Search Results (8)

Background/Objectives: β-Lapachone and triapine are compounds with recognized antitumor potential—the former is an ortho-naphthoquinone, and the latter a thiosemicarbazone inhibitor of ribonucleotide reductase. This study aimed to synthesize and evaluate new β-lapachone-based thiosemicarbazones (TSC1–TSC6) as potential antineoplastic agents. Methods: Lapachol was isolated from Tabebuia sp. and used to obtain ortho-naphthoquinones (2–4), which served as precursors for thiosemicarbazones (TSC1–TSC6). NMR and HRMS spectra were used to characterize the compounds. Their cytotoxic activity was evaluated in vitro against murine melanoma (B16–F10), colon carcinoma (CT26.WT), and breast cancer (4T1) cell lines, as well as normal fibroblasts (L929). Pharmacokinetic parameters were predicted in silico using ADMETLab 3.0. Results: β-Lapachone exhibited strong cytotoxicity toward tumor cells with moderate effects on normal cells, while thiosemicarbazones of β-lapachone, TSC1, and TSC3 demonstrated lower potency but greater selectivity. The β-lapachone-3-sulfonic acid showed high activity against melanoma and breast cancer cells and low toxicity toward normal cells, indicating tumor selectivity. In contrast, their thiosemicarbazones, TSC2, TSC4, and TSC6, showed weak or no antiproliferative activity. The 3-iodo-β-lapachone was cytotoxic to both tumor and normal cells, whereas its derivative TSC5 demonstrated moderate activity with reduced toxicity. β-Lapachone, β-lapachone-3-sulfonic acid, TSC1, and TSC3 exhibited favorable ADME profiles (QED ≈ 0.61–0.66), suggesting good oral bioavailability. Conclusions: The β-lapachone-3-sulfonic acid and the β-lapachone-based thiosemicarbazones TSC1 and TSC3 emerged as promising lead candidates, combining tumor selectivity, favorable pharmacokinetic properties, and structural innovation for the development of safer and more effective antineoplastic agents. Full article

COTI-2 is currently being evaluated in a phase I clinical trial for the treatment of gynecological and other solid cancers. As a thiosemicarbazone, this compound contains an N,N,S-chelating moiety and is, therefore, expected to bind endogenous metal ions. However, besides zinc, the metal interaction properties of COTI-2 have not been investigated in detail so far. This is unexpected, as we have recently shown that COTI-2 forms stable ternary complexes with copper and glutathione, which renders this drug a substrate for the resistance efflux transporter ABCC1. Herein, the complex formation of COTI-2, two novel terminal N-disubstituted derivatives (COTI-NMe₂ and COTI-NMeCy), and the non-substituted analogue (COTI-NH₂) with iron, copper, and zinc ions was characterized in detail. Furthermore, their activities against drug-resistant cancer cells was investigated in comparison to COTI-2 and Triapine. These data revealed that, besides zinc, also iron and copper ions need to be considered to play a role in the mode of action and resistance development of these thiosemicarbazones. Moreover, we identified COTI-NMe₂ as an interesting new drug candidate with improved anticancer activity and resistance profile. Full article

Ribonucleotide reductase (RR) is an essential multi-subunit enzyme found in all living organisms; it catalyzes the rate-limiting step in dNTP synthesis, namely, the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates. As expression levels of human RR (hRR) are high during cell replication, hRR has long been considered an attractive drug target for a range of proliferative diseases, including cancer. While there are many excellent reviews regarding the structure, function, and clinical importance of hRR, recent years have seen an increase in novel approaches to inhibiting hRR that merit an updated discussion of the existing inhibitors and strategies to target this enzyme. In this review, we discuss the mechanisms and clinical applications of classic nucleoside analog inhibitors of hRRM1 (large catalytic subunit), including gemcitabine and clofarabine, as well as inhibitors of the hRRM2 (free radical housing small subunit), including triapine and hydroxyurea. Additionally, we discuss novel approaches to targeting RR and the discovery of new classes of hRR inhibitors. Full article

The antioxidant/pro-oxidant activity of drugs and dietary molecules and their role in the maintenance of redox homeostasis, as well as the implications in health and different diseases, have not yet been fully evaluated. In particular, the redox activity and other interactions of drugs with essential redox metal ions, such as iron and copper, need further investigation. These metal ions are ubiquitous in human nutrition but also widely found in dietary supplements and appear to exert major effects on redox homeostasis in health, but also on many diseases of free radical pathology. In this context, the redox mechanistic insights of mainly three prototype groups of drugs, namely alpha-ketohydroxypyridines (alpha-hydroxypyridones), e.g., deferiprone, anthraquinones, e.g., doxorubicin and thiosemicarbazones, e.g., triapine and their metal complexes were examined; details of the mechanisms of their redox activity were reviewed, with emphasis on the biological implications and potential clinical applications, including anticancer activity. Furthermore, the redox properties of these three classes of chelators were compared to those of the iron chelating drugs and also to vitamin C, with an emphasis on their potential clinical interactions and future clinical application prospects in cancer, neurodegenerative and other diseases. Full article

A series of thiosemicarbazone-coumarin hybrids (HL¹-HL³ and H₂L⁴) has been synthesised in 12 steps and used for the preparation of mono- and dinuclear copper(II) complexes, namely Cu(HL¹)Cl₂ (1), Cu(HL²)Cl₂ (2), Cu(HL³)Cl₂ (3) and Cu₂(H₂L⁴)Cl₄ (4), isolated in hydrated or solvated forms. Both the organic hybrids and their copper(II) and dicopper(II) complexes were comprehensively characterised by analytical and spectroscopic techniques, i.e., elemental analysis, ESI mass spectrometry, 1D and 2D NMR, IR and UV–vis spectroscopies, cyclic voltammetry (CV) and spectroelectrochemistry (SEC). Re-crystallisation of 1 from methanol afforded single crystals of copper(II) complex with monoanionic ligand Cu(L¹)Cl, which could be studied by single crystal X-ray diffraction (SC-XRD). The prepared copper(II) complexes and their metal-free ligands revealed antiproliferative activity against highly resistant cancer cell lines, including triple negative breast cancer cells MDA-MB-231, sensitive COLO-205 and multidrug resistant COLO-320 colorectal adenocarcinoma cell lines, as well as in healthy human lung fibroblasts MRC-5 and compared to those for triapine and doxorubicin. In addition, their ability to reduce the tyrosyl radical in mouse R2 protein of ribonucleotide reductase has been ascertained by EPR spectroscopy and the results were compared with those for triapine. Full article

Copper(II) complexes of thiosemicarbazones (TSCs) often exhibit anticancer properties, and their pharmacokinetic behavior can be affected by their interaction with blood transport proteins. Interaction of copper(II) complexes of an {N,N,S} donor α-N-pyridyl TSC (Triapine) and an {O,N,S} donor 2-hydroxybenzaldehyde TSC (STSC) with human serum albumin (HSA) was investigated by UV–visible and electron paramagnetic resonance spectroscopy at physiological pH. Asp-Ala-His-Lys and the monodentate N-methylimidazole were also applied as binding models. Conditional formation constants were determined for the ternary copper(II)-TSC complexes formed with HSA, DAHK, and N-methylimidazole based on the spectral changes of both charge transfer and d-d bands. The neutral N-methylimidazole displays a similar binding affinity to both TSC complexes. The partially negatively charged tetrapeptide binds stronger to the positively charged Triapine complex in comparison to the neutral STSC complex, while the opposite trend was observed for HSA, which demonstrates the limitations of the use of simple ligands to model the protein binding. The studied TSC complexes are able to bind to HSA in a fast process, and the conditional constants suggest that their binding strength is only weak-to-moderate. Full article

Thiosemicarbazones continue to attract the interest of researchers as potential anticancer drugs. For example, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, or triapine, is the most well-known representative of this class of compounds that has entered multiple phase I and II clinical trials. Two new triapine derivatives HL¹ and HL² were prepared by condensation reactions of 2-pyridinamidrazone and S-methylisothiosemicarbazidium chloride with 3-N-(tert-butyloxycarbonyl) amino-pyridine-2-carboxaldehyde, followed by a Boc-deprotection procedure. Subsequent reaction of HL¹ and HL² with CuCl₂·2H₂O in 1:1 molar ratio in methanol produced the complexes [Cu^II(HL¹)Cl₂]·H₂O (1·H₂O) and [Cu^II(HL²)Cl₂] (2). The reaction of HL² with Fe(NO₃)₃∙9H₂O in 2:1 molar ratio in the presence of triethylamine afforded the complex [Fe^III(L²)₂]NO₃∙0.75H₂O (3∙0.75H₂O), in which the isothiosemicarbazone acts as a tridentate monoanionic ligand. The crystal structures of HL¹, HL² and metal complexes 1 and 2 were determined by single crystal X-ray diffraction. The UV-Vis and EPR spectroelectrochemical measurements revealed that complexes 1 and 2 underwent irreversible reduction of Cu(II) with subsequent ligand release, while 3 showed an almost reversible electrochemical reduction in dimethyl sulfoxide (DMSO). Aqueous solution behaviour of HL¹ and 1, as well as of HL² and its complex 2, was monitored as well. Complexes 1−3 were tested against ovarian carcinoma cells, as well as noncancerous embryonic kidney cells, in comparison to respective free ligands, triapine and cisplatin. While the free ligands HL¹ and HL² were devoid of antiproliferative activity, their respective metal complexes showed remarkable antiproliferative activity in a micromolar concentration range. The activity was not related to the inhibition of ribonucleotide reductase (RNR) R2 protein, but rather to cancer cell homeostasis disturbance—leading to the disruption of cancer cell signalling. Full article

An electron paramagnetic resonance (EPR) method was used to determine the concentration of the antitumor agent Triapine in BEAS-2B cells when Triapine was bound to iron (Fe). Knowledge of the concentration of Fe-Triapine in tumor cells may be useful to adjust the administration of the drug or to adjust iron uptake in tumor cells. An EPR spectrum is obtained for Fe(3+)-Triapine, Fe(3+)(Tp)₂⁺, in BEAS-2B cells after addition of Fe(3+)(Tp)₂⁺. Detection of the low spin signal for Fe(3+)(Tp)₂⁺ shows that the Fe(3+)(Tp)₂⁺ complex is intact in these cells. It is proposed that Triapine acquires iron from transferrin in cells including tumor cells. Here, it is shown that iron from purified Fe-transferrin is transferred to Triapine after the addition of ascorbate. To our knowledge, this is the first time that the EPR method has been used to determine the concentration of an iron antitumor agent in cells. Full article