A practical and novel approach for the regioselective synthesis of 3-arylthioindole derivatives has been accomplished using a combination of indole substrates with p-toluene sulfonyl hydrazide. This methodology employs NIS as the oxidant and PPh3 as the reductant to give the desired 3-arylthioindoles in good to excellent yields. This method offers several advantages, including simplicity, operational ease, and broad substrate scope.

We report the design, synthesis, and anticancer evaluation of some novel indole thioethers, constructed via an efficient and regioselective sulfenylation of indoles with sulfonyl hydrazides, facilitated by KSCN. This method offers a valuable tool for the synthesis of a variety of indole thioethers under mild reaction conditions with good to excellent yields. Initially, the drug like properties of all compounds were evaluated. Subsequently, six lead compounds were subjected to molecular docking studies targeting the active site of the B-RAF protein (PDB ID: 1UWH). These compounds demonstrated strong interactions with key amino acid residues, including Lys482 (3.47 & Aring;), Gln529 (3.28 & Aring;), Thr528 (2.85 & Aring;), Phe467 (2.85 & Aring;), Gly95 (2.86 & Aring;), Thr598 (3.30 & Aring;), His538 (3.37 & Aring;), Ser535 (3.22 & Aring;), and Asn579 (3.43 & Aring;), suggesting their potential as anticancer agents. DFT calculations of the novel thioethers revealed their energy gaps and binding affinities, while Hirshfeld surface analysis highlighted significant intermolecular interactions within their crystal structures. In vitro cell-based assays were conducted on selected compounds to assess their cytotoxicity against human cancer cell lines. The results suggest that extending the exposure duration beyond 24 h may uncover significant cytotoxic effects. In conclusion, these compounds exhibit promising potential as anticancer agents against the tested human cancer cell lines.

We report a novel metal-free approach for the desulfonylative halogenation of aryl sulfonyl chlorides and the C-H halogenation of arenes. This strategy employs hypervalent iodine(III) as both an oxidant and a group transfer agent with tetrabutylammonium halides (TBAX) as a halide source. The method offers several key benefits, including the use of inexpensive and readily available reagents, simple reaction conditions, compatibility with air, and the absence of transition metals.

A total of 10 benzopyrylium salts, 7 being novel, were synthesized by Claisen-Schmidt condensation reaction and characterized by H-1 and C-13 NMR, High-Resolution Mass Spectrometry, FT-IR, and UV-Vis spectroscopy. The purity of these synthesized compounds was determined by HPLC. The in-vitro anti-cancer evaluation of these synthesized benzopyrylium salts was done at National Cancer Institute (NCI), USA, against 60 human cancer cell lines. The compounds 4 and 8 showed promising anti-cancer activities against various human cancer cell lines. The docking studies of the compounds were carried out against the oncogenic target JNK and their docking scores were compared to that of the known JNK inhibitor SP600125 (Pyrazolanthrone). Compound 4 exhibited an outstanding docking score of -9.0 kcal/mol, comparable to the docking score of SP600125 (-9.3 kcal/mol). The ex-vivo studies in the hind-gut of Drosophila were carried out and the inhibitory activity of compound 4 supported the findings of the docking studies. Furthermore, the potent compounds 4 and 8 were taken up for their in-vivo anti-cancer evaluation in the colorectal cancer model (CRC) of Drosophila melanogaster. The toxicity studies of these potent compounds were carried out both in wild type and mutant type Drosophila and the lethal doses were determined to be 200 mu M.

Glioblastoma multiforme (GBM) is the most prevalent and aggressive brain tumor found in adult humans with a poor prognosis and average survival of 14-15 months. In order to have a comprehensive understanding of proteome and identify novel therapeutic targets, this study focused mainly on the differentially abundant proteins (DAPs) of Ras(V12)-induced GBM. Ras(V12) is a constitutively active Ras mutant form essential for tumor progression by continuously activating signaling pathways leading to uncontrolled tumor growth. This study used a transgenic Drosophila model with Ras(V12) overexpression using the repo-GAL4 driver line, specifically in glial cells, to study GBM. The high-resolution mass spectrometry (HRMS)-based proteomic analysis of the GBM larval central nervous system identified three novel DAPs specific to mitochondria. These DAPs, probable maleylacetoacetate isomerase 2 (Q9VHD2), bifunctional methylene tetrahydrofolate dehydrogenase (Q04448), and glutamine synthetase1 (P20477), identified through HRMS were further validated by qRT-PCR. The protein-protein interaction analysis revealed interactions between Ras(V12) and DAPs, with functional links to mitochondrial dynamics regulators such as Drp1, Marf, Parkin, and HtrA2. Notably, altered expressions of Q9VHD2, P20477, and Q04448 were observed during GBM progression, which offers new insights into the involvement of mitochondrial dynamic regulators in Ras(V12)-induced GBM pathophysiology.

A transition-metal-free synthesis of thiosulfonates has been accomplished by the disproportionate coupling of readily available and inexpensive sulfonyl hydrazides embracing hypervalent iodine(III)[phenyliodine(III) diacetate (PIDA)] as an oxidant. This synthesis involves cleavage of the S-N bond and is endowed with creation of a new S-S bond. The thiosulfonates were further reduced with CS2/KOH to obtain symmetrical disulfides. This protocol features mild reaction conditions in open air, an inexpensive oxidant, and high functional group tolerance with good to excellent product yields.

Cachexia and systemic organ wasting are metabolic syndrome often associated with cancer. However, the exact mechanism of cancer associated cachexia like syndrome still remain elusive. In this study, we utilized a scribble (scrib) knockdown induced hindgut tumor to investigate the role of JNK kinase in cachexia like syndrome. Scrib, a cell polarity regulator, also acts as a tumor suppressor gene. Its loss and mis-localization are reported in various type of malignant cancer-like breast, colon and prostate cancer. The scrib knockdown flies exhibited male lethality, reduced life span, systemic organ wasting and increased pJNK level in hindgut of female flies. Interestingly, knocking down of human JNK Kinase analogue, hep, in scrib knockdown background in hindgut leads to restoration of loss of scrib mediated lethality and systemic organ wasting. Our data showed that scrib loss in hindgut is capable of inducing cancer associated cachexia like syndrome. Here, we firstly report that blocking the JNK signaling pathway effectively rescued the cancer cachexia induced by scrib knockdown, along with its associated gut barrier disruption. These findings have significantly advanced our understanding of cancer cachexia and have potential implications for the development of therapeutic strategies. However, more research is needed to fully understand the complex mechanisms underlying this condition.

AIM:Design, synthesis and molecular docking studies of quinoline/naphthalene containing pyrazoline derivatives as PI3K inhibitors.BACKGROUND:Phosphatidylinositol 3-kinases (PI3Ks) belong to the family of enzymes, which are associated with various cellular functions such as cell growth, proliferation, differentiation etc. Overexpression or any changes in these functions may result in various abnormalities, which in turn cause cancer.OBJECTIVES:To perform synthesis and molecular docking studies of quinoline/naphthalene containing pyrazoline derivatives as PI3K inhibitors.METHODS:2-Chloroquinoline-3-carbaldehyde was synthesized by a reaction of acetanilide and POCl3. The latter was reacted with substituted acetophenones to synthesize chalcones, which were reacted with substituted phenyl hydrazines to yield pyrazoline derivatives (Series I). Similarly, pchloro benzaldehyde was reacted with 2-acetonapthone to yield chalcone with substituted phenyl hydrazines to yield pyrazoline derivatives (Series II).RESULTS:The synthetic compounds were subjected to molecular modelling experiments using Schrodinger 2016 software and evaluated in silico for their PI3K binding affinities. All the compounds had better docking scores than AMG-319 (-4.36 Kcal/mol) and comparable docking scores with PI-103 (-6.83 Kcal/mol).CONCLUSION:Compounds 5 and 3 had the best docking scores (-7.85 and -7.17 Kcal/mol, respectively). The synthesized compounds have better docking scores than the reference drug AMG-319. As a result, they might be used as lead molecules in investigating PI3K inhibitors.

Cancer alters host metabolism to meet its nutritional demands. The role of lipids and their association with colorectal cancer (CRC) remains elusive. Scribble (Scrib) is a cell polarity regulator protein that also functions as a tumor suppressor. Scrib dysregulation has been reported in various advanced cancers, including CRC.In this study, we used tissue-specific GAL4-UAS RNAi to knockdown Scrib in the Drosophila hindgut. Scrib knockdown led to the development of a CRC-like phenotype. Lipid droplets were enlarged in the adult fat body with tumor induction. We employed LC-MS-based untargeted lipidomics to explore global lipid changes in Scrib knockdown flies.Our analysis revealed alterations in total lipids, with 63 lipids upregulated, 48 downregulated, and 120 unaffected. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) revealed striking differences between wild-type and Scrib knockdown flies. Volcano plot analysis revealed that TAG 54:2, PIP2 35:6, PIP2 34:5, FFA 6:1, and PIP 37:2 were the top five significantly upregulated lipids, while TAG 52:1, GM3 38:2;3, GlcdE 2:6, PIP2 37:4, and PIP2 37:2 were the top five significantly downregulated lipids.Receiver operating characteristic (ROC) curve analysis identified TAG 54:2, PIP2 35:6, and PIP 42:2 as promising biomarker candidates.In summary, our results highlight the value of integrating LC-MS-based lipidomics with machine learning algorithms to explore significant lipid alterations at an organismal level in Scrib knockdown flies. These findings open avenues to investigate cancer-lipid interactions in CRC and related human cancers, potentially shedding light on new diagnostic and therapeutic opportunities.

This work presents the synthesis, characterization, crystal structure and spectroscopic investigations of isophthalohydrazide based probe. Among various tested metal ions, the probe selectively detects Al3+ and Cu2+ in aqueous ethanol via fluorometric and colorimetric methods, respectively. It displays a fluorescence "turn-on" response with Al3+ and visual colour change from colourless to yellow with Cu2+. Sensing mechanism is explored with UV-Vis, fluorescence spectroscopy and 1H NMR titration, and confirmed with computational results. Suppression of CN isomerization and photo-induced electron transfer (PET) along with chelation enhanced fluorescence emission (CHEF) result in "turn-on" fluorescence with Al3+ while ligand to metal charge transfer (LMCT) accounts for visual colour change with Cu2+. Job's plot and HRMS confirm 1:2 (L:M) stoichiometry. The probe also exhibits efficient reversibility and reproducibility with EDTA which are successfully mimicked with combinatorial logic gate and truth table. Additionally, solid state applications and bio-imaging investigation on gut tissue of Drosophila 3rd instar larvae are performed.

A total of eight novel spirobibenzopyrans were synthesized by Claisen-Schmidt condensation reaction and have been characterized by 1H NMR, 13C NMR, FT-IR, UV-Vis spectroscopy, and High-Resolution Mass Spectrometry. The purity of these synthesized compounds was determined by HPLC. The in vitro anti-cancer screening of these synthesized spirobibenzopyrans was carried out at National Cancer Institute (NCI), USA, against 60 human cancer cell lines. In light of the NCI results, the potent spirobibenzopyrans identified were compounds 1, 2, 4, and 5. COMPARE analyses of the potent compounds show a strong to considerable correlation to the marketed anti-cancer drug vinblastine sulfate (microtubule formation inhibitor). Furthermore, compounds 2 and 4 were taken up for their in vivo anti-cancer evaluation in the epithelial cancer model of Drosophila melanogaster and their lethal doses in both wild-type and mutant organisms were determined to be 300 μM . The anti-cancer studies of the spirobibenzopyrans have been supported with the molecular docking studies performed against the target protein c-Jun N-terminal kinase (JNK). Compound 4 showed the highest docking score of −8.3 kcal/mol among the compounds we have reported here. In addition, drug-likeness studies of the synthesized novel spirobibenzopyrans were carried out to find their potential as drugs.

Background: In Alzheimer Disease (AD) pathogenesis, aggregation of A beta(42) fibrils strongly correlates with memory dysfunction and neurotoxicity. Till date, no promising cures for AD. Report shows that flavonoids contributed anti-oxidant, anti-cancer and neuroprotection activity by regulating the mitochondrial machinery. Here, we first report the identification of flavonoids from Ascophyllum nodosum as having the ability to dissolve A beta(42) fibrils in an AD model of Drosophila. FRAN could be superior anti-AD agents for neuroprotection, their underlying mechanism and how they collectively halted amyloidogenesis is currently being investigated. Purpose: This study aimed to investigate the neuroprotective role of FRAN in the A beta(42) expressing AD model of Drosophila. Methods: Drosophila stocks: OregonR(+), ey-GAL4/CyO, elav(c155)-GAL4, UAS-mitoGFP, UAS-mcherry.mito.OMM, UAS-A beta(42)/CyO were used, cultured at 28 +/- 1 degrees C in a BOD incubator. Ascophyllum extract rich in flavonoids as revealed by LC-MS study and employed against the AD flies. The validation of A beta(42) expression was done by immunostaining and q-RT PCR. The eye roughness of AD flies was scored in a dose-dependent manner. Further, In vivo and in silico studies of FRAN extract was executed against A beta(42) induced neurotoxicity. Results: In order to determine the most effective lethal dose of FRAN extract concentration 1, 2, 5, 10 mg/ml were screened using OregonR(+)flies. Extract 1 and 2 mg/ml did not show any lethality. Hence, extract 2 mg/ml was employed on AD flies and a >= 50% rescue in the eye phenotype was observed using SEM images. This dose had a strong effect on cell apoptosis, viability, longevity, mitochondrial dysfunction and oxidative stress by regulating mitochondrial dynamic markers in comparable to control. Extract also scavenging free radicals in order to maintain in situ cellular ROS and prevent A beta(42)-induced neurotoxicity in vivo and in silico. Hence, we suggest its great potential as a future therapeutic agent for AD treatment. Conclusion: In conclusion, FRAN extract rich in flavonoids as having largest neuroprotective activity against A beta(42) aggregation in eye tissue of Drosophila. Extract shows strong effect against A beta(42)-induced neurotoxicity by altering the various cellular and molecular events. So, it could be considered as strong anti-AD agents for neuroprotection.

The present study was conducted to produce cattle embryos through in vitro culture by supplementing media with epidermal growth factor.Immature cattle oocytes were collected from slaughterhouse ovaries, washed 5-6 times and cultured in maturation media (TCM-199+10% FBS+5 µg ml -1 FSH-P+0.33 mM sodium pyruvate+50 µM β-Mercaptoethanol+50 µg ml -1 gentamicin sulfate) supplemented with epidermal growth factor with three different concentrations (5, 10 and 20 ng ml -1 ) for 24 h. in 5% CO 2 incubator at 38.5 °C with maximum humidity.After 24 h matured oocytes were allowed for fertilization with capacitated sperms in Fert-BO media at 38.5 °C in CO 2 incubator.After 15-18 h of sperm-oocyte co-incubation, the cumulus cells were washed off from the oocytes by gentle pipetting in washing medium.The oocytes were then washed 1-2 times with modified Charles Rosenkrans 2 amino acid (mCR2aa) media and cultured in 100 µl droplet supplemented with epidermal growth factor, and cultured for cleavage.After 48 h cleavage was checked and further co-cultured with oviductal cells for development.In the present study the cleavage rate and morula formation rate were significantly higher in the treatment group as compared to control group.The mean percentage of cleavage rate was 41.63±1.92 in control group.The highest mean percentage of cleavage rate was 55.13±1.45 in 10 ng ml -1 treatment groups.From the present study it could be concluded that epidermal growth factor may have induced the cleavage after fertilization.

The present study was conducted to produce cattle embryos through in vitro maturation, fertilization and culture by supplementing culture media with triiodothyronine (T3). Cattle ovaries were collected from Kolkata slaughter house and brought to the laboratory within 3-4 h in normal saline maintaining 30-35 oC. Oocytes were collected from visible surface follicles (3-8 mm) in the aspiration media (TCM-199 + DPBS + 3 mg/ml BSA + 50 g/ml gentamycin) by 19 g hypodermic needle. The COCs were washed thoroughly 5-6 times in washing media (TCM-199 + 10%FBS + 27 g/ml sod. pyruvate + 50 g/ml gentamycin sulfate) and matured in-vitro for 24 h in maturation media (TCM-199 + 10% FBS + 5 μg/ ml FSH-P + 0.33 mM sodium pyruvate +50 μM β-mercaptoethanol + 50μg/ml gentamicin sulfate)supplemented with triiodothyronine (T3) with three different concentrations (viz.20, 50 and 100 ng/ml) at 38.5 oC in CO2 incubator with maximum humidity. After 24 h matured oocytes were allowed for fertilization with in vitro capacitated sperms in Fert-BO media at 38.5 oC in CO2 incubator.After the 15-18 h of spermoocyte co-incubation, the cumulus cells were washed off from the oocytes by gentle pipetting in washing medium. The oocytes were then washed 1-2 times with RVCL media and cultured in 100 μl RVCL medium supplemented with T3,and cultured for cleavage. After 48 h of culture cleavage was checked and further co-cultured with oviductal cells for development.In the present study Corresponding Author email ID:subratakdas1@gmail.com 26 Aman Kumar Singh, et al the cleavage rate and morula rate were significantly higher in the treatment group as compared to control group. The mean percentage of cleavage rate was 21.02±1.38 in control group. The highest mean percentage of cleavage rate was 43.72±6.2 in 100 ng/ml treatment group. From the present study it could be concluded that triiodothyronine may have influenced to increase the cleavage rate after fertilization.