Potential Anticancer Agents against Melanoma Cells Based on an As-Synthesized Thiosemicarbazide Derivative

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.

New Potential Agents for Malignant Melanoma Treatment—Most Recent Studies 2020–2022

“…Kozyra et al obtained new 2,4-dichlorophenoxyacetic acid hydrazide thiosemicarbazide derivatives [ 122 ]. We based our current research on previously confirmed anticancer activity of this scaffold [ 123 ].…”

“…Compound (49) turned out to be the most active against melanoma cell line G-361 with an IC 50 = 99±4 µM. The proposed compound bore an iodine atom in the para position of the second phenyl ring [ 122 ]. The activity of the derivatives increased in the given series of substituents: 2-bromophenyl < napht-1-yl < 2-iodophenyl < 4-methylthiophenyl < 4-iodophenyl for the most potential agents.…”

Terminal Phenoxy Group as a Privileged Moiety of the Drug Scaffold—A Short Review of Most Recent Studies 2013–2022

“…The most active compound bore 1-naphtyl substituent [ 92 ]. Our last studies of 2,4-dichlorophenoxy hydrazide derivatives ( 31 ) revealed anti-melanoma activity on the G-361 melanoma cell line with an IC 50 = 112 ± 4.76 μM [ 93 ]. The proposed compound was not the most active, but it exhibited a safety profile for the normal fibroblast.…”

“…Our review of the literature on the latest anti-melanoma agents revealed that the phenoxy derivatives we have obtained are among the first in recent years [ 95 ]. The most active compound bore a 2-iodophenyl substituent [ 93 ].…”

New Derivatives of 5-((1-Methyl-Pyrrol-2-yl) Methyl)-4-(Naphthalen-1-yl)-1,2,4-Triazoline-3-Thione and Its Coordination Compounds with Anticancer Activity

“…In this paper, we focus on 5-((1-methyl-pyrrol-2-yl) methyl)-4-(naphthalen-1-yl)-1,2,4-triazoline-3-thione and its coordination compounds. We choose the naphthyl substituent because of its critical anticancer activity [ 55 , 56 ]. In continuation of the development of this subject, we focus here on filling the research gap on the coordination chemistry of disubstituted 1,2,4-triazole-3-thione derivatives and their chemical, physical and biological properties.…”