam: insights into the hepatotoxicity of sudoxicam[J].Chem Res Toxicol, 2008, 21(9): 1890-1899. DOI:10.1021/tx800185b.
[9] REDAELLI S, PIAZZA R, ROSTAGNO R, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants[J]. J Clin Oncol, 2009, 27(3): 469-471. DOI:10.1200/JCO.2008.19.8853.
[10] WALZ C, SATTLER M. Novel targeted therapies to overcome imatinib mesylate resistance in chronic myeloid leukemia(CML)[J]. Crit Rev Oncol Hematol, 2006, 57(2): 145-164. DOI:10.1016/j.critrevonc.2005.06.007.
[11] YANG C, LU P, LEE F Y, et al. Tyrosine kinase inhibition in diffuse large B-cell lymphoma: molecular basis for antitumor activity and drug resistance of dasatinib[J]. Leukemia, 2008, 22(9): 1755-1766. DOI:10.1038/leu.2008.163.
[12] ANDREANI A, GRANAIOLA M, LEONI A, et al. Synthesis and antitubercular activity of imidazo
[2,1-b]thiazoles[J]. Eur J Med Chem, 2001, 36(9): 743-746.
[13] 李娜, 魏学, 范会涛, 等. 2-氰基-3-(4-甲基苯并[d]噻唑-2-氨基)-3-苯基丙烯酸酯类化合物的合成及抗病毒活性[J]. 有机化学, 2011, 31(8): 1300-1311. LI N, WEI X, FAN H T, et al. Synthesis and antiviral activity of 2-cyano-3-(4-methylbenzo[d]thiazol-2-amino)-3-phenyl acrylate derivatives[J]. Chinese Journal of Organic Chemistry, 2011, 31(8): 1300-1311.
[14] 章浩, 李向阳, 胡德禹, 等. 2-氰基-3-甲硫基-3-(4-甲基或6-甲基苯并[d]噻唑-2-氨基)丙烯酸酯类化合物的合成和抗病毒活性研究[J]. 有机化学, 2011, 31(9): 1419-1424. ZHANG H, LI X Y, HU D Y, et al. Synthesis and antiviral activity of(e)-3-(4-or 6-methylbenzo[D]thiazol-2-Yl-Amino)-2-Cyano-3-(methylthio)acrylate derivatives[J]. Chinese Journal of Organic Chemistry, 2011, 31(9): 1419-1424.
[15] 周丽平, 李彦龙, 王俊春, 等. 新型二氯丙烯类杀虫剂的合成及杀虫活性[C]. 第七届全国新农药创制学术交流会, 2007: 231-237.
[16] DEKEYSER M A, MCPHEE D J, MCDONALD P T. Miticidal hydrazine compounds and their intermediates:US, US5567723 A[P]. 1996-10-22.
[17] El-GABY M S A, MICKY J A, TAHA N M, et al. Antimicrobial activity of some novel thiourea, hydrazine, fused pyrimidine and 2-(4-substituted)anilinobenzoazole derivatives containing sulfonamido moieties[J]. Journal of the Chinese Chemical Society, 2002, 49(3): 407-414. DOI:10.1002/jccs.200200064.
[18] ARKANJ B, MOLNAR M, CACIC M, et al. 4-Methyl-7-hydroxycoumarin antifungal and antioxidant activity enhancement by substitution with thiosemicarbazide and thiazolidinone moieties[J]. Food Chem, 2013, 139(1-4):488-495. DOI:10.1016/j.foodchem.2013.01.027.
基金
基金项目:江苏省生物质能源与材料重点实验室开放基金项目(JSBEM2014010); 教育部高等学校博士学科点科研基金项目(20123204120010)
第一作者:芮坚(1044603872@qq.com)。*通信作者:王石发(wsfyyq@njfu.com),教授。
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