慢性淋巴细胞白血病(CLL)是成熟B细胞的恶性肿瘤,它是西方国家最常见的白血病。它的特点是肿瘤B淋巴细胞在血液中的增殖和积累,淋巴结,骨髓和脾.我们报告了CLL细胞系中一系列新型乙蒽化合物的合成和抗增殖作用。通过9-(2-硝基乙烯基)蒽和3-(蒽-9-基)-1-芳基丙-2-烯-1-酮(蒽查耳酮)与亲二烯体的Diels-Alder反应实现结构修饰,包括马来酸酐和N-取代的马来酰亚胺,提供一系列9-(E)-(2-硝基乙烯基)-9,10-二氢-9,10-[3,4]表吡咯并蒽-12,14-二酮,9-(E)-3-氧代-3-苯基丙-1-烯-1-基)-9,10-二氢-9,10-[3,4]表吡咯并蒽-12,14-二酮和相关化合物。单晶X射线分析证实了新型乙蒽23f的结构,23h,24a,24g,25f和27在HG-3和PGA-1CLL细胞系(代表患者预后差和良好,分别)。最有效的化合物被确定为20a,20f,23a和25n,IC50值在0.17-2.69µM(HG-3)和0.35-1.97µM(PGA-1)范围内。有效化合物20a的促凋亡作用,20f,23a和25n在10µM的CLL细胞系HG-3(82-95%)和PGA-1(87-97%)中得到证实,在代表HG-3和PGA-1CLL细胞系的化合物IC50值的浓度下,在健康供体外周血单核细胞(PBMC)中观察到低毒性(12-16%)。所选化合物的抗增殖作用,20a,20f,23a和25n,通过ROS通量介导,在用抗氧化剂NAC预处理后细胞活力显着增加。25n还证明了NCI60癌细胞系组的亚微摩尔活性,平均GI50值为0.245µM。这种乙蒽系列化合物为进一步开发先导结构作为靶向CLL的新型化学治疗剂提供了潜力。
Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells, and it is the most frequent form of leukemia diagnosed in Western countries. It is characterized by the proliferation and accumulation of neoplastic B lymphocytes in the blood, lymph nodes, bone marrow and spleen. We report the synthesis and antiproliferative effects of a series of novel ethanoanthracene compounds in CLL cell lines. Structural modifications were achieved via the Diels-Alder reaction of 9-(2-nitrovinyl)anthracene and 3-(anthracen-9-yl)-1-arylprop-2-en-1-ones (anthracene chalcones) with dienophiles, including maleic anhydride and N-substituted maleimides, to afford a series of 9-(E)-(2-nitrovinyl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones, 9-(E)-3-oxo-3-phenylprop-1-en-1-yl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones and related compounds. Single-crystal X-ray analysis confirmed the structures of the novel ethanoanthracenes 23f, 23h, 24a, 24g, 25f and 27. The products were evaluated in HG-3 and PGA-1 CLL cell lines (representative of poor and good patient prognosis, respectively). The most potent compounds were identified as 20a, 20f, 23a and 25n with IC50 values in the ranges of 0.17-2.69 µM (HG-3) and 0.35-1.97 µM (PGA-1). The pro-apoptotic effects of the potent compounds 20a, 20f, 23a and 25n were demonstrated in CLL cell lines HG-3 (82-95%) and PGA-1 (87-97%) at 10 µM, with low toxicity (12-16%) observed in healthy-donor peripheral blood mononuclear cells (PBMCs) at concentrations representative of the compounds IC50 values for both the HG-3 and PGA-1 CLL cell lines. The antiproliferative effect of the selected compounds, 20a, 20f, 23a and 25n, was mediated through ROS flux with a marked increase in cell viability upon pretreatment with the antioxidant NAC. 25n also demonstrated sub-micromolar activity in the NCI 60 cancer cell line panel, with a mean GI50 value of 0.245 µM. This ethanoanthracene series of compounds offers potential for the further development of lead structures as novel chemotherapeutics to target CLL.