2-芳亚基环己烷-1,3-二酮的杂环化反应：具有潜在抗肿瘤活性的噻吩、噻唑和异噁唑衍生物的合成。
Heterocyclization of 2-Arylidenecyclohexan-1,3-dione: Synthesis of Thiophene, Thiazole, and Isoxazole Derivatives with Potential Antitumor Activities.
机构信息
Department of Chemistry, Faculty of Education, Alexandria University, Alexandria 21526, Egypt.
Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt.
出版信息
Anticancer Agents Med Chem. 2020;20(3):335-345. doi: 10.2174/1871520619666190730103425.
BACKGROUND
Thiophene, thiazole, and isoxazole derivatives are present in a wide range of natural and synthetic compounds with heterogeneous pharmacological activity. Due to their structural diversity, they are some of the most versatile classes of compounds for anticancer drug design and discovery.
OBJECTIVE
Thiophene, thiazole, and isoxazole derivatives were herein designed with a dual purpose: as antiproliferative agents and kinase inhibitors.
METHODS
The test compounds were synthesized in moderate to high yields through a simple methodology. Tetrahydrobenzo[b]thiophen-5-one derivatives 5a-f were prepared from the reaction of 2-arylidencyclohexan- 1,3-dione 3a-c with elemental sulfur and either of malononitrile (4a) or ethyl cyanoacetate (4b) in 1,4-dioxan in the presence of triethylamine. Compounds 5a,b were used for the synthesis of thiophene, thiazole, and isoxazole derivatives through their reactions with different chemical reagents.
RESULTS
Antiproliferative evaluations, c-Met kinase, and Pim-1 kinase inhibitions were performed where some compounds revealed high activities. In all cases, antiproliferative activity and the kinase inhibitions were performed against six cancer cell lines and five tyrosine kinases, respectively. Where the most cytotoxic compounds were 3c, 5d, and 16c with IC50's 0.29, 0.68, and 0.42μM, respectively, against the A549 cell line.
CONCLUSION
The anti-proliferative activities of the newly synthesized compounds were evaluated against the six cancer cell lines (A549, HT-29, MKN-45, U87MG, SMMC-7721, and H460). The most potent compounds toward the cancer cell lines (3a, 3c, 5d, 7c, 11c, 16a, and 16c) were further investigated towards the five tyrosine kinases (c-kit, FIT-3, VEGFR-2, EGFR, and PDGFR). Compounds 3c, 5d, and 16c were selected for testing of their inhibition for the Pim-1 kinase due to their anti-proliferation activities against the cancer cell lines and their high activities against the tyrosine kinases.
背景
噻吩、噻唑和异噁唑衍生物广泛存在于具有多种药理活性的天然和合成化合物中。由于其结构的多样性，它们是用于抗癌药物设计和发现的最通用的化合物类别之一。
目的
噻吩、噻唑和异噁唑衍生物的设计具有双重目的：作为增殖抑制剂和激酶抑制剂。
方法
通过简单的方法，以中等至高收率合成了测试化合物。通过 2-芳亚基环己-1,3-二酮 3a-c 与元素硫以及丙二腈（4a）或氰基乙酸乙酯（4b）在 1,4-二恶烷中在三乙胺存在下反应，制备了四氢苯并[b]噻吩-5-酮衍生物 5a-f。通过与不同化学试剂的反应，用化合物 5a,b 合成了噻吩、噻唑和异噁唑衍生物。
结果
进行了抗增殖评估、c-Met 激酶和 Pim-1 激酶抑制实验，其中一些化合物表现出高活性。在所有情况下，抗增殖活性和激酶抑制实验均针对六种癌细胞系和五种酪氨酸激酶进行。最具细胞毒性的化合物为 3c、5d 和 16c，其对 A549 细胞系的 IC50 分别为 0.29、0.68 和 0.42μM。
结论
新合成化合物的抗增殖活性针对六种癌细胞系（A549、HT-29、MKN-45、U87MG、SMMC-7721 和 H460）进行了评估。对癌细胞系最有效的化合物（3a、3c、5d、7c、11c、16a 和 16c）进一步针对五种酪氨酸激酶（c-kit、FIT-3、VEGFR-2、EGFR 和 PDGFR）进行了研究。由于化合物 3c、5d 和 16c 对癌细胞系的增殖抑制活性及其对酪氨酸激酶的高活性，选择它们用于测试对 Pim-1 激酶的抑制作用。
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