Abstract
In this paper, thiosemicarbazide derivatives were synthesized as potential anticancer agents. X-ray investigations for 1-(2,4-dichlorophenoxy)acetyl-4-(2-fluorophenyl) thiosemicarbazide, 1-(2,4-dichlorophenoxy)acetyl-4-(4-metylothiophenyl)thiosemicarbazide and 1-(2,4-di chlorophenoxy)acetyl-4-(4-iodophenyl)thiosemicarbazide were carried out in order to confirm the synthesis pathways, identify their tautomeric forms, analyze the conformational preferences of molecules, and identify intra- and intermolecular interactions in the crystalline state. TLC and RP-HPLC analyses were used to determine lipophilicity. The lipophilicity analysis revealed that the 4-substituted halogen derivatives of thiosemicarbazides showed greater lipophilicity compared with 2-substituted derivatives. The optimal range of lipophilicity for biologically active compounds logkw is between 4.14 and 4.78. However, as the analysis showed, it is not a decisive parameter. The cytotoxicity of the new compounds was evaluated against both the G-361 and BJ cell lines. Cytotoxicity analyses and cell-cycle and cell apoptosis assays were performed. The MTT test demonstrated that three compounds were cytotoxic to melanoma cells and not toxic to normal fibroblasts in the concentration range used. The cell cycle analysis showed that the compounds had no significant effect on the cell cycle inhibition. An extensive gene expression analysis additionally revealed that all compounds tested downregulated the expression of dihydroorotate dehydrogenase (DHODH). DHODH is a mitochondrial enzyme involved in the de novo synthesis of pyrimidines. Due to the rapid rate of cancer cell proliferation and the increased demand for nucleotide synthesis, it has become a potential therapeutic target.
Highlights
We examined their potential for melanoma which, according to the data of the National Cancer Institute (NCI), is malignant and the most common skin cancer [18,19]
dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme involved in the de novo synthesis of pyrimidines
The X-ray analysis performed for PK1, PK2 and PK7 confirmed the synthesis pathway and N1-amino/S3-thione/N4-amino/N5-amino/O7-keto tautomeric form in the crystalline state
Summary
Cancer is one of the main causes of death worldwide [1,2]. In 2021, in the United States alone, there were almost 1.9 million new cancer cases, of which almost one-third were fatal [3]. Antineoplastic drugs can be divided into inhibitors of mitotic pathways and/or DNA replication and inhibitors of molecular targets involved in tumor progression. The ability of some compounds to chelate metal ions has been recognized as a major factor in their antiproliferative effects. The complexation of thiosemicarbazones with Fe ions turned out to be of key importance for anti-tumor activity, causing oxidative damage and inhibiting ribonucleotide
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