苯并咪唑噻吩并[2,3-d]嘧啶-4(3H)-酮衍生物作为潜在的抗乳腺癌（MDA-MB-231，MCF-7）药物。
Thieno[2,3-d]pyrimidin-4(3H)-one Derivatives of Benzimidazole as Potential Anti- Breast Cancer (MDA-MB-231, MCF-7) Agents.
机构信息
Department of Organic Synthesis, University of Chemical Technology and Metallurgy, 8 Kliment Ohridski Blvd., 1756 Sofia, Bulgaria.
Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Build. 9, 1113 Sofia, Bulgaria.
出版信息
Anticancer Agents Med Chem. 2021;21(11):1441-1450. doi: 10.2174/1871520620666200721131431.
AIMS
The purpose of this study was the synthesis of some new thienopyrimidine derivatives of 1,3-disubstituted benzimidazoles and the evaluation of their cytotoxicity against MDA-MB-231, MCF-7, and 3T3 cells lines.
BACKGROUND
An overexpression or mutational activation of TK receptors EGFR and HER2/neu is characteristic of tumors. It has been found that some thieno[2,3-d]pyrimidines exhibited better inhibitory activity against Epidermal Growth Factor Receptor (EGFR/ErbB-2) tyrosine kinase in comparison to aminoquinazolines. Breast cancer activity towards MDA-MB-231 and MCF-7 cell lines by inhibiting EGFR was revealed by a novel 2-arylbenzimidazole. This motivated the synthesis of new thienopyrimidines possessing benzimidazole fragments in order to evaluate their cytotoxicity to the above-mentioned cell lines.
OBJECTIVE
The objectives of the study were to design and synthesize a novel series of thieno[2,3-d]pyrimidines bearing biologically active moieties, such as 1,3-disubstituted-benzimidazole heterocycle, structurally similar to diaryl ureas in order to evaluate their cytotoxicity against MDA-MB-231, and MCF-7 breast cancer cell lines.
METHODS
N,N-disubstituted benzimidazole-2-one carbonitriles were synthesized by Aza-Michael addition and used as precursors to generate some of the new thieno[2,3-d]pyrimidines in acidic medium The interaction of chloroethyl-2-thienopyrimidines, 2-amino-benzimidazole and benzimidazol-2-one nitriles under solid-liquid transfer catalysis conditions led to new thienopyrimidines. MTT assay for cell survival was performed in order to evaluate the cytotoxicity of the tested compounds. A fluorescence study was conducted to elucidate some aspects of the mechanism of action.
RESULTS
The effects of nine synthesized compounds were investigated towards MDA-MB-231, MCF-7 and 3T3 cell lines. Thieno[2,3-d]pyirimidine-4-one 16 (IC - 0.058μM) and 21 (IC - 0.029μM) possess high cytotoxicity against MDA-MB-231 cells after 24h. The most cytotoxic compounds against breast cancer MCF-7 cells was compound 21 (IC - 0.074μM), revealing lower cytotoxicity against mouse fibroblast 3T3 cells with IC - 0.20μM. SAR analysis was performed. Fluorescence study of the treatment of MDA-MB cells with compound 21 was carried out in order to clarify some aspects of the mechanism of action.
CONCLUSION
The relationship between cytotoxicity of compounds 14 and 20 against MCF-7 and 3T3 cells can suggest a similar mechanism of action. The antitumor potential of the tested compounds proves the necessity for further investigation to estimate the exact inhibition pathway in the cellular processes. The fluorescence study of the treatment of MDA-MB cells with compound 21 showed a rapid process of apoptosis.
目的
本研究的目的是合成一些新的噻吩并[2,3-d]嘧啶衍生物 1,3-二取代苯并咪唑，并评估它们对 MDA-MB-231、MCF-7 和 3T3 细胞系的细胞毒性。
背景
TK 受体 EGFR 和 HER2/neu 的过度表达或突变激活是肿瘤的特征。已经发现，一些噻吩并[2,3-d]嘧啶对表皮生长因子受体（EGFR/ErbB-2）酪氨酸激酶的抑制活性优于氨基喹唑啉。新型 2-芳基苯并咪唑对 MDA-MB-231 和 MCF-7 细胞系的乳腺癌活性表明，通过抑制 EGFR 可以揭示。这促使我们合成了具有苯并咪唑片段的新型噻吩嘧啶，以评估它们对上述细胞系的细胞毒性。
目的
本研究的目的是设计和合成一系列新型噻吩并[2,3-d]嘧啶，这些嘧啶具有生物活性部分，如 1,3-二取代苯并咪唑杂环，结构类似于二芳基脲，以评估它们对 MDA-MB-231 和 MCF-7 乳腺癌细胞系的细胞毒性。
方法
通过 Aza-Michael 加成合成 N,N-二取代苯并咪唑-2-甲腈，并将其用作前体，在酸性介质中生成一些新的噻吩并[2,3-d]嘧啶。在固液转移催化条件下，氯乙基-2-噻吩嘧啶、2-氨基苯并咪唑和苯并咪唑-2-甲腈之间的相互作用导致了新的噻吩嘧啶。通过 MTT 法测定细胞存活情况，评估测试化合物的细胞毒性。进行荧光研究以阐明作用机制的某些方面。
结果
研究了 9 种合成化合物对 MDA-MB-231、MCF-7 和 3T3 细胞系的影响。噻吩并[2,3-d]吡嗪-4-酮 16（IC-0.058μM）和 21（IC-0.029μM）在 24 小时后对 MDA-MB-231 细胞具有高细胞毒性。对乳腺癌 MCF-7 细胞最具细胞毒性的化合物是化合物 21（IC-0.074μM），对小鼠成纤维细胞 3T3 的细胞毒性较低，IC-0.20μM。进行了 SAR 分析。对 MDA-MB 细胞用化合物 21 进行了荧光处理研究，以阐明作用机制的某些方面。
结论
化合物 14 和 20 对 MCF-7 和 3T3 细胞的细胞毒性之间的关系可以提示类似的作用机制。测试化合物的抗肿瘤潜力证明需要进一步研究以估计细胞过程中确切的抑制途径。用化合物 21 处理 MDA-MB 细胞的荧光研究表明凋亡过程迅速。
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