Recent Advances in Macrocyclic Drugs and Microwave-Assisted and/or Solid-Supported Synthesis of Macrocycles

Abstract

Macrocycles represent attractive candidates in organic synthesis and drug discovery. Since 2014, nineteen macrocyclic drugs, including three radiopharmaceuticals, have been approved by FDA for the treatment of bacterial and viral infections, cancer, obesity, immunosuppression, etc. As such, new synthetic methodologies and high throughput chemistry (e.g., microwave-assisted and/or solid-phase synthesis) to access various macrocycle entities have attracted great interest in this chemical space. This article serves as an update on our previous review related to macrocyclic drugs and new synthetic strategies toward macrocycles (Molecules, 2013, 18, 6230). In this work, I first reviewed recent FDA-approved macrocyclic drugs since 2014, followed by new advances in macrocycle synthesis using high throughput chemistry, including microwave-assisted and/or solid-supported macrocyclization strategies. Examples and highlights of macrocyclization include macrolactonization and macrolactamization, transition-metal catalyzed olefin ring-closure metathesis, intramolecular C–C and C–heteroatom cross-coupling, copper- or ruthenium-catalyzed azide–alkyne cycloaddition, intramolecular SNAr or SN2 nucleophilic substitution, condensation reaction, and multi-component reaction-mediated macrocyclization, and covering the literature since 2010.

Does Hamiltonian Replica Exchange via Lambda-Hopping Enhance the Sampling in Alchemical Free Energy Calculations?

“…APA can be selectively obtained in the conformationally restricted Z or E forms. The Z isomer serves as the building block for the synthesis of macrocyclic pseudopeptides for the treatment of a variety of diseases [ 25 ].…”

“…APA can be selectively obtained in the conformationally restricted Z or E forms. The Z isomer serves as the building block for the synthesis of macrocyclic pseudopeptides for the treatment of a variety of diseases [25]. The E-form is used to synthesize cyclic macrolactames aggregating in remarkable supramolecular structures with potential application in drug delivery, photonics, material science and catalysis [26].…”

Enriching Proteolysis Targeting Chimeras with a Second Modality: When Two Are Better Than One

“… 124 Already 19 macrocyclic drugs, including three radiopharmaceuticals, have been approved by the FDA for the treatment of infectious and metabolic diseases, cancer, immunosuppression, etc. 125 …”

“…In the second case, macrocyclization is a design strategy for locking a known binder into its bioactive conformation and improving its PD profile . Already 19 macrocyclic drugs, including three radiopharmaceuticals, have been approved by the FDA for the treatment of infectious and metabolic diseases, cancer, immunosuppression, etc …”

“…124 Already 19 macrocyclic drugs, including three radiopharmaceuticals, have been approved by the FDA for the treatment of infectious and metabolic diseases, cancer, immunosuppression, etc. 125 Here, we review recent examples on how (i) macrocyclic molecules (Figure 16A) and (ii) macrocyclization strategies (Figure 16B) have been fused with the PROTAC concept to provide the so-called macrocycle-based PROTACs.…”