Synthesis and Pro-Apoptotic Effects of Nitrovinylanthracenes and Related Compounds in Chronic Lymphocytic Leukaemia (CLL) and Burkitt’s Lymphoma (BL)

Author:

Byrne Andrew J.1,Bright Sandra A.2,McKeown James. P.1,Bergin Adam1ORCID,Twamley Brendan3,McElligott Anthony M.4ORCID,Noorani Sara1,Kandwal Shubhangi2,Fayne Darren2,O’Boyle Niamh M.1ORCID,Williams D. Clive2,Meegan Mary J.1ORCID

Affiliation:

1. School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland

2. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland

3. School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland

4. Discipline of Haematology, School of Medicine, Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College, Dublin 8, D08 W9RT Dublin, Ireland

Abstract

Chronic lymphocytic leukaemia (CLL) is a malignancy of the immune B lymphocyte cells and is the most common leukaemia diagnosed in developed countries. In this paper, we report the synthesis and antiproliferative effects of a series of (E)-9-(2-nitrovinyl)anthracenes and related nitrostyrene compounds in CLL cell lines and also in Burkitt’s lymphoma (BL) cell lines, a rare form of non-Hodgkin’s immune B-cell lymphoma. The nitrostyrene scaffold was identified as a lead structure for the development of effective compounds targeting BL and CLL. The series of structurally diverse nitrostyrenes was synthesised via Henry–Knoevenagel condensation reactions. Single-crystal X-ray analysis confirmed the structure of (E)-9-chloro-10-(2-nitrobut-1-en-1-yl)anthracene (19f) and the related 4-(anthracen-9-yl)-1H-1,2,3-triazole (30a). The (E)-9-(2-nitrovinyl)anthracenes 19a, 19g and 19i–19m were found to elicit potent antiproliferative effects in both BL cell lines EBV−MUTU-1 (chemosensitive) and EBV+ DG-75 (chemoresistant) with >90% inhibition at 10 μM. Selected (E)-9-(2-nitrovinyl)anthracenes demonstrated potent antiproliferative activity in CLL cell lines, with IC50 values of 0.17 μM (HG-3) and 1.3 μM (PGA-1) for compound 19g. The pro-apoptotic effects of the most potent compounds 19a, 19g, 19i, 19l and 19m were demonstrated in both CLL cell lines HG-3 and PGA-1. The (E)-nitrostyrene and (E)-9-(2-nitrovinyl)anthracene series of compounds offer potential for further development as novel chemotherapeutics for CLL.

Funder

Irish Research Council Postgraduate Fellowship

Trinity College Dublin

Publisher

MDPI AG

Subject

Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science

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