ABSTRACT
The acetylome is important for maintaining the homeostasis of cells. Abnormal changes can result in the pathogenesis of immunological or neurological diseases, and degeneration can promote the manifestation of cancer. In particular, pharmacological intervention in the acetylome with pan-histone deacetylase (HDAC) inhibitors is clinically validated. However, these drugs exhibit an undesirable risk-benefit profile due to severe side effects. Selective HDAC inhibitors might promote patient compliance and represent a valuable opportunity in personalised medicine. Therefore, we envisioned the development of HDAC6-selective inhibitors. During our lead structure identification, we demonstrated that an alkoxyurea-based connecting unit proves to be beneficial for HDAC6 selectivity and established the synthesis of alkoxyurea-based hydroxamic acids. Herein, we report highly potent N-alkoxyurea-based hydroxamic acids with improved HDAC6 preference compared to nexturastatâ A. We further validated the biological activity of these oxa analogues of nexturastatâ A in a broad subset of leukaemia cell lines and demonstrated their superior anti-proliferative properties compared to nexturastatâ A.
Subject(s)
Antineoplastic Agents/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Phenylurea Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Histone Deacetylase 6 , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/chemistry , Molecular Docking Simulation , Molecular Structure , Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/chemistry , Structure-Activity RelationshipABSTRACT
A series of α,ß-unsaturated hydroxamic acid derivatives as novel HDAC inhibitors (HDACi) with structural modifications of the connecting unit and the CAP group was synthesized. The in vitro evaluation against the human cancer cell lines A2780 and Cal27 identified 6e and 7j as the most potent compounds regarding HDAC inhibitory activity and inhibition of proliferation. Isoform profiling against HDAC2, 4, 6 and 8 revealed a preference for HDAC2 and 6 for both compounds in contrast to the pan HDACi panobinostat. 6e and 7j enhanced significantly cisplatin-induced cytotoxicity in a combination treatment mediated by increased apoptosis induction and caspase-3/7 activation. The interaction between 6e or 7j and cisplatin was highly synergistic and more pronounced for the cisplatin resistant subline Cal27CisR. IC50 values of cisplatin were even lower in Cal27CisR pretreated with 6e or 7j than for the parental cell line Cal27. Based on our findings, the novel dual class I/HDAC6 inhibitors could serve as an option to overcome cisplatin resistance with fewer side effects in comparison to panobinostat.
