Havrylyuk Dmytro, Zimenkovsky Borys, Vasylenko Olexandr, Zaprutko Lucjusz, Gzella Andrzej, Lesyk Roman
Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv 79010, Ukraine.
Eur J Med Chem. 2009 Apr;44(4):1396-404. doi: 10.1016/j.ejmech.2008.09.032. Epub 2008 Oct 7.
To examine the anticancer activity several novel thiazolone-based compounds containing 5-aryl-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl framework were obtained. Reaction of 5-aryl-3-phenyl-4,5-dihydropyrazole with 4-thioxo-2-thiazolidinone or 2-carbethoxymethylthio-2-thiazoline-4-one yielded starting 4- (1 and 2) or 2-substituted (11 and 12) thiazolones which were utilized in Knoevenagel condensation for obtaining a series of 5-arylidene derivatives 3-10, 13-18. Alternatively 11, 12 and their 5-arylidene derivatives were synthesized by means of 3-phenyl-5-aryl-1-thiocarbamoyl-2-pyrazoline as S,N-binucleophile via [2+3]-cyclocondensation approach. The structures of compounds were determined by (1)H, (13)C NMR, LC-MS, EI-MS and X-ray analysis. The in vitro anticancer activity of synthesized compounds were tested by the National Cancer Institute and most of them displayed anticancer activity on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate and breast cancer cell lines. Relations between structure and activity are discussed, the most efficient anticancer compound 16 was found to be active with selective influence on colon cancer cell lines, especially on HT 29 (logGI(50)=-6.37).
为了研究抗癌活性，制备了几种含有5-芳基-3-苯基-4,5-二氢-1H-吡唑-1-基骨架的新型噻唑酮类化合物。5-芳基-3-苯基-4,5-二氢吡唑与4-硫代-2-噻唑烷酮或2-乙氧羰基甲基硫代-2-噻唑啉-4-酮反应，生成起始的4-（1和2）或2-取代（11和12）噻唑酮，将其用于Knoevenagel缩合反应以获得一系列5-亚芳基衍生物3-10、13-18。另外，通过3-苯基-5-芳基-1-硫代氨基甲酰基-2-吡唑啉作为S，N-双亲核试剂，采用[2+3]环缩合方法合成了11、12及其5-亚芳基衍生物。通过（1）H、（13）C NMR、LC-MS、EI-MS和X射线分析确定了化合物的结构。合成化合物的体外抗癌活性由美国国立癌症研究所进行测试，其中大多数对白血病、黑色素瘤、肺癌、结肠癌、中枢神经系统癌、卵巢癌、肾癌、前列腺癌和乳腺癌细胞系显示出抗癌活性。讨论了结构与活性之间的关系，发现最有效的抗癌化合物16具有活性，对结肠癌细胞系有选择性影响，尤其是对HT 29（logGI(50)=-6.37）。
