van der Westhuyzen Aletta E, Frolova Liliya V, Kornienko Alexander, van Otterlo Willem A L
Department of Chemistry and Polymer Science, University of Stellenbosch, Matieland, Stellenbosch, South Africa.
Department of Chemistry, New Mexico Institute of Mining and Technology, Socorro, NM, United States.
Alkaloids Chem Biol. 2018;79:191-220. doi: 10.1016/bs.alkal.2017.12.003. Epub 2018 Feb 6.
Rigidins (2-6) are pyrrolopyrimidine alkaloids isolated from marine tunicates. Since their isolation, refinement of their total syntheses, and biochemical evaluation, interest toward this pyrrolo[2,3-d]pyrimidine scaffold as a medicinal candidate has been triggered. The derivatization of these natural products has led to the discovery of a novel range of 7-deazahypoxanthines, which exhibit extremely potent anticancer activity in human cancer cell lines. A major breakthrough toward the synthesis of rigidin and various rigidin analogues has been the application of multicomponent reactions (MCRs). The rapid assembly of molecular diversity and flexibility displayed by MCRs makes it an attractive strategy for the preparation of rigidin-inspired small molecules. Furthermore, a number of rigidin-like 7-deazaxanthine compounds have been reported in the literature and the popularity of implementing MCRs to construct these 7-deazaxanthines is highlighted here. It is our hope that the synthetic methods described in this chapter will result in the further generation of rigidin-inspired compounds that will move on from being "hits" into "leads" in the medicinal chemistry drug discovery pipeline and potentially into anticancer therapeutics.
刚性菌素（2 - 6）是从海洋被囊动物中分离出的吡咯并嘧啶生物碱。自它们被分离、全合成得到优化以及进行生化评估以来，作为药物候选物的这种吡咯并[2,3 - d]嘧啶骨架已引发了人们的兴趣。这些天然产物的衍生化导致发现了一系列新型的7 - 脱氮次黄嘌呤，它们在人类癌细胞系中表现出极强的抗癌活性。多组分反应（MCRs）的应用是刚性菌素及各种刚性菌素类似物合成方面的一个重大突破。MCRs展现出的分子多样性和灵活性的快速组装使其成为制备受刚性菌素启发的小分子的一种有吸引力的策略。此外，文献中已报道了许多类刚性菌素的7 - 脱氮黄嘌呤化合物，本文强调了采用MCRs构建这些7 - 脱氮黄嘌呤化合物的普遍性。我们希望本章中描述的合成方法将促使进一步生成受刚性菌素启发的化合物，这些化合物在药物化学药物发现流程中能够从“命中”发展为“先导”，并有可能成为抗癌治疗药物。
