Vanillyl-benzyl-hydroxamate hybrids as selective histone deacetylase 6 inhibitors: design, synthesis and biological evaluation in hematological tumor cell lines

• Grant number: 22/02805-5
• Support Opportunities: Scholarships in Brazil - Master
• Start date: July 01, 2022
• End date: November 30, 2023
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Roberto Parise Filho
• Grantee: Lara Gimenez Borges
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Cancer has been a worldwide problem and figures out the second leading cause of death. It is characterized by the accelerated and disordered growth of cells that have mutations. Among the various tumor subtypes, there are hematologic malignancies, a collective term for neoplastic diseases of hematopoietic and lymphoid tissues. In several cases, these types of cancers are resistant to drug treatment and, among other factors such as toxicity, there is a need to develop new compounds with a better therapeutic profile. The enzyme histone deacetylase 6 (HDAC6) acts on the deacetylation of N-acetyllysines histones side chain and also on non-histonic proteins, such as ±-tubulins, and disturbances in the functioning of HDAC6 have been associated with solid malignant neoplasms, but mainly in hematological. In this sense, HDAC inhibitors, particularly isoform 6, have shown potential activity in cancer therapy. At the same time, capsaicin 13, a substance originated from peppers, and its synthetic analogues produced by our group, have made important contributions to the selection of compounds with superior antitumor activity. Molecular hybridization, which consists of merging two or more pharmacophores in the hope of obtaining a new, unprecedented, hybrid chemical entity with potential action on two or more targets is of great interest in multifactorial diseases such as cancer. Thus, this project aims to obtain compounds, designed by the molecular hybridization of nexturastate A 12 (selective HDAC6 inhibitor) and capsaicin 13, which have potential antitumor activity in hematological malignancies. The designed hybrid compounds will be subjected to molecular docking studies in order to understand relevant interactions between the designed molecules and the HDAC6 isoenzyme. Furthermore, after selecting the best ligands, the compounds will be synthetically obtained, and cytotoxicity studies and cell death mechanism will be conducted. In parallel, studies of enzymatic inhibition will be carried out in order to evaluate the potency and selectivity of the compounds against HDAC1 and HDA6.