Multiple Multicomponent Macrocyclizations (MiBs): A Strategic Development Toward Macrocycle Diversity

Abstract

Macrocycles are of high significance in areas as diverse as drug development and supramolecular chemistry. They can be considered as privileged molecules because they can combine flexibility and conformational bias. They allow a certain conformational adaptation for binding and at the same time can have an improved overall energy term while binding, compared to linear molecules. Recently, a diversityoriented macrocyclization strategy termed multiple multicomponent macrocyclization including bifunctional building blocks (MiB) was developed which allows producing constitutionally diverse and complex macrocycles from simple building blocks in one pot. The efficient search for novel molecular ligands of biological targets remains a continuing goal in drug discovery and chemical biology.1-3 In the past, the predominant interest of medicinal chemists in synthetic ligands has been devoted to small rings (especially heterocycles) because of their known capability to interact with defined protein motifs and their ease of preparation. Huge libraries, including combinatorial ones,4,5 have been synthesized by means of wellestablished processes and screened for biological activity. Lately, macrocycles have attracted increasing attention also by virtue of both their high success rate in medicinal and recognition chemistry and their widespread occurrence in nature.6-10 The demand for bioactive compounds with new application profiles has triggered the search for molecules with biological features that simple 5/6/7-ring (hetero)cycles do not bear.8-12 Macrocycles are usually endowed with a proper combination of more than one binding domain, conformational preorganization, and flexibility.8,13,14 Their structural, physicochemical, and biological features provide recognition and binding properties not found in linear or small ring counterparts.14 For example, their often increased biological stability compared to acyclic analogues (e.g., cyclopeptides compared to peptides) makes them a fascinating paradigm to design biologically active molecules.8-14 Combinatorial synthetic chemistry in the macrocycle field does not yet reflect the tremendous impact of naturally occurring macrocycles in areas such as antibiotics, immunosuppressants, ion chelators, or membrane active compounds, where their success rate appears to be overproportional (in relative terms) compared to other drug types.6-9,15