Design, synthesis, and characterization of molecular mechanisms of dipeptidyl nitrile derivatives inhibitors of cysteine cathepsins with antineoplastic activity

Abstract

Cysteine cathepsins B, L, and S are macromolecules associated with the progression of various types of cancer. The research group has been dedicated to studying cysteine protease inhibitors, with over 500 dipeptidyl nitriles and derivatives planned and synthesized in 9 years of activity. Some compounds show high affinity and potency against cysteine cathepsins B, L, and S, commonly involved in neoplastic processes. Thus, this project aims at the target-oriented synthesis of 15 novel dipeptidyl nitrile derivatives from assays involving approximately 100 molecules available to optimize physicochemical, pharmacological, and pharmacokinetic properties in various in vitro models. The 100 chemical substances are available in the research group with biochemical characterization. They will require cellular assays with estrogen-dependent breast cancer cell lines (MCF-7) and triple-negative (MDA-MB-231), as well as pancreatic adenocarcinoma (MIA PaCa-2, AsPC-1, PANC-1). The pharmacological activity has been sparsely described in the literature without understanding the cellular signaling and the mechanism involved. This project aims to connect the enzymatic activity to the cellular response mechanisms through the analysis of the active sites of cysteine cathepsins and their innovative inhibitors using bioinformatics and chemoinformatics tools, organic synthesis, solubility, and permeability studies, and pharmacological, cellular assays. The in vitro assays will be divided into two fronts to be performed simultaneously: (i) physicochemical analysis of water solubility and cell membrane permeability; (ii) cellular assays, aiming at the analysis of molecular mechanisms of cell death and the relationship with enzymatic inhibition, including the analysis of pharmacological activity in spheroids. These results will lead to exploring the complex chemical-biology interface involved in a drug candidate discovery project for breast and pancreatic cancer. (AU)