Synthesis of Alpha-Acyloxy-(1,2,5-Oxadiazole-2-Oxide) Carboxamides via Passerini Multicomponent Reaction. Evaluation of Nitric Oxide-Releasing and Anti-Proliferative Properties

IF 2 3区 化学 Q2 CHEMISTRY, ORGANIC
Nicolas S. Anjos, Gustavo S. Sant’Ana, João Vitor C. Santos, Caroline Alves, Ana Caroline S. Teodoro, Paulo Vinicius de Sousa, Hugo P. Monteiro, Luiz S. Longo Jr
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Abstract

High intracellular levels of nitric oxide (NO) lead to cytotoxic effects against tumor cells. In this context, organic compounds containing the 1,2,5-oxadiazole-2-oxide (furoxan) scaffold play an important role as exogenous NO donors under physiological conditions and, therefore, may act as potential antitumor agents. Multicomponent reactions are considered useful synthetic tools for the rapid and efficient construction of structurally diverse organic compounds, such as furoxan hybrid molecules. Herein, we report the Passerini multicomponent reaction applied to the synthesis of nitric oxide-releasing furoxan based α-acyloxy carboxamides as well as their NO release capacity and anti-proliferative activity. A total of 23 α-acyloxy-(1,2,5-oxadiazole-2-oxide) carboxamides were synthesized using the Passerini reaction under microwave heating, in moderate to excellent yields (67%–95%). The quantification of nitric oxide release demonstrated that all compounds were capable of releasing NO within the range of 0.8–7.4 μM. In vitro anti-proliferative assays were carried out with mama (MCF-7), melanoma (SK-MEL-28), and prostate (LNCaP) cancer cell lines, as well as normal cell line (HUVEC). Compounds 21 and 22 showed moderate anti-proliferative activity (IC50 = 95.5 and 66.6 μM, respectively) against LNCaP cells. This study demonstrated the potential of α-acyloxy-(1,2,5-oxadiazole-2-oxide) carboxamides as a promising class of compounds to be explored for antitumor activity.

Abstract Image

通过Passerini多组分反应合成α -酰基-(1,2,5-恶二唑-2-氧化物)羧酰胺。一氧化氮释放和抗增殖性能的评价
高水平的细胞内一氧化氮(NO)导致对肿瘤细胞的细胞毒性作用。在这种情况下,含有1,2,5-恶二唑-2-氧化物(呋喃嘧啶)支架的有机化合物在生理条件下作为外源性NO供体发挥重要作用,因此可能作为潜在的抗肿瘤药物。多组分反应被认为是快速有效地构建结构多样的有机化合物(如呋喃杂化分子)的有用合成工具。本文报道了用Passerini多组分反应合成一氧化氮释放呋喃嘧啶基α-酰基羧酰胺及其NO释放能力和抗增殖活性。采用微波加热的Passerini反应,合成了23个α-酰基-(1,2,5-噻二唑-2-氧化物)羧酰胺,产率为67% ~ 95%。一氧化氮的释放量测定表明,化合物在0.8 ~ 7.4 μM范围内均能释放一氧化氮。对mama (MCF-7)、黑色素瘤(SK-MEL-28)、前列腺癌(LNCaP)细胞系以及正常细胞系(HUVEC)进行体外抗增殖试验。化合物21和22对LNCaP细胞具有中等的抗增殖活性(IC50分别为95.5 μM和66.6 μM)。该研究表明α-酰基-(1,2,5-恶二唑-2-氧化物)羧酰胺是一类有潜力的抗肿瘤活性化合物。
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来源期刊
Journal of Heterocyclic Chemistry
Journal of Heterocyclic Chemistry 化学-有机化学
CiteScore
5.20
自引率
4.20%
发文量
177
审稿时长
3.9 months
期刊介绍: The Journal of Heterocyclic Chemistry is interested in publishing research on all aspects of heterocyclic chemistry, especially development and application of efficient synthetic methodologies and strategies for the synthesis of various heterocyclic compounds. In addition, Journal of Heterocyclic Chemistry promotes research in other areas that contribute to heterocyclic synthesis/application, such as synthesis design, reaction techniques, flow chemistry and continuous processing, multiphase catalysis, green chemistry, catalyst immobilization and recycling.
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