Search

Here, we explored the benzothiopyranoindole scaffold to develop antiproliferative agents with a polypharmacological profile targeting both G-quadruplex (G4)-structures and Topoisomerase (Topo) I enzyme. In a preliminary optimization phase, compound 1 was selected from an in-house collection as a suitable lead for the rational development of a small library of analogs ( 2 - 5 ). When assayed in NIH's NCI-60 Human Cancer Cell Line In Vitro Screen Program, compound 1 and its demethylated analogue 2 showed significant antiproliferative/cytotoxic activity. Furthermore, results suggested for 1 and 2 a dual mechanism of action, effectively binding and stabilizing G4 structures, while inhibiting the relaxation activity of TopoI and II. Notably, these compounds displayed a certain selectivity toward TopoI. The polypharmacological profile of 1 and 2 was validated in a human colon carcinoma cell line, underscoring their potential as lead candidates for developing novel and efficacious anticancer agents., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Oxidative stress and neuroinflammation play a pivotal role in triggering the neurodegenerative pathological cascades which characterize neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. In search for potential efficient treatments for these pathologies, that are still considered unmet medical needs, we started from the promising properties of the antidiabetic drug pioglitazone, which has been repositioned as an MAO-B inhibitor, characterized by promising neuroprotective properties. Herein, with the aim to broaden its neuroprotective profile, we tried to enrich pioglitazone with direct and indirect antioxidant properties by hanging polyphenolic and electrophilic features that are able to trigger Nrf2 pathway and the resulting cytoprotective genes' transcription, as well as serve as radical scavengers. After a preliminary screening on MAO-B inhibitory properties, caffeic acid derivative 2 emerged as the best inhibitor for potency and selectivity over MAO-A, characterized by a reversible mechanism of inhibition. Furthermore, the same compound proved to activate Nrf2 pathway by potently increasing Nrf2 nuclear translocation and strongly reducing ROS content, both in physiological and stressed conditions. Although further biological investigations are required to fully clarify its neuroprotective properties, we were able to endow the pioglitazone scaffold with potent antioxidant properties, representing the starting point for potential future pioglitazone-based therapeutics for neurodegenerative disorders.

Monoamine oxidases (MAOs) are well-known pharmacological targets in neurological and neurodegenerative diseases. However, recent studies have revealed a new role for MAOs in certain types of cancer such as glioblastoma and prostate cancer, in which they have been found overexpressed. This finding is opening new frontiers for MAO inhibitors as potential antiproliferative agents. In light of our previous studies demonstrating how a polyamine scaffold can act as MAO inhibitor, our aim was to search for novel analogs with greater inhibitory potency for human MAOs and possibly with antiproliferative activity. A small in-house library of polyamine analogs ( 2 - 7 ) was selected to investigate the effect of constrained linkers between the inner amine functions of a polyamine backbone on the inhibitory potency. Compounds 4 and 5 , characterized by a dianiline ( 4 ) or dianilide ( 5 ) moiety, emerged as the most potent, reversible, and mainly competitive MAO inhibitors (Ki < 1 μM). Additionally, they exhibited a high antiproliferative activity in the LN-229 human glioblastoma cell line (GI 50 < 1 μM). The scaffold of compound 5 could represent a potential starting point for future development of anticancer agents endowed with MAO inhibitory activity.

A potent nontoxic antitumor drug, 2-hydroxyoleic acid ( 6 , 2OHOA) used for membrane lipid therapy, was selected as a self-assembly inducer due to its ability to form nanoparticles (NPs) in water. For this purpose, it was conjugated with a series of anticancer drugs through a disulfide-containing linker to enhance cell penetration and to secure drug release inside the cell. The antiproliferative evaluation of the synthesized NP formulations against three human tumor cell lines (biphasic mesothelioma MSTO-211H, colorectal adenocarcinoma HT-29, and glioblastoma LN-229) showed that nanoassemblies 16 - 22a,bNPs exhibit antiproliferative activity at micromolar and submicromolar concentrations. Furthermore, the ability of the disulfide-containing linker to promote cellular effects was confirmed for most nanoformulations. Finally, 17bNP induced intracellular ROS increase in glioblastoma LN-229 cells similarly to free drug 8 , and such elevated production was decreased by pretreatment with the antioxidant N -acetylcysteine. Also, nanoformulations 18bNP and 21bNP confirmed the mechanism of action of the free drugs., Competing Interests: The authors declare no conflict of interest.

Cannabidiol (CBD) is a biologically active compound present in the plants of the Cannabis family, used as anticonvulsant, anti-inflammatory, anti-anxiety, and more recently, anticancer drug. In this work, its use as a new self-assembly inducer in the formation of nanoparticles is validated. The target conjugates are characterized by the presence of different anticancer drugs (namely N -desacetyl thiocolchicine, podophyllotoxin, and paclitaxel) connected to CBD through a linker able to improve drug release. These nanoparticles are formed via solvent displacement method, resulting in monodisperse and stable structures having hydrodynamic diameters ranging from 160 to 400 nm. Their biological activity is evaluated on three human tumor cell lines (MSTO-211H, HT-29, and HepG2), obtaining GI 50 values in the low micromolar range. Further biological assays were carried out on MSTO-211H cells for the most effective NP 8B , confirming the involvement of paclitaxel in cytotoxicity and cell death mechanism.

In the continuous effort to find new metal-based compounds as alternatives to platinum-related anticancer drugs, 11 th group metal phosphane compounds have been thoroughly taken into consideration. Tris-arylphosphane metal derivatives have been extensively considered as heteroleptic metal compounds exhibiting remarkable cytotoxic activities. Functional groups in the aryl moieties modulate the activity reinforcing or eliminating it. Previous works have highlighted that the presence of hydrophilic groups in the phosphane ligands, such as COOH or OH, hampers the anticancer activity of gold azolate/PPh 3 compounds. To increase the polarity of the triarylphosphane ligand without affecting the activity, we considered the preparation of esters starting from the 4-diphenylphosphane-benzoic acid. The resulting phosphanes are poorer donators than the PPh 3 , leading to poly-phosphane M(I) compounds, and they exhibit intense emissive properties. A homologous series of L 3 MX-type compounds (where M = Au and X = Cl, M = Cu and X = BF 4 , and M = Ag and X = PF 6 ) were obtained with the 4-methoxy-diphenylphosphane benzoate. The homologous metal compounds have been characterized by analytical and spectroscopic methods and, remarkably, their formation was associated with high frequencies of 31 P NMR chemical shift variations (5-35 ppm in CDCl 3 ). The new complexes and the ligand were evaluated on sensitive and cisplatin-resistant human tumor cell lines. The ligand is ineffective on cells while the complexes exert a notable antiproliferative effect. The homologous series of the L 3 MX complexes were able to significantly reduce the cell viability of human triple-negative breast cancer cells (MDA-MB-231), representing the most aggressive subtype of breast cancer, and of ovarian carcinoma (A2780). Among these coinage metal compounds, L 3 AgPF 6 results the most interesting, showing the lowest GI 50 values in all cell lines. Interestingly, this silver complex is more cytotoxic than cisplatin, taken as reference drug. The investigation of the mechanism of action of L 3 AgPF 6 in A2780 cells highlighted the induction of the apoptotic pathway, the depolarization of the mitochondrial inner membrane, and a significant accumulation in cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Luciani, Galassi, Wang, Marchini, Cogo, Di Paolo and Dalla Via.)

The high incidence of the resistance phenomenon represents one of the most important limitations to the clinical usefulness of cisplatin as an anticancer drug. Notwithstanding the considerable efforts to solve this problem, the circumvention of cisplatin resistance remains a challenge in the treatment of cancer. In this work, the synthesis and characterization of two trans -dichloro(triphenylarsino)( N , N -dialkylamino)platinum(II) complexes ( 1 and 2 ) were described. The trypan blue exclusion assay demonstrated an interesting antiproliferative effect for complex 1 in ovarian carcinoma-resistant cells, A2780cis. Quantitative analysis performed by ICP-AES demonstrated a scarce ability to platinate DNA, and a significant intracellular accumulation. The investigation of the mechanism of action highlighted the ability of 1 to inhibit the relaxation of supercoiled plasmid DNA mediated by topoisomerase II and to stabilize the cleavable complex. Cytofluorimetric analyses indicated the activation of the apoptotic pathway and the mitochondrial membrane depolarization. Therefore, topoisomerase II and mitochondria could represent possible intracellular targets. The biological properties of 1 and 2 were compared to those of the related trans -dichloro(triphenylphosphino)( N , N -dialkylamino)platinum(II) complexes in order to draw structure-activity relationships useful to face the resistance phenotype.

Resistance to platinum-based anticancer drugs represents an important limit for their clinical effectiveness and one of the most important field of investigation in the context of platinum compounds. From our previous studies, Pt II complexes containing the triphenylphosphino moiety have been emerging as promising agents, showing significant cytotoxicity to resistant ovarian carcinoma cells. Two brominated triphenylphosphino trans-platinum derivatives were prepared and evaluated on human tumor cell lines, sensitive and resistant to cisplatin. The new complexes exert a notable antiproliferative effect on resistant ovarian carcinoma cells, showing a remarkable intracellular accumulation and the ability to interact with different intracellular targets. The interaction with DNA, the collapse of mitochondrial transmembrane potential, and the impairment of intracellular redox state were demonstrated. Moreover, a selectivity towards the selenocysteine of thioredoxin reductase was observed. The mechanism of action is discussed with regard to the resistance phenomenon in ovarian carcinoma cells., (© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

A library of monosubstituted chalcones ( 1 - 17 ) bearing electron-donating and electron-withdrawing groups on both aromatic rings were selected. The cell viability on human tumor cell lines was evaluated first. The compounds unable to induce detectable cytotoxicity ( 1 , 13 , and 14 ) were tested using the monoamine oxidase (MAO) activity assay. Interestingly, they inhibit MAO-B, acting as competitive inhibitors, with 13 and 14 showing the best profiles. In particular, 13 exhibited a potency higher than that of safinamide, taken as a reference. Docking studies and crystallographic analysis showed that in human MAO-B 13 binds with the halogen-substituted aromatic ring in the entrance cavity, similar to safinamide, whereas 14 is accommodated in the opposite way. The main conclusion of this cell biology, biochemistry, and structural study is to highlights 13 as a chalcone derivative that is worth consideration for the development of novel MAO-B-selective inhibitors for the treatment of neurodegenerative diseases., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

A series of iminopyridine complexes of platinum(II), bearing a flexible diethereal, aryl terminated residue, where the size of aryl group is varied from phenyl to 9-anthracenyl, was synthesized. The new complexes are soluble and stable in DMSO/H 2 O mixtures. Besides the metal center, aryl groups are available for further interactions with DNA, due to the good side chain flexibility. The new aryl functionalized iminopyridine dichlorido platinum(II) complexes show a significant antiproliferative activity on ovarian carcinoma cells and notably, complex 13 is able to overcome cisplatin resistance. The study of the interaction mode of 13 with DNA highlighted the ability to form a molecular complex characterized by a dual (intercalative and groove binding) geometry. The complex is also able to covalently add to DNA even though interstrand cross-links appear significantly hampered with respect to cisplatin. The interactions with the macromolecule are discussed in view of the observed cell effect., (Copyright © 2020 Elsevier Inc. All rights reserved.)