Development of efficient di- and multi-component reactions for synthesis of versatile heterocycles and their hybrid compounds with antiparasitic, fungicidal and cytotoxic activities

开发高效的双组分和多组分反应，用于合成具有抗寄生虫、杀真菌和细胞毒活性的多功能杂环及其杂化化合物

• 批准号: 445367543
• 负责人: Professorin Dr. Svetlana Tsogoeva
• 金额: --
• 依托单位: N.D. Zelinsky Institute of Organic Chemistry
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/445367543?language=en
• 关键词: Development; efficient; di; multi; component

The present joint proposed research is aimed at development of novel facile synthetic methods towards new anticancer and antischistosomal agents, since schistosomiasis and cancer are two diseases that pose a challenge to physicians, pharmacists and chemists.At present, cyclic organic peroxides are very promising scaffolds for a wide range of drugs with an unusual mechanism of action. The first objective is, therefore, development of methods for synthesis of stable compounds with an O-O fragment which might provide lead structures with anticancer and antiparasitic activities. We will focus on the following studies: synthesis of structurally novel stable nitrogen-containing peroxides, especially cyclic azaperoxides and acyl peroxides and other peroxides. Most of existing methods for cyclic peroxide synthesis are based on condensation of ketones with hydrogen peroxide or ozonolysis of unsaturated moieties. In this project, new methods for synthesis of organic peroxides based on discovered free-radical reactions employing photoredox and electrochemical approaches will be proposed.Since most of known approved pharmaceuticals contain heterocyclic rings, a great deal of research in heterocyclic chemistry is concerned with development of new frameworks and of new convenient and efficient synthetic methods for their formation. Such synthetic strategies are desirable concerning environmental aspects and with respect to reduction of costs and of potentially hazardous waste. Thus, the second objective of the joint project is development of facile and environmentally friendly multi-step domino reactions towards unprecedented fused quinazoline-thiohydantoin heterocycles with and without quaternary carbon centers, demonstrating anticancer and antischistosomal activities. Chiral Brønsted acid-catalyzed methods will be developed for highly enantioselective formation of quaternary carbon centers. After the discovery that hybrids can be even more effective than monomers, many researchers started to consider hybrids of bioactive agents also to overcome e.g. multidrug resistance. This new concept, inspired by nature itself, constitutes a great opportunity for the fight against different diseases. In this project, hybrids of monomeric drugs (new stable peroxides and fused heterocyclic compounds, preselected through their systematic biological examination) are planned to be synthesized. By hybridisation of selected parent compounds via various linkers, fundamental lead structures for appearance of efficient anti-cancer and antiparasitic drugs are expected to be developed (third objective). Different linkers between monomeric components of hybrid drugs will be investigated to find out which type of linker is more suitable to get the strongest anti-cancer or antiparasitic activities. The range of linkers will reach from ester, ether, amide, triazole and other moieties. We intend to integrate organocatalyzed click-reactions in the synthesis of 1,2,3-triazole linkers.

目前联合提出的研究旨在开发新的抗癌和抗肿瘤药物的新的简便合成方法，因为血吸虫病和癌症是两种对医生，药剂师和化学家提出挑战的疾病。目前，环状有机过氧化物是非常有前途的支架，用于广泛的药物，具有不寻常的作用机制。因此，第一个目标是开发用于合成具有O-O片段的稳定化合物的方法，所述O-O片段可能提供具有抗癌和抗寄生虫活性的先导结构。本论文将重点研究以下几个方面：结构新颖、稳定的含氮过氧化物，特别是环状氮杂过氧化物和酰基过氧化物等过氧化物的合成。大多数现有的环状过氧化物合成方法是基于酮与过氧化氢的缩合或不饱和部分的臭氧分解。本项目将利用光氧化还原和电化学方法，在自由基反应的基础上，提出合成有机过氧化物的新方法。由于大多数已知的已批准的药物含有杂环，因此杂环化学的大量研究都与开发新的框架和新的方便有效的合成方法有关。这样的合成策略在环境方面以及在降低成本和潜在危险废物方面是理想的。因此，该联合项目的第二个目标是开发简便和环境友好的多步多米诺骨牌反应，以实现具有和不具有季碳中心的前所未有的稠合喹唑啉-硫代乙内酰脲杂环，展示抗癌和抗肿瘤活性。手性布朗斯台德酸催化的方法将被开发用于季碳中心的高度对映选择性形成。在发现杂交体可以比单体更有效之后，许多研究人员开始考虑生物活性剂的杂交体也可以克服例如多药耐药性。这一受自然本身启发的新概念为防治各种疾病提供了一个很好的机会。在该项目中，计划合成单体药物的混合物（新的稳定过氧化物和稠合杂环化合物，通过其系统的生物学检查进行预选）。通过经由各种连接体的所选母体化合物的杂交，预期开发用于出现有效抗癌和抗寄生虫药物的基本先导结构（第三目标）。将研究混合药物的单体组分之间的不同连接体，以找出哪种类型的连接体更适合获得最强的抗癌或抗寄生虫活性。接头的范围将达到酯、醚、酰胺、三唑和其它部分。我们打算将有机催化的点击反应整合到1，2，3-三唑连接体的合成中。