HepG2 Cancer Cell Lines Research Articles

Synthesis and Antimicrobial Activity of 3-Alkylidene-2-Indolone Derivatives

The escalating threat of antibiotic-resistant bacteria and fungi underscores an urgent need for new antimicrobial agents. This study aimed to synthesize and evaluate the antimicrobial activities of two series of 3-alkylidene-2-indolone derivatives. We synthesized 32 target compounds, among which 25 exhibited moderate to high antibacterial or antifungal activities. Notably, compounds 10f, 10g, and 10h demonstrated the highest antibacterial activity with a minimum inhibitory concentration (MIC) of 0.5 μg/mL, matching the activity of the positive control gatifloxacin against three Gram-positive bacterial strains: Staphylococcus aureus ATCC 6538, 4220, and Methicillin-resistant Staphylococcus aureus ATCC 43300. Moreover, the three most active compounds 10f, 10g, and 10h were evaluated for their in vitro cytotoxicity in the HepG2 cancer cell line and L-02; only compound 10h was found to exert some level of cytotoxicity. These findings suggest that the synthesized 3-alkylidene-2-indolone derivatives hold potential for further development as antibacterial agents.

A new tumor-treating device OM-100 with low-frequency magnetic fields inhibits proliferation and metastasis in liver cancer.

This study aims to investigate a novel instrument OM-100 with low-frequency magnetic fields (LFMFs) for its potential applicability in the treatment of liver cancer. Liver cancer cell lines (HepG2 and Huh7) and normal liver cell line THLE-2 were exposed to OM-100 at LFMFs of 0, 10, 25, 50, and 100kHz for 2h in the morning, noon, and evening, respectively. The effects of LFMF on cell viability, apoptosis, migration, and invasion capabilities were examined. Additionally, impacts of LFMF on ROS production was assessed. In vivo studies were conducted to examine the safety profile of OM-100 and its effects on tumor growth. In vitro, OM-100 reduced the viability of liver cancer cells, increased cell apoptosis, and inhibited cell migration and invasion abilities in a frequency-dependent manner (P < 0.05). In vivo, OM-100significantly slowed down tumor growth and promoted apoptosis in liver tumors (P < 0.05). Moreover, OM-100 rarely affected the viability of normal liver cells, as well as the health of normal mice. Finally, we further found that OM-100 significantly increased the production of ROS in liver cancer cells (P < 0.05), a key factor in inducing autophagy, which is very important for the progression of liver cancer. Our findings reveal the safety of OM-100 and its frequency at 100kHz significantly inhibits liver cancer progression.

Phytochemical Composition and Characterization of In Vitro Bioactivities from Pinus Using Green Process

Pinus species are notable in Mediterranean regions due to their ecological and economic importance. Various parts of these species are widely used in traditional medicine, especially pinecones, which are a significant source of bioactive compounds. The current study aimed to evaluate the phytochemical composition and biological properties of the aqueous extracts obtained by maceration from three Pinus petal fractions, from P. halepensis Mill., P. brutia Ten., and P. pinea L. (APW, BPW, and PPW respectively), and the core fractions of the same species (ACW, BCW, and PCW respectively). The results showed that APW demonstrated superior performance compared to other species and fractions (p ≤ 0.05), with the highest total polyphenol content (203.51 mg GAE/g DW) and the highest antioxidant potential (IC50 = 13.51 µg/mL) against DPPH free radical. All extracts showed high anticancer activity against HeLa and HepG2 cancer cell lines, and low inhibition against HEK-293, a normal cell line (&lt;15%), indicating that none of extracts have any toxicity effect. Furthermore, only APW exhibits a significant inhibition against α-glucosidase with 77.20% at 50 µg/mL. HPLC-DAD analysis was conducted to identify 14 compounds. GC-MS analysis was conducted to identify 28 compounds, of which 11 were detected for the first time in this species. This study offers valuable insights into phytochemistry and potential therapeutic applications of pinecones.

Rare Sesterterpenoids from the Soil Derived Fungus, Aspergillus variecolor Strain SDG, Therapeutic Potential of Stellatic Acid and Docking Studies.

Ethyl acetate extract of the cultures of the soil-derived filamentous fungus, Aspergillus variecolor SDG strain from Nallamala forest resulted in the isolation of extremely rare sesterterpenoids, stellatic acid (1) and andilesin C (2). We report a thorough chemical characterization of these compounds using various spectroscopic techniques and evaluation of their in vitro preclinical therapeutic potential. Stellatic acid exhibits potent antioxidant activity with an IC50 of 38 µg/mL and significant anticancer activity against HeLa, HepG2, MCF7, and A549 cancer cell lines with an IC50 of 7-12 µM. On the other hand, andilesin C displayed moderate cytotoxicity against DU145 and B16F10 cancer cell lines but lacked antioxidant activity. Furthermore, the potential hypoglycemic property of stellatic acid was evaluated by measuring its inhibitory effect against α-glucosidase. It exhibited tenfold potency against yeast α-glucosidase (IC50 101.73 µg/mL) than mammalian α-glucosidase (IC50 1000.00 µg/mL). Docking studies were also performed to suggest the interaction mode of stellatic acid in the α-glucosidase enzyme active site. Notably, yeast α-glucosidase shows a higher affinity towards stellatic acid than mammalian α-glucosidase (3TOP). Thus, the in vitro preclinical study of stellatic acid suggests its potential efficacy in therapeutic drug development.

Effective Synthesis of C20-Epi-Isothiocyanato-Salinomycin and its Thiourea Derivatives as Potential Anticancer Agents.

Salinomycin, a naturally occurring polyether ionophore antibiotic isolated from Streptomyces albus, has been demonstrated potent cytotoxic activity against a variety of cancer cell lines. In particular, it exhibits selective targeting of cancer stem cells. However, systemic toxicity, drug resistance and low bioavailability of the drug significantly limit its potential applications. In this study, the C20-epi-isothiocyanate of salinomycin was designed and synthesized, and then reacted with amines as a versatile synthon to assemble a series of salinomycin thiourea derivatives, which improved the druggability of salinomycin. The antiproliferative activities of the compounds were evaluated in vitro against A549, HepG2, HeLa, 4T1, and MCF-7 cancer cell lines using the CCK-8 assay. The pharmacological results showed that some salinomycin thiourea derivatives exhibited excellent inhibitory activity against at least one of the tested tumor cells and high selectivity. Further mechanistic studies showed that compound 9 f, containing a 3,5-difluorobenzyl moiety, could directly induce apoptosis, probably by increasing caspase-9 protein expression and cell cycle arrest in G1 phase in a concentration dependent manner.

Essential Oils from the Leaves and Stem Barks of Pluchea Indica (L.) Less.: Chemical Analysis, Cytotoxicity, Anti-inflammation, Antimicrobial Activity, Molecular Docking, and ADMET Profiling.

Pluchea indica (L.) Less. is a medicinal plant native to Asia. Traditionally, it is known for numerous traditional uses, such as treatments for fever, cough, and digestive issues. The present investigation aims to determine the chemical compositions of essential oils from its fresh leaves and stem barks. By using hydro-distillation and the GC-FID/MS (gas chromatography-flame ionization detection/mass spectrometry) analysis, the studied samples were dominated by sesquiterpene hydrocarbons (76.8-82.2 %) and their oxygenated derivatives (8.4-19.0 %). β-Selinene (42.0-43.5 %) and silphinene (21.1-22.9 %) were the main compounds. Significantly, the stem bark essential oil strongly monitored the growth of four cancer cell lines K562, HeLa, HepG2, and MCF-7 with IC50 values of 2.89-7.34 μg/mL. Both studied samples showed strong anti-inflammatory activity against NO (nitric oxide) production with IC50 values of 21.81-23.18 μg/mL. The studied sample also exhibited antimicrobial activity at different levels. The molecular docking study revealed that β-selinene exhibited the strongest binding affinity for all four cancer-related protein targets: epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), Abelson tyrosine-protein kinase 1 (ABL1), and phosphatidylinositol 3-kinase (PI3 K-α). The ADMET profiles of the major compounds were also predicted to provide insights for further research considerations.

Phytochemical composition, in vitro cytotoxicity, and in silico docking properties of Tamarix tetragyna L.

Tamarix tetragyna is a plant grows in Mediterranean area and some Arab countries. It possesses numerous medicinal values. Purpose of our study is to explore biological activity of tamarix tetragyna extracts of both leaves and stem with investigating their phytochemical composition. The investigated extracts’ phyto-constituent composition was determined using gas chromatographic-mass spectrometric method. In addition, in vitro cytoxicity activity versus cancer cell lines such MCF-7, HepG-2, HCT-116, and A-549 was examined by MTT assay method, together with exploring its apoptosis effect by flow cytometry and western blot analysis techniques. Moreover, some phytochemical compounds were identified, and in-silico evaluated against anticancer molecular targets. Plant extracts showed good cytotoxic activity against both A-549 and HCT-116 cancer cell lines. With an IC50 value of 23.90 µg/ml that led to apoptosis and G2/M-phase arrest in A-549 cells, cytotoxicity data demonstrate leaves’ extract effectiveness against these cells. Upon GC-MS analysis, it revealed presence of some bioactive components such as Stigmast-5-en-3-ol and 2-methoxy-4-vinyl phenol, which are known for their cytotoxic activity. Our findings suggest that methanolic extracts of Tamarix tetragyna parts may have potential therapeutic uses as anticancer against A-549 cells, which opens up further avenues for investigation into its industrial applications.

Chemical Composition, Anti-microbial, and Cytotoxic Activities of Essential Oil from Magnolia bidoupensis Q. N. Vu leaves, an Endemic Species to the Central Highlands of Vietnam.

An analysis was conducted on the essential oil extracted from the leaves of Magnolia bidoupensis utilizing GC-MS, revealing thirty-three constituents that account for 98.9% of the essential oil. The main components included pogostol (22.4%), δ-selinene (16.2%), and α-amorphene (14.7%). Bioassays were then performed to evaluate the oil's biological activity. The essential oil exhibited antimicrobial activity against all tested microorganisms (six bacterial strains and one fungal strain) using the minimum inhibitory concentration (MIC) method. Additional cytotoxicity tests were conducted on KB, HepG2, MCF-7, and A549 cancer cell lines using the MTT method. The essential oil exhibited strong cytotoxic effects on all four cell lines, with IC50 values ranging from 1.37 ± 0.05 μg/mL (KB) to 2.40 ± 0.06 μg/mL (A549).

Metabolic fate of the natural anticancer agent cucurbitacin B: an LC-MS/MS-enabled profiling of its major phase I and II conjugates in vivo.

Cucurbitacin B (CuB) is a natural triterpenoid with diverse pharmacological effects including potent anticancer activity. However, its oral bioavailability is hampered by limited metabolism in vivo. We characterized CuB's in vivo metabolism in rats to uncover bioactive metabolites retaining therapeutic potential, using a robust UHPLC-Q-TOF-MS/MS workflow. This workflow combined molecular networking, fragmentation filtering, and mass defect filtering to identify CuB metabolites in rat urine, plasma, and feces following oral administration. Thirteen metabolites were identified and seven were confirmed. Major phase I transformations involved hydrolysis, reduction, epoxidation, and amination. Phase II conjugation included cysteine, glutathione, glucuronide, and gluconic acid conjugates. Notably, one of the main metabolites formed was the cysteine conjugate CuB-Cys. CuB-Cys maintained similar in vitro antiproliferative activity to CuB on HepG2, MCF-7, and PANC-1 cancer cell lines. However, it demonstrated lower cytotoxicity towards non-cancerous L02 cells, highlighting improved therapeutic selectivity. Mechanistically, CuB-Cys induced greater apoptotic signaling in HepG2 cells than CuB via enhanced caspase activation and disrupted BAX-Bcl-2 balance. This represents the first systematic characterization of CuB's in vivo metabolic pathway. The identification and confirmation of CuB-Cys provide insight for drug development efforts aiming to maintain therapeutic efficacy while reducing toxicity, via metabolite-based approaches. Our findings shed light on strategies for improving CuB's clinical potential.

Synthesis of Sulfonamide-Based Schiff Bases as Potent Anticancer Agents: Spectral Analyses, Biological Activity, Molecular Docking, ADME, DFT, and Pharmacophore Modelling Studies.

The current study focuses on the synthesis and characterization of six benzenesulfonamide-based Schiff base derivatives (7-12) with various electron-withdrawing and electron-donating substituents (-F, -CI, -Br, -CH3, and -OCH3) and the assessment of their antiproliferative activities against human lung (A549) and liver (HepG2) cancer cell lines using in vitro and in silico approaches. The structures of the synthesized compounds (7-12) were elucidated by elemental analysis and FT-IR, 1D (1H, 13C, APT, and DEPT-135), and 2D (HMQC and HMBC) NMR spectroscopies. The cytotoxic activities of the targeted compounds were determined at various concentrations against these cancer cell lines for 72 h, using the MTT method. The targeted molecules (7-12) demonstrated remarkable antiproliferative activities, with IC50 values ranging from 6.032-9.533 μM against the A549 cell line and 5.244-9.629 μM against the HepG2 cell line. These compounds showed activities at lower or very similar concentrations to cisplatin against the A549 cell line and at much lower concentrations than cisplatin against the HepG2 cell line. Among them, compounds 10 and 12 were found to be more effective against A549 and HepG2 cells, respectively, than cisplatin. These compounds were analyzed by interacting with the 1BNA, 4HJO, and 4ASD crystal structures in molecular docking studies.

Synthesis and Characterization of TiO2 -CQDs Nanocomposites and Testing of Their Anticancer Potential

This work used a green approach to produce carbon quantum dots (CQDs). TiO2 nanoparticles (NPs) and TiO2–CQDs nanocomposites with different weight ratios of CQDs were organized through a facile sol-gel method. XRD showed that the anatase and rutile phases of TiO2 were polycrystalline with a tetragonal structure and that the CQDs exhibited a broad peak at (002) and a hexagonal structure. High resolution-transmission-electron microscopy revealed that the TiO2 NPs agglomerated in mostly spherical shapes and that the anatase and rutile phases of TiO2 had sizes of less than 15 and 25 nm, respectively. The CQDs had a relatively uniform diameter, a spherical shape with a highly crystalline structure, and a size below 2 nm. UV–visible spectroscopy revealed that the absorbance of the TiO2- CQDs nanocomposites increased with the increase in CQD ratio. The energy band gaps of the anatase and rutile phases were 3.07 and 2.7 eV, respectively, whereas that of CQDs was 3.14 eV. Meanwhile, the energy band gaps of the TiO2–CQDs nanocomposites decreased with the increase in CQDs ratio. The growth inhibition rates of the liver cancer HepG2 cell line and the normal cell line RD were measured after 24 hours of experience to the two TiO2 phases and TiO2–CQDs nanocomposites. The cytotoxicity test presented that the tested substances were extremely harmful to cells in cancer. Inhibition rates increased with the increase in CQDs ratio. The inhibition rate of growth in cancer cells, including the liver cancer HepG2 cell line and the normal cell line (RD), was measured for 24 hours after they were exposed to TiO2 (two phases) and TiO2-CQDs nanocomposites. The samples showed a slight effect on the normal line (RD) compared to HepG2 cancer. The highest inhibition rate was 12.11% for the CQD 0.7 sample.

Diversity Oriented Strategy (DOS) for the Efficient Synthesis of Benzofuro[2,3-b]pyridine Derivatives with Anticancer Activity.

Benzofuropyridines (BFP) are polycyclic compounds with known applications in neuronal diseases. However, its derivatization patterns and anticancer potential remains unexplored. Leveraging the idea of diversity-oriented synthesis (DOS), we developed a highly efficient synthetic route for BFP to increase the library of available analogs producing three compounds in one reaction set up, including the 2O-, 6O-, and the 1N-substituted species, also producing the unusual 2-pyridone derivatives. Key bromination reaction of the BFP moiety was successfully described which can widen the available variation in the compounds' structure. The cytotoxic activity of the compounds was assessed against SH-SY5Y (neuroblastoma), HepG2 (hepatocellular carcinoma), Kb (human oral epidermoid), HeLa (cervical) and MCF-7 (breast) cancer cell lines. In the series, the m-bromobenzyl (5b), methylcyano (5g) and propargyl (5h) 2O-derivatives demonstrated good selectivity against cancer cells with selectivity index (SI) of >71 for 5g against HeLa over the normal cells, as compared to the standard drug, Doxorubicin (SI = 6.7). The quantitative structure-activity relationship (QSAR) analysis revealed an impressive correlation of the defined descriptors with the bioactivity having an R2 value of 0.971 and 0.893 for Kb and HeLa respectively. Altogether, our work highlighted new information on the synthesis of BFP derivatives with potent cytotoxic activity.

Polyprenylated Benzoylphloroglucinols Isolated from Garcinia Species and Their Cytotoxic Effects on Cancer Cell Lines.

Polyprenylated benzoylphloroglucinols (PPBPs) make up a group of complex natural products with anticancer potentials that are mainly distributed in Garcinia plants. As part of our intensive exploration on new bioactive substances from this genus, we report two undescribed PPBPs, picrorhizones I (1) and J (2), along with four known analogues (3-6) from the stem bark of Garcinia picrorhiza and Garcinia gracilis. The new structures were elucidated on the basis of spectroscopic analysis, particularly 1D and 2D NMR and HRESIMS, whereas the absolute configurations were determined by a combination of ECD and NMR calculations coupled with a DP4+ probability analysis. Being the least class in genus Garcinia, picrorhizone I possesses a type-A structure with the position of a benzoyl moiety attaching to one of the bridgehead carbons of a bicyclo[3.3.1]nonane skeleton, which differs from its major type-B counterparts. This work also represents the first report on the occurrence of PPBPs in G. gracilis. The cytotoxic evaluation of the isolated compounds revealed that isogarcinol (4) and garciyunnanin L (5) significantly inhibited the growth of KB and Hela S3 cancer cells with IC50 values lower than 10 μM, while 5 was also strongly active against the Hep G2 cancer cell line with an IC50 value of 8.02 μM. Among the B-class derivatives bearing a lavandulyl side chain, cyclization of the moiety in the bicyclic phloroglucinol skeleton enhanced the cytotoxic properties on cancer cells.

The Anti-proliferative Effect, Apoptotic Induction, and Cell Cycle Arrest of Tetra Halo Ruthenate Nanocomposites in Different Human Cancer Cell Lines.

Chemotherapy is the most common cancer treatment, and metallic anticancer compounds have generated increasing amounts of interest since the discovery of cisplatin. More recently, scientists have focused on ruthenium-based compounds as alternatives for platinum compounds, which seem like ideal therapeutic anticancer alternatives to platinum derivatives. The present study aims to assess whether one or more of three Ruthenium-based nanocomposites, namely Ru+Lysine+CTAB (RCTL), Ru+CTAB (RCT), and Ru+Lysine (RL) exhibit pronounced anti-proliferative properties against different cancer cells. Three Ruthenium nanocomposites have been synthesized by standard chemical methods and characterized by Dynamic light scattering (DLS) and Transmission electron microscopy (TEM). The cytotoxic effect of the three composites has been evaluated by MTT in-vitro assay for different human cancer cell lines, namely MCF7, HepG2, A549, and PC3 versus normal human skin cell line (BJ1). The molecular underlying mechanisms of cytotoxicity have been assessed via qRT-PCR for pro-apoptotic makers P53 and Casp-3, and anti-apoptotic marker Bcl-2 as well as flow cytometric analysis of the cell cycle. Among the 3 nanocomposites, RCTL gave the best sensitivity and cytotoxicity especially on HepG2 with IC50 0.55 µg/ml but was still toxic on normal cell line with dose <12.5 µg/ml. RCTL and RCT nanocomposites have demonstrated a significant increase in the expression of P53 and Casp-3 markers versus untreated controls, but a significant reduction in the expression of Bcl-2. There was a direct correlation between the cytotoxic effect and the degree of apoptosis in the different cancer cell lines. The present study has also proved cell cycle arrest at G2-M and pre-G1 phases under the effect of IC50 of RCTL and RCT nanocomposites in different cancer lines with the best effect being achieved in HepG2 cells. Ruthenium nanocomposites seem to open a new avenue in cancer therapy.

Chemical profiling, cytotoxicity and mode of action of sea urchin Echinometra mathaei exoskeleton extract in HepG2 cancer cell line

Marine organisms contain several secondary metabolites with potent biological and pharma­cological activities. This research aimed to study the cytotoxicity and mechanism of action of methanol (MeOH) extract from the exoskeleton (shell and spines) of the sea urchin Echinometra Mathaei on human liver cancer cell line (HepG2). E. mathaei was collected from the intertidal zone of the Red Sea, Al-Ain Al-Sokhna, Egypt. HepG2 cells were treated with the MeOH extract for 24 and 48 hours to assess the cytotoxic activity and the potential molecular mechanisms. The expression levels of apoptosis-, autophagy-, and cell proliferation-related genes and/or proteins were measured. In addition, metabolomic profiling of the extract was performed by gas chromatography-mass spectrometry (GC-MS) analysis. The extract displayed cytotoxic activity on the liver cancer cells (IC50 29.47 and 14.97 µg/ml at 24 and 48 hours, respectively). It induced apoptosis, autophagy and inhibited cell proliferation of HepG2 cells. The metabolomic profiling showed that the extract is rich in fatty acids. These results demonstrated that the exoskeleton MeOH extract of E. mathaei induced apoptosis in HepG2 cells, confirming its cytotoxic effect. Therefore, a thorough investigation of its molecular target and structure is necessary to develop novel anticancer therapeutics from marine Sea urchins.

Computational quest, synthesis and anticancer profiling of 3-methyl quinoxaline-2-one-based active hits against the tyrosine kinase

BackgroundCancer is the predominant cause of mortality and a remarkable obstacle to elevating life anticipation in every nation on globe. Hepatocellular carcinoma (HCC), a hyper-vascular tumour, develops and progresses due to angiogenesis, a key feature of malignancy. HCC exhibits high neoangiogenic activity because of the need to generate new blood vessels for tumour growth.MethodsThe present work includes the construction of virtual library of ligands, virtual screening using the Dockthor-VS server, ADMET study using the SwissADME and Osiris property explorer. All the synthesized compounds were characterized by UV, IR, NMR and mass spectroscopic techniques. MTT assay was done to find the IC50 of the synthesized compounds against HepG2 cell line. The more active compound found is subjected to the molecular dynamics simulation study.ResultsThe ligands exhibited good docking scores, ADMET profile compared to the reference drugs. The target compounds were obtained with the satisfactory yields of 66–82%. The best activity against the HepG2 cancer cell line is observed with the compound SA-4 with IUPAC name (2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)-N-(5-(3-nitrophenyl)-5H-thiazolo[4,3-b] [1,3,4] thiadiazol-2-yl) acetamide). The experimental results obtained show correlation with the in silico results. MD simulation of the compound SA-4 indicates the moderate stability of the protein-ligand complex in real time environment.ConclusionThe results obtained suggest that the compound SA-4 has the potential to be a promising anticancer agent effective against the VEGFR-2 and FGFR-4.Graphical abstract

Shielding characteristics of a new epoxy resin reinforced by PbO nanoparticles and PbO micro for protection against X-ray and investigation of their cytotoxicity effects and photocatalytic activity

In this research, for the first time, lead oxide nanoparticles (PbO-NPs) were synthesized using Trigonella feonumgraecum plant seeds as a stabilizer and Pb (NO3)2 salt as lead precursor. The results of the XRD pattern displayed the synthesized NPs have an orthorhombic crystalline structure. According to FESEM images, the NPs had a mean size of about 18.62 nm with a spherical morphology. Also, the cytotoxicity of NPs was evaluated on the Hep G2 cancer cell line, and the IC50 value was reported as 267.07 μg/mL. Next, the photocatalytic performance of the synthesized PbO-NPs was investigated for removing methylene orange (MO) pigment under UVA light, which led to the destruction of about 94% after 120 min. Finally, to investigate the protective property of PbO-NPs against X-ray, a polymer nanocomposite of epoxy resin/PbO-NPs was prepared with different weight percentages. In the same way, other samples were also prepared, and then their ability to attenuate X-ray was studied with an X-ray tube with a voltage of 52 kV for the palm and 80 kV for the thigh of an average person, respectively. The measurement results show that with the increasing weight percentage of the fillers, the samples' linear and mass attenuation coefficient increases, which means an increase in the efficiency of the samples in X-ray attenuation. Generally, epoxy resin/PbO-NPs samples show a better effect than other samples. Therefore, these types of shields can attract more attention due to their lightness, cost-effectiveness, and far fewer environmental hazards than common lead shields.

Picoplatin (II)-loaded chitosan nanocomposites as effective drug delivery systems: Preparation, mechanistic investigation of BSA/5-GMP/GSH binding and biological evaluations

The goal of the current study is to improve the characteristics and bioavailability of the drug picoplatin (PPt) by encapsulating it in chitosan nanoparticles (CS NPs) which allows for the targeted delivery of cytotoxic cargo to cancerous tissue, reducing toxic side effects and raising the therapeutic index. When picoplatin was delivered into the CS, it was able to produce an complex with CS (PPt@CS NPs) that had an appropriate particle size of 275 ± 10 nm, a reasonably low PDI of 0.15 ± 0.05, and high stability (ζ = −22.1 ± 0.3 mV). Since almost all pharmaceuticals work by binding to specific proteins or DNA, the in vitro binding mechanism and affinity of bovine serum albumin (BSA), low molecular building units of nucleic acids (5−GMP), and Glutathione (GSH) (considering that cisplatin resistance could be due to a reaction between cisplatin and GSH) to PPt and PPt@CS NPs were examined using stopped-flow and other spectroscopic approaches. Through two reversible processes, a rapid second-order binding followed by a slower first-order isomerization reaction, and a static quenching mechanism, PPt and PPt@CS NPs bind to BSA with relative reactivity of around (PPt)/(PPt@CS NPs) = 1/2.5. The 5−GMP interaction studies demonstrated that, in addition to changing the binding mechanism, PPt's encapsulation in CS increases its rate of reaction through coordination affinity. PPt interacted with 5-GMP via two reversible processes, a rapid second-order binding to phosphate followed by a slower first−order migration to the N7 of pyrimidine moiety. PPt@CS NPs showed weaker binding to GSH compared to PPt and hence PPt@CS NPs exhibits a lower resistance factor. It was also found that the in vitro drug release of PPt@CS NPs in PBS at pH 7.4 was steady, releasing 30% of the PPt in just 5 hours. Nonetheless, 75% of the release in a pH 5.4 solution containing 10 mM GSH—a solution that mimics the tumor microenvironment—shows that the PPt@CS NPs system is sensitive to GSH and specifically targets malignant tissue. The encapsulation of PPt in CS complex maintained its anticancer activity, as shown by an in vitro cell-survival assay on HepG2 cancer cell lines and also cleavage efficiency toward the minor groove of pBR322 DNA via the hydrolytic way. These findings collectively suggested that inclusion PPt in CS would be an effective strategy to formulate a novel picoplatin formulation intended for use as targeted anticancer treatment.

Further Probing the Properties of a Unique Sponge-derived Alkaloid Through the Isolation of a New (-)-(5E)-(8R)-(14Z)-Mycothiazole Analogue.

Scale-up isolation of (+)-(5Z)-(8S)-(14Z)-mycothiazole (1) from Vanuatu specimens of C. mycofijiensis to semisynthesize (+)-(5Z)-(8S)-8-O-acetyl-(14Z)-mycothiazole (2) revealed a new diastereomer, (-)-(5E)-(8R)-(14Z)-mycothiazole (4). The structure of 4 was determined using HRMS, NMR, and comparing optical rotation to (-)-(5Z)-(8R)-(14Z)-mycothiazole (3) and 2. The maximum tolerated dose of 2 in mice was 0.1 mg/kg. The IC50 of 4 in PANC-1 and HepG2 cancer cell lines was 111.6 and 115.0 nM. Evaluation of 4 in C. elegans showed similar oxygen consumption compared to 1-2, and all compounds significantly increased the lifespan. The Z orientation at Δ5,6 is crucial for picomolar cytotoxicity but not for mitochondrial inhibition.

Determination of the interactions of a schiff base with different targets via molecular docking and cytotoxic activity studies

The pyrimidine nucleus is a vital pharmacophore that exhibits excellent pharmacological activity. A Schiff base containing a pyrimidine nucleus was obtained in two steps. This compound was assessed on the human prostate (PC3) and liver (HepG2) cancer cell lines using the MTT method. The prepared compound 3 was determined to have a high cytotoxic effect towards prostate cancer with an IC50 value of 9.32 μM. Since experimental prostate and liver cancer studies were examined, the molecular docking study's target structures were determined accordingly. In molecular docking studies, compound 3 interacted in silico with the crystal structure of the human HER2 kinase domain (PDB Id: 3PP0), the crystal structure of VEGFR-2 (PDB Id: 4ASD), and the crystal structure of EGFR tyrosine kinase (PDB Id: 4HJO), respectively. As a result of these interactions, binding energy values were calculated, and binding modes were determined. Additional in vitro and in vivo experiments targeting other cancer cell lines will provide deeper insight into the anticancer spectrum of this compound and new studies on this compound will be planned in the following years. Furthermore, optimizing and studying such pyrimidine-based Schiff base compounds for improved selectivity and potency against prostate cancer is also considered to be valuable as it may increase the potential to capture potential drug candidates.