Łowicki Daniel, Przybylski Piotr
Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznan, Poland.
Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznan, Poland.
Eur J Med Chem. 2022 May 5;235:114303. doi: 10.1016/j.ejmech.2022.114303. Epub 2022 Mar 18.
Nature often uses cascade reactions in a highly stereocontrolled manner for assembly structurally diverse nitrogen-containing heterocyclic scaffolds, i.e. secondary metabolites, important for medicinal chemistry and pharmacy. Five-membered nitrogen-containing heterocycles as standalone rings, as well as spiro and polycyclic systems are pharmacophores of drugs approved in various therapies, i.a. antibacterial or antiviral, antifungal, anticancer, antidiabetic, as they target many key enzymes. Furthermore, a large number of pyrrolidine derivatives are currently considered as drug candidates. Cascade transformations, also known as domino or tandem reactions, offer straightforward methods to build N-heterocyclic libraries of the great structural variety desired for drawing SAR conclusions. The tandem transformations are often atom economic and time-saving because they are performed as the one-pot, so no need for purification after each 'virtual' step and the limited necessity of protective groups are characteristic for these processes. Thus, the same results as in classical multistep synthesis can be achieved at markedly lower costs and shorter time, which is in line with modern green chemistry rules. Great advantage of cascade reactions is often reflected in their high regio- and stereoselectivities, enabling the preparing of the heterocyclic compound better fitted to the expected target in cells. This review reveals the biological relevance of N-heterocyclic scaffolds based on saturated 5-membered rings since we showed a number of examples of approved drugs together with the recent biologically attractive leading structures of drug candidates. Next, novel cascade synthetic procedures, taking into account the structure of the reactants and reaction mechanisms, enabling to obtain biological-relevant heterocyclic frameworks with good yields and relatively high stereoselectivity, were reviewed and compared. The review covers the advances of designing biological active N-heterocycles mainly from 2018 to 2021, whereas the synthetic part is focused on the last 7 years.
自然界常常以高度立体控制的方式利用级联反应来组装结构多样的含氮杂环骨架，即对药物化学和药学至关重要的次生代谢产物。五元含氮杂环作为独立的环，以及螺环和多环体系是各种疗法中获批药物的药效基团，如抗菌或抗病毒、抗真菌、抗癌、抗糖尿病药物，因为它们作用于许多关键酶。此外，大量吡咯烷衍生物目前被视为候选药物。级联转化，也称为多米诺或串联反应，为构建绘制构效关系结论所需的结构多样的氮杂环文库提供了直接的方法。串联转化通常具有原子经济性且节省时间，因为它们是一锅法进行的，所以在每个“虚拟”步骤后无需纯化，并且这些过程的特征是保护基团的必要性有限。因此，可以以显著更低的成本和更短的时间获得与经典多步合成相同的结果，这符合现代绿色化学规则。级联反应的一大优势通常体现在其高区域和立体选择性上，能够制备更适合细胞中预期靶点的杂环化合物。本综述揭示了基于饱和五元环的氮杂环骨架的生物学相关性，因为我们展示了许多获批药物的实例以及近期具有生物学吸引力的候选药物先导结构。接下来，对考虑反应物结构和反应机理的新型级联合成方法进行了综述和比较，这些方法能够以良好的产率和相对较高的立体选择性获得与生物学相关的杂环骨架。本综述涵盖了主要从2018年到2021年设计生物活性氮杂环的进展，而合成部分则聚焦于过去7年。
