Co-delivery of carboplatin and doxorubicin using ZIF-8 coated chitosan-poly(N-isopropyl acrylamide) nanoparticles through a dual pH/thermo responsive strategy to breast cancer cells.

A dual pH/temperature sensitive core-shell nanoformulation has been developed based on ZIF-8 coated with chitosan-poly(N-isopropyl acrylamide) (CS-PNIPAAm) for co-delivery of doxorubicin (DOX) and carboplatin (CBP) in breast cancer cells. The resulting nanoparticles (NPs) had particle sizes around 200 nm and a zeta potential of about +30 mV. The CBP and DOX loading contents in the final NPs were 11.6 % and 55.54 %, respectively. NPs showed a pH and thermoresponsive drug release profile with a sustained prolonged release under physiological conditions. The in vitro cytotoxicity experiments showed a significant synergism of CBP and DOX to induce the IC50 of 1.96 µg/mL in MCF-7 cells and 4.54 µg/mL in MDA-MB-231 cells. Also, the final NPs were safer than free DOX and CBP on normal cells. The in vitro study confirmed the higher potency of the designed NPs in combination therapy against breast cancer cells with lower side effects than free drugs.

Dihydropyrimidine derivatives as MDM2 inhibitors.

One of the chief pathways to regulate p53 levels is MDM2 protein, which negatively controls p53 by direct inhibition. Many cancers overproduce MDM2 protein to interrupt p53 functions. Therefore, impeding MDM2's binding to p53 can reactivate p53 in tumor cells may suggest an effective approach for tumor therapy. Here, some Monastrol derivatives were designed in silico as MDM2 inhibitors, and their initial cytotoxicity was evaluated in vitro on MFC-7 and MDA-MB-231 cells. A small library of Monastrol derivatives was created, and virtual screening (VS) was performed on them. The first-ranked compound, which was extracted from VS, and the other six compounds 5a-5f were selected to carry out the single-docking and docking with explicit waters. The compound with the best average results was then subjected to molecular dynamic (MD) simulation. Compounds 5a-5f were chemically synthesized and evaluated in vitro for their initial cytotoxicity on MFC-7 and MDA-MB-231 cells by MTT assay. The best compound was compound 5d with ΔGave = -10.35 kcal/mol. MD simulation revealed a median potency in comparison with Nutlin-3a. The MTT assay confirmed the docking and MD experiments. 5d has an IC50 of 60.09 µM on MCF-7 cells. We attempted to use Monastrol scaffold as a potent inhibitor of MDM2 rather than an Eg5 inhibitor using in silico modification. The results obtained from the in silico and in vitro evaluations were noteworthy and warranted much more effort in the future.

Predicted deleterious variants in the human genome relevant to gene therapy with adeno-associated virus vectors.

Based on the observation that humans have variable responses of gene expression with the same dose of an adeno-associated vector, we hypothesized that there are deleterious variants in genes coding for processes required for adeno-associated virus (AAV)-mediated gene transfer/expression that may hamper or enhance the effectiveness of AAV-mediated gene therapy. To assess this hypothesis, we evaluated 69,442 whole genome sequences from three populations (European, African/African American, and Qatari) for predicted deleterious variants in 62 genes known to play a role in AAV-mediated gene transfer/expression. The analysis identified 5,564 potentially deleterious mutations of which 27 were classified as common based on an allele frequency ≥1% in at least one population studied. Many of these deleterious variants are predicated to prevent while others enhance effective AAV gene transfer/expression, and several are linked to known hereditary disorders. The data support the hypothesis that, like other drugs, human genetic variability contributes to the person-to-person effectiveness of AAV gene therapy and the screening for genetic variability should be considered as part of future clinical trials.

Anti HER-2 aptamer functionalized gold nanoparticles of dasatinib for targeted chemo-radiotherapy in breast cancer cells.

In the present study, gold nanoparticles functionalized with anti HER-2 aptamer were designed for effective targeted delivery of dasatinib (DSB) to breast cancer cells. Anti HER-2 aptamer attached to porous or plain gold nanoparticles were compared for dasatinib delivery. Activated drug with succinic anhydride and L-cysteine linker was used for conjugation of DSB to gold nanoparticles. The loading efficiency of the activated drug on plain and porous gold nanoparticles was 52 and 68 %, respectively, which was significantly more than the loading of free DSB in gold nanoparticles (1-2.5 %). The anti HER-2 aptamer was conjugated to porous gold nanoparticles loaded with the activated drug. Various characterization techniques such as FESEM, TEM, AFM, zeta potential and ICP-MS were used to confirm the binding of the drug to gold nanoparticles. 1HNMR and FTIR spectroscopic analyses were employed to examine the structural characteristics of the conjugated drug. These analytical techniques confirmed the successful incorporation of succinyl and thiol groups onto the drug molecule. The amount of aptamer binding to different types of gold nanoparticles was obtained from the intensity of the light emitted from the bands observed in electrophoresis gel and due to the presence of porosity in porous gold nanoparticles, the amount of aptamer conjugation on porous gold nanoparticles increased compared to plain ones. Cell cytotoxicity and cellular uptake were evaluated by MTT assay and TEM in BT-474 and MCF-7 cells. Aptamer-functionalized porous gold nanoparticles containing activated dasatinib showed higher cytotoxicity and cellular uptake than modified DSB-loaded nanoparticles and un-activated DSB. The combination of radiation therapy with the modified dasatinib attached to porous gold nanoparticles and aptamer demonstrated a notable reduction in the IC50 values for both the BT-474 and MCF-7 cell lines. Specifically, the IC50 value for the BT-474 cells decreased from 6.95 µM (for unmodified dasatinib) to 2.57 µM, while for the MCF-7 cells, it decreased from 13.97 µM to 8.57 µM. These findings indicate a significant improvement in the efficacy of the modified dasatinib compared to its unmodified counterpart when used in conjunction with radiation therapy.

Serial Sampling of the Small Airway Epithelium to Identify Persistent Smoking-dysregulated Genes.

Rationale: The small airway epithelium (beyond the sixth generation), the initiation site of smoking-induced airway disorders, is highly sensitive to the stress of smoking. Because of variations over time in smoking habits, the small airway epithelium transcriptome is dynamic, fluctuating not only among smokers but also within each smoker. Objectives: To perform accurate assessment of the smoking-related dysregulation of the human small airway epithelium despite the variation of smoking within the same individual and of the effects of smoking cessation on the dysregulated transcriptome. Methods: We conducted serial sampling of the same smokers and nonsmoker control subjects over time to identify persistent smoking dysregulation of the biology of the small airway epithelium over 1 year. We conducted serial sampling of smokers who quit smoking, before and after smoking cessation, to assess the effect of smoking cessation on the smoking-dysregulated genes. Measurements and Main Results: Repeated measures ANOVA of the small airway epithelium transcriptome sampled four times in the same individuals over 1 year enabled the identification of 475 persistent smoking-dysregulated genes. Most genes were normalized after 12 months of smoking cessation; however, 53 (11%) genes, including CYP1B1, PIR, ME1, and TRIM16, remained persistently abnormally expressed. Dysregulated pathways enriched with the nonreversible genes included xenobiotic metabolism signaling, bupropion degradation, and nicotine degradation. Conclusions: Analysis of repetitive sampling of the same individuals identified persistent smoking-induced dysregulation of the small airway epithelium transcriptome and the effect of smoking cessation. These results help identify targets for the development of therapies that can be applicable to smoking-related airway diseases.

Chitosan-Imidazolium Core-Shell Nanoparticles of Gd-Mn-Mo Polyoxometalate as Novel Potential MRI Nano-Agent for Breast Cancer Detection.

Polyoxometalates (POMs) are mineral nanoclusters with many advantages in various diagnostic fields, in particular cancer detection. This study aimed to synthesize and evaluate the performance of gadolinium-manganese-molybdenum polyoxometalate (Gd-Mn-Mo; POM) nanoparticles coated with chitosan-imidazolium (POM@CSIm NPs) for detecting 4T1 breast cancer cells by magnetic resonance imaging in vitro and in vivo. The POM@Cs-Im NPs were fabricated and characterized by FTIR, ICP-OES, CHNS, UV-visible, XRD, VSM, DLS, Zeta potential, and SEM. Cytotoxicity, cellular uptake, and MR imaging in vivo and in vitro of L929 and 4T1 cells were also assessed. The efficacy of nanoclusters was demonstrated using MR images of BALB/C mice bearing a 4T1 tumor in vivo. The evaluation of the in vitro cytotoxicity of the designed NPs showed their high biocompatibility. In fluorescence imaging and flow cytometry, NPs had a higher uptake rate by 4T1 than L929 (p < 0.05). Furthermore, NPs significantly increased the signal strength of MR images, and its relaxivity (r1) was calculated as 4.71 mM-1 s-1. MR imaging also confirmed the attachment of nanoclusters to cancer cells and their selective accumulation in the tumor region. Overall, the results showed that fabricated POM@CSIm NPs have considerable potential as an MR imaging nano-agent for early 4T1 cancer detection.

Pyrimido[4,5-b]indole derivatives bearing 1,2,4-oxadiazole moiety as MDM2 inhibitor candidates in cancer treatment.

Aim: In this study, novel hybrid structures of pyrimido-indole-oxadiazole were developed as MDM2 inhibitors for restoring the regular function of the p53. Materials & methods: A multistep chemical pathway was used to synthesize the derivatives. Nutlin-3a was used as a standard lead in molecular docking and molecular dynamics simulations. Finally, cytotoxicity was evaluated against MCF-7 cancer cells versus Doxorubicin. Results: The most promising candidate was 12c, which had an NO2 group in the para position of the oxadiazole ring (IC50: 1.1 µM). A satisfactory result was obtained with the combined application of 12c and Doxorubicin (IC50 decreased to 0.63 µM), which could be potentially attributed to MDM2 inhibition. Conclusion: These hybrid structures can be further investigated as potential MDM2 inhibitors.

Thermosensitive TMPO-oxidized lignocellulose/cationic agarose hydrogel loaded with deferasirox nanoparticles for photothermal therapy in melanoma.

Deferasirox (DFX) is an iron-chelating agent effective in treating various kinds of cancers, which inhibits iron metabolism in cancer cells. The recent study aimed to prepare an injectable thermosensitive hydrogel based on lignocellulose and agarose containing deferasirox-loaded polypyrrole nanoparticles for local drug delivery in a combined chemo-photothermal therapy by laser light irradiation. Polypyrrole nanoparticles containing DFX were made by the emulsification method and optimized. Thermosensitive hydrogels were prepared by quaternary ammonium substituted agarose and TMPO-oxidized lignocellulose at different ratios, and the optimal hydrogel was selected based on gelation time, gelation temperature, and injectability. DFX- loaded polypyrrole nanoparticles were then added to the hydrogel, and the drug release, rheology test, injectability, degradation, and swelling percent, as well as cytotoxicity, and photothermal properties, were studied on B16F10, human melanoma cells. The hydrogel with 2 % anionic lignocellulose and 0.5 % cationic agarose showed the shortest gelation time and the highest mechanical strength. It transferred from a liquid state at 4 °C into a semisolid form at 37 °C with a gelation time of 10.3 min. The nanoparticles loaded in hydrogel showed dose-dependent cytotoxicity. The cytotoxic dose of the drug was reduced by laser light irradiation.

Safety of Intravenous Administration of an AAV8 Vector Coding for an Oxidation-Resistant Human α1-Antitrypsin for the Treatment of α1-Antitrypsin Deficiency.

α1-antitrypsin (AAT) deficiency is a common autosomal recessive hereditary disorder, with a high risk for the development of early-onset panacinar emphysema. AAT, produced primarily in the liver, functions to protect the lung from neutrophil protease; with AAT deficiency, unimpeded neutrophil proteases destroy the lung parenchyma. AAT is susceptible to oxidative damage resulting in an inability to inhibit its target proteases, neutrophil elastase, and cathepsin G. The major sites of oxidative modification on the AAT molecule are methionine residues 351 and 358. We have previously demonstrated that an engineered variant of AAT that resists oxidation by modifying both protein surface methionines (M351V and M358L) provides antiprotease protection, despite oxidative stress. In mice, intravenous delivery of the modified AAT(AVL) variant by AAV serotype 8, AAV8hAAT(AVL), primarily to the liver resulted in long-term expression of an AAT that resists oxidative inactivation. In this study, we evaluated the safety of intravenous administration of AAV8hAAT(AVL) in a dose-escalating, blinded, placebo-controlled toxicology study in wild-type mice. The study assessed organ histology and clinical pathology findings of mice, intravenously administered AAV8hAAT(AVL) at three doses (5.0 × 1011, 5.0 × 1012, and 5.0 × 1013 genome copies [gc]/kg), compared to control mice injected intravenously with phosphate-buffered saline. As previously demonstrated, administration of AAV8hAAT(AVL) resulted in dose-dependent expression of high, potentially therapeutic, levels of serum human AAT protein that persist for at least 6 months. Antibodies against the AAV8 capsid were elicited as expected, but there was no antibody detected against the AAT(AVL) protein generated by the AAV8hAAT(AVL) vector. There was no morbidity or mortality observed in the study. The data demonstrate that intravenous administration of AAV8hAAT(AVL) is safe with no significant adverse effect attributed to AAV8hAAT(AVL) vector at any dose. This study demonstrates that AAV8hAAT(AVL) has a safety profile consistent with the requirements for proceeding to a clinical study.

Oral epithelium response of electronic cigarette users to electronic cigarette.

BACKGROUND: Electronic cigarettes are increasing in popularity, but there is only little information on their biologic effects on the oral epithelium, the initial site exposed to electronic cigarette smoke. METHODS: We assessed the oral epithelium response to electronic cigarettes by comparing the histology and RNA transcriptome (mRNA and miRNA) of healthy electronic cigarette vapers to nonsmokers. mRNA was assessed based on: (1) genome-wide; (2) genes previously identified as dysregulated in the oral epithelium of electronic cigarette vapers versus nonsmokers; (3) immune and inflammatory-related genes previously identified as dysregulated in the nasal epithelium of electronic cigarette vapers compared to nonsmokers; (4) genes previously identified as dysregulated in the small airway epithelium of nonsmokers following an acute exposure to electronic cigarette; and (5) genes related to the initial steps of COVID-19 infection. In addition, miRNA was assessed genome-wide. Comparisons were performed using analysis of variance, and Benajmini-Hochberg corrected p < 0.05 was considered significant. RESULTS: The histology of the epithelium, lamina propria and basal layer in electronic cigarette vapers appeared normal. Assessment of mRNA and miRNA, based on all gene lists, did not identify any genes significantly modified in the oral epithelium of electronic cigarette vapers in response to electronic cigarette use. CONCLUSION: An average history of 2 years of vaping results in no detectable histologic or transcriptome abnormalities in the buccal mucosa.

Novel MR imaging nanoprobe for hepatocellular carcinoma detection based on manganese-zinc ferrite nanoparticles: in vitro and in vivo assessments.

PURPOSE: Achieving new contrast enhancer agents that can produce high-resolution images in magnetic resonance imaging (MRI) with a minimum dose and side effects has always been important. METHODS: Herein, the pegylated curcumin-coated manganese-zinc ferrite nanoparticles (MZF@CA-PEG-CUR NPs) have been reported as an MR imaging nanoprobe in hepatocellular carcinoma detection in the murine model for the first time. In vitro studies were done on HEPA 1-6 cancer cells and L929 as normal cells, and in vivo studies were done on hepatocellular carcinoma (HCC) using xenograft models of HCC. RESULTS: The prepared NP had a diameter of 105 nm with narrow size distribution and was superparamagnetic with a saturated magnetization (Ms) of 39 emu/g. The NP was biocompatible without any significant hemolysis and cytotoxicity. Prussian blue staining showed more cellular uptake of HEPA 1-6 compared to L929 control cells after incubation (P < 0.05). The concentration of Fe in mice blood confirmed the plasma half-life of about 3 h; it seems the PEGylation increased the circulation time. ICP-OES of Fe showed the highest tumor localization for MZF@CA-CUR-PEG NPs, due to passive accumulation, compared to the other mice studied organs. The r2 relaxivity of NPs was 134.89 mM- 1 s- 1, and in vitro MRI demonstrated better effects in HEPA 1-6 cells than in L929 (P < 0.05). Also, in vivo MR images showed signal enhancement efficacy in tumor-bearing mice. CONCLUSION: This study demonstrated that the MZF@CA-CUR-PEG nanoprobe could be a promising candidate as an MR imaging agent in hepatocellular carcinoma early detection.

Design, synthesis, and cytotoxicity evaluation of novel indole-acylhydrazone derivatives of 4-pyridinone as potential histone deacetylase-2 inhibitors.

Background and purpose: Histone deacetylation is one of the essential cellular pathways in the growth and spread of cancer, so the design of histone deacetylase (HDAC) inhibitors as anticancer agents is of great importance in pharmaceutical chemistry. Here, a series of indole acylhydrazone derivatives of 4-pyridone have been introduced as potential histone deacetylase inhibitors. Experimental approach: Seven indole-acylhydrazone-pyridinone derivatives were synthesized via simple, straightforward chemical procedures. The molecular docking studies were accomplished on HDAC2 compared to panobinostat. The cytotoxicity of all derivatives was studied on MCF-7 and MDA-MB-231 breast cancer cell lines by MTT assay. Findings / Results: Molecular docking studies supported excellent fitting to the HADC2 active site with binding energies in the range of -10 Kcal/mol for all derivatives. All compounds were tested for their cytotoxicity against MCF-7 and MDA-MB-231 cell lines; derivatives A, B, F, and G were the best candidates. The half-maximal inhibitory concentration (IC50) values on MCF-7 were below 25 mg/mL and much lower than those obtained on the MDA-MB-231 cell line. Conclusion and implications: The derivatives showed selectivity toward the MCF-7 cell line, probably due to the higher HDAC expression in the MCF-7 cell line. In this regard, debenzylated derivatives F and G showed slightly better cytotoxicity, which should be more studied in the future. Derivatives A, B, F, and G were promising for future enzymatic studies.

Copper-Curcumin-Bipyridine Dicarboxylate Complexes as Anticancer Candidates.

In this study, copper complexes with Curcumin (Cur) and 2,2'-bipyridine-5,5'-dicarboxylic acid (BPYD) were synthesized and their cytotoxicity on the MDA-MB-231 cell lines was evaluated. The resulting complex was characterized using FTIR, UV/VIS, CHNS, TGA, ICP-MS, and Mass spectroscopy techniques. The in-vitro cytotoxicity was studied on the MDA-MB-231 as a cancerous cell line and the HUVEC as a normal cell line. Reactive oxygen species (ROS) production was measured using the 2',7'-dichlorofluorescein diacetate (DCFDA) test in the MDA-MB-231 cancer cell lines. The in-vitro assays revealed that all synthesized copper complexes exhibited a higher cytotoxicity effect than carboplatin as a positive control on the MDA-MB-231 cells. While the synthesized complexes exhibited cytotoxic effects on cancerous cell lines, they are practically safe on normal cells. The Cu-Cur-BPYD complexes (a5 & b5) exhibited higher cytotoxicity on MDA-MB-231 cells with IC50 s around 4.9 and 2.3 mM, respectively. It can be concluded that the synthesized Cu-Cur-BPYD complexes (a5 & b5) could be considered effective anticancer candidates in complementary studies.

Redox responsive polymeric micelles of gellan gum/abietic acid for targeted delivery of ribociclib.

In most breast tumors level of glutathione reductase is much higher than in healthy tissues. In the current study, a redox-glutathione sensitive micelle based on Abietic acid-Cystamine-Gellan gum (AB-ss-GG) was designed for targeted delivery of Ribociclib (RIB) to breast cancer cells. AB is a monocarboxylic acid and a diterpenoid abietane with anti-tumor effects. Successful synthesis of the conjugate was confirmed by FT-IR and 1HNMR spectroscopy. Critical micelle concentration (CMC) was measured by pyrene as a fluorescent probe. Micelles of AB-GG and AB-ss-GG were loaded with different RIB/polymer ratios, and their redox-sensitivity was measured in the presence and absence of dithiothreitol (DTT) by determining the particle size and RIB release efficiency. Cell cytotoxicity and cellular uptake were assessed by MTT assay and flow-cytometry method on MCF-7 cells. CMC of AB-ss-GG and AB-GG micelles were estimated to be 40.15 and 37.33 mg/mL, respectively. In the presence of DTT, the particle size and release efficiency of AB-ss-GG micelles increased specially at a 1:1 drug/polymer ratio. AB-ss-GG micelles containing RIB showed higher cytotoxicity (IC50 = 47.86 µmol/L) and cellular uptake than AB-GG micelles (IC50 = 190.25 µmol/L) and free RIB (IC50 = 75.26 µmol/L) at 48 h. AB-ss-GG micelles showed a promising redox-sensitive polymeric carrier for RIB delivery.

pH-responsive glucosamine anchored polydopamine coated mesoporous silica nanoparticles for delivery of Anderson-type polyoxomolybdate in breast cancer.

AIM: This study aimed to develop novel pH-sensitive Glucosamine (Glu) targeted Polydopamine (PDA) coated mesoporous silica (SBA-15) nanoparticles (NPs) for selective delivery of anticancer Anderson-type manganese polyoxomolybdate (POMo) to breast cancer. METHODS: The POMo@SBA-PDA-Glu NPs were prepared via direct hydrothermal synthesis of SBA, POMo loading, in situ PDA post functionalization, and Glu anchoring; the chemical structures were fully studied by different characterisation methods. The anticancer activity was studied by MTT method and Annexin V-FITC apoptosis detection kit. RESULTS: The optimised NPs had a hydrodynamic size (HS) of 195 nm, a zeta potential (ZP) of -18.9 mV, a loading content percent (LC%) of 45%, and a pH-responsive release profile. The targeted NPs showed increased anticancer activity against breast cancer cell lines compared to the free POMo with the highest cellular uptake and apoptosis level in the MDA-MB-231 cells. CONCLUSIONS: POMo@SBA-PDA-Glu NPs could be a promising anticancer candidate for further studies.

Synthesis, characterization, molecular docking, antimalarial, and antiproliferative activities of benzyloxy-4-oxopyridin benzoate derivatives.

Background and purpose: Malaria and cancer are two major health issues affecting millions of lives annually. Maltol complexes and derivatives have been extensively investigated as chemotherapeutic and antimalarial activities. In this study, the design, synthesis, biological activities, and docking study of a novel series of pyridinones derivatives were reported. Experimental approach: The chemical structures of synthesized compounds were approved by FTIR, 1HNMR, 13CNMR, and mass spectroscopies. The antimalarial activity was evaluated through ß-hematin inhibition assay and the cytotoxicity activities were evaluated against PC12 and fibroblast cell lines via MTT and cell uptake assays. To theoretically investigate the ability of compounds to inhibit hemozoin formation, the synthesized compounds were docked in a heme sheet to explore their binding mode and possible interactions. Findings/Results: ß-Hematin inhibition assay showed acceptable activity for 7f, 7c, and 7d compounds and the molecular docking study showed 7h and 7f had effective interactions with the heme sheet. The cytotoxic study revealed compound 4b (IC50 = 18 µM) was significantly more active against PC12 cells than docetaxel (IC50 = 280 µM). The observations of cell uptake images were also shown both cell penetration and monitoring potential of synthesized compounds. Conclusion and implications: The compounds showed a moderate ability to inhibition of heme polymerization and also good interaction with heme through molecular docking was observed. Additionally, some of them have a good cytotoxic effect on the study2 cell line. So further study on these compounds can lead to compounds that can be considered as anti-malarial and/or anticancer agents.

The QChip1 knowledgebase and microarray for precision medicine in Qatar.

Risk genes for Mendelian (single-gene) disorders (SGDs) are consistent across populations, but pathogenic risk variants that cause SGDs are typically population-private. The goal was to develop "QChip1," an inexpensive genotyping microarray to comprehensively screen newborns, couples, and patients for SGD risk variants in Qatar, a small nation on the Arabian Peninsula with a high degree of consanguinity. Over 108 variants in 8445 Qatari were identified for inclusion in a genotyping array containing 165,695 probes for 83,542 known and potentially pathogenic variants in 3438 SGDs. QChip1 had a concordance with whole-genome sequencing of 99.1%. Testing of QChip1 with 2707 Qatari genomes identified 32,674 risk variants, an average of 134 pathogenic alleles per Qatari genome. The most common pathogenic variants were those causing homocystinuria (1.12% risk allele frequency), and Stargardt disease (2.07%). The majority (85%) of Qatari SGD pathogenic variants were not present in Western populations such as European American, South Asian American, and African American in New York City and European and Afro-Caribbean in Puerto Rico; and only 50% were observed in a broad collection of data across the Greater Middle East including Kuwait, Iran, and United Arab Emirates. This study demonstrates the feasibility of developing accurate screening tools to identify SGD risk variants in understudied populations, and the need for ancestry-specific SGD screening tools.

Some novel hybrid quinazoline-based heterocycles as potent cytotoxic agents.

BACKGROUND AND PURPOSE: In this study, some new cytotoxic hybrid structures were synthesized by combining pyrazolinone and imidazolinone rings with quinazoline pharmacophores. EXPERIMENTAL APPROACH: The benzoxazinone, pyrazolo-quinazoline fused ring, and imidazolinone anchored quinazoline derivatives were synthesized by simple ring-opening, ring expansion, and ring closure strategies from oxazolones. The molecular docking studies of the final derivatives were accomplished on the epidermal growth factor receptor enzyme. The cytotoxic effect of the final compounds on the MCF-7 cell line was evaluated by MTT assay. FINDINGS/RESULTS: The docking results confirmed the optimized electrostatic, H-bonding, and hydrophobic interactions of structures with the key residues of the active site (ΔGbin< -9Kcal/mol). The derivatives have been obtained in good yield and purity, and their structures were confirmed by different methods (FT-IR, 1H-NMR, 13C-NMR, and CHNS analysis). The IC50s of all final derivatives against the MCF-7 cell line were lower than 10 µM, and between all, the IXa from pyrazolo-quinazolinone class (IC50: 6.43 µM) with chlorine substitute was the most potent. Furthermore, all derivatives showed negligible cytotoxicity on HUVEC normal cell line which would be a great achievement for a novel cytotoxic agent. CONCLUSION AND IMPLICATIONS: Based on the obtained results, pyrazolo[1,5-c] quinazolin-2-one series were more cytotoxic than imidazolinone methyl quinazoline-4(3H)-ones against MCF-7 cells. Chlorine substitute in the para position of the aromatic ring improved the cytotoxicity effect in both classes. It could be related to the polarizability of a chlorine atom and making better intermolecular interactions. Further pre-clinical evaluations are required for the promising synthesized cytotoxic compounds.

Synthesis and Antiplatelet Activity Evaluation of a Group of Novel Ethyl Acetoacetate Phenylhydrazone Derivatives.

A group of Novel phenylhydrazone derivatives of ethyl acetoacetate was synthesized and evaluated for their antiplatelet activities. Fourteen ethyl acetoacetate phenylhydrazone derivatives were synthesized using the diazonium salt of various aromatic primary amines with good yields and purity. The structure of the final compounds was confirmed and approved by spectroscopic techniques such as 1HNMR, FTIR, and ESI-Mass. We examined the antiplatelet activity of the derivatives against Arachidonic Acid (AA) and Adenosine Diphosphate (ADP) as platelet aggregation inducers. The final results indicated the acceptable potency for different derivatives. In this regard, the para-hydroxyphenylhydrazine derivative of ethyl acetoacetate has the best activity among all derivatives, both on AA and ADP pathways. It seems that the derivatives with electron-releasing substituents (hydroxyl, methoxy, and methyl group) have better inhibition activities against the aggregation induced by AA. In contrast, those with an electron-withdrawing group showed a significant decrease in their potency. Based on the results of this study, we would proceed with further assessments both in-vitro and in-vivo to get success in introducing some new antiplatelet agents to the clinic.

Smoking shifts human small airway epithelium club cells toward a lesser differentiated population.

The club cell, a small airway epithelial (SAE) cell, plays a central role in human lung host defense. We hypothesized that subpopulations of club cells with distinct functions may exist. The SAE of healthy nonsmokers and healthy cigarette smokers were evaluated by single-cell RNA sequencing, and unsupervised clustering revealed subpopulations of SCGCB1A1+KRT5loMUC5AC- club cells. Club cell heterogeneity was supported by evaluations of SAE tissue sections, brushed SAE cells, and in vitro air-liquid interface cultures. Three subpopulations included: (1) progenitor; (2) proliferating; and (3) effector club cells. The progenitor club cell population expressed high levels of mitochondrial, ribosomal proteins, and KRT5 relative to other club cell populations and included a differentiation branch point leading to mucous cell production. The small proliferating population expressed high levels of cyclins and proliferation markers. The effector club cell cluster expressed genes related to host defense, xenobiotic metabolism, and barrier functions associated with club cell function. Comparison of smokers vs. nonsmokers demonstrated that smoking limited the extent of differentiation of all three subclusters and altered SAM pointed domain-containing Ets transcription factor (SPDEF)-regulated transcription in the effector cell population leading to a change in the location of the branch point for mucous cell production, a potential explanation for the concomitant reduction in effector club cells and increase in mucous cells in smokers. These observations provide insights into both the makeup of human SAE club cell subpopulations and the smoking-induced changes in club cell biology.