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

Paulina Strzyga-Łach,Anna Bielenica,Alicja Chrzanowska,Katarzyna Podsadni

doi:10.3390/ph14111097

Paulina Strzyga-Łach, Anna Bielenica + Show 2 more

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https://doi.org/10.3390/ph14111097

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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%.

Highlights

IntroductionCancer is considered as the second cause of death after cardiovascular disorders
Cancer is considered as the second cause of death after cardiovascular disorders.It is estimated that the number of newly diagnosed tumor cases will increase to 15 million episodes every year [1]
The final 1,3-disubstituted thioureas 1–12 were 1–12 synthesized in a single-step reac- reactio

Summary

Introduction

Cancer is considered as the second cause of death after cardiovascular disorders. It is estimated that the number of newly diagnosed tumor cases will increase to 15 million episodes every year [1]. The most common method used for the treatment of cancer is chemotherapy. Powerful chemotherapeutics have an adverse impact on non-cancerous cells, slowing their growth and/or inducing apoptosis. The main challenge for the pharmaceutical industry is to synthesize new anticancer agents that are more effective and selective but less toxic for normal cells. The (thio)urea branch is an element of several medicines with anticancer profiles, such as sorafenib, multikinase-inhibitory diarylthiorea derivative, or tenovin-1, the benzylthiourea, which acts as a reversible inhibitor of class III HDAC sirtuins (Figure 1). It was reported that (hetero)aryl terminal fragments of thiourea moiety, enriched with electron-negative substituents, could provide biological responses, cytotoxic [2,3,4], and antibacterial [2,3,4,5,6,7,8], antiviral [2,9,10,11,12], antimycobacterial [5,13], antioxidant [14], and anti-inflammatory [6] properties, as well as central nervous system activation [15,16,17,18]

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