Novel naphthoquinone-1H-1,2,3-triazole hybrids: Design, synthesis and evaluation as inductors of ROS-mediated apoptosis in the MCF-7 cells.

The search for novel anticancer drugs is essential to expand treatment options, overcome drug resistance, reduce toxicity, promote innovation, and tackle the economic impact. The importance of these studies lies in their contribution to advancing cancer research and enhancing patient outcomes in the battle against cancer. Here, we developed new asymmetric hybrids containing two different naphthoquinones linked by a 1,2,3-1H-triazole nucleus, which are potential new drugs for cancer treatment. The antitumor activity of the novel compounds was tested using the breast cancer cell lines MCF-7 and MDA-MB-231, using the non-cancer cell line MCF10A as control. Our results showed that two out of twenty-two substances tested presented potential antitumor activity against the breast cancer cell lines. These potential drugs, named here 12g and 12h were effective in reducing cell viability and promoting cell death of the tumor cell lines, exhibiting minimal effects on the control cell line. The mechanism of action of the novel drugs was assessed revealing that both drugs increased reactive oxygen species production with consequent activation of the AMPK pathway. Therefore, we concluded that 12g and 12h are novel AMPK activators presenting selective antitumor effects.

Cobalt(III)-py2en systems as potential carriers of ß-ketoester-based ligands.

Two cobalt(III) complexes containing different ß-ketoesters, namely [CoIII(L1)(py2en)](ClO4)2·H2O (1) and [CoIII(L2)(py2en)](ClO4)2 (2) (py2en = N,N'-bis(pyridin-2-ylmethyl)ethylenediamine; L1- = methylacetoacetate; L2- = ethyl 4-chloroacetoacetate) have been prepared and investigated as prototypes of bioreductive prodrugs. The presence of ß-ketoester and py2en ligands in 1 and 2, as well as the perchlorate counterions, was supported by IR spectroscopy and CHN elemental analysis. The composition molecular structure of both complexes was confirmed by NMR spectroscopy and ESI mass spectrometry. Structural information was also obtained for 2via X-ray diffraction analysis. The redox properties indicate that 1 and 2 are suitable for reduction under biological conditions. Investigation of DNA-interacting suggest that 1 and 2 bind DNA via electrostatic forces. Both complexes may be employed as possible platforms for the delivery of biologically active compounds, since their reaction with ascorbic acid in PBS at pH 6.2 and 7.4 at 37°C results in the release of the ß-ketoester ligands upon Co(III)/Co(II) reduction.

Chalcones identify cTXNPx as a potential antileishmanial drug target.

With current drug treatments failing due to toxicity, low efficacy and resistance; leishmaniasis is a major global health challenge that desperately needs new validated drug targets. Inspired by activity of the natural chalcone 2',6'-dihydroxy-4'-methoxychalcone (DMC), the nitro-analogue, 3-nitro-2',4',6'- trimethoxychalcone (NAT22, 1c) was identified as potent broad spectrum antileishmanial drug lead. Structural modification provided an alkyne containing chemical probe that labelled a protein within the parasite that was confirmed as cytosolic tryparedoxin peroxidase (cTXNPx). Crucially, labelling is observed in both promastigote and intramacrophage amastigote life forms, with no evidence of host macrophage toxicity. Incubation of the chalcone in the parasite leads to ROS accumulation and parasite death. Deletion of cTXNPx, by CRISPR-Cas9, dramatically impacts upon the parasite phenotype and reduces the antileishmanial activity of the chalcone analogue. Molecular docking studies with a homology model of in-silico cTXNPx suggest that the chalcone is able to bind in the putative active site hindering access to the crucial cysteine residue. Collectively, this work identifies cTXNPx as an important target for antileishmanial chalcones.

Evaluation of cobalt(III) complexes as potential hypoxia-responsive carriers of esculetin.

Differentiation between hypoxic and normoxic tissues have been exploited for the development of selective chemotherapeutic agents. In this context, cobalt(III)-based coordination compounds have been designed and investigated as prospective hypoxia-responsive drug delivery systems. Three cobalt(III) complexes, namely [CoIII(esc)(py2en)]ClO4·(CH3OH)2 (1) [CoIII(esc)(TPA)]ClO4·3H2O (2) and [CoIII(bipy)2(esc)]ClO4·2.5H2O (3) (py2en = N,N'-bis(pyridin-2-ylmethyl)ethylenediamine, TPA = tris(2-pyridylmethyl)amine, bipy = 2,2'-bipyridine and esc = 6,7-dihydroxycoumarin or esculetin), were prepared and investigated as potential carriers of esculetin. The spectroscopic and electrochemical properties of 1-3 were investigated and compared. Reactions of the complexes with biologically relevant reducing agents, viz. ascorbic acid, cysteine and glutathione, were monitored spectroscopically for 24 h, in pH 6.2 and 7.4 PBS phosphate buffer saline (PBS) solutions at 37 °C, under air, argon and dioxygen atmospheres. Dissociation of esculetin was observed upon Co3+/Co2+ reduction preferably under hypoxic conditions, with more effective conversion rates for 3 > 2 > 1. These results illustrate the importance to modulate the Co3+/Co2+ redox potential through the donor-acceptor properties of the ancillary ligands. Complex 3 is cytotoxic against HCT-116 but not against HT-29 and HEK-293 cells. In addition, DNA-binding studies indicate that interactions of 1 and 3 with the biomolecule are electrostatic.