Proapoptotic effects of novel pentabromobenzylisothioureas in human leukemia cell lines

Abstract

A series of new pentabromobenzylisothioureas [ZKK-1–ZKK-5; (ZKKs)] carrying additional substituents on nitrogen atoms has been synthesized. The ZKKs were found to induce apoptosis in HL-60 (human promyleocytic leukemia) and K-562 (human chronic erythromyeloblastoid leukemia) cell lines in a concentration-dependent manner at low micromolar concentrations. ZKK-3 [(N,N′-dimethyl-S-2,3,4,5,6-pentabromobenzyl)isothiouronium bromide] showed the highest proapoptotic activity in HL-60 cells, whereas ZKK-2 [N-methyl-S-(2,3,4,5,6-pentabromobenzyl)isothiouronium bromide] was most effective in this respect in K-562 cells. During the ZKKs-induced apoptosis, an 85 kDa fragment of cleaved PARP (caspase-3 and caspase-7 substrate) was detected in both cell lines tested. The studied compounds also decreased mitochondrial transmembrane potential in both these cell lines and caused the cells to accumulate in G1 and at the G1/S border of the cell cycle in a concentration-dependent manner. These results show promise for their study as new compounds in the treatment of leukemia, after an appropriate preclinical toxicity profile.

Crystal structure of (Z)-3-(adamantan-1-yl)-1-(3-chlorophenyl)-S-benzylisothiourea, C24H27ClN2S

“…Several substituted isothiourea derivatives were reported to possess significant cardiovascular properties as nitric oxide synthase inhibitors [1][2][3][4][5], and calcium channel blockers [6]. Isothiourea derivatives were also reported to display potent antimicrobial [7,8], anticancer [9,10], and anti-anthelmintic [11] activities. The incorporation of the highly lipophilic adamantyl group positively modulates the therapeutic index of several compounds through various mechanisms [12,13].…”

Potent Antitumour Effects of Novel Pentabromobenzylisothioureas Studied on Human Glial-derived Tumour Cell Lines

“…Tested chemicals. ZKKs were synthesized in a reaction of pentabromobenzylobromide with N-substituted thioureas, according to previously described procedures (20). Five ZKK derivatives were used in this study: ZKK-1, ZKK-2, ZKK-3, ZKK-13 and TRIM, as well as BEN.…”

“…Previous studies demonstrated that low micromolar concentrations of novel ZKKs (ZKK-1 to ZKK-5) induced concentration-dependent, proapoptotic effects on HL-60 and K-562 human leukaemia cell lines (21). These effects may be related to CK2 inhibition because CK2 is known to suppress apoptosis.…”

“…That study showed that this representative ZKK agent effectively inhibited seven protein kinases: PIM1, PIM3, IGF1R, ERK8, PKD1, NEK2a, and the IR. All these kinases are important for cell survival and for the proper functioning of both normal and neoplastic cells (20). Among these kinases, PKD1 has been increasingly implicated in multiple biological and molecular events that regulate tumour proliferation or invasion in many cancer types (37)(38)(39)(40)(41).…”

“…Moreover, ZKKs exhibit anticancer properties. In previous studies, the effects of ZKKs were tested on several neoplastic cell lines, including human prostate adenocarcinoma (20), HL-60 promyelocytic leukemia and K-562 human chronic erythromyeloblastoid leukemia cell line (58,59). However, only one previous report investigated ZKK efficacy against brain malignancies; they studied cultured C6 rat glioma cells and two human highgrade glioma cell lines, LN229 (astrocytoma, WHO grade III) and T98G (glioblastoma, WHO grade IV).…”