Abstract
Macrocyclic scaffolds are commonly found in bioactive natural products and pharmaceutical molecules. So far, a large number of macrocyclic natural products have been isolated and synthesized. The construction of macrocycles is generally considered as a crucial and challenging step in the synthesis of macrocyclic natural products. Over the last several decades, numerous efforts have been undertaken toward the synthesis of complex naturally occurring macrocycles and great progresses have been made to advance the field of total synthesis. The commonly used synthetic methodologies toward macrocyclization include macrolactonization, macrolactamization, transition metal-catalyzed cross coupling, ring-closing metathesis, and click reaction, among others. Selected recent examples of macrocyclic synthesis of natural products and druglike macrocycles with significant biological relevance are highlighted in each class. The primary goal of this review is to summarize currently used macrocyclic drugs, highlight the therapeutic potential of this underexplored drug class and outline the general synthetic methodologies for the synthesis of macrocycles.
Highlights
Macrocyclic motifs are commonly found in natural products and pharmaceutical molecules; and provide privileged scaffolds for medicinal chemistry programs in modern drug discovery [1,2].From a historic and clinical point of view, macrocyclic molecules have had an enormous impact on the fields of chemistry, biology, and medicine [1,3,4,5]
Many naturally occurring macrocycles have been successfully introduced to the clinic; as such, macrocyclic natural products continue to serve as invaluable starting points and to drive and inspire organic and medicinal chemists to discover new and better drugs [1,6,7]
Combined with emerging schemes to control the outcome of stereochemistry, the utility of the Ring-Closing Metathesis (RCM) macrocyclization would be greatly enhanced in the course of total synthesis of natural products
Summary
Macrocyclic motifs are commonly found in natural products and pharmaceutical molecules; and provide privileged scaffolds for medicinal chemistry programs in modern drug discovery [1,2]. From a historic and clinical point of view, macrocyclic molecules have had an enormous impact on the fields of chemistry, biology, and medicine [1,3,4,5]. Different from synthetic small molecule drugs, characteristics of macrocyclic natural products typically include a 12 or more membered ring architecture and often do not possess the druglike “rule of five” properties [8]. This unique structural feature and conformational flexibility of the macrocyclic ring can offer subsequent functional advantages, e.g., it has the potential of being highly potent as well as being selective when key functional groups interact with biological targets [1]. Macrocycles can demonstrate favorable druglike properties, including good solubility, increased lipophilicity, enhanced membrane penetration, improved metabolic stability, and good oral bioavailability with desirable pharmacokinetic and pharmacodynamic properties [1,2,4]
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