Tested Cancer Cell Research Articles

1,2,3-triazole and chiral Schiff base hybrids as potential anticancer agents: DFT, molecular docking and ADME studies

A series of novel 1,2,3-triazole and chiral Schiff base hybrids 2–6 were synthesized by Schiff base condensation reaction from pre-prepared parent component of the hybrids (1,2,3-triazole 1) and series of primary chiral amines and their chemical structure were confirmed using NMR and FTIR spectroscopies, and CHN elemental analysis. Compounds 1–6 were evaluated for their anticancer activity against two cancer PC3 (prostate) and A375 (skin) and MRC-5 (healthy) cell lines by Almar Blue assay method. The compounds exhibited significant cytotoxicity against the tested cancer cell lines. Among the tested compounds 3 and 6 showed very good activity for the inhibition of the cancer cell lines and low toxicity for the healthy cell lines. All the compounds exhibited high binding affinity for Androgen receptor modulators (PDB ID: 5t8e) and Human MIA (PDB ID: 1i1j) inhibitors compared to the reference anticancer drug (cisplatin). Structure activity relationships (SARs) of the tested compounds is in good agreement with DFT and molecular docking studies. The compounds exhibited desirable physicochemical properties for drug likeness.

Abstract 3164: The in vivo Hollow Fiber model is a valuable tool in drug development of selective KRas inhibitors

Abstract The proto-oncogene KRas is a well-described small GTPase that functions as a molecular switch for major physiological signaling pathways involved in cell proliferation, differentiation and survival. It has been shown that activating mutations in KRas are among the most common oncogenic drivers of tumorigenesis. Missense mutations of KRas result in constitutive activation due to impaired hydrolysis of GTP which enhances tumor-promoting downstream signaling pathways. Most KRas mutations are located in exon 2 or 3 including the most frequently altered glycine 12, which is present in most pancreatic cancers as well as in colorectal cancers and lung adenocarcinomas. A panel of cancer cell lines harboring different KRas mutations such as G12C, G12V or G12D was selected to test KRas inhibitors in several cellular assays: phosphorylation assays, 2D and 3D proliferation assays. Applying the cellular pERK AlphaLISA assay showed high selectivity of several inhibitors for specific KRas mutants, while RAF and MEK inhibitors did not show significant selectivity in the tested cancer cell lines. The KRas inhibitors were then examined in a cellular 2D and a 3D spheroid proliferation assay to determine the inhibitory effect on cell growth. These cellular assays revealed a high selectivity for a specific KRas mutant, which was even more pronounced in the 3D format than in the 2D setup. The transferability of the cellular data obtained to in vivo was tested in the Hollow Fiber mouse model. The Hollow Fiber model allows the simultaneous study of multiple cell lines implanted in separated drug-(but not cell-) permeable fibers in a single mouse with a study duration of only 16 days. AMG510 (Sotorasib), a drug approved for tumors with a G12C Kras mutation, and MRTX1133, which is currently in clinical phase and shows activity in tumors with a G12D Kras mutation, were screened for their inhibitory effect on the pancreatic tumor cells MiaPaCa-2 (G12C Kras mutation), AsPC-1 (G12D Kras mutation) and BxPC-3 (wt Kras) in the in vivo Hollow Fiber model in female NMRI nude mice. While the growth of BxPC-3 tumor cells was not affected by either inhibitor, the growth of AsPC-1 tumor cells in particular was selectively and significantly inhibited by MRTX1133. In summary, the in vivo Hollow Fiber model is a fast and cost-effective model that can play an prominent role in drug development as a link between in vitro and in vivo xenograft studies by providing rapid and transferable evidence for in vivo efficacy. Citation Format: Philipp Metzger, Claus-Werner Franzke, Ezgi Dikici, Gregor Sommerkamp, Franziska Fimm-Todt, Jan E. Ehlert, Cynthia Obodozie, Holger Weber. The in vivo Hollow Fiber model is a valuable tool in drug development of selective KRas inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3164.

Optimization of Aqueous Extraction of Polyphenols from Cuminum cyminum Seeds Using Response Surface Methodology and Assessment of Biological Activity.

(1) Background: Cumin seeds, extracted from the plant Cuminum cyminum, are abundant in phenolic compounds and have been extensively researched for their chemical makeup and biological effects. The objective of this research is to enhance the water extraction of polyphenols through the water bath (WB) technique and to evaluate the antiradical, antibacterial, and anticancer effects of the extract. (2) Methods: Response Surface Methodology was used to find the best parameters to extract polyphenols. Three experimental parameters, time, temperature, and solid-liquid ratio, were tested. The disc diffusion method has been used to determine the antimicrobial activities against Salmonella Typhimurium, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and Candida albicans. The antiradical activity was performed using the DPPH method, while total phenolic content was performed using Folin-Ciocalteu. High-Performance Liquid Chromatography (HPLC) was conducted to analyze the phytochemical profile of WB extracts. The anticancer activity of the lyophilized extract was assessed against three cancer cell lines (colon (HT29), lung (A549), and breast (MCF7) cancer cell lines).; (3) Results: The optimal conditions for water extraction were 130 min at 72 °C. The total phenolic compounds yield (14.7 mg GAE/g DM) and antioxidant activity (0.52 mg trolox eq./mL) were obtained using a 1:40 solid-liquid ratio. The primary polyphenols identified were the flavonoids rutin (0.1 ppm) and ellagic acid (3.78 ppm). The extract had no antibacterial or antifungal activities against the microorganisms tested. The extract showed anticancer activity of about 98% against MCF7 (breast cancer cell line), about 81% against HT29 (colon cancer cell line), and 85% against A549 (lung cancer cell line) at high doses. (4) Conclusions: Extraction time and a high solid-liquid ratio had a positive impact on polyphenol recovery and in maintaining their quantity and quality. Furthermore, the optimal aqueous extract exhibited strong antiradical activity reflected by the inhibition of free radicals in addition to a significant specificity against the tested cancer cell lines.

USP28 promotes tumorigenesis and cisplatin resistance by deubiquitinating MAST1 protein in cancer cells

Cisplatin is a chemotherapy drug that causes a plethora of DNA lesions and inhibits DNA transcription and replication, resulting in the induction of apoptosis in cancer cells. However, over time, patients develop resistance to cisplatin due to repeated treatment and thus the treatment efficacy is limited. Therefore, identifying an alternative therapeutic strategy combining cisplatin treatment along with targeting factors that drive cisplatin resistance is needed. CRISPR/Cas9 system-based genome-wide screening for the deubiquitinating enzyme (DUB) subfamily identified USP28 as a potential DUB that governs cisplatin resistance. USP28 regulates the protein level of microtubule-associated serine/threonine kinase 1 (MAST1), a common kinase whose expression is elevated in several cisplatin-resistant cancer cells. The expression level and protein turnover of MAST1 is a major factor driving cisplatin resistance in many cancer types. Here we report that the USP28 interacts and extends the half-life of MAST1 protein by its deubiquitinating activity. The expression pattern of USP28 and MAST1 showed a positive correlation across a panel of tested cancer cell lines and human clinical tissues. Additionally, CRISPR/Cas9-mediated gene knockout of USP28 in A549 and NCI-H1299 cells blocked MAST1-driven cisplatin resistance, resulting in suppressed cell proliferation, colony formation ability, migration and invasion in vitro. Finally, loss of USP28 destabilized MAST1 protein and attenuated tumor growth by sensitizing cells to cisplatin treatment in mouse xenograft model. We envision that targeting the USP28-MAST1 axis along with cisplatin treatment might be an alternative therapeutic strategy to overcome cisplatin resistance in cancer patients.

Design, synthesis and mechanism study of coumarin-sulfonamide derivatives as carbonic anhydrase IX inhibitors with anticancer activity

In this study, twenty-nine coumarin-3-sulfonamide derivatives, twenty-seven of which are original were designed and synthesized. Cytotoxicity assay indicated that most of these derivatives exhibited moderated to good potency against A549 cells. Among them, compound 8q showed potent inhibition against the four tested cancer cell lines, especially A549 cells with IC50 value of 6.01 ± 0.81 μM, and much lower cytotoxicity on the normal cells was observed compared to the reference compounds. Bioinformatics analysis revealed human carbonic anhydrase IX (CAIX) was highly expressed in lung adenocarcinoma (LUAD) and associated with poor prognosis. The inhibitory activity of compound 8q against CAIX was assessed by using molecular docking and molecular dynamics simulations, which revealed prominent interactions of both compound 8q and CAIX at the active site and their high affinity. The results of ELISA assays verified that compound 8q possessed strong inhibitory activity against CAIX and high subtype selectivity, and could also down-regulate the expression of CAIX in A549 cells. Furthermore, the significant inhibitory effects of compound 8q on the migration and invasion of A549 cells were also found. After treatment with compound 8q, intracellular reactive oxygen species (ROS) levels increased and mitochondrial membrane potential (MMP) decreased. Mechanistic investigation using western blotting revealed compound 8q exerted the anti-migrative and anti-invasive effects probably through mitochondria-mediated PI3K/AKT pathway by targeting CAIX. In summary, coumarin-3-sulfonamide derivatives were developed as potential and effective CAIX inhibitors, which were worthy of further investigation.

Novel Titanocene Y derivative with albumin affinity exhibits improved anticancer activity against platinum resistant cells

The antitumor activity of Ti(IV)-based compounds put them in the spotlight for cancer treatment in the past, but their lack of stability in vivo due to a high rate of hydrolysis has hindered their development as antitumor drugs. As a possible solution for this problem, we have reported a synthesis strategy through which we combined a titanocene fragment, a tridentate ligand, and a long aliphatic chain. This strategy allowed us to generate a titanium compound (Myr-Ti) capable of interacting with albumin, highly stable in water and with cytotoxic activity in tumor cells[1]. Following a similar strategy, now we report the synthesis of a new compound (Myr-TiY) derived from titanocene Y that shows antitumoral activity in a cisplatin resistant model with a 50% inhibitory concentration (IC50) of 41–76 μM. This new compound shows high stability and a strong interaction with human serum albumin. Myr-TiY has a significant antiproliferative and proapoptotic effect on the tested cancer cells and shows potential tumor selectivity when assayed in non-tumor human epithelial cells being more selective (1.3–3.8 times) for tumor cells than cisplatin. These results lead us to think that the described synthesis strategy could be useful to generate compounds for the treatment of both cisplatin-sensitive and cisplatin-resistant cancers.

Chemical compositions and cytotoxicity effects of essential oils from the leaves and pseudo-stems of Curcuma zedoaroides Chaveer. & Tanee collected in Vietnam

In this study, chemical components and cytotoxic effects of essential oils from Curcuma zedoaroides Chaveer. & Tanee growing wild in Thai Nguyen province, Vietnam, were investigated. The essential oils of C. zedoaroides were obtained through hydrodistillation with contents of 0.38% and 0.1% in C. zedoaroides leaves (CZL) and C. zedoaroides pseudo-stems (CZPS), respectively (based on dried herbal materials). Using Gas chromatography-mass spectrometry (GC/MS) analysis, 48 volatile compounds were identified in the CZL essential oil. The major components of the CZL essential oil were curdione (14.05%), 1,8-cineole (8.88%), camphor (7.06%), trans-β-elemenone (6.65%), (E)-β-farnesene epoxide (6.44%), curzerene (5.20%), isoborneol (4.75%), β-elemene (3.41%), endo-borneol (3.07%), camphene (2.87%), humulene (2.47%), and γ-elemene (2.22%). Besides, 47 components were determined in the CZPS essential oil with the significant components of curzerene (11.72%), trans-β-elemenone (10.64%), curdione (9.79%), β-elemene (6.77%), (E)-β-farnesene epoxide (6.71%), humulene (6.37%), cis-β-elemenone (3.81%), γ-elemene (3.55%), camphor (3.41%), germacrone (2.83%), and isoborneol (2.39%). The CZL essential oil showed weak cytotoxic activity against tested cancer cell lines (A549, MCF-7, HepG2, HT29, HL-60, K562, and MDA-MB-231) with IC50 values in the range of 43.88 to 81.32 μg/mL. This study is the first information on the chemical compositions of the CZL and CZPS essential oils of C. zedoaroides, as well as the cytotoxicity of the CZL essential oil.

Design, synthesis, and antiproliferative activities of novel substitutedhydrazone/triazolo-linked quinazoline derivatives

A series of novel hydrazonoquinazolines and triazoloquinazolines analogues of Erlotinib were synthesized and evaluated for their antiproliferative as well as EGFR kinase inhibitory activities. Most of the quinazoline compounds showed significant antiproliferative against different cancer cells. Among these, both compounds 4b and 5b were the best members of all the tested cancer cell lines with IC50 in the range 1.25–4.92 μM and 1.95–7.60 μM, respectively (c.f. erlotinib (IC50 7.52–16.02 μM) and inhibited EGFR with IC50 0.80 and 0.66 μM, sequentially. Additionally, these two compounds effectively induced cell cycle arrest and triggered apoptosis in HL-60 cancer cells by regulating the pro-apoptotic protein BAX and anti-apoptotic protein Bcl-2 expression. The docking studies revealed that there are interactions like that of erlotinib at the EGFR active site. In conclusion, the synthesized quinazoline compounds 4b and 5b effectively inhibit EGFR. Such a finding can be sited as a good starting point for the development of novel antitumor compounds targeting EGFR kinase.

Evaluation of Saudi Juniperus procera Extracts Cytotoxicity and Regulatory Mechanisms of Tumorigenesis Against Two Breast Cancer Cell Lines

Background Breast cancer poses a major threat to female health worldwide. One of the medicinal plants used in traditional Saudi medicine is the Juniperus procera (Arar) plant, which is used to cure various illnesses, including cancer. Objectives The cytotoxic properties of Saudi J. procera extracts and their regulatory mechanisms against tumorigenesis in breast cancer were investigated. Methods The antioxidant capacities of the fruit and leaf extracts were detected by the 2,2′-azino-bis 3-ethylbenzothiazoline-6-sulfonic acid (ABTS) assay and 2,2-diphenyl-1-1picrylhydrazyl (DPPH) assay. The cell viability of the extracts was determined by 3-(4,5-dimethylthiazoyl)-2,5-diphenyl-tetrazolium bromide assay. The cell migration was detected by a wound healing assay. The cell cycle and cell apoptosis were analyzed by flow cytometry. The reactive oxygen species (ROS) was evaluated using a DCFDA-cellular (the cell permeant reagent 2',7' –dichlorofluorescein diacetate) reactive oxygen species detection assay. The protein and gene expression levels were estimated by western blotting and Reverse transcription polymerase chain reaction (RT-PCR), respectively. Results Phytochemical analysis revealed a high content of phenolic and flavonoids in fruit and leaf extracts. Relative to leaf extract, the fruit extract showed higher antioxidant activities and exhibited more potent cytotoxic effects against two breast cancer cell lines: MCF-7 and MDA-MB-231. The fruit extract arrested the cell cycle of the tested cancer cell lines in S phase and G1 phase, and downregulated PI3K (phosphoinositide 3-kinase-protein kinase)/Akt (protein kinase B)/mTOR (Mammalian target of rapamycin) pathway. It also suppressed aromatase expression in MCF-7 but upregulated it in MDA-MB-231. Conclusion J procera fruit and leaf extracts have significant antitumor activities against MCF-7 and MDA-MB-231 breast cancer cell lines.

Synthesis, Characterization, in silico DFT, Molecular docking, ADMET Profiling Studies and Toxicity Predictions of Ag(I) Complex Derived from 4‐Aminoacetophenone

AbstractThe reaction of the synthesized (E)‐1‐(4‐((2,4‐dihydroxy‐6‐methylphenyl)diazenyl)phenyl)ethan‐1‐one, (DMPDE) ligand with Ag(I) ion at room temperature resulted in the formation of the complex; [Ag(DMPDE)(H2O)2]. 1H NMR, 13C NMR, FTIR, UV‐Vis, mass spectra, elemental analyses, thermal analysis (TGA/DTA), and molar conductance measurements were done to elucidate the structure of synthetic compounds. The results revealed an interesting geometrical variation; tetrahedral for Ag(I) complex. FT‐IR spectra demonstrated that the ligand (DMPDE) under investigation behaves as a bidentate ligand (N,O) through the nitrogen atom of the azo group which is the farthest of the acetophenone moiety and oxygen phenolic for benzene moiety and forms a stable five‐membered chelating ring. The electronic structure, molecular electrostatic potential (MEP) and quantum chemical calculations of the newly synthesized compounds are investigated theoretically at the DFT/B3LYP level of theory. Additionally, the ligand (DMPDE) and Ag(I) complex were screened against the growth of pathogenic bacteria [Actinomycosis (G+), E. Escherichia Coli (G−)] and fungi (Penicillium spp.) compared with the reference antibiotics, Chloramphenicol and Nystatin. Furthermore, 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) was used to evaluate the antioxidant activities of the ligand and its complex, which showed they both possess significant antioxidant properties in comparison with L‐ascorbic acid (Vit. C) as standard. Based on docking studies, (DMPDE) and Ag(I) complex demonstrated a greater affinity for (PDB ID: 3T88), which corresponds to Escherichia coli protein (−6.7818 kcal/mol) and (−6.7928 kcal/mol), respectively. Interestingly, the most active Ag(I) complex inside the active site of cervical cancer receptor (PDB ID: 4XR8) demonstrated a higher binding energy (−6.2631 kcal/mol) than free ligand (−5.8561 kcal/mol). In silico, ADMET displayed that compounds obey the Lipinski rule and the “Veber's rule. Consequently, is likely to exhibit oral bioavailability with good LD50 and a safety profile that includes non‐cytotoxicity, non‐immunotoxicity, and non‐skin sensitization. Finally, the compounds synthesized showed significant anticancer activity in human cervical cancer cell lines HeLa and SiHa compared with positive controls (cisplatin) and normal human hepatic cells (WRL‐68). In the present study, all tested cancer cell lines showed promising activity against Ag(I) complex, whose IC50 value ranged from (61.02 to 71.09) μg/mL.

Design, synthesis and bioactivity evaluation of the combination of evodiamine and erlotinib linked by indolequinone

Compared with single-targeted therapy, the design and synthesis of heterozygous molecules is still a significant challenge for the discovery of antitumor drugs. Quinone oxidoreductase-1 (NQO1) is a potential target for selective cancer therapy due to its overexpression in many cancer cells and its unique bioredox properties. Based on the principle of combinatorial drug design, we successfully synthesized a new hybrid molecules 13 with an indolequinone structure. We found that the synthesized compounds exhibited much higher cytotoxicity against the tested cancer cells than free drugs. Further mechanism studies confirmed that compound 13 induced cell apoptosis was achieved by regulating p53-dependent mitochondrial pathway and cell cycle arrest at the G0/G1 phase.

Synergistic Cytotoxicity of Extracts of Chaga Mushroom and Microalgae against Mammalian Cancer Cells In Vitro.

Chaga mushroom (Inonotus obliquus) contains bioactive metabolites and has been used to treat various ailments, including cancer. Similarly, marine microalgae are considered a sustainable food supplement with anticancer and antioxidant properties. This study investigated the cytotoxicity of different extracts prepared from I. obliquus and microalgae using cultured human and canine cancer cell lines (MCF-7, HepG2, HOS, D-17, and DH-82). MTS cell viability assay was used to study the cytotoxicity of I. obliquus and microalgae extracts, and a synergy matrix effect was used to study the combined effect of the extracts. Isobologram analysis and the highest single agent synergy model were applied to study and validate the synergy between the extracts from I. obliquus and microalgae. Ethanol-based extraction and supercritical water extract significantly inhibited the growth of various mammalian cancer cells compared to aqueous extracts. Osteosarcoma cells were more susceptible to the supercritical extracts of I. obliquus and chlorophyll-free and sugar-free ethanol extracts of microalgae. A combination of ethanol-based I. obliquus extract and chlorophyll-free microalgae extract resulted in a synergistic interaction with various tested cancer cells. This study provides experimental evidence supporting the potential therapeutic application of I. obliquus and microalgae extracts with a synergistic effect to inhibit the growth of various mammalian cancer cells. Additional in vivo studies are required to fully explore possible therapeutic applications of these unique mixtures to be used in treating cancers.

Imparting aromaticity to 2-pyridone derivatives by O-alkylation resulted in new competitive and non-competitive PIM-1 kinase inhibitors with caspase-activated apoptosis

New aromatic O-alkyl pyridine derivatives were designed and synthesised as Proviral Integration Moloney (PIM)-1 kinase inhibitors. 4c and 4f showed potent in vitro anticancer activity against NFS-60, HepG-2, PC-3, and Caco-2 cell lines and low toxicity against normal human lung fibroblast Wi-38 cell line. Moreover, 4c and 4f induced apoptosis in the four tested cancer cell lines with high percentage. In addition, 4c and 4f significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, 4c and 4f showed potent PIM-1 kinase inhibitory activity with IC50 = 0.110, 0.095 µM, respectively. Kinetic studies indicated that 4c and 4f were both competitive and non-competitive inhibitors for PIM-1 kinase enzyme. In addition, in silico prediction of physiochemical properties, pharmacokinetic profile, ligand efficiency, ligand lipophilic efficiency, and induced fit docking studies were consistent with the biological and kinetic studies, and predicted that 4c and 4f could act as PIM-1 kinase competitive non-adenosine triphosphate (ATP) mimetics with drug like properties.

Synthesis, antiproliferative activity, 3D‐QSAR, and molecular docking studies of novel L‐carvone‐derived pyrimidine‐urea compounds

AbstractTo explore novel natural product‐based nitrogen‐containing heterocyclic compounds with antiproliferative activity, 20 L‐carvone‐derived pyrimidine‐urea compounds 4a–4t were synthesized through the multi‐step reaction of L‐carvone, and structurally characterized by Fourier transform infrared (FT‐IR), hydrogen‐1 nuclear magnetic resonance (1H‐NMR), Carbon‐13 nuclear magnetic resonance (13C‐NMR), and High‐resolution mass spectrometry (HRMS). Besides, the in vitro antiproliferative activity of the target compounds against HepG2, Hela, and MCF‐7 cells was evaluated by methyl thiazolyl tetrazolium (MTT) assay. According to the results, the target compounds showed certain inhibitory activities against the tested cancer cell lines, and five compounds (4b, 4h, 4k, 4l, and 4t) exhibited better inhibition activities against Hela cells than the positive control (5‐FU). Among them, compound 4b held significant antiproliferative activities against Hela and HepG2 cells, and thus deserved further study as a leading compound of new anticancer drugs. In addition, an effective and reasonable three‐dimensional quantitative structure‐activity relationships (3D‐QSAR) model was built by the Comparative molecular field analysis (CoMFA) method to analyze the relationship between the structures of the target compounds and their antiproliferative activities (expressed as pIC50) against Hela cells, and proven to have good predictive ability. Molecular docking was carried out to study the possible binding modes of compound 4b and Survivin, and it was found that compound 4b could be well embedded into the active site, along with the formation of several hydrogen bonds and hydrophobic interactions.

Repurposing the antihistamine drug bilastine as an anti-cancer metallic drug entity: synthesis and single-crystal X-ray structure analysis of metal-based bilastine and phen [Co(II), Cu(II) and Zn(II)] tailored anticancer chemotherapeutic agents against resistant cancer cells.

Bilastine (BLA), 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazole-2-yl)-piperidin-1-yl)-ethyl)-phenyl)-2-methylpropanoic acid, is an active antihistamine drug. With the idea of repurposing drugs from the existing pool of 'active' pharmaceutical ingredients, the therapeutic potency of bilastine as an anticancer agent was investigated via the tailored synthesis of a metal-based anticancer drug formulation of the type [BLA(phen)2M(II)]+·X-, where M = Co, Cu, and Zn and X- = NO3 and ClO4. The synthesized metal-based chemotherapeutics derived from the bilastine drug that acts as a ligand were thoroughly characterized using spectroscopic techniques, namely, UV-vis, FT-IR, and EPR (in the case of 1 and 2); 1H-NMR and 13C-NMR (in the case of 3); ESI-MS and single-crystal X-ray diffraction studies. Comprehensive biological studies (DNA binding, cleavage, and cytotoxic activity) using various biophysical and gel electrophoretic methods were carried out to validate their potential as anticancer agents. The cytotoxic activity of 'therapeutically promising' copper(II)-based drug candidate 2 was evaluated against MCF-7, MBA-MD-231, HeLa, HepG2, and Mia-PaCa-2 cancer cells via an SRB assay, and the results demonstrated 2 as a potent anticancer agent at low nanomolar concentrations against all tested cancer cells, preferably with a much superior anticancer efficacy against human pancreatic cancer cells.

Synthesis, molecular docking analysis and in vitro evaluation of new heterocyclic hybrids of 4-aza-podophyllotoxin as potent cytotoxic agents.

Two different synthetic approaches to novel heterocyclic hybrid compounds of 4-azapodophyllotoxin were investigated. The obtained products were characterized by infrared spectroscopy, nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. MTT protocol was then performed to examine the cytotoxic activity of these products against KB, HepG2, A549, MCF7, and Hek-293 cell lines. The cytotoxic assessment indicated that all products displayed moderate to high cytotoxicity against all tested cancer cell lines. The most active compound 13k containing the 2-methoxypyridin-4-yl group exhibited selective cytotoxicity against KB, A549, and HepG2 cell lines with the IC50 values ranging from 0.23 to 0.27 μM, which were between 5- to 10-fold more potent than the positive control ellipticine. Compounds 13a (HetAr = thiophen-3-yl) and 13d (HetAr = 5-bromofuran-2-yl) displayed high cytotoxic selectivity for A549 and HepG2 cancer cell lines when compared to the other cancer cell lines and low toxicity to the normal Hek-293 cell line. Molecular docking study was conducted to evaluate the interaction of new synthesized compounds with the colchicine-binding-site of tubulin. Besides that, physicochemical and pharmacokinetic properties of the most active compounds 13h,k were predicted.

Cu(II) complexes with a salicylaldehyde derivative and α-diimines as co-ligands: synthesis, characterization, biological activity. Experimental and theoretical approach.

Copper(II) complexes with an α-diimine show a wide variety of biological activities, such as antibacterial, antifungal, antioxidant and anticancer. In this work, we synthesized and structurally characterized two novel Cu(II) complexes with methyl 3-formyl-4-hydroxybenzoate (HL) and α-diimines: 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen). Crystal structure analysis shows that the formulas of the compounds are [Cu(bipy)(L)(BF4)] (1) and [Cu(phen)(L)(H2O)](BF4)·H2O (2), with BF4- as a ligand in complex1, which is rarely coordinated to metals. Both complexes have a square pyramidal geometry, while DFT calculations showed that the most stable structures of complexes 1 and 2 in a water/DMSO mixture are square-planar derivatives [Cu(bipy)(L)]+ and [Cu(phen)(L)]+. The antibacterial activity of compounds was evaluated in vitro on four Gram-negative and four Gram-positive bacterial strains. Complex 2 showed greater antibacterial activity towards all bacterial strains comparable to the control compound Amikacin. Complex 2 exerted a strong cytotoxic effect against the tested cancer cell lines (IC50 values ranging from 0.32 to 0.44 μM). Both complexes caused apoptotic cell death in HeLa cells and a noticeable in vitro antiangiogenic effect. In the concentration range of 5 to 100 μM, the complexes showed the absence of a genotoxic effect and displayed a protective effect against oxidative DNA damage induced by H2O2 in human peripheral blood cells. The interaction between the compounds and calf-thymus DNA was evaluated by diverse techniques suggesting a tight binding, which was also confirmed by molecular docking. In addition, it was found that the complexes bind tightly and reversibly to bovine and human serum albumin.

Synthesis and antiproliferative potency of 1,3,4-thiadiazole and 1,3-thiazolidine-4-one based new binary heterocyclic molecules: in vitro cell-based anticancer studies.

Herein, we report the synthesis and anticancer properties of 21 new 1,3,4-thiadiazole-2-yl-imino-thiazolidine-4-one containing binary heterocyclic molecules. Cytotoxicity of the synthesized molecules was evaluated on various in vitro cancer cell lines (MCF-7, PC3, 4T1, MDA-MB-231, and MOC2) and normal human embryonic cell lines (HEK-293) via MTT assay. The cytotoxicity data of developed compounds was compared with the reference anticancer molecule BG45, a selective inhibitor of the HDAC3 enzyme. All compounds showed a significant cytotoxic effect higher than BG45 on tested cancer cell lines. Moreover, the compounds exhibited better selectivity on cancer cells than on normal cells. Among the molecules, compound 6e is the most potent in cytotoxic activity on MCF-7 cell lines (IC50 value of 3.85 μM). Additional mechanistic investigation revealed that compound 6e promotes apoptosis (25.3%) and G0/G1 phase cell cycle arrest of MCF-7 cells. Also, compound 6e induces intracellular ROS accumulation and subsequent nuclear fragmentation. Hence, this research finds new hybrid molecules active against in vitro cancer cells.

Thiophene-based N-phenyl pyrazolines: Synthesis, anticancer activity, molecular docking and ADME study

This investigation aimed to synthesize and evaluate the anticancer potential of thiophene-based N-phenyl pyrazoline derivatives containing methoxy groups using both in vitro and in silico assays. The N-phenyl pyrazolines were synthesized by reacting phenylhydrazine with chalcone derivatives. Using the 3-(4,5-dimethyl thiazole-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) assay, we assessed the anticancer activity of the compounds that were synthesized in vitro against four human cancer cell lines (4T1 and T47D for breast cancer, HeLa for cervical cancer, and WiDr for colorectal cancer), as well as a normal cell line (Vero). The in silico evaluation was carried out through molecular docking and absorption, distribution, metabolism, and excretion (ADME) prediction. Among the synthesized pyrazolines, pyrazoline 2 was revealed as the most active anticancer against 4T1, HeLa, and WiDr cancer cell lines, with IC50 values of 9.09, 9.27, and 0.25 μg/ml, respectively. Furthermore, pyrazoline 2 showed high selectivity with selectivity index values of more than 6 toward all tested cancer cell lines. In silico evaluation via molecular docking against epidermal growth factor receptor revealed that pyrazoline 2 had the lowest binding energy with a value of 8.8 kcal/mol, which was consistent with experimental data. The ADME study using the pkCSM webtool indicated that the N-phenyl pyrazoline derivatives had good pharmacokinetic properties. Therefore, the results of this study suggest that thiophene-based N-phenyl pyrazoline derivatives containing methoxy groups, especially pyrazoline 2, could be potential anticancer agents.

AVPI analogs and conjugates: Molecular docking studies and in vitro biological evaluation

In recent years, small peptide and non-peptide AVPI-/Smac-mimetics have been developed as IAP antagonists and are in clinical trials to overcome resistance to apoptosis in various cancer types. In this study, we present molecular modeling studies and in vitro biological evaluation of a set of AVPI-mimetics, including parent AVPI, tetrapeptide AVPI-mimetics and AVPI-conjugates.Combined molecular modeling studies and HYDE analyses provided valuable information regarding the protein–ligand interactions within the binding site of cIAP1-BIR3 and XIAP-BIR3 domains, showing that the binding part of both domains (cIAP1- and XIAP-BIR3) are formed from 22 amino acid residues, and their active part of 11 AAs. Moreover, 5 amino acids are defined common for both targets, namely Lys299, Gly306, Leu307, Trp310, and Trp323. Based on the observed docking models, six amino acid residues for cIAP1-BIR3 and five amino acids for XIAP-BIR3 are recognized actively involved in the formation of H-bonds with the respective ligand. The amino acid sequence 308 (Arg308 in cIAP1-BIR3, Thr308 in XIAP-BIR3), simultaneously forming two H-hydrogen bonds, seems to plays a key role in improvement of binding affinity.Apart from docking results the synthesized set of AVPI-mimetics was tested in vitro using cell biology (MTT assay) and parallel artificial membrane permeability assay (PAMPA). The results showed that the double modification of AVPI via substitution of Pro3 with Hyp3, as well as elongation of AVPI’s C-terminus by its conjugation with RGD-analogs, significantly increase the antiproliferative effects of AVPI-conjugates on all tested cancer cell lines (MDA-MB-231, MCF-7, HepG2 and HT-29 cells) compared to the parent AVPI peptide. SARs analysis defined this modification beneficial for the overall biological activity of the AVPI-mimetics and pointed out AVHypI-AgbGD as the most active conjugate with an IC50 of 348 µM for MDA-MB-231, 457 µM for MCF-7, 399 µM for HepG2, and 578 µM for HT-29 cells. Though the calculated IC50 values were still high, we consider AVHypI-AgbGD peptide as a good basis for further modifications. In addition, PAMPA results showed that substitution of Pro with Hyp improved the BBB permeability of AVHypI peptide compared to its parent molecule.