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Investigation of the Mechanisms of Cytotoxic Activity of 1,3-Disubstituted Thiourea Derivatives.

ABSTRACT: Substituted thiourea derivatives possess confirmed cytotoxic activity towards cancer but also normal cells. To develop new selective antitumor agents, a series of 3-(trifluoromethyl)phenylthiourea analogs were synthesized, and their cytotoxicity was evaluated in vitro against the cell line panel. Compounds 1-5, 8, and 9 were highly cytotoxic against human colon (SW480, SW620) and prostate (PC3) cancer cells, and leukemia K-562 cell lines (IC₅₀ ≤ 10 µM), with favorable selectivity over normal HaCaT cells. The derivatives exerted better growth inhibitory profiles towards selected tumor cells than the reference cisplatin. Compounds incorporating 3,4-dichloro- (2) and 4-CF₃-phenyl (8) substituents displayed the highest activity (IC₅₀ from 1.5 to 8.9 µM). The mechanisms of cytotoxic action of the most effective thioureas 1-3, 8, and 9 were studied, including the trypan blue exclusion test of cell viability, interleukin-6, and apoptosis assessments. Compounds reduced all cancerous cell numbers (especially SW480 and SW620) by 20-93%. Derivatives 2 and 8 diminished the viability of SW620 cells by 45-58%. Thioureas 1, 2, and 8 exerted strong pro-apoptotic activity. Compound 2 induced late apoptosis in both colon cancer cell lines (95-99%) and in K-562 cells (73%). All derivatives acted as inhibitors of IL-6 levels in both SW480 and SW620 cells, decreasing its secretion by 23-63%.

SUBMITTER: Strzyga-Lach P

PROVIDER: S-EPMC8623398 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The ortho-deprotonation of halide-substituted ferrocenes by treatment with lithium tetramethylpiperidide (LiTMP) has been investigated. Iodo-, bromo-, and chloro-substituted ferrocenes were easily deprotonated adjacent to the halide substituents. The synthetic applicability of this reaction was, however, limited by the fact that, depending on the temperature and the degree of halide substitution, scrambling of both iodo and bromo substituents at the ferrocene core took place. Iodoferrocenes could not be transformed selectively into ortho-substituted iodoferrocenes since, in the presence of LiTMP, the iodo substituents scrambled efficiently even at -78 °C, and this process had occurred before electrophiles had been added. Bromoferrocene and certain monobromo-substituted derivatives, however, could be efficiently ortho-deprotonated at low temperature and reacted with a number of electrophiles to afford 1,2- and 1,2,3-substituted ferrocene derivatives. For example, 2-bromo-1-iodoferrocene was synthesized by ortho-deprotonation of bromoferrocene and reaction with the electrophiles diiodoethane and diiodotetrafluoroethane, respectively. In this and related cases the iodide scrambling process and further product deprotonation due to the excess LiTMP could be suppressed efficiently by running the reaction at low temperature and in inverse mode. In contrast to the low-temperature process, at room temperature bromo substituents in bromoferrocenes scrambled in the presence of LiTMP. Chloro- and 1,2-dichloroferrocene could be ortho-deprotonated selectively, but in neither case was scrambling of a chloro substituent observed. As a further application of this ortho-deprotonation reaction, a route for the synthesis of 1,3-disubstituted ferrocenes was developed. 1,3-Diiodoferrocene was accessible from bromoferrocene in four steps. On a multigram scale an overall yield of 41% was achieved. 1,3-Diiodoferrocene was further transformed into symmetrically 1,3-disubstituted ferrocenes (1,3-R2Fc; R = CHO, COOEt, CN, CH=CH2).

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Investigation of the Mechanisms of Cytotoxic Activity of 1,3-Disubstituted Thiourea Derivatives.

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