Bioisosterism in the design of vanillyl-benzyl-hydroxamate derivatives: synthesis, enzymatic inhibition in HDAC6 and evaluation of antitumor activity in hematological lineages

• Grant number: 24/06048-0
• Support Opportunities: Scholarships in Brazil - Master
• Start date: December 01, 2024
• End date: May 31, 2026
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Roberto Parise Filho
• Grantee: Thais Nascimento de Oliveira Alves
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Cancer, the second leading cause of death worldwide, is characterized by the uncontrolled and disordered growth of cells that do not respond to programmed cell death mechanisms. Some types of cancer affect cells in the hematopoietic and lymphatic tissues and are called hematological malignancies. Due to their heterogeneous nature, these types of cancer often present remission, relapse, or resistance to known antitumor treatments, motivating the search for new treatment methods. One of these methods is the development of compounds that inhibit histone deacetylase 6 (HDAC6i), an enzyme directly related to gene expression and processes such as migration, proliferation and cell death. Dysregulation of this enzyme has been associated with solid and hematologic malignant neoplasms. Previously, our research group developed hybrid HDAC6 inhibitors of capsaicin and nexturastat A. These compounds were able to inhibit HDAC6 and exhibit antitumor activity at micromolar doses. However, there is still room for improvement through techniques such as bioisosterism. Thus, the current project proposes the design and synthesis of new bioisosteric compounds that are potential HDAC6 inhibitors, based on the structure of previously developed HDAC6i hybrids, in addition to evaluating their inhibition potency and selectivity for HDAC6, as well as their cytotoxic activity and cell death mechanisms in tumorigenic and non-tumorigenic cells.