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.

A Novel MDM2-Binding Chalcone Induces Apoptosis of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) represents ~90% of all oral cancers, being the eighth most common cancer in men. The overall 5-year survival rate is only 39% for metastatic cancers, and currently used chemotherapeutics can cause important side effects. Thus, there is an urgency in developing new and effective anti-cancer agents. As both chalcones and 1,2,3-triazoles are valuable pharmacophores/privileged structures in the search for anticancer compounds, in this work, new 1,2,3-triazole-chalcone hybrids were synthesized and evaluated against oral squamous cell carcinoma. By using different in silico, in vitro, and in vivo approaches, we demonstrated that compound 1f has great cytotoxicity and selectivity against OSCC (higher than carboplatin and doxorubicin) and other cancer cells in addition to showing minimal toxicity in mice. Furthermore, we demonstrate that induced cell death occurs by apoptosis and cell cycle arrest at the G2/M phase. Moreover, we found that 1f has a potential affinity for MDM2 protein, similar to the known ligand nutlin-3, and presents a better selectivity, pharmacological profile, and potential to be orally absorbed and is not a substrate of Pg-P when compared to nutlin-3. Therefore, we conclude that 1f is a good lead for a new chemotherapeutic drug against OSCC and possibly other types of cancers.

Menadione: a platform and a target to valuable compounds synthesis.

Naphthoquinones are important natural or synthetic compounds belonging to the general class of quinones. Many compounds in this class have become drugs that are on the pharmaceutical market for the treatment of various diseases. A special naphthoquinone derivative is menadione, a synthetic naphthoquinone belonging to the vitamin K group. This compound can be synthesized by different methods and it has a broad range of biological and synthetic applications, which will be highlighted in this review.

An Update on the Synthesis and Applications of Bis(Naphthoquinones): An Important Class of Molecules against Infectious Diseases and other Conditions.

Naphthoquinones are important molecules belonging to the general class of quinones, and many of these compounds have become drugs that are in the pharmaceutical market for the treatment of several diseases. A special subclass of compounds is that of the bis(naphthoquinones), which have two linked naphthoquinone units. In the last few years, several synthetic approaches toward such valuable compounds have been described, as well as their evaluation against numerous important biological targets. In this review, we provide a thorough discussion on the various synthetic methods reported for the synthesis of bis(naphthoquinone) analogues, also highlighting the biological activities of these substances.

Spin-frustration with two quasi-degenerated spin states of a copper(II) heptanuclear complex obtained from an amino acid ligand.

The Cu(ii) heptanuclear complex (Cu7atac) was synthesised using the hydrated amino acid ligand 2-(5-amino-1H-1,2,4-triazol-3-yl)acetic acid (Hatac·H2O). Single crystal X-ray diffraction analysis revealed a µ3-hydroxo bridged Cu(ii) heptanuclear complex, consisting of two triangular subunits and one Cu(ii) ion as a bridge with the formula [Cu7(atac)6(µ3-OH)2(NO3)2(H2O)10](NO3)4. The magnetic behaviour of this discrete 0D complex shows strong antiferromagnetic couplings between Cu(ii) mediated by N,N bonding and an anti-anti modes of the carboxylate anion of the ligand atac-. The magnetic data were fitted considering a 3J model. To support the model used to fit the magnetic data of the Cu7atac complex, theoretical calculation methods (complete active space self-consistent field, CASSCF, density functional theory (DFT) using the UKS TPSS/Def2-TZVP//Def2-SVP level and periodic boundary conditions (PBC) using PBE/DZVP-MOLOPT-GTH) were performed to obtain the spin states, spin density map and J couplings. The theoretical results suggest that Cu7atac is a spin-frustrated complex in the ground state, in which the doublet spin state co-exists with the quartet spin state.

3-Acyltetramic acids as a novel class of inhibitors for human kallikreins 5 and 7.

Human kallikreins 5 and 7 (KLK5 and KLK7) exhibit trypsin- and chymotrypsin-like activities and are involved in pathologies related to skin desquamation process. A series of new 3-acyltetramic acids were developed as a novel class of inhibitors of KLK5, KLK7 and trypsin enzymes. The nature and length of the acyl chain is crucial to the KLK5, KLK7 and trypsin inhibition activities, and the most potent compounds (but not the most selective) 2b, 2c and 2g showed low micromolar IC50 values. While very few of the compounds were selective for KLK5, the selective inhibition of trypsin against chymotrypsin was achieved. Our molecular modelling studies revealed that the double bond in 2g provided the best fit in the binding site of KLK5, while the hydrogen bonding interactions modulated the best fit of 2c in the binding site of KLK7 due to the hydrophobicity of the cavity.