Macrocyclic Proteasome Inhibitors

Abstract

Proteasome inhibitors have proven to be effective anticancer agents. Despite the success of the first on the market proteasome inhibitor bortezomib in chemotherapy, alternative clinically useful proteasome inhibitors are still urgently needed as bortezomib therapy causes severe side effects and is limited by arising drug resistance. Experience from previous proteasome inhibitor studies has thereby demonstrated that the identification of proteasome inhibitor structures with suitable pharmacological properties is a key factor for a successful development of clinically useful proteasome inhibitors. Macrocycles often show distinct and in comparison to linear small molecules superior pharmacological properties. Consequently, macrocyclic proteasome inhibitors might represent promising small molecules for drug development. Here, we want to highlight the current state of the art of macrocyclic proteasome inhibitor research. To this end, we give an overview and critically discuss currently known classes of macrocyclic proteasome inhibitors.

Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template-Induced Preorganization

“…88 The letter n denotes the number of monomers in the monocyclic polymer. RGD β-lactam peptidomimetics that induce differential gene expression in human endothelial cells, 49 G-quadruplex ligands for anticancer therapeutics, 50 the excellent tumor uptake and pharmacokinetics of 64 Cu-labeled cyclic RGD peptide dimers with Gly and PEG linkers, 51 macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity, 52,53 proteasome inhibitors, 54 inhibitors of HIV-1 capsid-human lysyl-tRNA synthetase, 55 macrocyclic lactams inspired on the skeleton of natural products with anticancer properties, 56 etc. Besides the considered biomedical applications, macrocyclic structures have found important applications in other fields such as chemical analysis 57,58 or nanotechnology.…”

A review on recent developments of indole-containing antiviral agents

“…It is reported that macrocyclic indole derivatives can demonstrate favorable druglike properties [120,121], including good solubility, increased lipophilicity, enhanced membrane penetration, improved metabolic stability, and good oral bioavailability with desirable pharmacokinetic and pharmacodynamic properties [122,123]. Compound 25 (TMC647055), the 17-membered macrocyclic indole derivative, is currently being evaluated in phase II clinical trials.…”

Anticancer Activities of Newly Synthesized Chiral Macrocyclic Heptapeptide Candidates

“…Among chemically synthesized pharmaceutical drugs, macrocyclic compounds with a ring of 12 or more atoms [2] are generally favored for synthesizing potential anticancer derivatives, mainly in the chemical, biological, and medical sectors [3][4][5]. Macrocyclic derivatives include peptideand non-peptide-derived compounds, synthesized peptides, and macrocyclic derivatives [6].…”