Cytotoxic Activity Research Articles

Synthesis, Docking Study of Some Novel Chromeno[4',3'-b]Pyrano [6,5-d]Pyrimidine Derivatives Against COVID-19 Main Protease (Mpro) (6LU7, 6M03).

In this work, some new chromeno[4',3'-b]pyrano[6,5-d]pyrimidines,3-amino and 3-methyl-5-aryl-4-imino-5(H)-chromeno[4',3'-b]pyrano[6,5-d]pyrimidine-6-ones derivatives were synthesized. Chromenopyrimidines have attracted significant attention recently because of their activities, such as antiviral and cytotoxic activity. All synthesized compounds were characterized using IR, 1H-NMR, Mass Spectroscopy, and elemental analysis data. Molecular docking studies were carried out to determine the inhibitory action of studied ligands against the Main Protease (6LU7, 6m03) of coronavirus (COVID-19). Moreover, the Lipinski Rule parameters were calculated for the synthesized compounds. The result of the docking studies showed a significant inhibitory action against the Main protease (Mpro) of SARS-CoV-2, and the binding energy (ΔG) values of the ligands against the protein (6LU7, 6M03) are -7.8 to -9.9 Kcal/mole. It may conclude that some ligands were likely to be considered lead-like against the main protease of SARS-CoV-2.

Murraya koenigii (Curry Tree): A review of its Phytochemistry, Ethnomedicinal uses, and Pharmacology with Respect to Molecular Mechanisms

Abstract: Medicinal plants have significant therapeutic value and are a gift to humanity in pursuing healthy living. The discovery of numerous rejuvenating compounds that can stop or reduce the pathology of many diseases will be a crucial advancement in the coming years. Synthetic compounds can cause health issues and side effects, necessitating the development of molecules derived from plants and other natural resources as viable substitutes for synthetic compounds. Several plant phytochemicals and extracts have been found to have significant effects on traditional medical therapy. Murraya koenigii (M. Koenigii) is a member of the Rutaceae family, well-known in the Ayurvedic system of medicine as a therapeutically important herb of Indian origin. M. Koenigii has been used in several ancient systems of medicine, including Siddha and Unani, as a multi-potential medicinal plant. Previous research has shown that this plant's bark, roots, and leaves are abundant sources of carbazole alkaloids, which have beneficial pharmacological and biological effects. These include antioxidant, antibacterial, antidiabetic, anti-inflammatory, antihypertensive, antifungal, antiprotozoal, hepatoprotective, antihypercholesterolemic, antiulcer, cytotoxic, antidiarrheal, phagocytic, neuroprotective, and antitumor activities. The key components of the M. koenigii plant and their pharmacological activities against various diseases using preclinical models are discussed in this review. Exhaustive studies on the molecular mechanism of action of M. koenigii are needed to validate the effectiveness of curry tree and their constituents as potent therapeutic agents. However, serious efforts are required to identify, isolate and evaluate the chemical components for nutritional and medicinal potentials.

Evaluation of the in vivo acute toxicity and in vitro genotoxicity and mutagenicity of synthetic β-carboline alkaloids with selective cytotoxic activity against ovarian and breast cancer cell lines

The aim of this study was to evaluate the in vitro cytotoxic, genotoxic, and mutagenic potential and to determine the in silico ADME parameters of two synthetic β-carboline alkaloids developed as prototypes of antitumor agents (NQBio-06 and NQBio-21). Additionally, acute toxicity of the compounds was evaluated in mice. The results from the MTT assay showed that NQBio-06 presented higher cytotoxicity in the ovarian cancer cell line TOV-21G (IC50 = 2.5 µM, selectivity index = 23.7). NQBio-21 presented an IC50 of 6.9 µM and a selectivity index of 14.5 against MDA-MB-231 breast cancer cells. Comet assay results showed that NQBio-06 did not induce chromosomal breaks in vitro, but NQBio-21 was genotoxic with and without metabolic activation (S9 fraction). Micronucleus assay showed that both compounds were mutagenic. In addition, metabolic activation enhanced this effect in vitro. The in silico predictions showed that the compounds met the criteria set by Lipinski's rules, had strong prediction for intestinal absorption, and were possible substrates for P-glycoprotein. The in vivo results demonstrated that both the compounds exhibited low acute toxicity. These results suggest that the mechanisms underlying the cytotoxicity of NQBio-06 and NQBio-21 are related to DNA damage induction and that the use of S9 enhanced these effects. In vivo analysis showed signs of toxicity after a single administration of the compounds in mice. These findings highlight the potential of β-carboline compounds as sources for the development of new anticancer chemotherapeutic agents.

Albusamides A–G: Hydroxylated Fatty Amine Derivatives from the Deep-Sea-Derived Actinomycete Streptomyces albus 228DD-066 and Their Cytotoxic Activity

Albusamides A–G: Hydroxylated Fatty Amine Derivatives from the Deep-Sea-Derived Actinomycete <i>Streptomyces albus</i> 228DD-066 and Their Cytotoxic Activity

Cytotoxic and ROS generation activity of anthraquinones chelate complexes with metal ions

Cytotoxic and ROS generation activity of anthraquinones chelate complexes with metal ions

Novel thiazole-based cyanoacrylamide derivatives: DNA cleavage, DNA/BSA binding properties and their anticancer behaviour against colon and breast cancer cells

A novel series of 2-cyano-3-(pyrazol-4-yl)-N-(thiazol-2-yl)acrylamide derivatives (3a–f) were synthesized using Knoevenagel condensation and characterized using various spectral tools. The weak nuclease activity of compounds (3a–f) against pBR322 plasmid DNA was greatly enhanced by irradiation at 365 nm. Compounds 3b and 3c, incorporating thienyl and pyridyl moieties, respectively, exhibited the utmost nuclease activity in degrading pBR322 plasmid DNA through singlet oxygen and superoxide free radicals’ species. Furthermore, compounds 3b and 3c affinities towards calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) were investigated using UV–Vis and fluorescence spectroscopic analysis. They revealed good binding characteristics towards CT-DNA with Kb values of 6.68 × 104 M−1 and 1.19 × 104 M−1 for 3b and 3c, respectively. In addition, compounds 3b and 3c ability to release free radicals on radiation were targeted to be used as cytotoxic compounds in vitro for colon (HCT116) and breast cancer (MDA-MB-231) cells. A significant reduction in the cell viability on illumination at 365 nm was observed, with IC50 values of 23 and 25 µM against HCT116 cells, and 30 and 9 µM against MDA-MB-231 cells for compounds 3b and 3c, respectively. In conclusion, compounds 3b and 3c exhibited remarkable DNA cleavage and cytotoxic activity on illumination at 365 nm which might be associated with free radicals’ production in addition to having a good affinity for interacting with CT-DNA and BSA.Graphical

Seven New Noroleanane Triterpenoids from Mastic and their NO Inhibitory and Cytotoxic Activities.

Mastic is a natural resin produced by Pistacia lentiscus L. (Anacardiaceae) with high medicinal value and have been traditionally used as Uighur imported medicine for centuries. In this study, 16 triterpenoids including seven new norleananetriterpenoids (1-7), along with nine known oleanane triterpenoids (8-16), were isolated from the mastic. Their chemical structures were determined on the basis of extensive spectroscopic analyses (including IR, UV, ESI-HR-MS and NMR spectroscopy) and single-crystal X-ray diffraction. Compounds 4-7, 11, 14 and 16 showed strong inhibitory NO productionin LPS-induced RAW264.7 cells with IC50 values 7.44-9.76 μM, respectively (positive control dexamethasone, 9.93 ± 1.17 μM). Furthermore,compounds 3 and 12 significantly inhibited the growth of SW480 cells, compound 3 showed the most pronounced inhibitory effect with an IC50 of 2.30 ± 0.38 μM.

New Flavan Derivatives from the Leaves and Stems of Cassia nodosa.

Three new flavan derivatives including two methylene-linked flavan-3-ol dimers, bis(8-epiafzelechinyl)methane (1), and 8,8-(epiafzelechin-afzelechin)methane (2), a flavan-3-ol monomer, (-)-3-O-acetyl-epiafzelechin (3) and four known related compounds (4-7) were isolated from the leaves and stems of Cassia nodosa. Their structures were elucidated by extensive spectroscopic analyses and CD data. The isolates were evaluated for their antioxidant, α-glucosidase inhibitory, cytotoxic and neuroinflammatory activities, and compound 3 exhibited remarkable radical scavenging activities in both the DPPH and ABTS models with IC50 values of 2.65±1.25, and 4.78±0.91 μg/mL, respectively.

P‐Terphenyl and Orsellinic Acid Derivatives from the European Polyporales Terana coerulea and Sparassis brevipes

Investigation of the secondary metabolites of the solid‐state rice cultures from the European basidiomycetes Terana coerulea and Sparassis brevipes afforded three previously undescribed secondary metabolites identified as two p‐terphenyl derivatives (1 and 2) and one orsellinic acid congener (3) in addition to another known, isoeverninic acid (4). Chemical structures of the isolated compounds were elucidated through comprehensive 1D and 2D NMR spectroscopic analyses, coupled with HR‐MS and other spectral methods. The isolated compounds were assessed for their cytotoxic and antimicrobial activities. Compound 1 revealed weak antimicrobial properties, whereas the inseparable mixture of 3 and 4 featured moderate cytotoxic and antimicrobial effects.

Synthesis, Characterization, and Biological Evaluation of N-Methyl Derivatives of Norbelladine

Norbelladine derivatives have garnered attention in recent years due to their diverse biological activities and pivotal role in the biosynthetic pathway of Amaryllidaceae alkaloids. This study reports the synthesis and biological evaluation of four O,N-methylated derivatives of norbelladine. These derivatives were synthesized through a three-step process: forming imine intermediates from benzaldehydes with tyramine, hydrogenating them to secondary amines, and N-methylating these amines. The products were purified and characterized by 1H and 13C NMR spectroscopy. Their biological activities were assessed by evaluating their ability to inhibit Alzheimer’s disease-related enzymes acetylcholinesterase and butyrylcholinesterase. Additionally, the cytotoxic activity of the novel derivatives was tested against cancer cell lines derived from hepatocarcinoma (Huh7), adenocarcinoma (HCT-8), and acute myeloid leukemia (THP-1) cells, and their antiviral properties against a human coronavirus (HCoV-OC43), a flavivirus (dengue virus), and a lentivirus (pseudotyped HIV-1). Docking analysis was performed to understand the impact of the N-methylation on their pharmacological relevance. The results indicate that while N-methylation does not significantly affect antiviral activity, it enhances butyrylcholinesterase inhibition for N-methylnorbelladine and 4′-O,N-dimethylnorbelladine. Overall, this work enhances our understanding of norbelladine derivatives, provides new tools for Alzheimer’s disease research, and lays the groundwork for future pharmaceutical developments.

Design, Synthesis and Evaluation of Photophysical and Biological Properties of Tetrafluoroacridine

Abstract1,4,5,8‐Tetrafluoroacridine was successfully synthesized from 1,4,5,8‐tetrafluoroacridone through transfer hydrogenation using an in‐house ruthenium pincer catalyst followed by in situ dehydration. The synthetic protocol involves the copper‐catalyzed coupling of 2‐amino‐3,6‐difluorobenzoic acid 1 and 1,4‐difluoro‐2‐iodobenzene 2 to obtain 3 followed by cyclization using polyphosphoric acid to get the 1,4,5,8‐tetrafluoroacridone 4. Common synthetic strategies for converting 4 to the 1,4,5,8‐tetrafluoroacridine 5 were unsuccessful and the transfer hydrogenation approach proved to be most fruitful. 1,4,5,8‐Tetrafluoroacridone 4 can be N‐methylated to give 9. The investigation into the photophysical properties of 4, 5, and 9 revealed that the average photoluminescence (PL) lifetime of the acridine derivatives was longer in the aqueous medium than in ethanol and methanol, indicating the influence of the solvent environment on the excited‐state dynamics. To assess their potential therapeutic applications, the cytotoxic activity of these compounds was evaluated against AGS and IMR‐32 cells, and compound 9 showed significant activity. The addition of methyl group to the acridone was found helpful in enhancing the solubility and biological activity.

Semicarbazone, thiosemicarbazone tailed isoxazoline-pyrazole: synthesis, DFT, biological and computational assessment.

Aim: A series of semicarbazone and thiosemicarbazone-tailed hybrids comprising pyrazole and acetylisoxazoline were prepared from (R)-carvone and characterized by technique spectroscopies Nuclear Magnetic Resonance (NMR), IR and High-Resolution Mass Spectrometry. Density Functional Theory (DFT)determined the structural parameters. Their cytotoxic activity was evaluated in vitro against four human cancer cell lines.Methods & results: All the studied semi and thiosemicarbazone demonstrate a promising potential as anticancer agents. The mechanism of action of these compounds involves apoptosis in HT-1080 cells, supported by an increase in the level of caspase-3/7 activity, which also arrests the cell cycle in the G0/G1 phase. Molecular docking studies were performed to establish the potential of the most active compounds 4a and 5a. ADMET analysis showed appropriate pharmacokinetic properties, allowing structure prediction for anticancer activity.

Preparation and characterization of polyethylene glycol/sodium alginate aerogel beads loaded with biogenic zinc oxide nanoparticles: potential therapeutic option for treating multidrug-resistant bacteria and cytotoxic activity

Preparation and characterization of polyethylene glycol/sodium alginate aerogel beads loaded with biogenic zinc oxide nanoparticles: potential therapeutic option for treating multidrug-resistant bacteria and cytotoxic activity

Preclinical Evaluation of STI-8811, a Novel Antibody Drug Conjugate Targeting BCMA for the Treatment of Multiple Myeloma.

Treatment for patients with Multiple Myeloma (MM) has experienced rapid development and improvement in recent years, however, patients continue to experience relapse and MM remains largely incurable. B cell maturation antigen (BCMA) has been widely recognized as a promising target for treatment of MM due to its exclusive expression in B cell linage cells and its critical role in the growth and survival of malignant plasma cells. Here, we introduce STI-8811, a BCMA-targeting antibody drug conjugate linked to an auristatin-derived duostatin payload via an enzymatically cleavable peptide linker, using our proprietary C-lock technology. STI-8811 exhibits target specific binding activity and rapid internalization, leading to G2/M cell cycle arrest, caspase 3/7 activation and apoptosis in BCMA-expressing tumor cells in vitro. Soluble BCMA (sBCMA) is shed by MM cells into the blood and increases with disease progression, competing for ADC binding and reducing its efficacy. We report enhanced cytotoxic activity in the presence of high levels of sBCMA compared to a belantamab mafodotin biosimilar (J6M0-mcMMAF). STI-8811 demonstrated greater in vivo activity than J6M0-mcMMAF in solid and disseminated multiple myeloma models, including tumor models with low BCMA expression and/or in large solid tumors representing soft tissue plasmacytomas. In Cynomolgus monkeys, STI-8811 was well tolerated, with toxicities consistent with other BCMA targeting ADCs with auristatin payloads in clinical studies. STI-8811 has the potential to outperform current clinical candidates with lower toxicity and higher activity under conditions found in patients with advanced disease.

Cytotoxic activity of callus extract from Vachellia farnesiana (L) Wight &amp; Arn.

Cytotoxic activity of callus extract from Vachellia farnesiana (L) Wight &amp; Arn.

Anti-Tumor Immunity to Patient-Derived Breast Cancer Cells by Vaccination with Interferon-Alpha-Conditioned Dendritic Cells (IFN-DC)

Background: Breast cancer represents one of the leading causes of death among women. Surgery can be effective, but once breast cancer has metastasized, it becomes extremely difficult to treat. Conventional therapies are associated with substantial toxicity and poor efficacy due to tumor heterogeneity, treatment resistance and disease relapse. Moreover, immune checkpoint blockade appears to offer limited benefit in breast cancer. The poor tumor immunogenicity and the immunosuppressive tumor microenvironment result in scarce T-cell infiltration, leading to a low response rate. Thus, there is considerable interest in the development of improved active immunotherapies capable of sensitizing a patient’s immune system against tumor cells. Methods: We evaluated the in vitro anti-tumor activity of a personalized vaccine based on dendritic cells generated in the presence of interferon (IFN)-α and granulocyte-macrophage colony-stimulating factor (IFN-DC) and loaded with an oxidized lysate from autologous tumor cells expanded as 3D organoid culture maintaining faithful tumor antigenic profiles. Results: Our findings demonstrate that stimulation of breast cancer patients’ lymphocytes with autologous IFN-DC led to efficient Th1-biased response and the generation in vitro of potent cytotoxic activity toward the patients’ own tumor cells. Conclusions: This approach can be potentially applied in association with checkpoint blockade and chemotherapy in the design of new combinatorial therapies for breast cancer.

Copper(I) Complexes With Phenanthroline‐Functionalized NHC Ligands Achieve Effective Anticancer Activity via Mitochondrial and Endoplasmic Reticulum Stress

ABSTRACTCopper complexes exhibit promising anticancer properties, which can be further promoted by suitable ligands. In this study, we synthesized and investigated the anticancer effects of three copper(I) complexes with N‐heterocyclic carbene (NHC) ligands derived from phenanthroline‐functionalized imidazole salts. The synthesis of these NHC‐copper(I) complexes (Cu1‐Cu3) was meticulously characterized using NMR and elemental analysis; their crystal structures were further delineated by X‐ray diffraction. Our findings illustrate the unique geometric configurations of these complexes: Cu1 features a dinuclear arrangement with off‐linear geometry; Cu2 and Cu3 are characterized by a bi‐copper core stabilized by two phenanthroline‐modified carbene ligands. Crucially, in vitro cytotoxic evaluations revealed that these complexes possess suitability anticancer activity. Among them, Cu2 exhibited enhanced cytotoxicity activity, achieving a half‐maximal inhibitory concentration (IC50) of 4.36 ± 0.25 μM in colon cancer cell line HCT‐116, markedly surpassing the efficacy of cisplatin. Subsequent investigations elucidated that Cu2 notably increases intracellular reactive oxygen species (ROS) levels and induces mitochondrial membrane depolarization and endoplasmic reticulum stress, leading to oxidative stress‐mediated apoptosis of colon cancer cells.

Synthesis and evaluation of in vitro antioxidant, anticancer, and antibacterial properties of new benzylideneiminophenylthiazole analogues

A series of new benzylideneiminophenylthiazole analogues were designed and synthesized. Common spectroscopic methods, such as FT-IR, 1H-, 13C-NMR, and MASS spectra, and elemental analysis, were used to confirm the molecular structures. Then, the antioxidant, cytotoxicity, and anti-bacterial effects of synthesized analogues were assessed against 2,2-diphenyl-1-picrylhydrazyl (DPPH), three cancer cell lines, and two bacterial strains, respectively. Among the analogues, 7f was detected as the most potent compound for antioxidant activity. Moreover, the compounds 7b, 7f, and 7 g exhibited the maximum cytotoxicity activity against MCF-7, HepG-2, and A549 cell lines, respectively. Finally, 7e showed the highest anti-bacterial activity against both S. aureus and E. coli strains. It was concluded from the antioxidant, cytotoxicity, and anti-bacterial effects that the benzylideneiminophenylthiazoles might serve as candidate molecules for the development of small molecules with medicinal potential.

Design, Synthesis and In-Vitro Antimicrobial and Cytotoxic Activity Screening of 5-Carboxamide Substituted 3, 4-Dihydropyrimidine-2 (1H) Ones

This paper describes the synthesis and in vitro biological evaluation of new compounds designated as 5(a-h) and 8(a-f). These compounds were synthesized by the reaction of thiazole derivative (3) or thiadiazole derivative (7) with urea and various aromatic aldehydes 4(a-h) in ethanol. The structures of the synthesized compounds were checked by IR,1H,13C NMR, and Mass spectroscopy. The antibacterial and antifungal activities of the compounds were evaluated against Escherichia coli (Gram-negative), Staphylococcus aureus (Gram-positive), and Candida albicans (fungus) using agar well diffusion, minimum inhibitory concentration (MIC), and minimum bactericidal/fungicidal concentration methods. The cytotoxic activities of these compounds against HT-29 and A-549 cancer cell lines were assessed in vitro by the MTT method. Our studies showed compounds 8c and 8f to have the most expressed antibacterial activity against S. aureus, while compounds 8c and 8d were the most potent against E. coli. Compounds 5h and 8e showed the highest antifungal activity against C. albicans, and compound 5f showed the most potent activity against the tested cancer cell lines.

Discovery of Structural Diversity Guided N‐S Heterocyclic Derivatives Based on Natural Benzothiazole Alkaloids as Potential Cytotoxic Agents

ABSTRACTBenzothiazole alkaloids are a class of rare heterocyclic alkaloids with unique structures and exhibit a wide range of biological activities. So, the aim of this work is to investigate structural diversity‐guided N‐S heterocyclic derivatives based on natural benzothiazole alkaloids as potential cytotoxic agents. Three series of novel benzothiazole derivatives, including 22 compounds, were designed and synthesized using pharmacophore hybridization, and their in vitro cytotoxic activities against Huh‐7 and A875 were fully evaluated. The results indicated that some of these benzothiazole derivatives had significantly good cytotoxic activities against two tested cell lines compared with the positive control 5‐fluorouracil, and other compounds 3f–3i displayed good selectivity between A875 and Huh‐7 cell lines, which might be used as promising lead molecule for discovery of novel benzothiazole‐type cytotoxic agents.