Targeting hematological malignancies with isoxazole derivatives.

Compounds with a heterocyclic isoxazole ring are well known for their diverse biologic activities encompassing antimicrobial, antipsychotic, immunosuppressive, antidiabetic and anticancer effects. Recent studies on hematological malignancies have also shown that some of the isoxazole-derived compounds feature encouraging cancer selectivity, low toxicity to normal cells and ability to overcome cancer drug resistance of conventional treatments. These characteristics are particularly promising because patients with hematological malignancies face poor clinical outcomes caused by cancer drug resistance or relapse of the disease. This review summarizes the knowledge on isoxazole-derived compounds toward hematological malignancies and provides clues on their mechanism(s) of action (apoptosis, cell cycle arrest, ROS production) and putative pharmacological targets (c-Myc, BET, ATR, FLT3, HSP90, CARM1, tubulin, PD-1/PD-L1, HDACs) wherever known.

Design, Synthesis, and Evaluation of Novel Indole Hybrid Chalcones and Their Antiproliferative and Antioxidant Activity.

The synthesis, anticancer, and antioxidant activities of a series of indole-derived hybrid chalcones are reported here. First, using the well-known Claisen-Schmidt condensation method, a set of 29 chalcones has been designed, synthesized, and consequently characterized. Subsequently, screening for the antiproliferative activity of the synthesized hybrid chalcones was performed on five cancer cell lines (HCT116, HeLa, Jurkat, MDA-MB-231, and MCF7) and two non-cancer cell lines (MCF-10A and Bj-5ta). Chalcone 18c, bearing 1-methoxyindole and catechol structural features, exhibited selective activity against cancer cell lines with IC50 values of 8.0 ± 1.4 µM (Jurkat) and 18.2 ± 2.9 µM (HCT116) and showed no toxicity to non-cancer cells. Furthermore, antioxidant activity was evaluated using three different methods. The in vitro studies of radical scavenging activity utilizing DPPH radicals as well as the FRAP method demonstrated the strong activity of catechol derivatives 18a-c. According to the ABTS radical scavenging assay, the 3-methoxy-4-hydroxy-substituted chalcones 19a-c were slightly more favorable. In general, a series of 3,4-dihydroxychalcone derivatives showed properties as a lead compound for both antioxidant and antiproliferative activity.

Derivatives Incorporating Acridine, Pyrrole, and Thiazolidine Rings as Promising Antitumor Agents.

Derivatives combining acridine, pyrrole, and thiazolidine rings have emerged as promising candidates in the field of antitumor drug discovery. This paper aims to highlight the importance of these three structural motifs in developing potent and selective anticancer agents. The integration of these rings within a single molecule offers the potential for synergistic effects, targeting multiple pathways involved in tumor growth and progression. Spiro derivatives were efficiently synthesized in a two-step process starting from isothiocyanates and 2-cyanoacetohydrazide. The thiourea side chain in spiro derivatives was utilized as a key component for the construction of the thiazolidine-4-one ring through regioselective reactions with bifunctional reagents, namely methyl-bromoacetate, dietyl-acetylenedicarboxylate, ethyl-2-bromopropionate, and ethyl-2-bromovalerate. These reactions resulted in the formation of a single regioisomeric product for each derivative. Advanced spectroscopic techniques, including 1D and 2D NMR, FT-IR, HRMS, and single-crystal analysis, were employed to meticulously characterize the chemical structures of the synthesized derivatives. Furthermore, the influence of these derivatives on the metabolic activity of various cancer cell lines was assessed, with IC50 values determined via MTT assays. Notably, derivatives containing ester functional groups exhibited exceptional activity against all tested cancer cell lines, boasting IC50 values below 10 µM. Particularly striking were the spiro derivatives with methoxy groups at position 3 and nitro groups at position 4 of the phenyl ring. These compounds displayed remarkable selectivity and exhibited heightened activity against HCT-116 and Jurkat cell lines. Additionally, 4-oxo-1,3-thiazolidin-2-ylidene derivatives demonstrated a significant activity against MCF-7 and HCT-116 cancer cell lines.

Chalcone-Acridine Hybrid Suppresses Melanoma Cell Progression via G2/M Cell Cycle Arrest, DNA Damage, Apoptosis, and Modulation of MAP Kinases Activity.

This study was focused on investigating the antiproliferative effects of chalcone hybrids in melanoma cancer cells. Among seven chalcone hybrids, the chalcone-acridine hybrid 1C was the most potent and was selected for further antiproliferative mechanism studies. This in vitro study revealed the potent antiproliferative effect of 1C via cell cycle arrest and apoptosis induction. Cell cycle arrest at the G2/M phase was associated with modulation of expression or phosphorylation of specific cell cycle-associated proteins (cyclin B1, p21, and ChK1), tubulins, as well as with the activation of the DNA damage response pathway. Chalcone 1C also induced apoptosis accompanied by mitochondrial dysfunction evidenced by a decrease in mitochondrial membrane potential, increase in Bax/Bcl-xL ratio and cytochrome c release followed by caspase 3/7 activation. In addition, increased phosphorylation of MAP kinases (Erk1/2, p38 and JNK) was observed in chalcone 1C-treated melanoma cells. The strong antiproliferative activities of this chalcone-acridine hybrid suggest that it may be useful as an antimelanoma agent in humans.

Programmed Cell Death Alterations Mediated by Synthetic Indole Chalcone Resulted in Cell Cycle Arrest, DNA Damage, Apoptosis and Signaling Pathway Modulations in Breast Cancer Model.

Although new chemotherapy significantly increased the survival of breast cancer (BC) patients, the use of these drugs is often associated with serious toxicity. The discovery of novel anticancer agents for BC therapy is expected. This study was conducted to explore the antiproliferative effect of newly synthesized indole chalcone derivative ZK-CH-11d on human BC cell lines. MTT screening, flow cytometry, Western blot, and fluorescence microscopy were used to evaluate the mode of cell death. ZK-CH-11d significantly suppressed the proliferation of BC cells with minimal effect against non-cancer cells. This effect was associated with cell cycle arrest at the G2/M phase and apoptosis induction. Apoptosis was associated with cytochrome c release, increased activity of caspase 3 and caspase 7, PARP cleavage, reduced mitochondrial membrane potential, and activation of the DNA damage response system. Furthermore, our study demonstrated that ZK-CH-11d increased the AMPK phosphorylation with simultaneous inhibition of the PI3K/Akt/mTOR pathway indicating autophagy initiation. However, chloroquine, an autophagy inhibitor, significantly potentiated the cytotoxic effect of ZK-CH-11d in MDA-MB-231 cells indicating that autophagy is not principally involved in the antiproliferative effect of ZK-CH-11d. Taking together the results from our experiments, we assume that autophagy was activated as a defense mechanism in treated cells trying to escape from chalcone-induced harmful effects.

The Newly Synthetized Chalcone L1 Is Involved in the Cell Growth Inhibition, Induction of Apoptosis and Suppression of Epithelial-to-Mesenchymal Transition of HeLa Cells.

Over the past decades, natural products have emerged as promising agents with multiple biological activities. Many studies suggest the antioxidant, antiangiogenic, antiproliferative and anticancer effects of chalcones and their derivatives. Based on these findings, we decided to evaluate the effects of the newly synthetized chalcone L1 in a human cervical carcinoma cell (HeLa) model. Presented results were obtained by western blot and flow cytometric analyses, live cell imaging and antimigratory potential of L1 in HeLa cells was demonstrated by scratch assay. In the present study, we proved the role of L1 as an effective agent with antiproliferative activity supported by G2/M cell cycle arrest and apoptosis. Moreover, we proved that L1 is involved in modulating Transforming Growth Factor-ß1 (TGF-ß) signal transduction through Smad proteins and it also modulates other signalling pathways including Akt, JNK, p38 MAPK, and Erk1/2. The involvement of L1 in epithelial-to-mesenchymal transition was demonstrated by the regulation of N-cadherin, E-cadherin, and MMP-9 levels. Here, we also evaluated the effect of conditioned medium from BJ-5ta human foreskin fibroblasts in HeLa cell cultures with subsequent L1 treatment. Taken together, these data suggest the potential role of newly synthesized chalcone L1 as an anticancer-tumour microenvironment modulating agent.

Design and synthesis of novel tacrine-indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease.

The authors report on the synthesis and biological evaluation of new compounds whose structure combines tacrine and indole moieties. Tacrine-indole heterodimers were designed to inhibit cholinesterases and ß-amyloid formation, and to cross the blood-brain barrier. The most potent new acetylcholinesterase inhibitors were compounds 3c and 4d (IC50 = 25 and 39 nM, respectively). Compound 3c displayed considerably higher selectivity for acetylcholinesterase relative to human plasma butyrylcholinesterase in comparison to compound 4d (selectivity index: IC50 [butyrylcholinesterase]/IC50 [acetylcholinesterase] = 3 and 0.6, respectively). Furthermore, compound 3c inhibited ß-amyloid-dependent amyloid nucleation in the yeast-based prion nucleation assay and displayed no dsDNA destabilizing interactions with DNA. Compounds 3c and 4d displayed a high probability of crossing the blood-brain barrier. The results support the potential of 3c for future development as a dual-acting therapeutic agent in the prevention and/or treatment of Alzheimer's disease.

Mechanochemical Synthesis and Isomerization of N-Substituted Indole-3-carboxaldehyde Oximes †.

Performing solution-phase oximation reactions with hydroxylamine hydrochloride (NH2OH·HCl) carries significant risk, especially in aqueous solutions. In the present study, four N-substituted indole-3-carboxaldehyde oximes were prepared from the corresponding aldehydes by solvent-free reaction with NH2OH·HCl and a base (NaOH or Na2CO3) using a mechanochemical approach, thus minimizing the possible risk. In all cases, the conversion to oximes was almost complete. The focus of this work is on 1-methoxyindole-3-carboxaldehyde oxime, a key intermediate in the production of indole phytoalexins with useful antimicrobial properties. Under optimized conditions, it was possible to reach almost 95% yield after 20 min of milling. Moreover, for the products containing electron-donating substituents (-CH3, -OCH3), the isomerization from the oxime anti to syn isomer under acidic conditions was discovered. For the 1-methoxy analog, the acidic isomerization of pure isomers in solution resulted in the formation of anti isomer, whereas the prevalence of syn isomer was observed in solid state. From NMR data the syn and anti structures of produced oximes were elucidated. This work shows an interesting and possibly scalable alternative to classical synthesis and underlines environmentally friendly and sustainable character of mechanochemistry.

Liquid chromatographic chiral recognition of phytoalexins on immobilized polysaccharides chiral stationary phases. Unusual temperature behavior.

Three immobilized polysaccharide chiral stationary phases, Chiralpak IA, Chiralpak IB and Chiralpak IC, were used for the study of enantioseparation of 36 derivatives of natural indole phytoalexins, in most cases bioactive, including racemic spirobrassinin, 1-methoxyspirobrassinin and 1-methoxyspirobrassinol methyl ether. Almost all analytes were baseline resolved at least on two different polysaccharide columns in normal phase mode. The effects of mobile phase composition, the analyte structure and the column temperature on the retention and enantioseparation were investigated. Evaluation of the corresponding thermodynamic parameters using van´t Hoff plots (ln k versus 1/T) in the temperature range -15 to 50 °C indicated that separations were enthalpy controlled in most cases, but some entropy controlled separations were also observed. Moreover, unusual phenomenon, an increase retention with increasing temperature accompanied with increased resolution was observed on the Chiralpak IC column. The elution order of enantiomers was determined in some cases and reversed elution order was also observed.

New chalcone derivative exhibits antiproliferative potential by inducing G2/M cell cycle arrest, mitochondrial-mediated apoptosis and modulation of MAPK signalling pathway.

In the present study, we investigated antiproliferative activity of seven newly synthesized chalcone derivatives. Among tested compounds, (2 E)-3-(acridin-9-yl)-1-(2,6-dimethoxyphenyl)prop-2-en-1-one (1C) was the most potent with IC50 = 4.1 µmol/L in human colorectal HCT116 cells and was selected for further studies. Inhibition of cell proliferation was associated with cell cycle arrest in G2/M phase and dysregulation of α, α1 and ß5 tubulins. Moreover, 1C caused disruption of the mitochondrial membrane potential and increased number of cells with sub G0/G1 DNA content which is considered as marker of apoptosis. Apoptosis was confirmed by annexin V/PI and AO/PI staining. Furthermore, we found increased concentration of cytochrome c, Smac/Diablo and increased caspase-3 and caspase-9 activity, cleavage of PARP as well as activation of DNA repair mechanisms in 1C-treated HCT116 cancer cells. Moreover this chalcone derivative up-regulated proapoptotic Bax expression and down-regulated antiapoptotic Bcl-2 and Bcl-xL expression. Additionally, 1C treatment led to modulation of MAPKs and Akt signalling pathways. In conclusion, our data showed ability of 1C to suppress cancel cell growth and provide the rationale for further in vivo study.