Synthetic strategies to pyrimido [4,5-B]indole: A privileged fused-indole scaffold

Pyrimido-indoles are tricyclic ring systems produced when an indole group is fused with a pyrimidine ring. Of the two possible isomers of this ring system, the pyrimido[4,5-b]indoles are of particular interest relative to pyrimido[5,4-b]indoles, due to their presence in a wide range of pharmacologically active molecules. Compounds containing the pyrimido[4,5-b]indole chemotype have demonstrated affinity towards multiple anticancer biological targets including receptor tyrosine kinases, thymidylate synthase, BET bromodomains, and tubulin. In addition, derivatives bearing this scaffold exhibit antiviral, diuretic, antiopportunistic infection, and hematopoietic stem-cell expansion activities. Multiple synthetic approaches to construct this notable tricycle have been reported including the Nenitzescu reaction, Fisher-type cyclization, palladium catalysis, and aza-Wittig type reaction among others. This book chapter provides an overview of the diverse synthetic approaches to generate pyrimido[4,5-b]indoles.