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Subcritical water (SCW) hydrolysis was applied to valorize the low-valued ray-finned fish (Labeobarbus nedgia) into valuable protein hydrolysates, employing N2 and CO2 as pressurization agents at varying temperatures (140, 160, 180, and 200 °C). The degree of hydrolysis (DH) and total free amino acid content increased with temperature for both pressurizing agents. The highest DH (54.5 ± 0.4%) and total free amino acid content (210 ± 1 mg/gprot) were observed at 200 °C when CO2 gas was used as the pressurizing agent. Predominantly, glycine and alanine were released for both pressurizing agents. The antioxidant activity, evaluated through three different assays, increased with temperature and was found to be the highest at 200 °C. This study illustrated the advantages of the intensified SCW technology by using CO2 as a pressurization agent in valorizing low-valued ray-finned fish (Labeobarbus nedgia), as animal residue rich in proteins, for the production of valuable protein hydrolysates with a high fraction of valuable free amino acids, which could offer potential applications as a functional ingredient in the food industry.
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Ranunculin, a glucoside, serves as a chemotaxonomic marker in Ranunculaceae plants. When these plants are damaged, an enzyme ß-glucosidase triggers the conversion of ranunculin into protoanemonin through hydrolysis. Subsequently, protoanemonin undergoes cyclodimerization to form anemonin. The inherent instability of ranunculin and the rapid dimerization of protoanemonin render them unsuitable for use in biological assays. Conversely, anemonin stands out as the optimal molecule for bioassays and demonstrates diverse biological properties, including anti-inflammatory, anti-infective, and anti-oxidant effects. Among these, anemonin exhibits the greatest promise in addressing conditions such as arthritis, cerebral ischemia, and ulcerative colitis. Its potential medical uses are enhanced by its capacity to inhibit nitric oxide synthesis and successfully counteract lipopolysaccharide-induced inflammation. This review describes the chemistry and biological properties of anemonin and its precursors, including discussions on extraction, isolation, synthesis, and investigations into bioactivity and pharmacokinetics.
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Feroxyhite (δ-FeOOH) nanomaterials were successfully synthesized through the atmospheric AC microplasma method at room temperature from ferrous sulfate aqueous solutions. Various syntheses conditions, including electric voltage, electric field strength, ferrous concentration, hydrogen peroxide concentration, and reaction duration, were systematically investigated. The synthesized products were characterized through x-ray diffraction, UV-vis absorption spectroscopy, photoluminescence spectroscopy, infra-red spectroscopy, and electron microscopy. The bandgap of the produced materials were strongly dependent of the ferrous concentration while the product ratio was dependent on all experimental conditions. The synthesis mechanism was thoroughly discussed. The synthesized nanomaterials were amorphous nanospheres, showing superparamagnetic properties at room temperature. The synthesized oxyhydroxide is a potential photovoltaic material besides its reported applications in photocatalysts and supercapacitors. The application of this synthesis technique could be extended to synthesize other oxy-hydroxide nanomaterials for renewable energy applications facilely, scalablely, cost-effectively, and environmentally.
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A new rhodamine 6G derivative R1 has been synthesized by condensation of rhodamine hydrazide and 6-hydroxymethyl-pyridine using microwave-assisted reaction. Naked-eye colorimetric and photo physical studies show the synthesized compound is selectively sensing Cu2+ in CH3CN/H2O (9:1, v/v) solution. Upon coordination with Cu2+ ion, the spirolactam of R1 is opened, which results in a formation of highly fluorescent complex and change in color of the solution. The Job's plot indicates 1:2 binding stoichiometry between Cu2+ ion and R1. Limit of detection for Cu2+ was determined to be 1.23 µM. The sensor was successfully applied to fluorescent imaging of Cu2+ ion in living cells.
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Background: In Ethiopian traditional medicine, V. sinaiticum is one of the most often utilized medicinal herbs for the treatment of diarrhea. Therefore, this study was conducted to validate the use of the plant for the treatment of diarrhea in the traditional medical practice of Ethiopia. Methods: Castor oil-induced diarrhea, enteropooling, and intestinal motility test models in mice were used to evaluate the antidiarrheal properties of the 80% methanol crude extract and the solvent fractions of the root component of V. sinaiticum. The effects of the crude extract and the fractions on time for onset, frequency, weight, and water content of diarrheal feces, intestinal fluid accumulation, and intestinal transit of charcoal meal were evaluated and compared with the corresponding results in the negative control. Results: The crude extract (CE), aqueous fraction (AQF), and ethyl acetate fraction (EAF) at 400 mg/kg (p < 0.001) significantly delayed the onset of diarrhea. Besides, the CE and AQF at 200 and 400 mg/kg (p < 0.001) of the doses, and EAF at 200 (p < 0.01) and 400 mg/kg (p < 0.001) significantly decreased the frequency of diarrheal stools. Furthermore, CE, AQF, and EAF at their three serial doses (p < 0.001), significantly reduced the weights of the fresh diarrheal stools as compared to the negative control. The CE and AQF at 100 (p < 0.01), and 200 and 400 mg/kg (p < 0.001) of their doses and EAF at 200 (p < 0.01) and 400 mg/kg (p < 0.001) significantly decreased the fluid contents of diarrheal stools compared to the negative control. In the enteropooling test, the CE at 100 (p < 0.05), and 200 and 400 mg/kg (p < 0.001), AQF at 200 (P < 0.05) and 400 mg/kg (p < 0.01), and EAF at 200 (p < 0.01) and 400 mg/kg (p < 0.001) significantly decreased the weights of intestinal contents compared to the negative control. Additionally, the CE at 100 and 200 (p < 0.05) and 400 mg/kg (p < 0.001), AQF at 100 (p < 0.05), 200 (p < 0.01), and 400 mg/kg (p < 0.001) of the doses, and EAF at 400 mg/kg (p < 0.05), produced significant reductions in the volumes of intestinal contents. In the intestinal motility test model, the CE, AQF, and EAF at all their serial doses (p < 0.001), significantly suppressed the intestinal transit of charcoal meal and peristaltic index compared to the negative control. Conclusion: Overall, the results of this study showed that the crude extract and the solvent fractions of the root parts of V. sinaiticum had considerable in vivo antidiarrheal activities. Besides, the crude extract, especially at 400 mg/kg, produced the highest effect followed by the aqueous fraction at the same dose. This might indicate that the bioactive compounds responsible for the effects are more of hydrophilic in nature. Moreover, the antidiarrheal index values were increased with the doses of the extract and the fractions, suggesting that the treatments might have dose-dependent antidiarrheal effects. Additionally, the extract was shown to be free of observable acute toxic effects. Thus, this study corroborates the use the root parts of V. sinaiticum to treat diarrhea in the traditional settings. Furthermore, the findings of this study are encouraging and may be used as the basis to conduct further studies in the area including chemical characterization and molecular based mechanism of actions of the plant for its confirmed antidiarrheal effects.
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BACKGROUND: The patients' perception of the health service is a vital tool for measuring health service quality. Besides, Patient satisfaction is an essential feature in assessing the quality of health services. Health institution leaders are considering quantifiable patient satisfaction data as a means to evaluate the health care service. METHOD: An institution-based cross-sectional study was employed from 21/8/2022 to 21/9/2022 among 308 patients attending ART pharmacy services in three health institutions of Dembia distinct. Data were collected by using a questionnaire and reviewing medical charts. Results were calculated and presented in the form of texts, tables, and graphs. Variables with a p-value of 0.05 were considered significant determinants of patient satisfaction. RESULT: A total of 308 HIV patients were recruited with a response rate of 100%. The overall prevalence of satisfaction among respondents was 231(75%). Being unable to read and write [1.21(AOR = 1.07-4.31)] and patient age greater than 48 years 1.9(0.73-2.59) were significantly associated with the level of patient satisfaction. Among the participants 66.9% were satisfied with clear and organized service, and 76% were satisfied with the convenience of a private counseling room. CONCLUSION: The general patient satisfaction at the antiretroviral therapy clinic did not achieve the national target of 85% satisfaction with significant differences among health centers. Being educated to a higher level, absence of signs and directions to ART clinics, and not having the opportunity to ask questions were the factors influencing patient satisfaction with ART service.
Subject(s)
HIV Infections , Humans , Middle Aged , HIV Infections/drug therapy , Patient Satisfaction , Ethiopia , Cross-Sectional Studies , Pharmacists , Surveys and Questionnaires , Ambulatory Care FacilitiesABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Psydrax schimperianus (A. Rich.) Bridson. roots are used for the treatment of diarrhea in West Arsi zone, Ethiopia. AIM OF THE STUDY: This study aimed to investigate the in vivo antidiarrheal activity of crude extract and coumarins isolated from the roots of Psydrax schimperianus to provide a pharmacological basis for its traditional use as an antidiarrheal agent in Ethiopia. MATERIALS AND METHODS: The crude root extract of P. schimperianus was tested in vivo for antidiarrheal efficacy in mice utilizing castor oil-induced diarrhea, gastrointestinal transit time, and enteropooling models at doses of 100, 200, and 400 mg/kg. Phytochemical investigation of the crude root extract led to the isolation of two coumarins, isoscopoletin, and scoparone. Isoscopoletin and scoparone were evaluated for antidiarrheal activity against castor oil-induced diarrhea model at 10 mg/kg and 20 mg/kg doses. RESULTS: The crude root extract of P. schimperianus, at doses of 100, 200, and 400 mg/kg, inhibited defecation by 37.5%, 46.2%, and 61.2%, respectively. At a dose of 20 mg/kg, scoparone and isoscopoletin reduced defecation by 61.2% and 66.6%, respectively. CONCLUSION: The study warrants further investigation of isoscopoletin and scoparone towards development as a novel treatment for diarrheal diseases.
Subject(s)
Antidiarrheals , Castor Oil , Mice , Animals , Antidiarrheals/pharmacology , Antidiarrheals/therapeutic use , Plant Extracts/adverse effects , Diarrhea/chemically induced , Diarrhea/drug therapy , Coumarins/pharmacology , Coumarins/therapeutic useABSTRACT
Deregulation of cyclin-dependent kinase 2 (CDK2) and its activating partners, cyclins A and E, is associated with the pathogenesis of a myriad of human cancers and with resistance to anticancer drugs including CDK4/6 inhibitors. Thus, CDK2 has become an attractive target for the development of new anticancer therapies and for the amelioration of the resistance to CDK4/6 inhibitors. Bioisosteric replacement of the thiazole moiety of CDKI-73, a clinically trialled CDK inhibitor, by a pyrazole group afforded 9 and 19 that displayed potent CDK2-cyclin E inhibition (Ki = 0.023 and 0.001 µM, respectively) with submicromolar antiproliferative activity against a panel of cancer cell lines (GI50 = 0.025-0.780 µM). Mechanistic studies on 19 with HCT-116 colorectal cancer cells revealed that the compound reduced the phosphorylation of retinoblastoma at Ser807/811, arrested the cells at the G2/M phase, and induced apoptosis. These results highlight the potential of the 2-anilino-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine series in developing potent and selective CDK2 inhibitors to combat cancer.
Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Cyclin-Dependent Kinase 2 , Cyclin-Dependent Kinases/metabolism , Antineoplastic Agents/pharmacology , Pyrimidines/pharmacology , Pyrazoles/pharmacologyABSTRACT
In the present study, we use knipholone as a prototype molecule to identify new anti-infective agents. Since knipholone is insoluble in water, which would have a detrimental effect on its bioavailability and efficacy, we synthesized knipholone Mannich base derivatives (2-4) that have better predicted solubility and investigated their in vitro antimicrobial activity against eight pathogenic bacterial and fungal strains. The chemical structures of compounds 1-4 were elucidated from their 1H and 13C NMR data, and their antimicrobial activity evaluation was carried out by a broth microdilution MTT assay. Compound 3 exhibited the strongest efficacy against Staphylococcus epidermidis, with MIC value of 9.7 µg/mL. While 4 exhibited the best activity against Staphylococcus aureus, with an MIC value of 19.5 µg/mL, and was the only one to significantly inhibit the fungus Trichophyton mentagrophytes (MIC = 78.2 µg/mL). The study provides evidence for the antibacterial activity of aminoalkyl derivatives of knipholone.
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ETHNOPHARMACOLOGICAL RELEVANCE: Around 80% of Ethiopians rely on traditional medicinal plants to treat a variety of ailments, and the country is home to a number of endemic plants, making it part of East Africa's hotspot of biodiversity. Despite widespread acceptance of endemic medicinal plants among the local community, comprehensive documentation of their therapeutic uses and phytochemistry is lacking. This review thus provides the first comprehensive appraisal of traditional use, pharmacological properties and phytochemistry of Ethiopian endemic medicinal plants. By storing and preserving indigenous and scientific knowledge about the medicinal benefits of the plants, such documentation generates information database for the future. It also aids the conservation of key medicinal plants along with translational research to accelerate the development of pharmaceuticals. AIM OF THE REVIEW: The aims of this review are to collect and document current information on the ethnopharmacological uses, phytochemistry, and biological activities of Ethiopian endemic medicinal plants, identify research gaps, and provide perspectives and suggestions for future research on the plants as potential sources of pharmaceuticals. MATERIALS & METHODS: A comprehensive literature review using electronic databases such as Medline, Web of Science, Google Scholar, ScienceDirect, SpringerLink, and Wiley Online Library was conducted for collecting relevant information. The World Flora Online (WFO) database and the International Plant Names Index (IPNI) were utilized to authenticate the taxonomic information of the plants. Chemical structures were drawn using ChemBioDraw Ultra 12.1 and verified via PubChem. RESULTS: The present review has identified 412 Ethiopian endemic plants. Out of the 412 endemic plants species recorded for Ethiopia 44 are medicinally valuable to mitigate a myriad of diseases, and nine (27.3%) of them are endangered. Our literature survey also found out that a total of 74 compounds were isolated and characterized from the endemic plants, with phenolics accounting for the majority of them (66.2%). The plants exhibited antimalarial, antimicrobial, anticancer, anthelmintic, mosquitocidal, antidiabetic, antioxidant, and anti-inflammatory properties. CONCLUSION: The work has resulted in an up-to-date inventory of Ethiopia's endemic flora, as well as the identification of species with traditional medicinal uses. The pharmacological activity and phytochemistry of numerous endemic plants with various traditional therapeutic claims are yet to be researched scientifically. Scientific validation of the herbal remedies, including evidence-based safety and efficacy studies are, therefore, crucial. The endangered medicinal plants must be conserved in order for local communities to have access to them in the future.
Subject(s)
Anti-Infective Agents , Plants, Medicinal , Ethiopia , Ethnopharmacology , Humans , Medicine, Traditional/methods , Pharmaceutical Preparations , Phytochemicals/chemistry , Phytochemicals/pharmacology , Phytochemicals/therapeutic use , Phytotherapy , Plant Extracts/chemistry , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Plants, Medicinal/chemistryABSTRACT
Lobelia giberroa Hemsl. is an endogenous Ethiopian medicinal plant with a long history of use in the treatment of malaria, bacterial and fungal diseases, and cancer. Here, we present the in vivo bioassay-guided fractionation of the 80% methanol extract of L. giberroa roots, which led to the isolation of lobetyolin. L. giberroa roots were extracted with 80% methanol, and the dried 80% methanol extract was fractionated with hexane, ethyl acetate, methanol, and water. Acute oral toxicity study was conducted according to the Organisation for Economic Co-operation and Development Guideline 425 by using female Swiss albino mice. Antimalarial activity was assessed in Plasmodium berghei-infected Swiss albino mice. Through in vivo bioassay-guided fractionation processes lobetyolin, a C14-polyacetylene glucoside, was isolated from the methanol fraction by silica gel column chromatography as the main active ingredient from the plant. The chemical structure of lobetyolin was elucidated by interpretation of spectroscopic data (1HNMR, 13CNMR, IR. MS) including two dimensional NMR. The plant extract was considered safe for administration up to 2000 mg/kg. In the four-day suppressive test, the 80% methanol extract (400 mg/kg), methanol fraction (400 mg/kg), and lobetyolin (100 mg/kg) exhibited antimalarial activity, with chemosuppression values of 73.05, 64.37, and 68.21%, respectively. Compared to the negative control, which had a mean survival time of 7 days, the lobetyolin (100 mg/kg) and methanol fraction (400 mg/kg) treated groups had mean survival times of 18 and 19 days, respectively. The current study supports the traditional use of the plant for the treatment of malaria. The structural differences between lobetyolin and existing antimalarials, as well as its previously unknown antimalarial activity, make it of interest as an early lead compound for further chemical optimization.
Subject(s)
Antimalarials , Lobelia , Animals , Female , Mice , Plant Extracts/chemistry , Plasmodium berghei , Plasmodium falciparum , PolyynesABSTRACT
BACKGROUND: Kniphofia foliosa is a flamboyant robust perennial herb which has dense clumps and tick upright rhizomes with leaves at the base. In Ethiopia, it has several vernacular names including Abelbila, Ashenda, Amelmela, Yeznjero Ageda, Shemetmetie and Yezinjero Ageda. The plant is endemic to Ethiopian highlands, where its rhizomes are traditionally used for the treatment of malaria, abdominal cramps and wound healing. In the present study, the 80% methanol extract of K. foliosa rhizomes and its constituents are tested against Plasmodium berghei in mice. METHODS: Isolation was carried out using column and preparative thin layer chromatography (PTLC). The chemical structures of the compounds were elucidated by spectroscopic methods (ESI-MS, 1D and 2D-NMR). Peters' 4-day suppressive test against P. berghei in mice was utilized for in vivo anti-malarial evaluation of the test substances. RESULTS: Two compounds, namely knipholone and dianellin were isolated from the 80% methanolic extract of K. foliosa rhizomes, and characterized. The hydroalcoholic extract (400 mg/kg) and knipholone (200 mg/kg) showed the highest activity with chemosuppression values of 61.52 and 60.16%, respectively. From the dose-response plot, the median effective (ED50) doses of knipholone and dianellin were determined to be 81.25 and 92.31 mg/kg, respectively. Molecular docking study revealed that knipholone had a strong binding affinity to Plasmodium falciparum l-lactate dehydrogenase (pfLDH) target. CONCLUSION: Results of the current study support the traditional use of the plant for the treatment of malaria.
Subject(s)
Antimalarials/pharmacology , Asphodelaceae/chemistry , Plant Extracts/pharmacology , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Animals , Anthraquinones/chemistry , Anthraquinones/pharmacology , Antimalarials/chemistry , Female , Male , Mice , Plant Extracts/chemistry , Rhizome/chemistry , Toxicity Tests, AcuteABSTRACT
CDK12 and CDK13 are Ser/Thr protein kinases that regulate transcription and co-transcriptional processes. Genetic silencing of CDK12 is associated with genomic instability in a variety of cancers, including difficult-to-treat breast, ovarian, colorectal, brain and pancreatic cancers, and is synthetic lethal with PARP, MYC or EWS/FLI inhibition. CDK13 is amplified in hepatocellular carcinoma. Consequently, selective CDK12/13 inhibitors constitute powerful research tools as well as promising anti-cancer therapeutics, either alone or in combination therapy. Herein the authors discuss the role of CDK12 and CDK13 in normal and cancer cells, describe their utility as a biomarker and therapeutic target, review the medicinal chemistry optimization of existing CDK12/13 inhibitors and outline strategies for the rational design of CDK12/13 selective inhibitors.
Subject(s)
Antineoplastic Agents/chemistry , Biomarkers, Tumor/metabolism , Cyclin-Dependent Kinases/antagonists & inhibitors , Neoplasms/drug therapy , Protein Kinase Inhibitors/chemistry , Animals , Antineoplastic Agents/pharmacology , Combined Modality Therapy , Drug Screening Assays, Antitumor , Gene Expression Regulation , Humans , Protein Binding , Protein Conformation , Protein Kinase Inhibitors/pharmacology , RNA Polymerase II/genetics , RNA Polymerase II/metabolism , Structure-Activity RelationshipABSTRACT
Crinum abyscinicum Hochst. ExA. Rich bulb is traditionally used in Ethiopia for the treatment of various ailments including internal parasites, mastitis, rabies, colic diseases of animals, and cancer. Despite its importance in traditional cancer treatment, no research work has been reported on the antiproliferative activity of the bulb extract and its major constituents. Phytochemical investigation of the bulb extract of C. abyscinicum by PTLC over silica gel resulted in the isolation of two alkaloids, which were unequivocally identified as 6-hydroxycrinamine and lycorine on the basis of 1H- and 13C-NMR and MS analysis. The bulb extract, 6-hydroxycrinamine, and lycorine possessed significant antiproliferative activity, lycorine being the most active exhibiting GI50 values of 2.8 µg/ml and 3.4 µg/ml against A2780 and MV4-11 cells, respectively. Cell cycle analysis and annexin V/propidium iodide double staining in A2780 cells revealed that both compounds increased the percentage of cells in the S-phase at 30 µg/ml without inducing apoptosis. Our results suggest that the antiproliferative activities of the bulb extract of C. abyscinicum, 6-hydroxycrinamine, and lycorine could support the traditional claim of the plant against cancer.
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Recently, the demand for functional foods in the global market has increased rapidly due to the increasing occurrences of non-communicable diseases and technological advancement. Antioxidant peptides have been suggested as ingredients used to produce health-promoting foods. These peptides are encrypted from various food derived protein sources by chemical and enzymatic hydrolysis, and microbial fermentation. However, the industrial-scale production of antioxidant peptides is hampered by different problems such as high production cost, and low yield and bioactivity. Accordingly, novel processing technologies, such as high pressure, microwave and pulsed electric field, have been recently emerged to overcome the problems associated with the conventional hydrolysis methods. This particular review, therefore, discussed the current processing technologies used to produce antioxidant peptides. The review also suggested further perspectives that should be addressed in the future.
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INTRODUCTION: Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are involved in the initiation and progression of various cancers. Deregulation of the CDK4/6-cyclin D-retinoblastoma (Rb) pathway is common in ovarian cancer and is associated with an aggressive phenotype and poor prognosis. Patients with advanced ovarian cancer whose tumor demonstrates Rb-positivity, a low expression of p16 and overexpression of cyclin D1 are most likely to benefit from CDK4/6 inhibition. MATERIALS AND METHOD: Anti-proliferative activity and mechanistic investigations for CDDD2-94, employing palbociclib as comparator, were evaluated by MTT assay, cell cycle and apoptosis analysis, western blotting as well as senescence and colony formation assay. In vivo safety and efficacy studies were done in A2780 tumor-bearing nude mice. Combinations of CDDD2-94 with mTOR, MEK, PI3K or PARP inhibitors were evaluated in A2780 and OVCAR5 ovarian cancer cells. RESULTS: Consistent with a CDK4-targeted mechanism, CDDD2-94 arrested the G1/G0 cell cycle, induced senescence and inhibited the proliferation of Rb-proficient ovarian cancer cells. CDDD2-94 exhibited synergistic anti-proliferative activities with mTOR, MEK, PI3K or PARP inhibitors. Importantly, unlike palbociclib which caused significant reductions in the number of lymphocytes and neutrophils, CDDD2-94 had little effect. CDDD2-94, as single agent and in combination with everolimus, delayed tumor growth and significantly increased survival of mice. CONCLUSION: Given its high specificity in targeting CDK4 and excellent anti-tumor efficacy with low toxicity, CDDD2-94 has potential to be developed as a standalone agent or in combination with targeted therapeutics for the treatment of ovarian cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Ovarian Neoplasms/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Synergism , Everolimus/pharmacology , Everolimus/therapeutic use , Female , Humans , Mice , Ovarian Neoplasms/pathology , Ovary/pathology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Xenograft Model Antitumor AssaysABSTRACT
Two new chemosensors, rhodamine B derivative bearing 3-formyl-6-nitrochromone (L 1 ) and 3-formyl-6-methylchromone (L 2 ) units were designed and synthesized using microwave irradiation for the selective detection of Cu2+ in aqueous media. Copper triggers the formation of highly fluorescent ring-open spirolactam. The fluorescence intensity was remarkably increased upon the addition of Cu2+ within a minute, while the other metal ions caused no significant effect. More importantly, the resulting complexes can be used as a reversible fluorescence sensor for CN-. The recognition ability of the sensors was investigated by fluorescence titration, Job's plot, 1H NMR spectroscopy and density functional theory (DFT) calculations.
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Parasitic roundworms (nematodes) are significant pathogens of humans and animals and cause substantive socioeconomic losses due to the diseases that they cause. The control of nematodes in livestock animals relies heavily on the use of anthelmintic drugs. However, their extensive use has led to a widespread problem of drug resistance in these worms. Thus, the discovery and development of novel chemical entities for the treatment of parasitic worms of humans and animals is needed. Herein, we describe our medicinal chemistry optimization efforts of a phenotypic hit against Haemonchus contortus based on a pyrrolidine-oxadiazole scaffold. This led to the identification of compounds with potent inhibitory activities (IC50 = 0.78-22.4 µM) on the motility and development of parasitic stages of H. contortus, and which were found to be highly selective in a mammalian cell counter-screen. These compounds could be used as suitable chemical tools for drug target identification or as lead compounds for further optimization.
Subject(s)
Anthelmintics/pharmacology , Haemonchus/drug effects , Oxadiazoles/pharmacology , Pyrrolidines/pharmacology , Animals , Anthelmintics/chemical synthesis , Anthelmintics/toxicity , Cell Line , Humans , Molecular Structure , Motor Activity/drug effects , Oxadiazoles/chemical synthesis , Oxadiazoles/toxicity , Parasitic Sensitivity Tests , Pyrrolidines/chemical synthesis , Pyrrolidines/toxicity , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Cyclin-dependent kinase 2 (CDK2) plays a pivotal part in cell cycle regulation and is involved in a range of biological processes. CDK2 interacts with and phosphorylates proteins in pathways such as DNA damage, intracellular transport, protein degradation, signal transduction, DNA and RNA metabolism and translation. CDK2 and its regulatory subunits are deregulated in many human cancers and there is emerging evidence suggesting CDK2 inhibition elicits antitumor activity in a subset of tumors with defined genetic features. Previous CDK2 inhibitors were nonspecific and limited by off-target effects. The development of new-generation CDK2 inhibitors represents a therapeutic opportunity for CDK2-dependent cancers.