Repurposing of Strychnine as the Potential Inhibitors of Aldo-keto Reductase Family 1 Members B1 and B10: Computational Modeling and Pharmacokinetic Analysis.

AKR1B1 and AKR1B10 are important members of aldo-keto reductase family which plays a significant role in cancer progression by modulating cellular metabolism. These enzymes are involved in various metabolic processes, including the synthesis and metabolism of hormones, detoxification of reactive aldehydes, and the reduction of various endogenous and exogenous compounds. This study aimed to explore the potential of strychnine as an anticancer agent by targeting AKR1B1 and AKR1B10 via drug repurposing approach. To assess the drug-like properties of strychnine, a physiologically based pharmacokinetic (PKPB) model and High Throughput Pharmacokinetics (HTPK) approach were employed. The obtained results fell within the expected range for drug molecules, confirming its suitability for further investigation. Additionally, density functional theory (DFT) studies were conducted to gain insight into the electronic properties contributing to the drug molecule's reactivity. Building upon the promising DFT results, molecular docking analysis using the AutoDock tool was performed to examine the binding interactions between strychnine and the proposed targets, AKR1B1 and AKR1B10. Findings from the molecular docking studies suggested a higher probability of strychnine acting as an inhibitor of AKR1B1 and AKR1B10 with docking scores of - 30.84 and - 29.36 kJ/mol respectively. To validate the stability of the protein-ligand complex, Molecular Dynamic Simulation (MDS) studies were conducted, revealing the formation of a stable complex between the enzymes and strychnine. This comprehensive approach sheds light on the potential effectiveness of strychnine as a treatment for breast, lung, liver, and pancreatic cancers, as well as related malignancies. The novel insights gained from the physiologically based pharmacokinetic modeling, density functional theory, molecular docking, and molecular dynamics simulations collectively support the prospect of strychnine as a promising molecule for anticancer therapy. Further investigations are warranted to validate these findings and explore the therapeutic potential of strychnine in preclinical and clinical settings.

Computational Exploration of Fluorocyclopentenyl-purines and-pyrimidines Derivatives as Potential Inhibitors of Epidermal Growth Factor Receptor (EGFR) for the Treatment of Breast Cancer.

The Epidermal Growth Factor Receptor (EGFR) is an important therapeutic target for the treatment of a variety of epithelial malignancies, including breast cancer, in which EGFR is aberrantly expressed.The fluorocyclopentenyl-purine-pyrimidines derivatives, which have previously been described as powerful compounds against breast cancer, were selected to investigate their potential against EGFR using computational tools in an effort to obtain potent inhibitors with fewer adverse effects. The molecule's chemical reactivity and stability were assessed by determining the HOMO-LUMO energy gap using density functional theory (DFT) calculations. Among all the selected compounds, PU4 displayed a HOMO-LUMO gap of 0.191 eV. Additionally, molecular docking analysis was performed to assess the binding affinities of PU4 within the active pocket of EGFR-TK. The compound PU4 showed potent interactions with EGFR exhibiting -32.3 kJ/mol binding energy which was found best as compared to gefitinib i. e., -27.4 kJ/mol which was further validated by molecular dynamics simulations and ADMET analysis. The results of these analyses indicate that the top hits obtained from the virtual screening possess the ability to act as effective EGFR inhibitor. Therefore, it is recommended to further investigate the inhibitory potential of these identified compounds using in vitro and in vivo approaches.

In Silico Prospects and Therapeutic Applications of Ouabagenin and Hydroxylated Corticosteroid Analogues in the Treatment of Lung Cancer.

Lung cancer is the second most prevalent carcinoma around the world, and about 80% of patients are of non-small cell lung cancer (NS-CLC). Epidermal growth factor receptor (EGFR) is the most expressed protein kinases in lung cancer and hence can be used in target-related anti-cancer therapy. Here, computational approach is used for the exploration of the anti-cancer potential of new steroid derivatives as previously no in vitro data was available for them. Initially, DFT calculations of all compounds were determined to analyze the electronic density of optimized structures. The HOMO and LUMO orbital analysis of all derivatives was analyzed, to investigate the reactivity of compounds. Afterwards, optimized structures were used for molecular docking studies in which all ouabagenin derivatives were docked within the EGFR active site using MOE software. Moreover, anti-cancer potential of selected derivatives was evaluated on the basis of binding interactions with three anti-cancer proteins. The binding scores of these compounds were compared with the FDA-approved drug, i.e., gefitinib. The findings of current study suggested that selected derivatives exhibited significant inhibiting potential of anti-cancer proteins and EGFR. Particularly, compound OD3 is the potent inhibitor of anti-cancer and EGFR protein with the highest binding energies. These novel steroidal derivatives are subjected to in silico analysis for the first time against lung cancer. These compounds possess potential anti-cancerous properties and can be explored further for in vitro and in vivo studies.

Appraisal of novel azomethine-thioxoimidazolidinone conjugates as ecto-5'-nucleotidase inhibitors: synthesis and molecular docking studies.

Purinergic signaling is regulated by a group of extracellular enzymes called ectonucleotidases. One of its members i.e., ecto-5'-nucleotidase (h-e5'NT) is involved in the final step of the enzymatic hydrolysis cascade that is the conversion of adenosine monophosphate (AMP) to adenosine and therefore, involves the regulation of adenosine level in extracellular space. The overexpression of h-e5'NT has been observed in various pathological conditions such as hypoxia, inflammation and cancers, and led to various complications. Hence, the identification of a potent as well as selective inhibitor of h-e5'NT is of greater importance in therapeutic treatment of various diseases. Azomethine-thioxoimidazolidinone derivatives were studied for their inhibition potential against e5'NT enzyme along with cytotoxic potential against cancer cell lines possessing overexpression of e5'NT enzyme. The derivative (E)-3-((4-((3-methoxybenzyl)oxy)benzylidene)amino)-2-thioxoimidazolidin-4-one (4g) displayed selective and significant inhibition towards h-e5'NT with an IC50 value of 0.23 ± 0.08 µM. While two other derivatives i.e., (E)-3-(((5-bromothiophen-2-yl)methylene)amino)-2-thioxoimidazolidin-4-one (4b) and 2-thioxo-3-((3,4,5-trimethoxybenzylidene)amino)imidazolidin-4-one (4e), exhibited non-selective potent inhibitory behavior against both human and rat enzymes. Moreover, these derivatives (4b, 4e and 4g) were further investigated for their effect on the expression of h-e5'NT using quantitative real time polymerase chain reaction. Additionally, molecular docking and DFT studies were also performed to determine the putative binding mode of potent inhibitors within the enzyme active site. HOMO, LUMO, ΔE, and molecular electrostatic potential maps were computed by DFT and the charge transfer regions within the molecules were identified to find out the regions for electrophilic and nucleophilic attack.

Ectonucleotidase Inhibitory and Redox Activity of Imidazole-Based Organic Salts and Ionic Liquids.

Cytotoxicity against cancer and normal cells, inhibition of ectonucleotidase, and redox properties of a new group of imidazole-based organic salts and ionic liquids were studied. The tetrachloroferrate salt of a 1-methylimidazole derivative of salicylic aldehyde had most prominent inhibitory activity against ectonucleotidase as well as a higher cytotoxicity against HeLa cells and lower cytotoxicity against BHK-21 cells than the reference compound carboplatin. The studied compounds exhibited a moderate level of antioxidant activity with better results for the salicylic aldehyde derivatives than for spiropyrans. Moreover, these compounds did not generate singlet oxygen.

Phytocosmeceutical formulation development, characterization and its in-vivo investigations.

Several plants found rich in flavonoid, polyphenols, and antioxidants reported antiaging, oppose inflammation and carcinogenic properties but have rarely been applied in dermatology. The present study was an active attempt to formulate a stable phytocosmetic emulsion system loaded with 2% pre-concentrated Prosopis cineraria bark extract, aiming to revive facial skin properties. In order to obtain potent therapeutic activities, we first prepared extracts of stem, leaves, and bark and screen them on basis of phenolic, flavonoids contents and antioxidant, antibacterial, lipoxygenase and tyrosinase inhibition activities. Furthermore, cytocompatibility of the extract was also determined prior starting in vivo investigations. Then the in vivo performance of 2% bark extract loaded emulsion formulation was determined by using non-invasive probe cutometer and elastometer with comparison to base formulation. The preliminary experiment showed that bark extract has a significant amount of phenolic and flavonoid compounds with eminent antioxidant potential. Furthermore, indicated an efficient antibacterial, lipoxygenase, and tyrosinase enzyme inhibition activities. Importantly, the bark extract did not induce any toxicity or apoptosis, when incubated with HaCat cells. Moreover, the in vivo results showed the formulation (size 3 µm) decreased the skin melanin, erythema and sebum contents up to 2.1-,2.7-and 79%, while increased the skin hydration and elasticity up to 2-folds and 22% as compared to the base, respectively. Owing to enhanced therapeutic effects the phytocosmetic formulation proved to be a potential skin whitening, moisturizer, anti-acne, anti-wrinkle, anti-aging therapy and could actively induce skin rejuvenation and resurfacing.

Synthesis of novel (E)-1-(2-(2-(4(dimethylamino) benzylidene) hydrazinyl)-4-methylthiazol-5-yl)ethanone derivatives as ecto-5'-nucleotidase inhibitors.

Ecto-5'-nucleotidase (e5'NT), a membrane-bound enzyme and an essential member of ecto-nucleotidases which regulates extracellular purinergic signalling. Their upregulation results in various disease conditions, for example, inflammation, hypoxia and cancer. Therefore, efforts have been made to synthesize potent and selective inhibitors of e5'NT. Here we have synthesized, characterized and evaluated six thiazole derivatives (3a-3f) as potent e5'NT inhibitors. Among all derivatives, the compound (E)-1-(4-methyl-2-(2-(pyridin-3-ylmethylene)hydrazinyl) thiazol-5-yl)ethanone (3a) exhibited maximum inhibition towards both human and rat enzymes. However, their potency against h-e5'NT was 24-fold higher than r-e5'NT. Only two compounds exhibited inhibitory behaviour towards r-e5'NT. The molecular structures of these derivatives were confirmed with the help of solid-state characterization through NMR (1H and 13C), FTIR and elemental analysis. Additionally, molecular docking was also implemented to explain putative bonding interaction between the active site of an enzyme and potent inhibitors.

4-Aminopyridine based amide derivatives as dual inhibitors of tissue non-specific alkaline phosphatase and ecto-5'-nucleotidase with potential anticancer activity.

Ecto-nucleotidase members i.e., ecto-5'-nucleotidase and alkaline phosphatase, hydrolyze extracellular nucleotides and play an important role in purinergic signaling. Their overexpression are implicated in a variety of pathological states, including immunological diseases, bone mineralization, vascular calcification and cancer, and thus they represent an emerging drug targets. In order to design potent and selective inhibitors, new derivatives of 4-aminopyridine have been synthesized (10a-10m) and their structures were established on the basis of spectral data. The effect of nature and position of substituent was interestingly observed and justified on the basis of their detailed structure activity relationships (SARs) against both families of ecto-nucleotidase. Compound 10a displayed significant inhibition (IC50 ±â€¯SEM = 0.25 ±â€¯0.05 µM) that was found ≈168 fold more potent as compared to previously reported inhibitor suramin (IC50 ±â€¯SEM = 42.1 ±â€¯7.8 µM). This compound exhibited 6 times more selectivity towards h-TNAP over h-e5'NT. The anticancer potential and mechanism were also established using cell viability assay, flow cytometric analysis and nuclear staining. Molecular docking studies were also carried out to gain insight into the binding interaction of potent compounds within the respective enzyme pockets and herring-sperm DNA.

Isonicotinohydrazones as inhibitors of alkaline phosphatase and ecto-5'-nucleotidase.

A series of isonicotinohydrazide derivatives was synthesized and tested against recombinant human and rat ecto-5'-nucleotidases (h-e5'NT and r-e5'NT) and alkaline phosphatase isozymes including both bovine tissue-non-specific alkaline phosphatase (b-TNAP) and tissue-specific calf intestinal alkaline phosphatase (c-IAP). These enzymes are implicated in vascular calcifications, hypophosphatasia, solid tumors, and cancers, such as colon, lung, breast, pancreas, and ovary. All tested compounds were active against both enzymes. The most potent inhibitor of h-e5'NT was derivative (E)-N'-(1-(3-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)ethylidene)isonicotinohydrazide (3j), whereas derivative (E)-N'-(4-hydroxy-3-methoxybenzylidene)isonicotinohydrazide (3g) exhibited significant inhibitory activity against r-e5'NT. In addition, the derivative (E)-N'-(4'-chlorobenzylidene)isonicotinohydrazide (3a) was most potent inhibitor against calf intestinal alkaline phosphatase and the derivative (E)-N'-(4-hydroxy-3-methoxybenzylidene)isonicotinohydrazide (3g) was found to be most potent inhibitor of bovine tissue-non-specific alkaline phosphatase. Furthermore, putative binding modes of potent compounds against e5'NT (human and rat e5'NT) and AP (including b-TNAP and c-IAP) were determined computationally.

Malignant phyllodes tumor in an 11-year-old girl with fatal clinical outcome. A case report.

BACKGROUND: Phyllodes tumors are rare biphasic tumors occur predominantly in middle aged women. Malignant phyllodes tumor in children is very rare. OBJECTIVE: To report a case of malignant phyllodes tumor in a pre-menarchal girl. METHODS: H&E slides of the case were reviewed and follow up was obtained. RESULTS: The patient was 11-year-old girl who noticed a lump in her right breast 1 year back which grew rapidly in size. Wide local excision of the mass was done and histopathology revealed a malignant phyllodes tumor. Patient underwent mastectomy one month later due to recurrence. Two years later, she presented with dyspnea and chest pain. CT showed lung metastasis. The patient died of disease 1 year later due to widespread metastasis in liver and bone. CONCLUSION: We report a case of malignant phyllodes tumor in an 11-year-old girl, which behaved aggressively and patient died of disease due to widespread metastases 3 years after diagnosis.