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

Author(s)

Tavares, Mauricio Temotheo ^{[1, 2]} ; de Almeida, Larissa Costa ^[3] ; Kronenberger, Thales ^{[4, 5]} ; Ferreira, Glaucio Monteiro ^[6] ; de Divitiis, Thaina Fujii ^[1] ; Toledo, Monica Franco Zannini Junqueira ^[1] ; Hassimotto, Neuza Mariko Aymoto ^{[7, 8]} ; Machado-Neto, Joao Agostinho ^[3] ; Costa-Lotufo, Leticia Veras ^[3] ; Parise-Filho, Roberto ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Pharm, Sao Paulo - Brazil

^[2] Scripps Res, Dept Mol Med, Jupiter, FL 33458 - USA

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Sao Paulo - Brazil

^[4] Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, Kuopio 70211 - Finland

^[5] Univ Hosp Tubingen, Internal Med 8, Dept Oncol & Pneumonol, Otfried Muller Str 10, DE-72076 Tubingen - Germany

^[6] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Pharm, Lab Mol Biol Appl Diag LBMAD, Sao Paulo, SP - Brazil

^[7] Univ Sao Paulo, Fac Pharmaceut Sci, Food Res Ctr FoRC CEPID, Sao Paulo, SP - Brazil

^[8] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Food Sci & Nutr, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: Bioorganic & Medicinal Chemistry; v. 35, APR 1 2021.
• Web of Science Citations: 0

Abstract

Histone deacetylases (HDACs) are a family of enzymes that modulate the acetylation status histones and nonhistone 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 11ad increased acetylated ?-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. (AU)

• FAPESP's process: 15/17177-6 - Integrative approach on the sustainable prospection of marine natural products: from diversity to anticancer compounds
• Grantee: Leticia Veras Costa Lotufo
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants
• FAPESP's process: 13/19311-6 - Design, synthesis and antitumor activity of aryl-sulfonylhydrazone compounds
• Grantee: Thais Batista Fernandes
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 17/00689-0 - New antineoplastic agents: synthesis, molecular docking and antitumoral activity of capsaicinoids analogues
• Grantee: Roberto Parise Filho
• Support Opportunities: Regular Research Grants