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Potential Anticancer Agents against Melanoma Cells Based on an As-Synthesized Thiosemicarbazide Derivative
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-iod...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8961551/ https://www.ncbi.nlm.nih.gov/pubmed/35204651 http://dx.doi.org/10.3390/biom12020151 |
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author | Kozyra, Paweł Korga-Plewko, Agnieszka Karczmarzyk, Zbigniew Hawrył, Anna Wysocki, Waldemar Człapski, Michał Iwan, Magdalena Ostrowska-Leśko, Marta Fornal, Emilia Pitucha, Monika |
author_facet | Kozyra, Paweł Korga-Plewko, Agnieszka Karczmarzyk, Zbigniew Hawrył, Anna Wysocki, Waldemar Człapski, Michał Iwan, Magdalena Ostrowska-Leśko, Marta Fornal, Emilia Pitucha, Monika |
author_sort | Kozyra, Paweł |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8961551 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-89615512022-03-30 Potential Anticancer Agents against Melanoma Cells Based on an As-Synthesized Thiosemicarbazide Derivative Kozyra, Paweł Korga-Plewko, Agnieszka Karczmarzyk, Zbigniew Hawrył, Anna Wysocki, Waldemar Człapski, Michał Iwan, Magdalena Ostrowska-Leśko, Marta Fornal, Emilia Pitucha, Monika Biomolecules Article 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. MDPI 2022-01-18 /pmc/articles/PMC8961551/ /pubmed/35204651 http://dx.doi.org/10.3390/biom12020151 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kozyra, Paweł Korga-Plewko, Agnieszka Karczmarzyk, Zbigniew Hawrył, Anna Wysocki, Waldemar Człapski, Michał Iwan, Magdalena Ostrowska-Leśko, Marta Fornal, Emilia Pitucha, Monika Potential Anticancer Agents against Melanoma Cells Based on an As-Synthesized Thiosemicarbazide Derivative |
title | Potential Anticancer Agents against Melanoma Cells Based on an As-Synthesized Thiosemicarbazide Derivative |
title_full | Potential Anticancer Agents against Melanoma Cells Based on an As-Synthesized Thiosemicarbazide Derivative |
title_fullStr | Potential Anticancer Agents against Melanoma Cells Based on an As-Synthesized Thiosemicarbazide Derivative |
title_full_unstemmed | Potential Anticancer Agents against Melanoma Cells Based on an As-Synthesized Thiosemicarbazide Derivative |
title_short | Potential Anticancer Agents against Melanoma Cells Based on an As-Synthesized Thiosemicarbazide Derivative |
title_sort | potential anticancer agents against melanoma cells based on an as-synthesized thiosemicarbazide derivative |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8961551/ https://www.ncbi.nlm.nih.gov/pubmed/35204651 http://dx.doi.org/10.3390/biom12020151 |
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