Promising Cytotoxicity Research Articles

A New Saponin (Zygo-albuside D) from Zygophyllum album Roots Triggers Apoptosis in Non-Small Cell Lung Carcinoma (A549 Cells) through CDK-2 Inhibition.

Phytochemical study of the ethyl acetate root extract of Zygophyllum album has resulted in the isolation of a new saponin, Zygo-albuside D (1), along with two known compounds; (3-O-[β-D-quinovopyranosyl]-quinovic acid) (2), which is first reported in the root, and catechin (3), first reported in the genus. Their chemical structures were established by NMR and high-resolution mass spectrometry (HRMS). The new saponin (1) exhibited promising cytotoxicity with IC50 values of 3.5 and 5.52 μM on A549 and PC-3 cancer cell lines, respectively, compared to doxorubicin with IC50 values of 9.44 and 11.39 μM on A549 and PC-3 cancer cell lines, respectively. While it had an IC50 value of 46.8 μM against WISH cells. Investigating apoptosis-induction, compound 1 induced total apoptotic cell death in A549 lung cancer cells by 32-fold; 21.53% compared to 0.67% in the untreated control cells. Finally, it upregulated the pro-apoptotic genes and downregulated the antiapoptotic gene using gene expression levels. Compound 1 exhibited remarkable CDK-2 target inhibition by 96.2% with an IC50 value of 117.6 nM compared to Roscovitine. The molecular docking study further confirmed the binding affinity of compound 1 as CDK2 and Bcl2 inhibitors that led to apoptosis induction in A549 cancer cells. Hence, this study highlights the importance of compound 1 in the design of a new anticancer agent with specific mechanisms.

Antineoplastic activity of plant-derived compounds mediated through inhibition of histone deacetylase: a review.

In the combat of treating cancer recent therapeutic approaches are focused towards enzymatic targets as they occupy a pivotal participation in the cascade of oncogenesis and malignancy. There are several enzymes that modulate the epigenetic pathways and chromatin structure related to cancer mutation. Among several epigenetic mechanisms such as methylation, phosphorylation, and sumoylation, acetylation status of histones is crucial and is governed by counteracting enzymes like histone acetyl transferase (HAT) and histone deacetylases (HDAC) which have contradictory effects on the histone acetylation. HDAC inhibition induces chromatin relaxation which forms euchromatin and thereby initiates the expression of certain transcription factors attributed with apoptosis, which are mostly correlated with the expression of the p21 gene and acetylation of H3 and H4 histones. Most of the synthetic and natural HDAC inhibitors elicit antineoplastic effect through activation of various apoptotic pathways and promoting cell cycle arrest at various phases. Due to their promising chemo preventive action and low cytotoxicity against normal host cells, bioactive substances like flavonoids, alkaloids, and polyphenolic compounds from plants have recently gained importance. Even though all bioactive compounds mentioned have an HDAC inhibitory action, some of them have a direct effect and others enhance the effects of the standard well known HDAC inhibitors. In this review, the action of plant derived compounds against histone deacetylases in a variety of in vitro cancer cell lines and in vivo animal models are articulated.

Design, synthesis and development of a dual inhibitor of Topoisomerase 1 and poly (ADP-ribose) polymerase 1 for efficient killing of cancer cells

Combinatorial inhibition of Topoisomerase 1 (TOP1) and Poly (ADP-ribose) polymerase 1 (PARP1) is an attractive therapeutic strategy which is under active investigation to address chemoresistance to TOP1 inhibitors. However, this combinatorial regimen suffers from severe dose limiting toxicities. Dual inhibitors often offer significant advantages over combinatorial therapies involving individual agents by minimizing toxicity and providing conducive pharmacokinetic profiles. In this study, we have designed, synthesized and evaluated a library of 11 candidate conjugated dual inhibitors for PARP1 and TOP1, named as DiPT-1 to DiPT-11. Our extensive screening showed that one of the hits i.e.DiPT-4 has promising cytotoxicity profile against multiple cancers with limited toxicities towards normal cells. DiPT-4 induces extensive DNA double stand breaks (DSBs), cell cycle arrest and apoptosis in cancer cells. Mechanistically, DiPT-4 has the propensity to bind catalytic pockets of TOP1 and PARP1, leading to significant inhibition of both TOP1 and PARP1 at in vitro and cellular level. Interestingly, DiPT-4 causes extensive stabilization of TOP1-DNA covalent complex (TOP1cc), a key lethal intermediate associated with induction of DSBs and cell death. Moreover, DiPT-4 inhibited poly (ADP-ribosylation) i.e. PARylation of TOP1cc, leading to long lived TOP1cc with a slower kinetics of degradation. This is one of the important molecular processes which helps in overcoming resistance in cancer in response to TOP1 inhibitors. Together, our investigation showed DiPT-4 as a promising dual inhibitor of TOP1 and PARP1, which may have the potential to offer significant advantages over combinatorial therapy in clinical settings.

Mechanistic elucidation of Juglanthraquinone C targeting breast Cancer: A network Pharmacology-based investigation

Breast cancer is the leading cause of death among women worldwide. Despite the recent treatment options like surgery, chemotherapy etc. the lethality of breast cancer is alarming. Natural compounds are considered a better treatment option against breast carcinoma because of their lower side effects and specificity in targeting important proteins involved in the aberrant activation of pathways in breast cancer. A recently discovered compound called Juglanthraquinone C, which is found in the bark of the Juglans mandshurica Maxim (Juglandaceae) tree has shown promising cytotoxicity in hepatocellular carcinoma. However, not much data is available on the molecular mechanisms followed by this compound. Therefore, we aimed to investigate the molecular mechanism followed by Juglanthraquinone C against breast cancer. We used the network pharmacology technique to analyse the mechanism of action ofJuglanthraquinone Cin breast cancer and validated our study by applying various computational tools such as UALCAN, cBioportal, TIMER, docking and simulation. The results showed the compound and breast cancer target network shared 31 common targets. Moreover, we observed thatJuglanthraquinone C targets multiple deregulated genes in breast cancer such as TP53, TGIF1, IGF1R, SMAD3, JUN, CDC42, HBEGF, FOS and signaling pathways such as PI3K-Akt pathway, TGF-β signaling pathway, MAPK pathway and HIPPO signaling pathway. A docking examination revealed that the investigated drug had a high affinity for the primary target TGIF1 protein. A stable protein–ligand combination was generated by the best hit molecule, according to molecular dynamics modeling. The main aim of this study was to examine Juglanthraquinone C's significance as a prospective breast cancer treatment and to better understand the molecular mechanism this substance uses in breast cancer since there is a need to discover new therapeutics to decrease the load on current therapeutics which also are currently ineffective due to several side effects and development of drug resistance.

Synthesis of novel mono- and bis-pyrazolylthiazole derivatives as anti-liver cancer agents through EGFR/HER2 target inhibition

3-Bromoacetyl-4-(2-naphthoyl)-1-phenyl-1H-pyrazole (6) was synthesized from 2-acetylnaphthalene and was used as a new key building block for constructing the title targets. Thus, the reaction of 6 with the thiosemicarbazones 7a–d and 9–11 afforded the corresponding simple naphthoyl-(3-pyrazolyl)thiazole hybrids 8a–d and 12 ~ 14. The symmetric bis-(2-naphthoyl-pyrazol-3-yl)thiazol-2-yl)hydrazono)methyl)phenoxy)alkanes 18a-c and 21a-c were similarly synthesized from reaction of 6 with the appropriate bis-thiosemicarbazones 17a-c and 19a-c, respectively. The synthesized two series of simple and symmetrical bis-molecular hybrid merging naphthalene, thiazole, and pyrazole were evaluated for their cytotoxicity. Compounds 18b,c and 21a showed the most potent cytotoxicity (IC50 = 0.97–3.57 µM) compared to Lapatinib (IC50 = 7.45 µM). Additionally, they were safe (non-cytotoxic) against the THLE2 cells with higher IC50 values. Compounds 18c exhibited promising EGFR and HER-2 inhibitory activities with IC50 = 4.98 and 9.85 nM, respectively, compared to Lapatinib (IC50 = 6.1 and 17.2 nM). Apoptosis investigation revealed that 18c significantly activated apoptotic cell death in HepG2 cells, increasing the death rate by 63.6-fold and arresting cell proliferation at the S-phase. Compound 18c upregulated P53 by 8.6-fold, Bax by 8.9-fold, caspase-3,8,9 by 9, 2.3, and 7.6-fold, while it inhibited the Bcl-2 expression by 0.34-fold. Thereby, compound 18c exhibited promising cytotoxicity against EGFR/HER2 inhibition against liver cancer.

Homobimetallic Au(I)-Au(I) and Heterotrimetallic Au(I)-Fe(II)-Au(I) Complexes with Dialkyldithiophosphates and Phosphine Ligands: Structural Characterization, DFT Analysis, and Tyrosinase Inhibitory and Biological Effects.

The role of bridging and terminal ligand electronic and steric properties on the structure and antiproliferative activity of two-coordinated gold(I) complexes was investigated on seven novel binuclear and trinuclear gold(I) complexes synthesized by the reaction of either Au2(dppm)Cl2, Au2(dppe)Cl2, or Au2(dppf)Cl2 with potassium diisopropyldithiophosphate, K[(S-OiPr)2], potassium dicyclohexyldithiophosphate, K[(S-OCy)2], or sodium bis(methimazolyl)borate, Na(S-Mt)2, which afforded air-stable gold(I) complexes. In 1-7, the gold(I) centers adopt a two-coordinated linear geometry and are structurally similar. However, their structural features and antiproliferative properties highly depend upon subtle ligand substituent changes. All complexes were validated by 1H, 13C{1H}, 31P NMR, and IR spectroscopy. The solid-state structures of 1, 2, 3, 6, and 7 were confirmed using single-crystal X-ray diffraction. A density functional theory geometry optimization calculation was used to extract further structural and electronic information. To investigate the possible cytotoxicities of 2, 3, and 7, in vitro cellular tests were carried out on the human cancerous breast cell line MCF-7. 2 and 7 show promising cytotoxicity.

Cyanopyridinone- and Cyanopyridine-Based Cancer Cell Pim-1 Inhibitors: Design, Synthesis, Radiolabeling, Biodistribution, and Molecular Modeling Simulation.

In this study, two new series of 3-cyanopyridinones (3a-e) and 3-cyanopyridines (4a-e) were synthesized and evaluated for their cytotoxicity and Pim-1 kinase inhibitory activity adopting 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay and in vitro Pim-1 kinase inhibition assay, respectively. Most of the tested compounds revealed promising cytotoxicity against HepG-2, HCT-116, MCF-7, and PC-3 cell lines. Among them, compounds 4c and 4d showed more potent cytotoxicity against the HePG2 cell line with IC50 = 8.02 ± 0.38 and 6.95 ± 0.34 μM, respectively, than that of the reference 5-FU (IC50 = 9.42 ± 0.46 μM). Moreover, compound 4c was more potent against HCT-116 (IC50 = 7.15 ± 0.35 μM) than 5-FU (IC50 = 8.01 ± 0.39 μM), while compound 4d with IC50 = 8.35 ± 0.42 μM displayed comparable activity to that of the reference drug. Furthermore, high cytotoxic activity was manifested by compounds 4c and 4d against MCF-7 and PC3 cell lines. Our results have also indicated that compounds 4b, 4c, and 4d elicited remarkable inhibition of Pim-1 kinase; 4b and 4c showed equipotent inhibitory activity to that of the reference quercetagetin. Meanwhile, 4d displayed IC50 = 0.46 ± 0.02 μM, showed the best inhibitory activity among the tested compounds, and was more potent than quercetagetin (IC50 = 0.56 ± 0.03 μM). For optimization of the results, docking study of the most potent compounds 4c and 4d in the Pim-1 kinase active site was carried out and compared with both quercetagetin and the reported Pim-1 inhibitor A (VRV), and the results were consistent with those of the biological study. Consequently, compounds 4c and 4d are worthy of further investigations toward the discovery of Pim-1 kinase inhibitors as drug candidates for cancer therapy. Compound 4b was successfully radiolabeled with radioiodine-131, and its biodistribution in Ehrlich ascites carcinoma (EAC)-bearing mice showed more observable uptake in tumor sites, and hence, it can be introduced as a new radiolabeled agent for tumor imaging and therapy.

Bioactivity and molecular docking of lactones isolated from Centaurea pseudosinaica Czerep

Two cytotoxic sesquiterpene lactones, 17-epichlorohyssopifolin A (1) and chlorjanerin (2), and a monoterpene lactone, loliolide (3) were isolated from Centaurea pseudosinaica. The cytotoxicity of the total extract and terpenoids 1–3 were evaluated against three human cancer cells (HepG2, PC-3, and HT-29), along with the human normal primary epidermal keratinocytes (HEKa) cells. With IC50 values ranging between 0.6 ± 0.04 and 5.0 ± 0.61 μg/mL against HepG2; 0.2 ± 0.01 and 11.9 ± 1.31 μg/mL against PC-3, and 0.04 ± 0.013 and 8.9 ± 0.97 μg/mL against HT-29, the total extract, and lactones 1–3 demonstrated cytotoxic effects. Compound 1 displayed the strongest impact on all cancer cells and a slightly safe effect on the normal cells HEKa. Compound 1 caused accumulation of HepG2 and HT-29 cells in G1 phase as displayed cell cycle analysis. On the other hand, the cell distributions were increased in the S phase in PC-3 cells. Furthermore, 1 caused apoptosis in PC-3 and HePG2 cells with 91.50%, and 79.72 %, respectively. A higher fraction of necrotic cells was observed in HT-29 cells amounting to 23.60%. These results suggested that the promising cytotoxicity exhibited by 1 is brought by the apoptosis induction in the cancer cells, which were evaluated. As the compounds showed antiproliferative effect against the HT-29 cells, the docking simulation was performed aiming at determining how they would interact with the EGFR enzyme, whose PDB: 4I23 is considered one of the two distinct wild types of EGFR enzymes. The antibacterial activity results revealed that 3 showed the most remarkable antibacterial effects, especially against the examined Gram-positive bacteria. The total extract exhibited potent activity against all examined bacteria. The total extract showed a potent antifungal effect against two Candida and two Aspergillus pathogens. The antioxidant activity revealed the potency of the total extract and 3 as antioxidant candidates. The obtained results refer to the importance of Centaurea pseudosinaica as a source of potent antiproliferative agents and the whole plant as an antipathogenic and antioxidant agent.

Fig Leaves (Ficus carica L.): Source of Bioactive Ingredients for Industrial Valorization

The fig tree (Ficus carica L.) was one of the first domesticated trees. In 2019, the world’s fig fruit production was estimated at 1153 tons. However, fig leaves are not utilized, resulting in copious quantities of bio-waste. To identify promising fig tree varieties, hydroethanolic extracts were prepared from the leaves of five fig tree varieties (Pasteliere—PA, Longue d’Aout—LA, Dauphinie—DA, Boujassote Noire—BN, and Marseille—MA). The variety with the highest concentration of organic acids was BN (146.5 mg/g dw), while glucose, fructose, and sucrose were the predominant sugars across all varieties. All extracts present α-tocopherol as the prevalent tocopherol isoform (above 78%), while PUFA fatty acids were predominant, ranging from 53% to 71% of total fatty acids. BN showed moderate antioxidant activity (EC50 0.23 ± 0.01 mg/mL), while the DA variety presented promising cytotoxicity against the tumor AGS and MCF-7 cell line (GI50 158 ± 13 and 223 ± 21 μg/mL) and especially in the inhibition of Nitric Oxide Production evaluation (IC50 20 ± 5 μg/mL). The DA activities are probably related to high concentrations of flavonoids, specifically the predominant apigenin-C-hexoside-C-pentoside and quercetin-O-deoxyhexosyl-hexoside. Finally, the BN and DA varieties showed good antimicrobial activity, especially against Yersinia enterocolitica. Fig leaves can be considered sustainable sources of industrially valuable bioactive molecules, and several potential applications were highlighted.

Cytotoxicity and Antibacterial Potentials of Mixed Ligand Cu(II) and Zn(II) Complexes: A Combined Experimental and Computational Study.

[Cu(C15H9O4)(C12H8N2)O2C2H3]·3H2O (1) and [Zn(C15H9O4)(C12H8N2)]O2C2H3 (2) have been synthesized and characterized by ultraviolet-visible (UV-vis) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, mass spectrometry, thermogravimetric analysis/differential thermal analysis (TGA/DTA), X-ray diffraction (XRD), scanning electron microscopy-energy-dispersive X-ray spectroscopy (SEM-EDX), and molar conductance, and supported by density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations. Square pyramidal and tetrahedral geometries are proposed for Cu(II) and Zn(II) complexes, respectively, and the XRD patterns showed the polycrystalline nature of the complexes. Furthermore, in vitro cytotoxic activity of the complexes was evaluated against the human breast cancer cell line (MCF-7). A Cu(II) centered complex with an IC50 value of 4.09 μM was more effective than the Zn(II) centered complex and positive control, cisplatin, which displayed IC50 values of 75.78 and 18.62 μM, respectively. In addition, the newly synthesized complexes experienced the innate antioxidant nature of the metal centers for scavenging the DPPH free radical (up to 81% at 400 ppm). The biological significance of the metal complexes was inferred from the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy band gap, which was found to be 2.784 and 3.333 eV, respectively for 1 and 2, compared to the ligands, 1,10-phenathroline (4.755 eV) and chrysin (4.403 eV). Moreover, the molecular docking simulations against estrogen receptor alpha (ERα; PDB: 5GS4) were strongly associated with the in vitro biological activity results (E B and K i are -8.35 kcal/mol and 0.76 μM for 1, -7.52 kcal/mol and 3.07 μM for 2, and -6.32 kcal/mol and 23.42 μM for cisplatin). However, more research on in vivo cytotoxicity is suggested to confirm the promising cytotoxicity results.

Facile, Single-Step Synthesis of a Series of D-Ring Ethisterones Substituted with 1,4-1,2,3-Triazoles: Preliminary Evaluation of Cytotoxic Activities.

A series of new D-ring ethisterones substituted with 1,4-1,2,3-triazoles were obtained in a facile manner via click chemistry reactions. The new compounds were characterized by multinuclear NMR spectroscopy, mass spectrometry, IR and unequivocally by single crystal X-ray diffraction studies for compound 1. The cytotoxic activity of these derivatives was tested against a series of human cancer cell lines including human glioblastoma (U-251), human prostatic adenocarcinoma (PC-3), human colorectal adenocarcinoma (HCT-15), human mammary adenocarcinoma (MCF-7), human chronic myelogenous leukemia (K562), and human lung adenocarcinoma (SKLU-1). Derivatives (3, X=Cl) and (5, X=I) showed promising cytotoxicity activities for leukemia adenocarcinoma (K562) and lung adenocarcinoma (SKLU). CI50% of K562: 11.72±0.9 μM (3) and 24.50±1.0 μM (5). CI50% of SKLU: 14.9±0.8 μM (3) and 46.0±2.8 μM (5). In addition, DNA docking simulations showed that all compounds interact with DNA through crosslink instrastrand p-alkyl-like interactions.

Synthesis and cytotoxicity of starch nanocrystals produced by unconventional acid hydrolysis subjected to a factorial design

An experimental design was applied to obtain starch nanocrystals (SNCs) by an unconventional acid mixture of HCl/H3PO4, as well as to evaluate its cytotoxicity (study never before reported in the literature). The results indicated SNCs at the nanometer scale with better stability for SNCs/Exp2 (96.5 ± 1.4 nm and –32.15 ± 0.95 mV), which was chosen for the other characterizations. An increase in crystallinity was observed resulting from the high degree of hydrolysis (95.51%), loss of molar mass (19.45%) and reduced polydispersity (26.90%). Another corroborating factor was the narrowing of signals in FTIR analysis (bands at 995 and 1047 cm−1) and XRD (%C = 39.17%). Their thermal properties (TGA/DSC) showed mass losses of 9.29% (dehydration), 82.30% (thermal decomposition) and 8.41% (waste) and three thermal events (glass transition, endothermic transition and thermal decomposition), respectively. In this way, through the pre-established conditions and the results obtained for the SNCs/Exp2, new studies will be conducted to incorporate it in formulations for food applications (coatings or packaging) and hydrogels/films for wound healing, as they showed promising colloidal properties and low cytotoxicity against human cells.

Pyridine-Based 1,2,4-Triazolo-Tethered Indole Conjugates Potentially Affecting TNKS and PI3K in Colorectal Cancer.

A library of pyridine-based 1,2,4-triazolo-tethered indole conjugates were designed, synthesized, and evaluated for anti-proliferative activity against a panel of six human cancer cell lines. All the synthesized conjugates (14a-q) were found to be effective against the HT-29 cell line. Particularly conjugates 14a, 14n, and 14q exhibited promising cytotoxicity, with IC50 values of 1 μM, 2.4 μM, and 3.6 μM, respectively, compared to the standard 5-fluorouracil (IC50 = 5.31 μM). Cell cycle arrest at the G0/G1 phase was observed with these compounds, the mitochondrial membrane potential was interrupted, and the total ROS production was enhanced. Western blot and immunofluorescence experiments illustrated that these compounds inhibit the expression of markers that are involved in β-catenin and PI3K pathways. Molecular dynamics simulations demonstrated that compound 14a has major hydrophobic interactions and few H-bonding interactions with both PI3K and tankyrase proteins.

Exploring novel fluorine-rich fuberidazole derivatives as hypoxic cancer inhibitors: Design, synthesis, pharmacokinetics, molecular docking, and DFT evaluations.

Sixteen fuberidazole derivatives as potential new anticancer bioreductive prodrugs were prepared and characterized. The in vitro anticancer potential was examined to explore their cytotoxic properties by employing apoptosis, DNA damage, and proliferation tests on chosen hypoxic cancer cells. Eight substances (Compound 5a, 5c, 5d, 5e, 5g, 5h, 5i, and 5m) showed promising cytotoxicity values compared to the standard control. The potential of compounds was also examined through in silico studies (against human serum albumin), including chem-informatics, to understand the structure-activity relationship (SAR), pharmacochemical strength, and the mode of interactions responsible for their action. The DFT calculations revealed that only the 5b compound showed the lowest ΔET (2.29 eV) while 5i showed relatively highest βtot (69.89 x 10-31 esu), highest αave (3.18 x 10-23 esu), and dipole moment (6.49 Debye). This study presents a novel class of fuberidazole derivatives with selectivity toward hypoxic cancer cells.

N-Containing α-Mangostin Analogs via Smiles Rearrangement as the Promising Cytotoxic, Antitrypanosomal, and SARS-CoV-2 Main Protease Inhibitory Agents.

New N-containing xanthone analogs of α-mangostin were synthesized via one-pot Smiles rearrangement. Using cesium carbonate in the presence of 2-chloroacetamide and catalytic potassium iodide, α-mangostin (1) was subsequently transformed in three steps to provide ether 2, amide 3, and amine 4 in good yields at an optimum ratio of 1:3:3, respectively. The evaluation of the biological activities of α-mangostin and analogs 2-4 was described. Amine 4 showed promising cytotoxicity against the non-small-cell lung cancer H460 cell line fourfold more potent than that of cisplatin. Both compounds 3 and 4 possessed antitrypanosomal properties against Trypanosoma brucei rhodesiense at a potency threefold stronger than that of α-mangostin. Furthermore, ether 2 gave potent SARS-CoV-2 main protease inhibition by suppressing 3-chymotrypsinlike protease (3CLpro) activity approximately threefold better than that of 1. Fragment molecular orbital method (FMO-RIMP2/PCM) indicated the improved binding interaction of 2 in the 3CLpro active site regarding an additional ether moiety. Thus, the series of N-containing α-mangostin analogs prospectively enhance druglike properties based on isosteric replacement and would be further studied as potential biotically active chemical entries, particularly for anti-lung-cancer, antitrypanosomal, and anti-SARS-CoV-2 main protease applications.

Autophagic-Related Anticancer Effect of Grapes Extract and Tomatoes Extract: Ex-Vivo Study

Cells undergo autophagy to save themselves from injury, but progressive autophagy can cause cell death. This study characterized and compared the effect of grape (resveratrol) and tomato (lycopene) extracts and their combination on modulating autophagy-related miRNA and its target gene in squamous cell carcinoma cell line. Docking analysis for extracts and selected genes was performed. Methyl Thiazol Tetrazolium assays were used to assess the cytotoxicity of extracts and their combination toward HEp-2 cells. qRT-PCR was used to quantify changes in gene expression. Data were statistically analyzed. miRNA-20a was identified as a potential effector in laryngeal cancer, and sequestosome-1 (SQSTM1) was its target gene. Docking analysis showed that resveratrol interacted with miRNA-20a and showed less affinity toward SQSTM1. Hydrogen bonds and hydrophobic interactions were predicted. In contrast, lycopene showed less affinity toward miRNA-20a than resveratrol. Increasing doses of resveratrol, lycopene, and their combination induced a statistically significant reduction in mean percent viability and mean fold changes of miRNA-20a and SQSTM1 expression in treated HEp-2 cells. Pearson’s correlation showed a statistically significant positive correlation between miRNA-20a and SQSTM1 (R=0.812, p≤0.001). Grape and tomato extracts and their combination display promising cytotoxicity against HEp-2 cells in a dose- and time-dependent fashion. Both extracts reduce the expression of miRNA-20a and SQSTM1 with subsequent inhibition autophagy and promotion of apoptosis in HEp-2 cells.

Organocatalytic atroposelective synthesis of axially chiral N,N'-pyrrolylindoles via de novo indole formation.

The first organocatalytic atroposelective synthesis of axially chiral N,N'-pyrrolylindoles based on o-alkynylanilines was successfully established via de novo indole formation catalyzed by chiral phosphoric acid (CPA). This new synthetic strategy introduced CPA-catalyzed asymmetric 5-endo-dig cyclization of new well-designed o-alkynylanilines containing a pyrrolyl unit, resulting in a wide range of axially chiral N,N'-pyrrolylindoles in high yields with exclusive regioselectivity and excellent enantioselectivity (up to 99% yield, >20 : 1 rr, 95 : 5 er). Considering the potential biological significance of N-N atropisomers, preliminary biological activity studies were performed and revealed that these structurally important N,N'-pyrrolylindoles had a low IC50 value with promising impressive cytotoxicity against several kinds of cancer cell lines. DFT studies reveal that the N-nucleophilic cyclization mediated by CPA is the rate- and stereo-determining step, in which ligand-substrate dispersion interactions facilitate the axial chirality of the target products.

Synthesis, Characterization and Evaluation of Anticancer Activity of New Pyrazole-5-carboxamide Derivatives

In recent years, pyrazole derivatives have emerged as a potentially game-changing new family of cancer chemotherapeutic drugs. Thus, present work used six distinct cancer cell lines to test the new pyrazole-5-carboxamide derivatives for the anticancer activity. Present study includes synthesis, characterization and the ligand-based molecular docking of the compounds. The process begins with ethyl 2,4-dioxopentanoate and methylhydrazine, which was cyclized to form ethyl 1,3-dimethyl-1H-pyrazole- 5-carboxylate (2), which is then transformed to 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (3) through PCl3/I2. All the pyrazole-4-carboxamides (4a-n) were obtained by the acidic condensation of intermediate 3 with various substituted aryl amines (a-n). The antitumor activity against six cancer cell lines and one regular human cell line was measured using the MTT test. Two target proteins, human c-Met kinase and JAK1, were used in docking studies of the proposed compounds. When compared against the standard drug doxorubicin, most of the synthesized compounds (4a-n) showed the promising cytotoxicity profiles.

Dinuclear doubly bridged phenoxido copper(II) complexes as efficient anticancer agents

Two cationic [Cu2(L1-2)2](ClO4)2 (1, 2), and four neutral doubly bridged-phenoxido-copper(II) complexes [Cu2(L3-4)2] (3, 4) and [Cu2(L5-6)2(H2O)]‧2H2O (5, 6) as well as 1D polymeric catena-[Cu(L7)] (7), where HL1-2 and H2L3-7 represent tripodal tetradentate pyridyl or aliphatic-amino groups based 2,4-disubstituted phenolates, were synthesized and thoroughly characterized by various spectroscopic methods and single crystal X-ray analysis. The molecular structures of the complexes exhibited diverse geometrical environments around the central Cu(II) atoms. The in vitro antiproliferative activity of the isolated complexes and selected parent free ligands were screened against some human cancer cell lines (A2780, A2780R, PC-3, 22Rv1, MCF-7). The most promising cytotoxicity against cancer cells were obtained for 1–6, while complex 6 was found as the best performing as compared to the reference drug cisplatin. The cytotoxicity study of complex 6 was therefore extended to wider variety of cancer cell lines (HOS, A549, PANC-1, CaCo2, HeLa) and results revealed its significant cytotoxicity on all investigated human cancer cells. The cell uptake study showed that cytotoxicity of 6 (3 μM concentration and 24 h of incubation) against A2780 cells was almost independent from the intracellular levels of copper. The effect of complexes 4, 6 and 7 on cell cycle of A2780 cells indicates that the mechanism of action in these complexes is not only different from that of cisplatin but also different among them. Complex 7 was able to induce apoptosis in A2780 cells, while complexes 4 and 6 did not and on the other hand, they showed considerable effect on autophagy induction and there are some clues that these complexes were able to induce cuproptosis in A2780 cells.

Silyl-functionalised silver rhodium and iridium N-heterocyclic carbene complexes with promising cytotoxicity and antimicrobial potential

In the present study, we have synthesized Ag, Rh, and Ir complexes of a silyl-substituted NHC ligand in order to investigate their biological properties. Firstly, Ag-NHC ( 2 ) complex was synthesized by the interaction of Ag 2 O with benzimidazolium iodide ( 1 ). Rh- ( 3 ) and Ir-NHC ( 4 ) complexes were synthesized by the transmetalation reaction between Ag-NHC and [M(cod)Cl] 2 (M = Rh or Ir) dimers. The complexes were characterised by NMR spectroscopy and elemental analyses, and crystal structures of Rh- and Ir-NHC ( 3 and 4 ) were also reported. The cytotoxic effects of the complexes were tested on four human cancer cell lines and the antimicrobial activities of the complexes were tested against a panel of nine pathogenic microorganisms. The complexes performed comparable or better activity than standards, cisplatin and AgNO 3 .