2. Academic Validation
  3. Structure-activity relationship and mechanistic studies for a series of cinnamyl hydroxamate histone deacetylase inhibitors

Structure-activity relationship and mechanistic studies for a series of cinnamyl hydroxamate histone deacetylase inhibitors

  • Bioorg Med Chem. 2021 Apr 1:35:116085. doi: 10.1016/j.bmc.2021.116085.
Maurício Temotheo Tavares 1,  Larissa Costa de Almeida 2,  Thales Kronenberger 3,  Glaucio Monteiro Ferreira 4,  Thainá Fujii de Divitiis 1,  Mônica Franco Zannini Junqueira Toledo 1,  Neuza Mariko Aymoto Hassimotto 5,  João Agostinho Machado-Neto 2,  Letícia Veras Costa-Lotufo 2,  Roberto Parise-Filho 6
Affiliations

Affiliations

  • 1 Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
  • 2 Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
  • 3 Department of Oncology and Pneumonology, Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Straße 10, DE 72076 Tübingen, Germany; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
  • 4 Laboratory of Molecular Biology Applied to Diagnosis (LBMAD), Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
  • 5 Food Research Center-(FoRC-CEPID) and Department of Food Science and Nutrition, Faculty of Pharmaceutical Science, University of São Paulo, São Paulo, SP, Brazil.
  • 6 Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: roberto.parise@usp.br.
PMID: 33668008 DOI: 10.1016/j.bmc.2021.116085
Abstract

Histone deacetylases (HDACs) are a family of Enzymes that modulate the acetylation status histones and non-histone proteins. Histone deacetylase inhibitors (HDACis) have emerged as an alternative therapeutic approach for the treatment of several malignancies. Herein, a series of urea-based cinnamyl hydroxamate derivatives is presented as potential Anticancer HDACis. In addition, structure-activity relationship (SAR) studies have been performed in order to verify the influence of the linker on the biological profile of the compounds. All tested compounds demonstrated significant antiproliferative effects against solid and hematological human tumor cell lines. Among them, 11b exhibited nanomolar potency against hematological tumor cells including Jurkat and Namalwa, with IC50 values of 40 and 200 nM, respectively. Cellular and molecular proliferation studies, in presence of compounds 11a-d, showed significant cell growth arrest, Apoptosis induction, and up to 43-fold selective cytotoxicity for leukemia cells versus non-tumorigenic cells. Moreover, compounds 11a-d increased acetylated α-tubulin expression levels, which is phenotypically consistent with HDAC inhibition, and indirectly induced DNA damage. In vitro enzymatic assays performed for 11b revealed a potent HDAC6 inhibitory activity (IC50: 8.1 nM) and 402-fold selectivity over HDAC1. Regarding SAR analysis, the distance between the hydroxamate moiety and the aromatic ring as well as the presence of the double bond in the cinnamyl linker were the most relevant chemical feature for the antiproliferative activity of the series. Molecular modeling studies suggest that cinnamyl hydroxamate is the best moiety of the series for binding HDAC6 catalytic pocket whereas exploration of Ser568 by the urea connecting unity (CU) might be related with the selectivity observed for the cinnamyl derivatives. In summary, cinnamyl hydroxamate derived compounds with HDAC6 inhibitory activity exhibited cell growth arrest and increased Apoptosis, as well as selectivity to acute lymphoblastic leukemia cells. This study explores interesting compounds to fight against neoplastic hematological cells.

Keywords

Acetylated α-tubulin; Cytotoxicity; HDAC6; Hematological malignancies; Selectivity.

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