Simultaneous estimation of paclitaxel and bortezomib via LC-MS/MS: pharmaceutical and pharmacokinetic applications.

Aim & Objective: This study evaluates the potential of combining paclitaxel (PTX) and bortezomib (BTZ) for breast cancer therapy. Materials & Methods: The nanoformulation was optimized via Box-Behnken Design (BBD), with method validation adhering to US-FDA guidelines. Results: Multiple reaction monitoring transitions for PTX, BTZ and internal standard were m/z 855.80→286.60, 366.80→226.00 and 179.80→110.00, respectively. Elution done on C18 Luna column with 0.1% FA in MeOH:10 mM ammonium acetate. The size of nanoformulation was 133.9 ± 1.97 nm, PDI 0.19 ± 0.01 and zeta potential -19.20 ± 1.36 mV. Pharmacokinetics showed higher Cmax for PTX-BTZ-NE (313.75 ± 10.71 ng/ml PTX, 11.92 ± 0.53 ng/ml BTZ) versus free PTX-BTZ (104 ± 13.06 ng/ml PTX, 1.9 ± 0.08 ng/ml BTZ). Conclusion: Future findings will contribute to the treatment of breast cancer using PTX and BTZ.

[Box: see text].

Serum and salivary interleukin-1ß level in oral precancer: An observational study.

BACKGROUND AND AIM: Precancer biomarkers help in early detection and management of oral potentially malignant disorders (OPMDs). Interleukin-1ß (IL-1ß), a biomarker, is known to be altered in oral submucous fibrosis (OSMF) and oral leukoplakia (OL). Therefore, we evaluated and compared the serum and salivary IL-1ß levels in patients with OSMF/oral leukoplakia and in gender- and age-matched healthy individuals. MATERIALS AND METHODS: An in vivo, prospective, observational study was conducted on 40 subjects. Subjects were divided into two groups with 20 individuals in each group, that is, Group I: OSMF/oral leukoplakia and Group II: control group. Salivary and serum IL-1ß levels were quantitatively estimated using enzyme-linked immunosorbent assay (ELISA). The statistical tests used were unpaired t-test and Chi-square test. RESULTS: The serum IL-1ß levels were significantly (P 0.001) lesser in Group I in comparison to Group II. The salivary IL-1ß levels remained insignificant between both the groups. However, in both the groups, the salivary IL-1ß levels were significantly higher compared to the serum IL-1ß levels. CONCLUSION: We found that the serum IL-1ß level can be considered as a prospective biomarker for dysplasia, whereas salivary IL-1ß alone needs more elaborated studies to account for its application as a potential biomarker in OPMD.

A Review on Picrosides Targeting NFκB and its Proteins for Treatment of Breast Cancer.

Breast cancer is the most frequently diagnosed disease causing most deaths in women worldwide. Chemotherapy and neo-adjuvant therapy are the standard method of treatment in early stages of breast cancer. However drug resistance in breast cancer limit the use of these methods for treatment. Research focus is now shifted towards identifying natural phytochemicals with lower toxicity. This review illustrates the NF κB interaction with different signaling pathways in normal condition, breast cancer and other cancer and thus represent a potential target for treatment. No reports are available on the action of picrosides on NFκB and its associated proteins for anticancer activity. In the present review, potential interaction of picrosides with NF-κB and its associated proteins is reviewed for anticancer action. Further, an important facet of this review entails the ADMET analysis of Picroside, elucidating key ADMET properties which serves to underscore the crucial characteristics of Picroside as a potential drug for treating breast cancer. Furthermore, in silico analysis of Picrosides was executed in order to get potential binding modes between ligand (Picrosides II) and NFκB.

Advancements in nanotechnology for the delivery of phytochemicals.

Phytosomes (phytophospholipid complex) are dosage forms that have recently been introduced to increase the stability and therapeutic effect of herbal medicine. Currently, bioactive herbs and the phytochemicals they contain are considered to be the best remedies for chronic diseases. One promising approach to increase the efficacy of plant-based therapies is to improve the stability and bioavailability of their bio-active ingredients. Phytosomes employ phospholipids as their active ingredients, and use their amphiphilic properties to solubilize and protect herbal extracts. The unique properties of phospholipids in drug delivery and their use in herbal medicines to improve bioavailability results in significantly enhanced health benefits. The introduction of phytosome nanotechnology can alter and revolutionize the current state of drug delivery. The goal of this review is to explain the application of phytosomes, their future prospects in drug delivery, and their advantages over conventional formulations. Please cite this article as: Chauhan D, Yadav PK, Sultana N, Agarwal A, Verma S, Chourasia MK, Gayen JR. Advancements in nanotechnology for the delivery of phytochemicals. J Integr Med. 2024; 22(4): 385-398.

In vitro study on anti-proliferative and anti-cancer activity of picrosides in triple-negative breast cancer.

Picrorhiza kurroa, an "Indian gentian," a known Himalayan medicinal herb with rich source of phytochemicals like picrosides I, II, and other glycosides, has been traditionally used for the treatment of liver and respiratory ailments. Picrosides anti-proliferative, anti-oxidant, anti-inflammatory and other pharmacological properties were evaluated in treating triple-negative breast cancer (TNBC). Picroside I and II were procured from Sigma-Aldrich and were analyzed for anti-cancer activity in triple-negative breast cancer (MDA-MB-231) cells. Cell viability was analyzed using MTT and trypan blue assays. Apoptosis was analyzed through DNA fragmentation and Annexin V/PI flow cytometric analysis. Wound healing and cell survival assays were employed to determine the inhibition of invasion capacity and anti-proliferative activity of picrosides in MDA-MB-231 cells. Measurement of intracellular ROS was studied through mitochondrial membrane potential assessment using DiOC6 staining for anti-oxidant activity of picrosides in MDA-MB-231 cells. Both Picroside I and II have shown decreased cell viability of MDA-MB-231 cells with increasing concentrations. IC50 values of 95.3 µM and 130.8 µM have been obtained for Picroside I and II in MDA-MB-231 cells. Early apoptotic phase have shown an increase of 20% (p < 0.05) with increasing concentrations (0, 50, 75, and 100 µM) of Picroside I and 15% (p < 0.05) increase with Picroside II. Decrease in mitochondrial membrane potential of 2-2.5-fold (p < 0.05) was observed which indicated decreased reactive oxygen species (ROS) generation with increasing concentrations of Picroside I and II. An increasing percentage of 70-80% (p < 0.05) cell population was arrested in G0/G1 phase of cell cycle after Picroside I and II treatment in cancer cells. Our results suggest that Picroside I and II possess significant anti-proliferative and anti-cancer activity which is mediated by inhibition of cell growth, decreased mitochondrial membrane potential, DNA damage, apoptosis, and cell cycle arrest. Therefore, Picroside I and II can be developed as a potential anti-cancer drug of future and further mechanistic studies are underway to identify the mechanism of anti-cancer potential.

Early Drainage of Suprachoroidal Hemorrhage Combined with Surgical Correction of Hypotony after Trabeculectomy.

Aims and background: Delayed suprachoroidal hemorrhage (DSCH) is a vision-threatening complication of intraocular surgeries with a higher prevalence in postglaucoma filtering surgeries. Through these case series of trabeculectomy complicated with DSCH, we aim to emphasize that correction of hypotony (inciting factor) is fundamental for complete resolution and prevention of recurrence. Case description: All three glaucoma patients underwent trabeculectomy surgery followed by DSCH on postoperative day 1. Drainage of DSCH using a 23 gauge trocar cannula within 48 hours of onset was performed along with exploration for the cause of hypotony. All three patients had satisfactory visual and anatomical outcomes. Conclusion: Early drainage using 23 gauge trocar cannulas gives good results in DSCH. The cause of hypotony must simultaneously be corrected during the drainage of DSCH. Preventive measures against hypotony should be taken while doing glaucoma filtering surgery. Clinical significance: Surgical exploration for the cause of hypotony must simultaneously be performed during drainage of DSCH. Primary preventive measures against hypotony and bleeding during glaucoma filtering surgeries, like the use of releasable sutures, viscoelastic in the anterior chamber, and discontinuation of anticoagulants, can be done. Early drainage using trocar cannulas gives satisfactory results in DSCH postglaucoma surgeries. How to cite this article: Beri N, Verma S, Bukke AN, et al. Early Drainage of Suprachoroidal Hemorrhage Combined with Surgical Correction of Hypotony after Trabeculectomy. J Curr Glaucoma Pract 2024;18(1):23-27.

Diabetes: a review of its pathophysiology, and advanced methods of mitigation.

Diabetes mellitus (DM) is a long-lasting metabolic non-communicable disease often characterized by an increase in the level of glucose in the blood or hyperglycemia. Approximately, 415 million people between the ages of 20 and 79 years had DM in 2015 and this figure will rise by 200 million by 2040. In a study conducted by CARRS, it's been found that in Delhi the prevalence of diabetes is around 27% and for prediabetic cases, it is more than 46%. The disease DM can be both short-term and long-term and is often associated with one or more diseases like cardiovascular disease, liver disorder, or kidney malfunction. Early identification of diabetes may help avoid catastrophic repercussions because untreated DM can result in serious complications. Diabetes' primary symptoms are persistently high blood glucose levels, frequent urination, increased thirst, and increased hunger. Therefore, DM is classified into four major categories, namely, Type 1, Type 2, Gestational diabetes, and secondary diabetes. There are various oral and injectable formulations available in the market like insulin, biguanides, sulphonylureas, etc. for the treatment of DM. Recent attention can be given to the various nano approaches undertaken for the treatment, diagnosis, and management of diabetes mellitus. Various nanoparticles like Gold Nanoparticles, carbon nanomaterials, and metallic nanoparticles are some of the approaches mentioned in this review. Besides nanotechnology, artificial intelligence (AI) has also found its application in diabetes care. AI can be used for screening the disease, helping in decision-making, predictive population-level risk stratification, and patient self-management tools. Early detection and diagnosis of diabetes also help the patient avoid expensive treatments later in their life with the help of IoT (internet of medical things) and machine learning models. These tools will help healthcare physicians to predict the disease early. Therefore, the Nano drug delivery system along with AI tools holds a very bright future in diabetes care.

Development of tubulin polymerization inhibitors as anticancer agents.

INTRODUCTION: Microtubules are intracellular, filamentous, polymeric structures that extend throughout the cytoplasm, composed of α-tubulin and ß-tubulin subunits. They regulate many cellular functions including cell polarity, cell shape, mitosis, intracellular transport, cell signaling, gene expression, cell integrity, and are associated with tumorigenesis. Inhibition of tubulin polymerization within tumor cells represents a crucial focus in the pursuit of developing anticancer treatments. AREAS COVERED: This review focuses on the natural product and their synthetic congeners as tubulin inhibitors along with their site of interaction on tubulin. This review also covers the developed novel tubulin inhibitors and important patents focusing on the development of tubulin inhibition for cancer treatment reported from 2018 to 2023. The scientific and patent literature has been searched on PubMed, Espacenet, ScienceDirect, and Patent Guru from 2018-2023. EXPERT OPINION: Tubulin is one of the promising targets explored extensively for drug discovery. Compounds binding in the colchicine site could be given importance because they can elude resistance mediated by the P-glycoprotein efflux pump and no colchicine site binding inhibitor is approved by FDA so far. The research on the development of antibody drug conjugates (ADCs) for tubluin polymerization inhibition could be significant strategy for cancer treatment.

Privileged Scaffolds in Drug Discovery against Human Epidermal Growth Factor Receptor 2 for Cancer Treatment.

HER2 is the membrane receptor tyrosine kinase showing overexpression in several human malignancies, particularly breast cancer. HER2 overexpression causes the activation of Ras- MAPK and PI3K/Akt/ NF-κB cellular signal transduction pathways that lead to cancer development and progression. HER2 is, therefore, presumed as one of the key targets for the development of tumor-specific therapies. Several preclinical have been developed that function by inhibiting the HER2 tyrosine kinase activity through the prevention of the dimerization process. Most HER2 inhibitors act as ATP competitors and prevent the process of phosphorylation, and abort the cell cycle progression and proliferation. In this review, the clinical drug candidates and potent pre-clinical newly developed molecules are described, and the core chemical scaffolds typically responsible for anti-HER2 activity are deciphered. In addition, the monoclonal antibodies that are either used in monotherapy or in combination therapy against HER2-positive cancer are briefly described. The identified key moieties in this study could result in the discovery of more effective HER2-targeted anticancer drug molecules and circumvent the development of resistance by HER2-specific chemotherapeutics in the future.

The Art of Building Living Tissues: Exploring the Frontiers of Biofabrication with 3D Bioprinting.

The scope of three-dimensional printing is expanding rapidly, with innovative approaches resulting in the evolution of state-of-the-art 3D bioprinting (3DbioP) techniques for solving issues in bioengineering and biopharmaceutical research. The methods and tools in 3DbioP emphasize the extrusion process, bioink formulation, and stability of the bioprinted scaffold. Thus, 3DbioP technology augments 3DP in the biological world by providing technical support to regenerative therapy, drug delivery, bioengineering of prosthetics, and drug kinetics research. Besides the above, drug delivery and dosage control have been achieved using 3D bioprinted microcarriers and capsules. Developing a stable, biocompatible, and versatile bioink is a primary requisite in biofabrication. The 3DbioP research is breaking the technical barriers at a breakneck speed. Numerous techniques and biomaterial advancements have helped to overcome current 3DbioP issues related to printability, stability, and bioink formulation. Therefore, this Review aims to provide an insight into the technical challenges of bioprinting, novel biomaterials for bioink formulation, and recently developed 3D bioprinting methods driving future applications in biofabrication research.

In-silico and in-vitro study reveals ziprasidone as a potential aromatase inhibitor against breast carcinoma.

Aromatase enzyme plays a fundamental role in the development of estrogen receptors, and due to this functionality, the enzyme has gained significant attention as a therapeutic for reproductive disorders and cancer diseases. The currently employed aromatase inhibitors have severe side effects whereas our novel aromatase inhibitor is more selective and less toxic, therefore has greater potential to be developed as a drug. The research framework of this study is to identify a potent inhibitor for the aromatase target by profiling molecular descriptors of the ligand and to find a functional pocket in the target by docking and MD simulations. For assessing cellular and metabolic activities as indicators of cell viability and cytotoxicity, in-vitro studies were performed by using the colorimetric MTT assay. Aromatase activities were determined by a fluorometric method. Cell morphology was assessed by phase-contrast light microscopy. Flow cytometry and Annexin V-FITC/PI staining assay determined cell cycle distribution and apoptosis. This study reports that CHEMBL708 (Ziprasidone) is the most promising compound that showed excellent aromatase inhibitory activity. By using better drug design methods and experimental studies, our study identified a novel compound that could be effective as a high-potential drug candidate against aromatase enzyme. We conclude that the compound ziprasidone effectively blocks the cell cycle at the G1-S phase and induces cancer cell death. Further, in-vivo studies are vital for developing ziprasidone as an anticancer agent. Lastly, our research outcomes based on the results of the in-silico experiments may pave the way for identifying effective drug candidates for therapeutic use in breast cancer.

Immunometabolic impact of pancreastatin inhibitor PSTi8 in MCD induced mouse model of oxidative stress and steatohepatitis.

AIM: Pancreastatin, a dysglycemic hormone that encourages inflammation and steatosis in a variety of metabolic disorder animal models. The purpose of this study is to determine the effect of the pancreastatin inhibitor PSTi8 on immunometabolic changes in the liver of MCD-induced NASH mice. MAIN METHODS: Methionine and choline-deficient (MCD) diet was used for the development of NASH. Liver enzymes like SGOT, SGPT, and ALP and lipid profiles were also performed in the serum. Further, immunophenotyping study was performed in the liver through flowcytometer. Subsequently, Hematoxylin and Eosin, Picro Sirius Red and Masson's Trichrome staining were done to check the liver morphology and collagen staining, respectively. Inflammatory cytokines were measured through ELISA and gene expression through RT-PCR. The expression of α-SMA was examined using immunohistochemistry and immunofluorescence staining. KEY FINDINGS: PSTi8 inhibited the expression of lipogenic genes in the liver and attenuated bad cholesterol, SGOT, SGPT, and ALP in the serum. PSTi8 improved the liver morphology and attenuated collagen deposition. Subsequently, PSTi8 attenuated inflammatory M1-macrophages, CD8+T, CD4+T cells and increased anti-inflammatory M2 macrophages, T-reg and eosinophil populations in the liver. It also attenuated the expression of pro-inflammatory genes like Mcp1, Tnfα, and Il6. Apart from this, PSTi8 attenuated the oxidative stress marker, like ROS, and MDA and fibrosis marker α-SMA in the liver. It also decreased the apoptosis and ROS and MDA level in the liver. SIGNIFICANCE: Overall, these compressive studies revealed that PSTi8 exhibited beneficial effect on the liver of MCD-induced NASH mice by attenuating inflammation and oxidative stress.

Pancreastatin inhibitor PSTi8 ameliorates insulin resistance by decreasing fat accumulation and oxidative stress in high-fat diet-fed mice.

Abnormal fat accumulation, enhanced free fatty acids (FFA) release, and their metabolites cause insulin resistance (IR) in major glucose-lipid metabolic organs such as skeletal muscle and adipose tissue. However, excessive lipolysis and FFA release from adipose tissue elevate plasma FFA levels leading to oxidative stress and skeletal muscle IR. Indeed, in obese individuals, there is enhanced pro-inflammatory secretion from adipose tissue influencing insulin signaling in skeletal muscles. Here, we investigated the effect of PSTi8 on FFA-induced IR in both in vitro and in vivo models. Palmitate (Pal)-treated 3T3-L1 cells increased lipid accumulation as well as lipolysis, which reduced the insulin-stimulated glucose uptake. PSTi8 treatment significantly prevented Pal-induced lipid accumulation, and release and enhanced insulin-stimulated glucose uptake. It further reduced the release of pro-inflammatory cytokines from Pal-treated 3T3-L1 cells as well as from adipose tissue explants. In addition, PSTi8 treatment decreases M1 surface markers in Pal-treated bone marrow-derived monocytes (BMDM). PSTi8 treatment also significantly enhanced the Pal-mediated reduced skeletal muscle glucose disposal and reduced intracellular oxidative stress. In vitro effect of PSTi8 was consistent with in vivo HFD-fed mice IR model. PSTi8 treatment in HFD-fed mice significantly improved glucose metabolism and enhanced skeletal muscle insulin sensitivity with reduced adiposity and pro-inflammatory cytokines. Taken together, our results support that PSTi8 treatment can protect both adipose and skeletal muscles from FFA-induced IR.

Topographic distribution of retinal neovascularization in proliferative diabetic retinopathy using ultra-wide field angiography.

Purpose: To analyze the topographic distribution of neovascularization (NV) and capillary nonperfusion (CNP) using ultra-wide field fluorescein angiography (UWFFA) in patients with proliferative diabetic retinopathy (PDR). Methods: This was a prospective, single-center, observational study in which all patients who presented between March 2019 and December 2020 and satisfied the inclusion criteria were recruited. In our study, patients with treatment-naïve PDR without any fibrovascular proliferation underwent UWFFA. The images were analyzed qualitatively for the topographic distribution of NV and the CNP area was quantified. The number of lesions picked by UWFFA was compared with 7 standard field (7SF) image using overlay of 7SF. The main outcome measure was characteristics of neovascularization, such as the number, location, and area of CNP, measured using UWFFA, which was considered with 95% confidence intervals (CI). Results: Two hundred and fifty-three eyes of 187 patients with a mean age of 56.03 ± 8 years were included. Mean neovascularization elsewhere (NVE) was 2.91 ± 3.43. Maximum NVEs were seen in the superotemporal (ST; 0.9 ± 1.13) quadrant, followed by the inferotemporal (IT; 0.7 ± 1.08), inferonasal (IN; 0.66 ± 1.02) and superonasal (SN; 0.66 ± 1.01) quadrants. Maximum CNP area was seen in the SN (13.75 ± 8.83 disc diameter square [DD2]) quadrant, followed by the IN (13.48 ± 8.59 DD2), IT (11.34 ± 8.37 DD2), and ST (11.3 ± 8.34 DD2) quadrants. Mean CNP area was maximum in patients with only neovascularization of disc (NVD; 64.99 ± 41.47 DD2), followed by both NVD and NVE (61.37 ± 35.61 DD2), and was minimum in patients with only NVE (36.44 ± 22.03 DD2). Eighty-one (32%) eyes out of 253 had NVE and 189 (75%) out of 253 had CNP area outside 7SF (overlay) of Early Treatment Diabetic Retinopathy Study (ETDRS). Conclusion: Diabetic NV lesions and CNP areas are distributed asymmetrically throughout the retina and are not restricted to the posterior pole. Compared to conventional 7SF imaging, UWFFA reveals significantly more retinal vascular pathology in patients with PDR.

Simultaneous estimation of five biomarkers of neuroprotective herb Ashwagandha NMITLI-118R AF1 in rat plasma and brain using LC-ESI-MS/MS: Application to its pharmacokinetic and stability studies.

Withania Somnifera (WS) is a popular nutritional supplement in the USA, Europe, and Asia, known for its pharmacological effects on neurological disorders. However, the bioanalytical method development, validation, and pharmacokinetics of WS NMITLI-118R AF1 biomarkers Withanolide A (WLD A), Withanone (WNONE), Withanolide B (WLD B), Withaferin A (WF A), and 12 Deoxywithastramonolide (12 DEOXY) in rats have not been comprehensively explored. This study aimed to develop and validate a sensitive and selective LC-ESI-MS/MS method for these biomarkers in male Sprague Dawley rats plasma and brain matrix. Rats were divided into eight groups, each containing five rats. A plant extract of NMITLI-118R AF1 at 50 mg/kg was orally administered to the rats for in-vivo pharmacokinetic investigation. All the analytes had a linear calibration curve (r2 > 0.999), and intra-day and inter-day precision (%) were found in the range of 2.46 - 13.71% and accuracy were within the acceptable range (±15%). The biomarkers of NMITLI-118R AF1 were found stable in in-vitro plasma and simulated gastro-intestinal fluids. The observed (Cmax) and (Tmax) values for the biomarkers in the systemic circulation were WLD A (5.59 ± 0.34 ng/mL, Tmax 1.00 ± 0.00 h), WNONE (6.28 ± 0.41 ng/mL, Tmax 0.95 ± 0.11 h), WLD B (6.45 ± 2.87 ng/mL, Tmax 0.95 ± 0.11 h), WF A (6.50 ± 0.27 ng/mL, Tmax 1.00 ± 0.00 h), and 12 DEOXY (5.68 ± 0.39 ng/mL, Tmax 1.00 ± 0.00 h). In contrast to the old method, our approach exhibits a lower limit of quantification (LLOQ), shorter run time (less than10 min), and enables the detection of WF A and WNONE in fresh rat plasma by other quantitative analysis of mass spectrometry (m/z) [M]+. Shows high sample volumes for both, larger plasma volumes, costlier sample collection techniques dried blood spot (DBS), more expensive solid phase extraction techniques (SPE) and longer analysis time 14 min. Moreover, our method requires a smaller sample volume 10 µL, offers faster analysis time 4 min, and achieves a higher sensitivity 1 ng/mL. This is the first report of a comprehensive study on in-vitro and in-vivo pharmacokinetics of NMITLI-118R AF1 biomarkers, which may aid in further pre-clinical and clinical trial investigations.

Ratiometric codelivery of Paclitaxel and Baicalein loaded nanoemulsion for enhancement of breast cancer treatment.

The most prevalent clinical option for treating cancer is combination chemotherapy. In combination therapy, assessment and optimization for obtaining a synergistic ratio could be obtained by various preclinical setups. Currently, in vitro optimization is used to get synergistic cytotoxicity while constructing combinations. Herein, we co-encapsulated Paclitaxel (PTX) and Baicalein (BCLN) with TPP-TPGS1000 containing nanoemulsion (TPP-TPGS1000-PTX-BCLN-NE) for breast cancer treatment. The assessment of cytotoxicity of PTX and BCLN at different molar weight ratios provided an optimized synergistic ratio (1:5). Quality by Design (QbD) approach was later applied for the optimization as well as characterization of nanoformulation for its droplet size, zeta potential and drug content. TPP-TPGS1000-PTX-BCLN-NE significantly enhanced cellular ROS, cell cycle arrest, and depolarization of mitochondrial membrane potential in the 4T1 breast cancer cell line compared to other treatments. In the syngeneic 4T1 BALB/c tumor model, TPP-TPGS1000-PTX-BCLN-NE outperformed other nanoformulation treatments. The pharmacokinetic, biodistribution and live imaging studies pivoted TPP-TPGS1000-PTX-BCLN-NE enhanced bioavailability and PTX accumulation at tumor site. Later, histology studies confirmed nanoemulsion non-toxicity, expressing new opportunities and potential to treat breast cancer. These results suggested that current nanoformulation can be a potential therapeutic approach to effectively address breast cancer therapy.

In silico screening, synthesis, characterization and biological evaluation of novel anticancer agents as potential COX-2 inhibitors.

BACKGROUND: Cyclooxygenase enzyme is frequently overexpressed in various types of cancer and found to play a crucial role in poor prognosis in cancer patients. In current research, we have reported the new COX-2 inhibitors for cancer treatment using computer-aided drug design and experimental validation. METHODS: A total of 12,795 compounds from the different databases were used to screen against the COX-2 enzyme. It perceived three new compounds with better binding affinity to the enzyme. Afterwards, physicochemical properties and in silico bioactivity were assessed for efficacy, safety, and structural features required for binding. The molecules were synthesized and confirmed by spectroscopic techniques. Later on, molecules were evaluated for their anti-cancer activity using MCF-7, MDA-MB-231 and SiHa cancer cell lines. RESULTS: Compound ZINC5921547 and ZINC48442590 (4a, and 4b) reduced the MCF-7, MDA-MB-231, and SiHa cells proliferation potently than parent compounds. The PG-E2 estimation shown, both compounds act through the COX-2 PGE2 axis. Compound 4a and 4b block the cell cycle at G1-S phase and induce cancer cell death. CONCLUSIONS: We concluded that compounds 4a and 4b effectively promotes cancer cell death via COX-2 PGE2 axis, and further in vivo studies can be evaluated for development in both compounds as anticancer agents. The compilation of this information will help us to generate better outcome through robust computational methods. The high-quality experimental results may pave the way for identifying effective drug candidates for cancer treatment.