Synthesis and biological evaluation of new N-substituted 9-nitro-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl derivatives

Cancer is a disease characterised by the uncontrolled growth and spread of abnormal cells, and it is the second leading cause of death globally. The vast majority of patients require chemotherapy in conjunction with surgery or radiological treatments in some steps of their treatment. CLL (Chronic Lymphocytic Leukaemia) is the most common leukaemia in developed countries globally, primarily affecting the elderly. CLL is classed as a clonal disorder of mature B-lymphocytes and its clinical patient prognoses being affected mainly by the mutational status of the Immunoglobulin G Heavy Chain Variable region (IGHV) (with unmutated IGHV holding a better patient prognosis than the wild type variant).

We have developed a general procedure for the synthesis of N-substituted 9-nitro-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl derivatives to study their antiproliferative activity in leukaemia and breast cancer cells. The synthesis of these compounds involves the reaction between (E)-9-(R)-9,10-dihydro-9,10-[3,4]furanoanthracene-12,14-dione and different amines and diamines in acetic acid at 120 ºC. The products were spectroscopically characterised (¹H and ¹³C NMR, HRMS) and the stability profile was determined over pH range 4-9.

The effect on cancer cell viability of the compound panel was determined in CLL leukaemia cell lines HG3 (unmutated IGHV), PGA1 (mutated IGHV), ER positive (MCF-7) and triple negative breast cancer cells (MDA-MB-231). The effects on ROS levels was also studied. The dimeric ethanoanthracene 6g was identified as the most potent compound with IC₅₀ 9.44 mM (MCF-7) and 0.0017 mM (MDA-MB-231) and with superior activity to fludarabine in CLL cells. 6g is a potential candidate for future development.