Selected nitrostyrene compounds demonstrate potent activity in chronic lymphocytic leukaemia cells, including those with poor prognostic markers

Abstract

The nitrostyrene scaffold was previously identified as a lead target structure for the development of effective compounds targeting Burkitt's lymphoma. The present study aimed to develop these compounds further in haematological malignancies, including chronic lymphocytic leukaemia (CLL). Cellular viability, flow cytometry and lactate dehydrogenase assays, amongst others, were used to examine the effects of nitrostyrene compounds on CLL cells, including a cell line representing disease with poor prognosis (HG-3) and in ex vivo CLL patient samples (n=14). The results demonstrated that two representative nitrostyrene compounds potently induced apoptosis in CLL cells. The pro-apoptotic effects of the compounds were found to be reactive oxygen species and caspase-dependent, and had minimal effects on the viability of normal donor peripheral blood mononuclear cells. Nitrostyrene compounds exhibited synergistic augmentation of apoptosis when combined with the phosphatidylinositol 3-kinase inhibitor idelalisib and demonstrated potent toxicity in ex vivo CLL cells, including those co-cultured with bone marrow stromal cells, making them more resistant to apoptosis (n=8). These compounds also demonstrated activity in samples from patients with poor prognostic indicators; unmutated immunoglobulin heavy chain genes, expression of CD38 and deletions in chromosomes 17p and 11q. These results suggest that this class of pharmaceutically active compounds offer potential in the treatment of CLL.

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

“…The nitrostyrene-containing compounds such as 10a-c reduced cell viability effectively in both BL and CLL cell lines and were superior to the clinical drugs fludarabine phosphate and taxol [39,45]. The IC50 values in the CLL cell lines were in the low-micromolar range (2-5 µM) irrespective of IGVH mutational status (I83 and PGA-1: mutated-IGVH; HG-3 and CII: unmutated-IGVH).…”

“…Molecules 2023, 28, x FOR PEER REVIEW 4 of 43 potent antiproliferative agent in the BL cell lines MUTU-I (IC50 = 3 µM) and DG-75 (IC50 = 1.5 µM), which induced apoptosis in both BL cell lines [41,42]. The (E)-(2-nitrovinyl)benzene pharmacophore was thus identified as a scaffold that has demonstrated relevant anticancer activity [45]. The biological macromolecular target(s) of these compounds, driving the antiproliferative response, is as yet unknown, so we focussed our work on phenotypic cellular responses.…”

“…Subsequently, a series of substituted 9-anthraldehydes were synthesised from the appropriate anthracenes, anthrones and anthraquinones including chloro, bromo, methyl, phenyl, methoxy and isopropyl substitutions at C-10, from which the required (E)-9-(2-nitrovinyl)anthracenes were synthesised. The reduction of (E)-9-(2-nitrovinyl)anthracene was also investi- The nitrostyrene-containing compounds such as 10a-c reduced cell viability effectively in both BL and CLL cell lines and were superior to the clinical drugs fludarabine phosphate and taxol [39,45]. The IC 50 values in the CLL cell lines were in the low-micromolar range (2-5 µM) irrespective of IGVH mutational status (I83 and PGA-1: mutated-IGVH; HG-3 and CII: unmutated-IGVH).…”

Design, Synthesis and Biochemical Evaluation of Novel Ethanoanthracenes and Related Compounds to Target Burkitt’s Lymphoma

“…We have previously investigated the synthesis, characterisation and biochemical evaluation of a series of structurally diverse nitrostyrenes (e.g., compound 10a, Figure 1) and related nitrovinyl compounds in the MUTU-I and DG-75 cell lines and identified the potent apoptotic effect induced by (E)-1,3-bis(aryl)-2-nitro-1-propenes (e.g., compound 10b, Figure 1) [49] and related heterocycles containing the nitrovinyl pharmacophore e.g., 3-nitro-2-phenyl-2H-chromene (10c), (Figure 1) with antiproliferative effects superior to the cancer therapeutics fludarabine and taxol [50]. A subset of these lead nitrostyrene compounds were also shown to elicit a potent anti-proliferative and pro-apoptotic response towards a range of malignant cell lines e.g., MCF-7 (ER positive breast cancer), HL-60 (acute promyelocytic leukemia) and HeLa (human cervical cancer) [51]. We have also reported the pro-apoptotic effect of selected examples of these nitrostyrene compounds in chronic lymphocytic leukemia (CLL) cell lines and also in ex vivo CLL patient samples [51].…”

“…A subset of these lead nitrostyrene compounds were also shown to elicit a potent anti-proliferative and pro-apoptotic response towards a range of malignant cell lines e.g., MCF-7 (ER positive breast cancer), HL-60 (acute promyelocytic leukemia) and HeLa (human cervical cancer) [51]. We have also reported the pro-apoptotic effect of selected examples of these nitrostyrene compounds in chronic lymphocytic leukemia (CLL) cell lines and also in ex vivo CLL patient samples [51].…”