An Efficient Approach for the Synthesis and Antitumor Evaluation of Novel Azo- and Anil-Linked with 3-Aminopyrazolo[3,4-b]pyridine

In this project, an effective procedure for constructing a new combination of pyrazolo[3,4-b]pyridine was depicted through the coupling of diazonium salt 2 of heterocyclic amine 1 with active methylene, enamine, and amidine moieties such as 3 , 5 , 7 , and 9 at 0–5 °C in pyridine to afford hydrazinylhydrazonoyl derivatives 4 , and diazenylheterocyclic derivatives 6 , 8 , and 10 , respectively. Also, aminopyrazolo[3,4-b]pyridine 1 condensed with different aryl or heteroaryl aldehydes in EtOH/AcOH gave the corresponding aldimine 14 , 15 , 16 . Compound 15 was cyclized via refluxing in DMF for 6 h to afford 18 , while the transformation of compound 16 with an alkyl halide afforded 19a , b . The synthesized compounds, explicated by spectral data and elemental analysis, were examined for their antitumor activities. The in vitro cytotoxic activity of new pyrazolo[3,4-b]pyridines against the A2780CP, MCF-7, and HepG-2 cell lines was evaluated using the reference doxorubicin. Compounds 15 and 19a exhibited high reactivity against the A2780CP cell lines, with IC₅₀ values of 35 and 17.9 μM, respectively. Also, compound 28 had the cytotoxic potential for A2780CP and MCF-7 cell lines, with IC₅₀ values of 14.5, and 27.8 μM, respectively.     

Evaluation of the Potential Therapeutic Properties of Liquidambar orientalis Oil

Liquidambar orientalis Mill., commonly called the Anatolian sweetgum or Sigla tree, is endemic to southwestern Turkey. It has been historically significant in traditional medicine. In our research, we delved into the therapeutic attributes of its oil, emphasizing its antioxidant, antimicrobial, and antitumor properties. The primary chemical constituent of the gum is styrene, accounting for 78.5 %. The gum demonstrated antioxidant capabilities in several assays, including in 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), cupric reducing antioxidant capacity (CUPRAC) and ferric reducing antioxidant power (FRAP). It displayed bactericidal actions against various gram-positive bacteria, such as Staphylococcus aureus, and gram-negative strains, including Escherichia coli. Additionally, the oil showcased potent antitumor effects against breast (MDA-MB-231), lung (A549), and prostate (PC3) cancer cell lines. These effects were found to be both time- and dose-dependent. L. orientalis Mill. oil showed the best antitumor activity against breast, lung, and prostate cancer cell lines after the 24 h and 48 h treatment. Its oil might induce autophagy in the PC3 prostate cancer cell line, whereas its cytotoxicity against MDA-MB-231 and A549 cancer cell lines might not be correlated with autophagy or apoptosis pathways. In conclusion, the oil from the Sigla tree offers promising therapeutic potential and warrants further exploration.     

Profiling the physiological pitfalls of anti-hepatitis C direct-acting agents in budding yeast

Sofosbuvir and Daclatasvir are among the direct-acting antiviral (DAA) medications prescribed for the treatment of chronic hepatitis C (CHC) virus infection as combination therapy with other antiviral medications. DAA-based therapy achieves high cure rates, reaching up to 97% depending on the genotype of the causative hepatitis C virus (HCV). While DAAs have been approved as an efficient and well-tolerated therapy for CHC, emerging concerns about adverse cardiac side effects, higher risk of recurrence and occurrence of hepatocellular carcinoma (HCC) and doubts of genotoxicity have been reported. In our study, we investigated in detail physiological off-targets of DAAs and dissected the effects of these drugs on cellular organelles using budding yeast, a unicellular eukaryotic organism. DAAs were found to disturb the architecture of the endoplasmic reticulum (ER) and the mitochondria, while showing no apparent genotoxicity or DNA damaging effect. Our study provides evidence that DAAs are not associated with genotoxicity and highlights the necessity for adjunctive antioxidant therapy to mitigate the adverse effects of DAAs on ER and mitochondria.     

Design,Synthesis, Cytotoxic Screening and Molecular Docking Studies of Novel Hybrid Thiosemicarbazone Derivatives as Anticancer Agents

Thiosemicarbazones have been the focus of scientists owing to their broad clinical anticancer range. Herein, A Series of new thiosemicarbazone derivatives 5 – 9 were synthesized and confirmed through the use of different spectroscopic techniques along with elemental analysis. The in vitro cytotoxic activity of compounds 5 – 9 against MCF-7 and A549 cell lines and normal breast cells were assessed. Several compounds were found to be active. The most active compound 7 caused MCF-7 cell cycle arrest at G1/ S phases; and induced apoptosis at the pre-G1 phase. The apoptosis-inducing activity of compound 7 was proofed by the elevation of caspase 3/7 activity and also by up-regulation of the expression of Bax and p53 proteins together with the down-regulation of the expression of the Bcl-2 protein. It also had a strong inhibitory effect topoisomerase IIβ enzyme. Molecular Docking study revealed that the synthesized compounds had good docking scores compared to the standard drug Etoposide towards the topoisomerase IIβ protein (3QX3). Overall, these findings confirmed that the new thiosemicarbazone derivatives could aid in the development of promising cancer drug candidates.     

Effects of 1 vs. 2 sessions per week of equal-volume sprint training on explosive,high-intensity and endurance-intensive performances in young soccer players

The study aimed to evaluate the effects of 1 vs. 2 sessions per week of equal-volume sprint training on explosive, high-intensity and endurance-intensive performances among young soccer players. Thirty-six young male soccer players were randomly divided into 2 experimental groups that performed either a single weekly sprint training session (ST1, n = 18, age: 17.2 ± 0.8 years) or two weekly sprint training sessions (ST2, n = 18; age: 17.1 ± 0.9 years) of equal weekly and total volume, in addition to their regular soccer training regimen. Linear sprinting (10 m, 20 m, 30 m, and flying 10 m), T-test agility, countermovement jump (CMJ) and maximal oxygen consumption were assessed one week before (T1), in the middle (T2) and immediately after the 10 weeks of training (T3). A large magnitude and statistically significant main effect for time was found in all the assessed variables after both training interventions (all p < 0.001; ES ≥ 0.80). No main effect was observed between the 2 groups at any time in linear sprinting, T-test or CMJ test (p > 0.05; ES < 0.20). A significant interaction effect (F = 4.05; p = 0.04, ES = 0.21) was found for maximal oxygen consumption with ST2 inducing better performance than ST1 (p = 0.001; ES = 1.11). Our findings suggested that the two sprint training frequencies were effective in enhancing explosive, high-intensity and endurance-intensive performances. However, it is recommended for coaches and fitness coaches to use a biweekly sprint training modality as it was found to be more effective in improving endurance-intensive performance.     

Molecular characterization of endangered endemic plant Aloe pseudorubroviolacea using chloroplast matK and plastid rbcL gene

An endangered and rare species Aloe pseudorubroviolacea from the plant family Asphodelaceae which is presently recorded as endangered in Saudi Arabia collected from Al-Baha region of Saudi Arabia its GPS Latitude and Longitude coordinates 19.8345, 41.5481. The chloroplast matK and rbcL gene was considered in this study based on molecular identification the size is about 571 and 664 bp respectively. From the sequence analysis the gene matK and rbcL confirm that this species is very much closely related with A. rubroviolacea and also inter related with the species Astroloba rubriflora, Chrysopogon gryllus, Chortolirion angolense shows about 98.7% sequence homology. The partial matK and rbcL gene sequence discriminate Aloe pseudorubroviolacea from the closely related plant species, A. rubroviolacea. The gene sequence of rbcL discriminates the species from Chrysopogon gryllus and Chortolirion angolense, demonstrates the nucleotide variations in 3 different sites (623C/T; 653C/T; 700C/A). This study showed that matK and rbcL sequence region of chloroplast gene used to authenticate the samples of A. pseudorubroviolacea and which provide to help in correct identification and conservation process of this medicinally valuable endangered plant species.     

A sulfated polyphenols-rich extract from Sabal yapa exhibits antitumor activities in Ehrlich ascites carcinoma

Cancer is the second leading cause of mortality accounting for one in every six deaths globally. Plant secondary metabolites, among them polyphenols, represent an effective and much safer alternative approach to the currently available medications. In this work, utilizing LC-MS/MS, we characterized the constituents of S. yapa leaves extract and evaluated its antioxidant and anticancer properties. In total, 34 secondary metabolites, mainly flavonoids (Tricin, luteolin, and apigenin and their glucosides as well as sulfated derivatives) were identified. The extract manifested substantial antioxidant activity in DPPH assay, and high total phenolic content determined by Folin Ciocalteu method. The extract was safe up to 4800 mg/kg b.wt. when administered orally in mice and neither affected the hematological parameters nor the liver enzyme levels at the studied dose (LD₅₀, 480 mg, kg b.wt.). In the treated animals, the extract surpassed the reference drug (5-flouro uracil) and significantly reduced the tumor volume and weight by 71.50 and 85.46%, respectively, increased the median survival time to 53.2 days and the lifespan by 116%. The extract improved all the hematological parameters, where it increased the hemoglobin (Hb) concentration, red blood cell (RBC) count, packed cell volume (PVC) and platelets by 58.21, 8.98, 9.89 and 120%, respectively, compared to the untreated EAC bearing animals. Additionally, the extract significantly declined the elevated levels of ALT and AST enzymes by 29.18% and 59.88%, respectively. In molecular docking, the annotated flavonoids displayed appreciable binding affinities to the active sites of VEGFR1 and VEGFR2. In conclusion, Saba yapa is a promising plant that can be introduced to further advanced clinical studies for the development of novel anticancer drugs with lower side effects.     

Daltroban blocks thromboxane responses in the pulmonary vascular bed of the cat.

The influence of daltroban (BM13.505; SK&F 96148), a thromboxane (Tx) A2-receptor-blocking agent, on responses to the TxA2 mimics U-46619 and U-44069 was investigated in the pulmonary vascular bed of the intact-chest cat under constant-flow conditions. Daltroban (5 mg/kg iv) had no significant effect on mean baseline vascular pressures but significantly decreased responses to the TxA2 mimics without altering responses to prostaglandin (PG) F2 alpha or PGD2 or the PGD2 metabolite 9 alpha, 11 beta-PGF2. Dose-response curves for U-46619 and U-44069 were shifted to the right in a parallel manner, and daltroban had no significant effect on responses to norepinephrine, serotonin, angiotensin II, BAY K 8644, endothelin-(ET) 1, ET-2, or platelet-activating factor (PAF). After administration of daltroban, responses to U-46619 returned to 50% of control in 90 min and responses to the PG and TxA2 precursor arachidonic acid were decreased significantly. These results suggest that daltroban selectively antagonizes TxA2-receptor-mediated responses in a competitive and reversible manner. These data provide support for the hypothesis that discrete TxA2 receptors unrelated to receptors stimulated by PGF2 alpha, PGD2, or 9 alpha, 11 beta-PGF2 are present in the pulmonary vascular bed of the cat. The present data suggest that pulmonary vasoconstrictor responses to PAF and ET peptides are not dependent on activation of TxA2 receptors in the cat.