Macrocycles in new drug discovery

Over the past several years, the prevalence of biologically active macrocycles in medici­ nal chemistry literature has been increasing. Numerous recent review articles have dis­ cussed the role that macrocycles can play in medicinal chemistry, in particular looking beyond the established importance of natural product macrocycles in drug discovery [1–3]. Driggers et al. have argued that macrocyclic structures are underexploited in drug discov­ ery, and presented different classes of natural product macrocycles and their applications to highlight the suitability of the structural class for further development [1]. Oyelere has collated a selection of specialist articles with a particular focus upon some of the challeng­ ing molecular targets that macrocycles might be suited towards within the context of drug development [2,4–9]. Marsault and Peterson pro­ vided a comprehensive overview of the use of macrocycles in many therapeutic areas within drug discovery, along with some of the strate­ gies used to synthesize these molecules [3]. In the current review, we will focus on recent stud­ ies that aid the understanding of the effects of macrocyclization upon target potency, selectiv­ ity and compound physicochemical properties. The majority of examples presented here have been taken from literature sources from the past 5 years and are largely focused on applications within oncology drug discovery. Wherever pos­ sible, a comparison of the macrocycles to rel­ evant acyclic molecules has been highlighted, as such pairwise comparisons are the most direct means of determining the effects and potential benefits of macrocyclization. Macrocycles in drug discovery have been defined as a ring system consisting of 12 or more atoms [1]. Opinions differ on the definition of macrocycles based on ring size, but this option usefully captures the qualitative differences in behavior between large macrocyclic rings (≥12 atoms) and medium rings (8–11 atoms). The accessible conformations for these medium rings are dominated by transannular interactions and conformational strains that are not present in the larger macrocycles [10]. Macrocycles have a structure that affords a degree of conform­ ational pre­organization due to restricted rota­ tion. Many natural products have a macrocyclic core, suggesting that an evolutionary advantage may be associated with the production of second­ ary metabolites based upon these scaffolds [1,11]. There are different classes that macrocycles could fall into, including peptidic and nonpeptidic nat­ ural products, non­natural (synthetic) peptides and non­natural (synthetic) macro cycles. This review will primarily focus upon the last class, since considerable scope exists for the greater application of synthetic macrocycles to medicinal chemistry. The potential for macrocycles as drugs is already evident. Exploitation of natural product macro­ cycles has yielded several oncology drugs that are either approved for clinical use or have reached late­stage clinical development (Table 1), such as the mTOR inhibitor Torisel (temsirolimus) [12,13], the microtubulin stabilizer Ixempra (ixabepilone) [14–16] and the Hsp90 inhibitor 17­allylamino­geldanamycin [17]. A number of synthetic macrocycles have entered clinical development, such as the dual JAK2/FLT3 Macrocycles in new drug discovery