CLL (Chronic Lymphocytic Leukaemia) is the most common leukaemia in the Western world. Classed as a clonal disorder of mature B-lymphocytes, CLL patient prognoses are broadly subdivided 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)¹.

Structures related to tricyclic and tetracyclic anti-depressants (fluoxetine,maprotiline respectively) have previously been shown to exert potent, selective antiproliferative and pro-apoptotic effects in vitro and were met with marked success in related B cell malignancy cell lines, namely Burkitt’s Lymphoma (BL) cell lines DG-75 and MUTU-1².

Based on these preliminary studies, libraries of structurally related novel ethanoanthracene compounds were designed, based on the proven effectiveness of nitrostyrene core moiety derivatives and literature evidence of selective toxicity of chalcone moieties in leukaemic cell lines³.

The antiproliferative activity of each compound was determined using Alamar Blue assays on the two types of CLL cell lines: HG-3 and PGA-1, representative of bad and good prognosis respectively. The most promising activity was observed with maleimide dienophile based ethanoanthracene chalcones, particularly at a 10 µM across both cell lines. A ROS (reactive oxygen species) dependant activity was noted as both nitrostyrene and chalcone based analog biological activity markedly decreased on addition of NAC (N- acetyl cysteine) or Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid).

References

1. Scarfò, L.; Ferreri, A. J. M.; Ghia, P., Critical Reviews in Oncology/Hematology, 2016, 104, 169-182.
2. Mc Namara, Y. M., Bright, S.A., Byrne, A.J., Williams, D.C., Meegan, M.J., European Journal of Medicinal Chemistry 2014, 71, 333.
3. Zhuang, C.; Zhang, W.; Sheng, C.; Zhang, W.; Xing, C.; Miao, Z., Chemical Reviews, 2017, 117(12):7762-7810.