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Since the discovery of cisplatin, the search for metal-based compounds with therapeutic potential has been a challenge for the scientific community. In this landscape, thiosemicarbazones and their metal derivatives represent a good starting point for the development of anticancer agents with high selectivity and low toxicity. Here, we focused on the action mechanism of three metal thiosemicarbazones [Ni(tcitr)2], [Pt(tcitr)2], and [Cu(tcitr)2], derived from citronellal. The complexes were already synthesized, characterized, and screened for their antiproliferative activity against different cancer cells and for genotoxic/mutagenic potential. In this work, we deepened the understanding of their molecular action mechanism using an in vitro model of a leukemia cell line (U937) and an approach of transcriptional expression profile analysis. U937 cells showed a significant sensitivity to the tested molecules. To better understand DNA damage induced by our complexes, the modulation of a panel of genes involved in the DNA damage response pathway was evaluated. We analyzed whether our compounds affected cell cycle progression to determine a possible correlation between proliferation inhibition and cell cycle arrest. Our results demonstrate that metal complexes target different cellular processes and could be promising candidates in the design of antiproliferative thiosemicarbazones, although their overall molecular mechanism is still to be understood. [ABSTRACT FROM AUTHOR]

Triapine (3-AP), is an iron-binding ligand and anticancer drug that is an inhibitor of human ribonucleotide reductase (RNR). Inhibition of RNR by 3-AP results in the depletion of dNTP precursors of DNA, thereby selectively starving fast-replicating cancer cells of nucleotides for survival. The redox-active form of 3-AP directly responsible for inhibition of RNR is the Fe(II)(3-AP)2 complex. In this work, we synthesize 12 analogs of 3-AP, test their inhibition of RNR in vitro, and study the electronic properties of their iron complexes. The reduction and oxidation events of 3-AP iron complexes that are crucial for the inhibition of RNR are modeled with solution studies. We monitor the pH necessary to induce reduction in iron complexes of 3-AP analogs in a reducing environment, as well as the kinetics of oxidation in an oxidizing environment. The oxidation state of the complex is monitored using UV-Vis spectroscopy. Isoquinoline analogs of 3-AP favor the maintenance of the biologically active reduced complex and possess oxidation kinetics that allow redox cycling, consistent with their effective inhibition of RNR seen in our in vitro experiments. In contrast, methylation on the thiosemicarbazone secondary amine moiety of 3-AP produces analogs that form iron complexes with much higher redox potentials, that do not redox cycle, and are inactive against RNR in vitro. The catalytic subunit of human Ribonucleotide Reductase (RNR), contains a tyrosyl radical in the enzyme active site. Fe(II) complexes of 3-AP and its analogs can quench the radical and, subsequently, inactivate RNR. The potency of RNR inhibitors is highly dependent on the redox properties of the iron complexes, which can be tuned by ligand modifications. Complexes are found to be active within a narrow redox window imposed by the cellular environment.

The exploitation of bioactive natural sources to obtain new anticancer agents with novel modes of action may represent an innovative and successful strategy in the field of medicinal chemistry. Many natural products and their chemical analogues have been proposed as starting molecules to synthesise compounds with increased biological potential. In this work, the design, synthesis, and characterisation of a new series of N4,N4-dimethylated thiosemicarbazone Cu(II), Ni(II), and Pt(II) complexes are reported and investigated for their in vitro toxicological profile against a leukaemia cell line (U937). The antiproliferative activity was studied by MTS assay to determine the GI50 value for each compound after 24 h of treatment, while the genotoxic potential was investigated to determine if the complexes could cause DNA damage. In addition, the interaction between the synthesised molecules and DNA was explored by means of spectroscopic techniques, showing that for Pt and Ni derivatives a single mode of action can be postulated, while the Cu analogue behaves differently. [ABSTRACT FROM AUTHOR]

Since the discovery of cisplatin, the search for metal-based compounds with therapeutic potential has been a challenge for the scientific community. In this landscape, thiosemicarbazones and their metal derivatives represent a good starting point for the development of anticancer agents with high selectivity and low toxicity. Here, we focused on the action mechanism of three metal thiosemicarbazones [Ni(tcitr)2], [Pt(tcitr)2], and [Cu(tcitr)2], derived from citronellal. The complexes were already synthesized, characterized, and screened for their antiproliferative activity against different cancer cells and for genotoxic/mutagenic potential. In this work, we deepened the understanding of their molecular action mechanism using an in vitro model of a leukemia cell line (U937) and an approach of transcriptional expression profile analysis. U937 cells showed a significant sensitivity to the tested molecules. To better understand DNA damage induced by our complexes, the modulation of a panel of genes involved in the DNA damage response pathway was evaluated. We analyzed whether our compounds affected cell cycle progression to determine a possible correlation between proliferation inhibition and cell cycle arrest. Our results demonstrate that metal complexes target different cellular processes and could be promising candidates in the design of antiproliferative thiosemicarbazones, although their overall molecular mechanism is still to be understood.

The exploitation of bioactive natural sources to obtain new anticancer agents with novel modes of action may represent an innovative and successful strategy in the field of medicinal chemistry. Many natural products and their chemical analogues have been proposed as starting molecules to synthesise compounds with increased biological potential. In this work, the design, synthesis, and characterisation of a new series of N4,N4-dimethylated thiosemicarbazone Cu(II), Ni(II), and Pt(II) complexes are reported and investigated for their in vitro toxicological profile against a leukaemia cell line (U937). The antiproliferative activity was studied by MTS assay to determine the GI50 value for each compound after 24 h of treatment, while the genotoxic potential was investigated to determine if the complexes could cause DNA damage. In addition, the interaction between the synthesised molecules and DNA was explored by means of spectroscopic techniques, showing that for Pt and Ni derivatives a single mode of action can be postulated, while the Cu analogue behaves differently.

Abstract: When di-2-pyridyl ketone thiosemicarbazone (dpktsc) was allowed to react with [Re(CO)5Cl] in toluene under reflux, fac-[Re(CO)3(κ2-N,N-dpktsc)Cl] was isolated in good yield. The identity of fac-[Re(CO)3(κ2-N,N-dpktsc)Cl] was established from the results of its elemental analysis, spectroscopic, and electrochemical properties. The infrared spectra of fac-[Re(CO)3(κ2-N,N-dpktsc)Cl] show the facial coordination of the carbonyl groups, and the pyridyl N,N-coordination of dpktsc. 1H NMR measurements on fac-[Re(CO)3(κ2-N,N-dpktsc)Cl] in d 6-dmso and d 6-acetone confirmed the pyridyl N,N-coordination of dpktsc, and showed strong solvent dependence as manifested by the sensitivity of thioamide and ammine protons to their surroundings. The electronic absorption spectra of fac-[Re(CO)3(κ2-N,N-dpktsc)Cl] in protophilic solvents (dmso and dmf) display two intra-ligand charge transfer (ILCT) transitions at 476 and 360nm and in non-protophilic solvents a single ILCT transition at 346nm in CH3CN and 342nm in CH2Cl2. Reversible interconversion between fac-[Re(CO)3(κ2-N,N-dpktsc)Cl] and its conjugate base was established in protophilic solvents using a base to shift the equilibrium to the conjugate base and an acid to shift the equilibrium or conjugate base to the neutral form. Substrates in concentrations as low as 1×10−10 M can be detected and determined using protophilic solutions of fac-[Re(CO)3(κ2-N,N-dpktsc)Cl]. When MCl2 (M=Zn, Cd or Hg) was allowed to interact with fac-[Re(CO)3(κ2-N,N-dpktsc)Cl] in protophilic solvents, the intensity of the low energy ILCT band disappeared and a shift in the high energy ILCT electronic transition was observed that hints to the coordination of MCl2 to fac-[Re(CO)3(κ2-N,N-dpktsc)Cl]. Electrochemical measurements on fac-[Re(CO)3(κ2-N,N-dpktsc)Cl] in dmf showed sequential irreversible redox processes in accord with the electrochemical reduction or oxidation of the thiosemicarbazone moiety. [Copyright &y& Elsevier]

Triapine (3-AP), is an iron-binding ligand and anticancer drug that is an inhibitor of human ribonucleotide reductase (RNR). Inhibition of RNR by 3-AP results in the depletion of dNTP precursors of DNA, thereby selectively starving fast-replicating cancer cells of nucleotides for survival. The redox-active form of 3-AP directly responsible for inhibition of RNR is the Fe(II)(3-AP) 2 complex. In this work, we synthesize 12 analogs of 3-AP, test their inhibition of RNR in vitro, and study the electronic properties of their iron complexes. The reduction and oxidation events of 3-AP iron complexes that are crucial for the inhibition of RNR are modeled with solution studies. We monitor the pH necessary to induce reduction in iron complexes of 3-AP analogs in a reducing environment, as well as the kinetics of oxidation in an oxidizing environment. The oxidation state of the complex is monitored using UV-Vis spectroscopy. Isoquinoline analogs of 3-AP favor the maintenance of the biologically active reduced complex and possess oxidation kinetics that allow redox cycling, consistent with their effective inhibition of RNR seen in our in vitro experiments. In contrast, methylation on the thiosemicarbazone secondary amine moiety of 3-AP produces analogs that form iron complexes with much higher redox potentials, that do not redox cycle, and are inactive against RNR in vitro. The catalytic subunit of human Ribonucleotide Reductase (RNR), contains a tyrosyl radical in the enzyme active site. Fe(II) complexes of 3-AP and its analogs can quench the radical and, subsequently, inactivate RNR. The potency of RNR inhibitors is highly dependent on the redox properties of the iron complexes, which can be tuned by ligand modifications. Complexes are found to be active within a narrow redox window imposed by the cellular environment.

Malaria is a potentially life-threatening disease, affecting approx. 214 million people worldwide. Malaria is caused by a protozoan, Plasmodium falciparum, which is transmitted through the Anopheles mosquito. Malaria treatment is becoming more challenging due to rising resistance against the antimalarial drug, chloroquine. Novel compounds that target aspects of parasite development are being explored in attempts to overcome this wide-spread problem. Anti-malarial drugs target specific aspects of parasite growth and development within the human host. One of the most effective targets is the inhibition of hematin formation, either through inhibition of cysteine proteases or through iron chelation. Metal-thiosemicarbazone (TSC) complexes have been tested for antimalarial efficacy against drug-sensitive and drug-resistant strains of P. falciparum. An array of TSC complexes with numerous transition metals, including ruthenium, palladium, and gold has displayed antiplasmodial activity. Au(I)- and Pd(II)-TSC complexes displayed the greatest potency; 4-amino-7-chloroquine moieties were also found to improve antiplasmodial activity of TSCs. Although promising metal-TSC drug candidates have been tested against laboratory strains of P. falciparum, problems arise when attempting to compare between studies. Future work should strive to completely characterize synthesized metal-TSC structures and assess antiplasmodial potency against several drug-sensitive and drugresistant strains. Future studies need to precisely determine IC50 values for antimalarial drugs, chloroquine and ferroquine, to establish accurate standard values. This will make future comparisons across studies more feasible and potentially help reveal structure-function relationships. Investigations that attempt to link drug structures or properties to antiplasmodial mechanism(s) of action will aid in the design of antimalarial drugs that may combat rising drug resistance., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)