Low IC50 Values Research Articles

Evaluation and character association study for tuber yield, biochemical and antioxidant properties of sweet potato (Ipomoea batatas)

A study was carried out during 2022 and 2023 at ICAR-Research Complex for North-Eastern Hill Region, Umiam, Meghalaya to evaluate the yield, biochemical and antioxidant properties of 49 accessions of sweet potato [Ipomoea batatas (L.) Lam.] in mid hill condition of north-eastern region. The experiment was laid out in randomized block design (RBD) with 3 replications. Results indicate that Mynthlu Orange exhibited the highest tuber weight, length, diameter and yield. In terms of biochemical parameters, Meghalaya Local recorded the highest dry matter content; Col-6 recorded the highest starch content; and X-24 had the highest total sugar content. Among antioxidants, X-24 showed the highest total phenolic content, highest FRAP assay value and anthocyanin with lowest IC50 value which signified that X-24 had the highest antioxidant activity. Correlation study revealed significant positive correlation of tuber yield with tuber weight, diameter and total anthocyanin. Based on the mean performance, accessions Mynthlu Orange, X-24 and Col-6 were found promising for yield, biochemical and antioxidant parameters.

EXTH-53. THE PHARMACOLOGICAL ATLAS OF MENINGIOMAS

Abstract No systemic treatment options exist for recurrent or refractory meningioma patients. This study aimed to create a pharmacological atlas of all FDA-approved oncology drugs in a large cohort of patient-derived meningioma organoids (TOs). TOs were generated from single cell suspensions from freshly resected meningiomas and were treated with semi-logarithmic concentrations spanning from 10 nM to 30 µM by the automated liquid handler Hamilton MicroLAB STAR®. The drug library AODX from the National Cancer Institute consisted of 179 FDA-approved anticancer drugs. The viability was measured with the RealTimeGlo (Promega). Half-maximal inhibitory concentrations (IC50) were calculated by GraphPad Prism software. We created a pharmacological atlas of meningiomas by generating 8,413 dose-response curves of 179 current FDA-approved oncology drugs in patient-derived tumor organoids from 47 meningioma patients. The cohort consisted of 35 grade 1, 11 grade 2, and 1 grade 3 meningiomas, including 10 recurrent tumors. In total, 21% (n=39/179) of the drugs exhibited sensitivity (median IC50 < 30 µM), with significant enrichment for topoisomerase, RNA/protein synthesis, proteasome, and HDAC inhibitors. The top five drugs with the lowest IC50 values were romidepsin, dactinomycin, carfilzomib, plicamycin, and omacetaxine with median values of 10, 31, 145, 303, and 400 nM. Hierarchical clustering of IC50 data revealed at least two distinct drug response clusters defined by sensitivity to tyrosine kinase inhibitors. When considering the Cmax/IC50 ratio as a potential predictive marker of treatment response (>1), the HDAC inhibitors belinostat (74.5), romidepsin (69.7), the proteasome inhibitor carfilzomib (34.6), and the anthracyclines epirubicin (2.6), and doxorubicin (1.8), and the PI3K inhibitor idelalisib (1.6) are the most promising drug candidates for further in vivo evaluation. We provide the first comprehensive insight into the pharmacological landscape of meningiomas. This data might serve as the foundation for future clinical studies on the systemic treatment of aggressive meningiomas.

Transformer-Decoder GPT Models for Generating Virtual Screening Libraries of HMG-Coenzyme A Reductase Inhibitors: Effects of Temperature, Prompt Length, and Transfer-Learning Strategies.

Attention-based decoder models were used to generate libraries of novel inhibitors for the HMG-Coenzyme A reductase (HMGCR) enzyme. These deep neural network models were pretrained on previously synthesized drug-like molecules from the ZINC15 database to learn the syntax of SMILES strings and then fine-tuned with a set of ∼1000 molecules that inhibit HMGCR. The number of layers used for pretraining and fine-tuning was varied to find the optimal balance for robust library generation. Virtual screening libraries were also generated with different temperatures and numbers of input tokens (prompt length) to find the most desirable molecular properties. The resulting libraries were screened against several criteria, including IC50 values predicted by a dense neural network (DNN) trained on experimental HMGCR IC50 values, docking scores from AutoDock Vina (via Dockstring), a calculated quantitative estimate of druglikeness, and Tanimoto similarity to known HMGCR inhibitors. It was found that 50/50 or 25/75% pretrained/fine-tuned models with a nonzero temperature and shorter prompt lengths produced the most robust libraries, and the DNN-predicted IC50 values had good correlation with docking scores and statin similarity. 42% of generated molecules were classified as statin-like by k-means clustering, with the rosuvastatin-like group having the lowest IC50 values and lowest docking scores.

Evaluating the antidiabetes and antioxidant activities of halogenated Schiff bases derived from 4-(diethylamino)salicylaldehyde: in vitro antidiabetes, antioxidant and computational investigation

Six Schiff bases with general name 5-(diethylamino)-2-(((halophenyl)imino)methyl)phenol (where halo = 4-fluoro (H1), 2-fluoro (H2), 2-bromo (H3), 4-bromo (H4), 4-chloro (H5) and 3-chloro-4-fluoro (H6)) were prepared by the condensation reaction between 4-(diethylamino)salicylaldehyde and suitable halogenated aromatic amines. The six halogenated Schiff bases were elucidated using different spectroscopic techniques and the structure of H3 and H6 were confirmed using single-crystal X-ray crystallography. The bond lengths of C7–N1, C7–C8 and C8–C9 obtained from structural analysis for both compounds depicted their enol-tautomeric characteristic form. The Hirshfeld analysis revealed that H‧‧‧H intermolecular contacts contributed most towards the Hirshfeld surfaces of both H3 (47.6%) and H6 (39.9%). Quantum chemical calculation studies showed that H1 and H2 have the highest and lowest energy band gap (∆E = 3.80 eV for H1 and ∆E = 3.73 eV for H2), depicting H2 and H1 as the most and least chemically reactive respectively among all the compounds. α-Amylase and α-glucosidase assay were used to evaluate the antidiabetes prowess of the synthesized compounds. All the compounds exhibited lower IC50 values than acarbose (reference drug) in α-amylase assay experiments and H5 with lowest IC50 value of 63.54 μM could be suggested to have the highest α-amylase inhibitory potential among the test samples. For α-glucosidase assay, H1–H6 displayed good antidiabetic potential. However, none of the compounds outshined acarbose with H6 having highest α-glucosidase inhibitory potential when compared to others i.e., IC50 of H6 = 60.89 μM and IC50 of acarbose = 51.42 μM. We measured the antioxidant potential of H1–H6 exploring 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and ferric reducing ability power (FRAP) assays. The DPPH as well as NO radical scavenging assay showed that all the compounds exhibited excellent antioxidant results with some of the compounds surpassing catechin (reference drug). Compound H5 with IC50 values of 30.32 mM and 31.73 mM outshined catechin with IC50 values of 31.17 mM and 140.62 mM for DPPH and NO assays respectively. All the compounds fell within the threshold of Lipinski’s Ro5 projecting them as orally bioavailable and less toxic future therapeutics.

Crystal Structures and Biological Profiles of Novel Tridentate Schiff Bases Nickel (II) Complexes

ABSTRACTNovel bioactive ternary nickel (II) complexes, [Ni(5BrSal‐Phe)(phen)] (1) and [Ni(5BrSal‐Tyr)(phen)] (2) (5BrSal‐Tyr: Schiff base derived from 5‐bromosalicylaldehyde and L‐tyrosine, 5BrSal‐Phe: Schiff base derived from 5‐bromosalicylaldehyde and L‐phenylalanine, phen: 1,10‐phenanthroline), have been synthesized and characterized by electronic absorption spectroscopy, CHN, FTIR, ESI‐MS and X‐ray crystallography techniques. Interaction of the complexes with biomolecules (calf thymus DNA (CT‐DNA) and bovine serum albumin (BSA)) has been investigated by electronic absorption and fluorescence spectroscopy. The results show that the complexes can bind to CT‐DNA via a minor groove binding mode. Moreover, the fluorescence quenching mechanism between the complexes and BSA is a static quenching process. The antiproliferative activities of the complexes against breast cancer cells (MCF‐7 and MDA‐MB‐231) and healthy breast epithelial cells (MCF‐10A) were investigated. The complex 2 was found to have promising antiproliferative activity in selected cell line, with lower IC50 values than cisplatin. Molecular docking studies suggest that the complexes may serve as potential chemotherapeutic agents. These complexes have been observed to interact with various targets within cells, including the epidermal growth factor receptor (EGFR), bovine serum albumin (BSA), and B‐DNA. Analyses indicate that these interactions are supported not only by conventional hydrogen bonds but also van der Waals forces and π‐π interactions. Additionally, determining binding constants and regions enhances our understanding of how the complexes interact with target molecules. The results emphasize the importance of the complexes in cancer therapy by highlighting the necessity of understanding their molecular‐level interactions with targets.

Multicomponent Syntheses Enable the Discovery of Novel Quisinostat-Derived Chemotypes as Histone Deacetylase Inhibitors

In this study, we synthesized and evaluated novel histone deacetylase (HDAC) inhibitors derived from the clinical candidate quisinostat. A library of 16 compounds categorized in three novel chemotypes was rapidly generated using multicomponent reactions (MCRs), enabling efficient structure-activity relationship studies. First, the compounds were evaluated for their activity against the Plasmodium falciparum strains 3D7 and Dd2, the main malaria-causing parasite, identifying compound 18b of the type C series as the most potent. It demonstrated low nanomolar IC50 values (IC50 (3D7) = 0.023 μM; IC50 (Dd2) = 0.047 μM) and high parasite selectivity (SIMRC-5/Pf3D7 > 2174). HDAC inhibition assays confirmed substantial inhibition of the P. falciparum enzyme PfHDAC1 (IC50 = 0.037 μM) as well as of human HDAC1 (IC50 = 0.021 μM) and HDAC6 (IC50 = 0.25 μM). Docking studies suggested distinct binding modes of 18b in P. falciparum and human HDAC1. Additionally, the in vitro anticancer activity was evaluated in Cal27 (head-neck carcinoma), HepG2 (hepatocellular carcinoma), A2780 (ovarian carcinoma), and U87 (glioblastoma) cell lines. Compounds 9b, 9d, and 13f showed potent antiproliferative activity and caspase 3/7 activation, in contrast to 18b. Furthermore, these compounds caused hyperacetylation of histone H3 and α-tubulin, indicating robust cellular target engagement. Overall, in this work we have identified the HDAC inhibitor 18b with selective antiplasmodial and 9b, 9d, and 13f with selective anticancer activities, providing valuable hits for further drug development efforts aimed at creating derivatives with reduced cytotoxicity against non-cancer cells compared to quisinostat.

Biogenically synthesized gold nanocarrier ameliorated antiproliferative and apoptotic efficacy of doxorubicin against lung cancer.

Conventional chemotherapy treatment is commonly linked to significant side effects due to high therapeutic doses. In this regard, nanoformulations with chemotherapeutic medications hold promise in enhancing drug effectiveness through the reduction of therapeutic dosages, thereby mitigating the potential for adverse side effects. Because of numerous applications in the biomedical arena, there has been a rising interest in developing an environmentally acceptable, long-lasting, and affordable technique for the production of gold nanoparticles. In this particular context, the incorporation of plant extracts in the production of metallic nanoparticles has garnered the interest of numerous scholars. Here, we report the synthesis of gold particles by the green method using Cannabis sativa L. leaf extract and their conjugation with doxorubicin. The gold nanoparticles were synthesized by using Cannabis sativa extract and were characterized with various biophysical techniques. Subsequently, gold nanoparticles were conjugated with doxorubicin and their efficacy was tested on A549 cells. The biogenic synthesis of gold nanoparticles was ascertained through an absorption peak at a wavelength of 524nm, and it was shifted to 527nm when conjugated with doxorubicin. Nanoparticles were found to be stable exhibiting a zeta potential value of -20.1mV, and it changed to -12.7mV when loaded with doxorubicin. The hydrodynamic diameter of nanoparticles was determined to be 45.64nm and it was increased to 58.95nm when conjugated with the drug. The average size of nanoparticles analyzed by TEM was found to be approximately 17.2nm, while it was 23.5nm in the case of drug-nanoconjugate. Moreover, there was a significant amelioration in the antiproliferative potential of doxorubicin against lung cancer A549 cells when delivered with gold nanocarrier, which was evident by the lower IC50 and IC75 values of drug-nanoconjugates in comparison to drug alone. Furthermore, the inhibitory effect of drug-nanoconjugates and drug alone was characterized by alteration in the cell morphology, nuclear condensation, increased production of reactive oxygen species, abrogation of mitochondrial membrane potential, and enhanced caspase activities in A549 cells. In sum, our results suggested enhanced efficacy of doxorubicin-gold nanoconjugates, indicating effective delivery of doxorubicin inside the cell by gold nanoparticles.

Selective Metal‐Coordinated Nanodrugs Based on Thiazine Moiety for Anticancer Therapeutics: Spectroscopic, Theoretical, and Molecular Docking Studies

ABSTRACTThe current study involved production, comprehensive structural analysis, and physicochemical characterizing of two distinctive complexes namely, Cu(TBH) and Zn(TBH); TBH donor ligand: N′‐(1‐(3,6‐dihydro‐4‐hydroxy‐2,6‐dioxo‐2H‐1,3‐thiazin‐5‐yl)ethylidene)‐2‐hydroxybenzohydrazide) using a wide range of analytical methods, including elemental analysis, UV–Vis, FT‐IR, and 1HNMR spectrometry, molar conductivity and magnetic susceptibility measurements, and thermal analysis. According to the findings, chelation can occur through O, N, and O donor atoms of monoanionic chelator for generating mono‐nuclear chelates with tetrahedral geometry for Cu (II) and octahedral geometry for Zn (II). The anticarcinogenic ability of TBH chelator and its coordinated compounds against human liver cancer (HepG‐2) was investigated. The Cu(TBH) complex was found to have selective and promising anticancer activity against a liver cancer cell line, with lower IC50 (liver carcinoma cell line) and higher IC50 (normal human cell line) values than other produced compounds and standard drugs. Utilizing DFT computations, the molecular structures of the TBH and its complexes were verified, offering a detailed understanding of their quantum chemical characteristics. A quantitative structure–activity relationship (QSAR) model, which illustrates the association between DFT‐computed descriptors and biological activities pIC50, was also created using multiple linear regression (MLR) on the synthesized compounds as anticancer medicines. Additionally, there are no issues with the produced compounds' oral bioavailability according to (ROF) Lipinski's rule of five. Furthermore, docking studies of the synthesized TBH chelator and its chelates with CDK2 kinase have been performed to validate the biological findings. According to our findings, the novel Cu(TBH) nanodrug exhibits considerable cytotoxic activity, prompting further study into its pharmacological profile and exploring its potential in drug development.

N-[4-(Benzyloxy)-3-methoxybenzyl)]adamantane-1-amine (DZH2), a dual CCR5 and CXCR4 inhibitor as a potential agent against triple negative breast cancer.

DZH2, a dual inhibitor of the chemokine receptors CCR5 and CXCR4, was discovered from virtual screening for CCR5 antagonists. In specific Ca2+ chemokine signaling assays, DZH2 displayed low micromolar IC50 values at both chemokine receptors. Its binding to intracellular allosteric binding sites of CCR5 and CXCR4 was confirmed by MD simulations and binding free-energy calculations. DZH2 is superior to the CCR5 antagonist maraviroc in terms of its inhibitory activity on the growth of two breast cancer cell lines. In MCF7 and MDA-MB-231 cells, DZH2 was a >100-fold more potent inhibitor of cell viability compared to maraviroc. DZH2 (6.7 µM) reduced migration of MDA-MB-231 cells to 4% compared to 50% inhibition of migration caused by maraviroc (780 µM). Also, DZH2 was a significantly more potent inhibitor of colony formation in MDA-MB-231 cells than maraviroc. In MCF10 cells, DZH2 caused no alteration in the gene expression with respect to cellular pathways mediating cell death, indicating its selectivity to breast cancer cells.

Design and Synthesis of Ester Linked 1,2,3‐Triazole Quinoline Derivatives with Pancreatic β Cells Protective Activity against Oxidative Stress and Endoplasmic Reticulum Stress for Better Management of Type II Diabetes Mellitus

AbstractUnresolved endoplasmic reticulum (ER) stress and oxidative stress lead to the pathogenesis of type II diabetes mellitus (DM). Connecting links between the ER stress and oxidative stress pathways might play an important role in treatment and pathogenesis of diabetes. Here, we used network pharmacology approach to find the target proteins linking the ER stress and oxidative stress pathways. CHOP emerged as a hub protein from our results and was targeted by 16 newly designed and synthesized ester linked 1,2,3‐triazole quinoline derivatives by molecular docking. Drug likeliness prediction studies revealed all compounds as good druggable candidates. Compounds 5b (R = H, R1 = F), 5j (R = CH3, R1 = F), 5m (R = OCH3, R1 = H), and 5n (R = OCH3, R1 = F) were found to have considerable binding energies and active site amino acid interactions with CHOP. We further showed that compounds 5b, 5m, and 5n exhibited low toxicity with more than 50% cell survival and low IC50 values. These were therefore subjected to evaluate their effects on ER stress and oxidative stress. Finally, compound 5n (R = OCH3, R1 = F) was found to alleviate ER stress and is also a good antioxidant. Identification of such targets and compounds effective in improving ER stress and oxidative stress may provide new insights in the development of therapies and management of T2DM.

Enhancing glioblastoma cytotoxicity through encapsulating O6-benzylguanine and temozolomide in PEGylated liposomal nanocarrier: an in vitro study

Glioblastoma (GBM) (grade IV glioma) is the most fatal brain tumor, with a median survival of just 14 months despite current treatments. Temozolomide (TMZ), an alkylating agent used with radiation, faces challenges such as systemic toxicity, poor absorption, and drug resistance. To enhance TMZ effectiveness, we developed poly(ethylene glycol) (PEG) liposomes co-loaded with TMZ and O6-benzylguanine (O6-BG) for targeted glioma therapy. These liposomes, prepared using the thin-layer hydration method, had an average size of 146.33 ± 6.75 nm and a negative zeta potential (−49.6 ± 3.1 mV). Drug release was slower at physiological pH, with 66.84 ± 4.62% of TMZ and 69.70 ± 2.88% of O6-BG released, indicating stability at physiological conditions. The liposomes showed significantly higher cellular uptake (p < 0.05) than the free dye. The dual drug-loaded liposomes exhibited superior cytotoxicity against U87 glioma cells, with a lower IC50 value (3.99µg/mL) than the free drug combination, demonstrating enhanced anticancer efficacy. The liposome formulation induced higher apoptosis (19.42 ± 3.5%) by causing sub-G0/G1 cell cycle arrest. The novelty of our study lies in co-encapsulating TMZ and O6-BG within PEGylated liposomes, effectively overcoming drug resistance and improving targeted delivery for glioma treatment.

Development, optimization, and characterization of polymeric micelles to improve dasatinib oral bioavailability: Hep G2 cell cytotoxicity and in vivo pharmacokinetics for targeted liver cancer therapy

The efficacy of dasatinib (DAS) in treating hepatocellular carcinoma (HCC) is hindered by its poor bioavailability, limiting its clinical potential. In this study, we explored the use of TPGS-Soluplus micelles as an innovative drug delivery platform to enhance DAS solubility, stability, and therapeutic impact. A series of TPGS-Soluplus copolymers were synthesized, varying the D-α-tocopheryl polyethylene glycol succinate (TPGS) forms (1000, 2000, and 3500) and adjusting the TPGS to Soluplus weight ratios (1:1, 1:2, and 1:3). Our goal was to identify the optimal formulation with the highest entrapment efficiency, smallest particle size, and enhanced drug loading. The TPGS1000-Soluplus copolymer, with a DAS-to-polymer ratio of 1:30 and a TPGS ratio of 1:2, demonstrated superior performance, achieving an entrapment efficiency of 64.479 ± 1.45 % and drug loading of 5.05 ± 1.01 %. The DAS-loaded micelles (DAS-PMs) exhibited a notably small particle size of 64.479 ± 1.45 nm and demonstrated controlled release kinetics, with 85.60 ± 5.4 % of the drug released over 72 h.Cellular uptake studies using Hep G2 cells revealed significantly enhanced absorption of DAS-PMs compared to free DAS, reflected in lower IC50 values in MTT assays at 24 and 48 h. Pharmacokinetic analysis further highlighted the benefits of the DAS-PMs, with an AUC0-∞ 2.16 times higher and mean residual time (MRT) 1.3 times longer than free DAS, a statistically significant improvement (p < 0.01). These findings suggest that TPGS-Soluplus micelles offer a promising strategy for improving the bioavailability and efficacy of DAS in HCC treatment, presenting a potential new therapeutic avenue for patients with limited options. This innovative formulation could significantly enhance DAS delivery, potentially leading to improved clinical outcomes in liver cancer therapy.

Spots on 1H‐Indazole Incorporation into Thiazole Moiety‐Hybrid Heterocycles, Strong Efficacy as Small Molecules with Antimicrobial, Antineoplastic Activity, and In‐Silico Studies

AbstractAmidst the escalating cancer cases and the relentless spread of multidrug‐resistant microbes, the urgency for effective medication is undeniable. In this context, our lab's continuous efforts have led to a promising discovery. We have conducted an extensive study on a series of new heterocycles with an indazolylthiazole component, which holds great promise as antimicrobial and anticancer drugs. The bioactivity tests, conducted with meticulous methodology, have demonstrated that the synthesized compounds possess remarkable antibacterial activity against various pathogenic strains. In a controlled lab setting, we have observed that derivatives 9, 11, and 12a effectively induce apoptosis in HCT‐166 and Huh‐7 (liver carcinoma) cell lines. Among these, derivative 11 has shown the highest selectivity (SI=14.54±1.2 and 16.51±1.4) and the lowest IC50 value. These compounds also exhibit broad‐spectrum antimicrobial activity. The anticancer activity of the synthesized compounds has been computationally confirmed through molecular modeling using MOE software and pharmacokinetic studies. Most of the tested compounds have shown significant cytotoxic activity against tumor cell lines, with high safety against normal human cells, thereby paving the way for a hopeful and promising future of antimicrobial and anticancer drugs, with potential applications in [specific_application_1] and [specific_application_2].

Synthesis, characterization, DFT computational studies and biological activity of transition metal complexes derived from 4-(((6-nitrobenzo[d]thiazol-2-yl)imino)methyl)benzene-1,3-diol

A series of Co(II), Ni(II), Cu(II), Zn(II) complexes have been synthesized with a benzothiazole azo dye containing tridentate (NNO) donor ligand 4-(((6-nitrobenzo[d]thiazol-2-yl)imino)methyl)benzene-1,3-diol derived from 2-amino-6-nitrobenzothiazole and 2,4-dihydroxybenzaldehyde. The structures of the novel ligand and metal complexes were identified and confirmed via various spectroscopic techniques (FT-IR,1H NMR,13C NMR, UV-Vis, mass spectrometry), TGA-DTA, powder X-ray diffraction, and DFT calculations. The optimal structural parameters and chemical reactivity of the ligand and metal complexes have been investigated using Density Functional Theory calculations (DFT/B3LYP,6-31G** and LanL2DZ basis sets) to provide insight about their frontier molecular orbitals (FMO) and molecular electrostatic potential (MESP). In vitro DPPH radical scavenging techniques have been used to assess the antioxidant activity of the ligand and complexes, indicating good antioxidant activity. The Ni(II) complex was the most potent with the lowest IC50 values. The in vitro antibacterial activities have been explored by screening against bacteria (Bacillus subtilis) and bacteria (E. coli) exhibiting significant activity against the tested strains of bacteria with Zn(II) complex as most potent with the lowest MIC value against E. coli and B. subtilis) and highest zone of inhibition against E. coli and B. subtilis at 1000 μg/mL concentration). The antifungal activity of complexes against Aspergillus niger and Candida albicans indicate that the Co(II) complex is most active for C. albicans and Zn(II) complex for A. niger .

Different Doxorubicin Sensitivity Across Various Human Cancer Cell Lines

Doxorubicin (Dox) is a highly potent chemotherapeutic agent, approved by FDA since 1974, for treating a broad spectrum of cancers. However, development of severe side effects and drug resistance are main issues that limit the clinical use of Dox. Herein, we aimed to investigate the sensitivity of Dox in a variety of human cancer cell lines. Eleven cell lines were tested in this study including 2 hepatocellular carcinoma (HCC) cell lines (HepG2 and Huh7), 4 bladder cancer (BlCa) cell lines (UMUC-3, VMCUB-1, TCCSUP and BFTC-905), a lung cancer cell line (A549), a cervical carcinoma cell line (HeLa), a breast cancer cell line (MCF-7), a skin melanoma cell line (M21) and a noncancer human kidney cell line (HK-2). The MTT assay was employed for the determination of cytotoxicity. Cells were treated with various concentrations of Dox for 24 h. The half-maximal inhibitory concentration (IC50) of Dox was calculated to compare the Dox sensitivity among tested cell lines. The result showed that IC50 of Dox in HepG2, Huh7, UMUC-3, VMCUB-1, TCCSUP, BFTC-905, A549, HeLa, MCF-7, M21 and HK-2 cells were 12.2, &gt; 20, 5.1, &gt; 20, 12.6, 2.3, &gt; 20, 2.9, 2.5, 2.8 and &gt; 20 mM, respectively. BFTC-905 had the lowest IC50 value, therefore, it was the most sensitive to Dox. In contrast, Huh7, VMCUB-1 and A549 cells were resistant to Dox with IC50 values &gt; 20 mM. Conclusions, we demonstrated that different human malignant cell lines had different sensitivity to Dox. BFTC-905 BlCa cell line had the highest sensitivity to Dox. Huh7, VMCUB-1 and A549 cell lines were resistant to Dox. Perhaps, the different Dox sensitivity in different cell lines was due to the different acquisition of Dox resistance mechanisms. Huh7, VMCUB-1 and A549 cell lines could be suitable cell models to investigate the molecular mechanism of Dox resistance in different cancers. HIGHLIGHTS Different types of cancer cell lines exhibited different sensitivity to doxorubicin. BFTC-905, MCF-7 and M21 cell lines were sensitive to doxorubicin. HepG2, UMUC-3, TCCSUP and HeLa cells were moderately sensitive to doxorubicin. Huh7, VMCUB-1, A549 and HK-2 cells were resistant to doxorubicin. Huh7, VMCUB-1 and A549 cell lines could be suitable cell models for investigating the molecular pathways of Dox resistance in different types of cancers. GRAPHICAL ABSTRACT

Folic acid-targeted redox responsive polylactic acid-based nanoparticles co-delivering pirarubicin and salinomycin suppress breast cancer tumor growth in vivo.

Targeted cancer therapy using nanocarriers has emerged as a promising solution to the majority of drawbacks associated with conventional chemotherapy. The present research work describes the development of folic acid (FA)-targeted redox responsive [S-(PLA-b-PEG-CONH)]2 polymeric nanoparticles for the co-delivery of pirarubicin (Pira) and salinomycin (Sal). The nanoparticles' redox responsiveness arises from embedded disulfide bonds within the polymer, which gradually break in response to high GSH levels in tumors, enabling sustained drug release. The nanoparticles exhibited a hydrodynamic size of ∼104 nm and a surface charge density of -15.5 mV with low PDI values. Blank nanoparticles (w/o drug) showed negligible toxicity towards both non-malignant human and murine cells and exhibited excellent stability under different environmental conditions for up to 3 weeks. A cellular internalization study conducted using Rho B/C6 dual-dye-encapsulated nanoparticles showed efficient uptake of the nanoparticles after just 1 hour of incubation with SUM-149 2D adherent cells and 3D spheroids. The release of Pira and Sal from Pira/Sal dual-loaded nanoparticles increased significantly in a reducing environment. The % cumulative release of Pira increased from 20.5% ± 1.0 in PBS (pH 7.4) to 40.1% ± 0.4 in dithiothreitol (DTT) after 20 days; similarly, the % cumulative release of Sal increased from 36.2% ± 1.7 in PBS (pH 7.4) to 51.5% ± 1.7 in DTT. The cytotoxicity studies of FA-targeted Pira/Sal dual-loaded nanoparticles with varying Pira : Sal ratios (1 : 1, 3 : 1 and 1 : 3) revealed that the nanoparticles displayed 8-10 fold lower IC50 values than the respective free drug formulations across multiple breast cancer cell lines including SUM-149, MDA-MB-231 and EAC as well as in 3D mammospheres. Balb/c syngeneic mice bearing EAC tumors experienced ∼100% tumor regression upon treatment with FA-targeted Pira/Sal (3 : 1) dual-loaded nanoparticles, indicating synergistic anti-tumor potency. In vivo survival and histopathological studies indicated no significant toxicity in vital organs of the body as compared to free drugs. Based on the performance, the currently investigated FA-targeted Pira/Sal dual-loaded nano-formulation is recommended to be further explored in other cancer types as well as in higher animals for cancer therapy.

Photoactivated Anticancer Activity of Cobalt(III) Complexes with Naturally Occurring Flavonoids Chrysin and Silibinin.

Photoactive metal complexes of bioessential transition metal ions with natural chelators are gaining interest as photocytotoxic agents for cancer photodynamic therapy (PDT). We report six new cobalt(III) complexes with a mixed-ligand formulation [Co(B)2(L)](ClO4)2 (Co1-Co6), where B represents a N,N-donor α-diimine ligand, namely, phenanthroline (phen; Co1, Co2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq; Co3, Co4), and dipyrido[3,2-a:2',3'-c]phenazine (dppz; Co5, Co6), and L is the monoanionic form of the naturally occurring flavonoids chrysin (chry; Co1, Co3, Co5) and silibinin (sili; Co2, Co4, Co6). Complexes displayed a d-d absorption band within 500-700 nm and exhibited excellent dark and photostability in solution. Cytotoxicity studies indicated significant activity of Co5 and Co6 against cervical (HeLa) and lung (A549) cancer cells under visible light (400-700 nm) irradiation giving low micromolar IC50 values (2.3-3.4 μM, phototoxicity index~15-30). The complexes demonstrated notably low toxicity against normal HPL1D lung epithelial cells. Flow cytometry assay revealed an apoptotic mode of cell damage triggered by the complexes when irradiated. ROS generation assay indicated the involvement of singlet oxygen species in the cell death mechanism when irradiated with light. Overall, complexes Co5 and Co6 with coordinated dipyridophenazine and flavonoid ligands are potential candidates for cancer PDT applications.

Curcumin-loaded zein nanoparticles: A quality by design approach for enhanced drug delivery and cytotoxicity against cancer cells

Zein, a maize protein, has been explored for constructing potential biomaterial due to its hydrophobic nature, self-assembly capability, and biocompatibility. In its nanoparticulate form, zein is a promising material for drug delivery applications, particularly in cancer treatment. Despite the importance of colloidal stability for effective drug delivery, systematic studies investigating the effect of various surface modifying agents (MAs) on the zein nanoparticles (ZNPs)-based formulations are limited. This study employs quality-by-design (QbD) approach to optimize curcumin-loaded ZNPs, enhancing colloidal stability, size, and drug-encapsulation efficiency using different MAs for potential cancer therapy. Gum arabic (GA) emerged as the optimal stabilizer, with GA-stabilized curcumin-loaded ZNPs (GA-Cur-ZNPs) achieving a particle size of 184.8 ± 2.85 nm, zeta potential of −23.4 ± 0.56 mV and 87.1 ±1.55 % drug encapsulation efficiency, along with excellent colloidal stability over two months. The optimal formulation also demonstrated sustained release of Cur over 72 h. GA-Cur-ZNPs demonstrated lower IC50 values and higher anti-proliferative effects on three different cancer cell lines compared to the free drug, while also exhibiting superior intracellular uptake. With negligible toxicity to human dermal fibroblast cells, the optimized Cur-GA-ZNPs show promise for safe and effective killing of cancer cells.

Hypoglycemic and antioxidant activities of Jasminum officinale L. with identification and characterization of phytocompounds

The utilization of plant-derived chemicals with anti-diabetic properties is widely promoted for its advantageous tactics in managing diabetes, as they are cost-effective and have minimal or no adverse effects. Therefore, this work investigates the medicinal plant Jasminum officinale L. leaves by extraction and bio-guided fractionation. The ethyl acetate fraction showed a higher yield of 36.4 %. A phytochemical test on Jasminum officinale confirmed flavonoids, saponins, phenols, and tannins. The highest total phenol and flavonoid contents in the ethyl acetate fraction of J. officinale are 103.01 ± 1.1 mg GAE/g and 80.29 ± 1.03 mg QUE/ value found in methanol crude extract. Furthermore, HPTLC analysis of the ethyl acetate fraction detected the existence of flavonoids (kaempferol) and phenols (gallic acid, quercetin, and rutin). The compounds detected at the greatest concentrations in the LC-M/MS analysis of the ethyl acetate fraction were cirsiliol, kaempferol, and 2-tridecanone. Additionally, J. officinale (IC50 33.845 ± 1.09 μg/mL) demonstrated the highest DPPH scavenging activity in EAF like that of ascorbic acid (IC50 22.27 ± 0.96 μg/mL). Also, in the FRAP assay, the IC50 of this fraction is 15.14 ± 0.25 μM Fe equivalents. In the range of alpha-amylase deactivating action, from 13.25 % to 74.51 %, and IC50 value (47.40 ± 0.29 μg/mL) was significantly higher in the ethyl acetate fraction of J. officinale leaf extract. Moreover, J. officinale leaf extract had a substantially higher retention of glucose level (23.92 ± 0.85 % to 87.21 ± 0.6 %), significantly higher anti-inflammatory activity with the lowest IC50 value (66.00 ± 1.84), and lipid peroxidation (IC50 value 34.67 ± 1.69) by utilizing egg yolk as a substrate for lipids. Overall, the study revealed that J. officinale has considerable anti-diabetic characteristics. However, further comprehensive research is necessary to ascertain the medicinal purposes of J. officinale and its chemical components, pharmacological effects, and clinical uses.

Mechanistic insights into β-glucuronidase inhibition by isoprenylated flavonoids from Centaurea scoparia: Bridging experimental and computational approaches

Exploring the intricate mechanisms underlying the inhibition of β-glucuronidase, particularly the enzyme produced by gastrointestinal bacteria, is essential for the development of novel therapeutic interventions and pharmaceutical advancements. Inhibiting bacterial β-glucuronidase can prevent the reactivation of harmful drug metabolites in the gut, thereby reducing associated toxicities. The inhibitory potential of four isoprenylated flavonoids from Centaurea scoparia against β-glucuronidase was intensively investigated by combined in vitro and in silico tools. The results of in vitro inhibitory activity showed that Compounds 1 and 3 exhibited the highest inhibitory activity, as evidenced by their low IC50 values of 3.65 ± 0.28 and 3.97 ± 0.11 μM, respectively. The enzyme kinetics analysis revealed that Compound 1 and the positive control drug (EGCG) follow a mixed inhibition mechanism. In contrast, compounds 3 and 4 exhibited a noncompetitive inhibition mode, as suggested by the intersection patterns observed in the Lineweaver-Burk plots. The docking studies corroborated the in vitro inhibitory assay results, with Compounds 1 and 3 demonstrating the lowest binding affinities and the highest extent of polar and hydrophobic interactions with residues in the enzyme's binding site. Utilizing a 200 ns molecular dynamics (MD) simulation, we examined the interaction dynamics between isolated flavonoids and β-glucuronidase. The analysis of multiple MD parameters revealed that compounds 1 and 3 maintained consistent trajectories and demonstrated significant energy stabilization when interacting with β-glucuronidase. These computational findings align with experimental results, highlighting the potential of compounds 1 and 3 as potent inhibitors for β-glucuronidase.