Largazole Analogues as Histone Deacetylase Inhibitors and Anticancer Agents: An Overview of Structure–Activity Relationships

• Published in: ChemMedChem Vol. 12; no. 23; pp. 1917 - 1926
• Main Authors: Poli, Giulio, Di Fabio, Romano, Ferrante, Luca, Summa, Vincenzo, Botta, Maurizio
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 07-12-2017
• Subjects: Animals; Anticancer properties; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Antitumor agents; Cancer; Depsipeptides - chemical synthesis; Depsipeptides - chemistry; Depsipeptides - pharmacology; Dose-Response Relationship, Drug; Histone deacetylase; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - metabolism; Humans; hydrolases; Inhibitors; macrocyclic ligands; Molecular Conformation; natural products; Pharmacology; Structure-Activity Relationship; Structure-activity relationships; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Tumor cell lines; hydrolases; natural products; macrocyclic ligands; structure-activity relationships; antitumor agents
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201700563

Since the time of its identification, the natural compound largazole rapidly caught the attention of the medicinal chemistry community for its impressive potency as an inhibitor of histone deacetylases (HDACs) and its strong antiproliferative activity against a broad panel of cancer cell lines. The design of largazole analogues is an expanding field of study, due to their remarkable potential as novel anticancer therapeutics. At present, a large ensemble of largazole analogues has been reported, allowing the identification of important structure–activity relationships (SAR) that can guide the design of novel compounds with improved HDAC inhibitory profiles, anticancer activity, and pharmacokinetic properties. The aim of this review is to concisely summarize the information obtained by biological evaluations of the various largazole analogues reported to date, with particular attention given to the latest analogues, as well as to analyze the various SAR obtained from this data, with the purpose of providing useful guidelines for the development of novel potent and selective HDAC inhibitors to be used as anticancer agents.
The power of depsipeptides: This review summarizes the various analogues obtained by structural modification of largazole, a natural depsipeptide characterized by impressive activity as a histone deacetylase inhibitor and anticancer agent. The main structure–activity relationships derived by biological evaluation of these compounds are analyzed and discussed, providing useful guidelines for the design of new anticancer agents.