Discovery of therapies for lymphomas and leukaemia: Synthesis and antiproliferative action of novel ethanoanthracenes

Abstract

Cancer is a broad class of diseases responsible for up to 9.6 million deaths worldwide in 2018, accountable for approximately every one in six deaths globally. Cancer is second only in all-cause mortality to circulatory system diseases such as ischemic heart disease (IHD). By 2025, 20 million new cancer cases are expected to be diagnosed in the Western world. Globally, chronic lymphocytic leukaemia (CLL) is the most common leukaemic disease in developed countries, primarily affecting the elderly. CLL is classed as a clonal disorder of mature B-lymphocytes and its clinical patient prognoses is affected mainly by the mutational status of the immunoglobulin G heavy chain variable region (IGHV) and distinct chromosomal abnormalities such as trisomy of chromosome 12. Patients with unmutated IGHV have a better prognosis than those with the wild type variant. Structures related to the tetracyclic anti-depressant maprotiline demonstrate potent selective antiproliferative and pro-apoptotic effects in vitro in B-cell malignancies, namely Burkitt’s Lymphoma (BL) cell lines DG-75 and MUTU-1. Based on these preliminary studies, libraries of structurally related nitrostyrene and chalcone-based ethanoanthracenes were designed, based on the proven effectiveness of a nitrostyrene core structure and chalcone moieties in leukaemic cell lines. These ethanoanthracenes were synthesised using Henry-Knoevenagel condensation, Claisen-Schmidt condensation and Diels–Alder cycloaddition reactions. The products were structurally arranged into nine series and antiproliferative activity was determined using the alamar Blue assay on the two CLL cell lines HG-3 (unmutated IGHV) and PGA-1 (mutated IGHV). Lead compounds from these series were discovered to elicit potent antiproliferative activity, e.g. for compound (24) IC50 values 0.048 μM (HG-3) and 0.061 μM (PGA-1) which were superior to the clinically used chemotherapeutic agent for CLL, fludarabine. Pro-apoptotic cell death in both HG-3 and PGA-1 cell lines was observed. Low to moderate cytotoxicity was noted in CLL cell lines when tested close to the determined compound IC50 values. This finding was also supported by the low toxicity of representative nitrostyrene and chalcone ethanoanthracene lead compounds in peripheral blood mononuclear cells (PBMCs), indicating selective toxicity for chronic lymphocytic leukaemia. Analysis of the structure-activity relationships (SARs) identified the lead nitrostyrene and chalcone ethanoanthracene compounds from this study as potential agents for progression to preclinical drug development for the treatment of CLL