新型二酮缩二甲醇衍生的 4,5,6,7-四氢苯并[D]-噻唑-2-基衍生物的合成与生物评价及其对肿瘤、C-Met、酪氨酸激酶和 Pim-1 的抑制作用。
Synthesis and Biological Evaluation of Novel 4,5,6,7-Tetrahydrobenzo[D]-Thiazol-2- Yl Derivatives Derived from Dimedone with Anti-Tumor, C-Met, Tyrosine Kinase and Pim-1 Inhibitions.
机构信息
Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt.
National Organization for Drug Control & Research, Cairo, Egypt.
出版信息
Anticancer Agents Med Chem. 2019;19(12):1438-1453. doi: 10.2174/1871520619666190416102144.
BACKGROUND
Dimedone and thiazole moieties are privileged scaffolds (acting as primary pharmacophores) in many compounds that are useful to treat several diseases, mainly tropical infectious diseases. Thiazole derivatives are a very important class of compounds due to their wide range of pharmaceutical and therapeutic activities. On the other hand, dimedone is used to synthesize many therapeutically active compounds. Therefore, the combination of both moieties through a single molecule to produce heterocyclic compounds will produce excellent anticancer agents.
OBJECTIVE
The present work reports the synthesis of 47 new substances belonging to two classes of compounds: Dimedone and thiazoles, with the purpose of developing new drugs that present high specificity for tumor cells and low toxicity to the organism. To achieve this goal, our strategy was to synthesize a series of 4,5,6,7-tetrahydrobenzo[d]-thiazol-2-yl derivatives using the reaction of the 2-bromodimedone with cyanothioacetamide.
METHODS
The reaction of 2-bromodimedone with cyanothioacetamide gave the 4,5,6,7-tetrahydrobenzo[d]- thiazol-2-yl derivative 4. The reactivity of compound 4 towards some chemical reagents was observed to produce different heterocyclic derivatives.
RESULTS
A cytotoxic screening was performed to evaluate the performance of the new derivatives in six tumor cell lines. Thirteen compounds were shown to be promising toward the tumor cell lines which were further evaluated toward five tyrosine kinases.
CONCLUSION
The results of antitumor screening showed that many of the tested compounds were of high inhibition towards the tested cell lines. Compounds 6c, 8c, 11b, 11d, 13b, 14b, 15c, 15g, 21b, 21c, 20d and 21d were the most potent compounds toward c-Met kinase and PC-3 cell line. The most promising compounds 6c, 8c, 11b, 11d, 13b, 14b, 15c, 15g, 20c, 20d, 21b, 21c and 21d were further investigated against tyrosine kinase (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 6c, 11b, 11d, 14b, 15c, and 20d were selected to examine their Pim-1 kinase inhibition activity the results revealed that compounds 11b, 11d and 15c had high activities.
背景
二氢苯并[d]噻唑和噻唑部分是许多用于治疗多种疾病（主要是热带传染病）的化合物中的有效结构（充当主要药效团）。噻唑衍生物因其广泛的药物和治疗活性而成为一类非常重要的化合物。另一方面，二氢苯并[d]噻唑用于合成许多具有治疗活性的化合物。因此，通过单个分子将这两个部分结合起来生成杂环化合物将产生出色的抗癌剂。
目的
本工作报道了属于两类化合物的 47 种新物质的合成：二氢苯并[d]噻唑和噻唑，目的是开发对肿瘤细胞具有高特异性和对机体低毒性的新药。为了实现这一目标，我们的策略是使用 2-溴代二氢苯并[d]噻唑与氰基硫代乙酰胺反应合成一系列 4,5,6,7-四氢苯并[d]噻唑-2-基衍生物。
方法
2-溴代二氢苯并[d]噻唑与氰基硫代乙酰胺反应得到 4,5,6,7-四氢苯并[d]噻唑-2-基衍生物 4。观察了化合物 4 对一些化学试剂的反应活性，以生成不同的杂环衍生物。
结果
进行了细胞毒性筛选，以评估新衍生物在六种肿瘤细胞系中的性能。发现 13 种化合物对肿瘤细胞系具有良好的活性，进一步对五种酪氨酸激酶进行了评估。
结论
抗肿瘤筛选结果表明，许多测试化合物对测试细胞系具有高度抑制作用。化合物 6c、8c、11b、11d、13b、14b、15c、15g、21b、21c、20d 和 21d 对 c-Met 激酶和 PC-3 细胞系具有最强的抑制作用。最有前途的化合物 6c、8c、11b、11d、13b、14b、15c、15g、20c、20d、21b、21c 和 21d 进一步针对酪氨酸激酶（c-Kit、Flt-3、VEGFR-2、EGFR 和 PDGFR）进行了研究。选择了化合物 6c、11b、11d、14b、15c 和 20d 来检查它们对 Pim-1 激酶的抑制活性，结果表明化合物 11b、11d 和 15c 具有很高的活性。
Zotero 插件