Network pharmacology and experimental insights into STAT3 inhibition by novel isoxazole derivatives of piperic acid in triple negative breast cancer.

STAT3 is a crucial member within a family of seven essential transcription factors. Elevated STAT3 levels have been identified in various cancer types, notably in breast cancer (BC). Consequently, inhibiting STAT3 is recognized as a promising and effective strategy for therapeutic intervention against breast cancer. We herein synthesize a library of isoxazole (PAIs) from piperic acid [2E, 4E)-5-(2H-1,3-Benzodioxol-5-yl) penta-2,4-dienoic acid] on treatment with propargyl bromide followed by oxime under prescribed reaction conditions. Piperic acid was obtained by hydrolysis of piperine extracted from Piper nigrum. First, we checked the binding potential of isoxazole derivatives with breast cancer target proteins by network pharmacology, molecular docking, molecular dynamic (MD) simulation and cytotoxicity analysis as potential anti-breast cancer (BC) agents. The multi-source databases were used to identify possible targets for isoxazole derivatives. A network of protein-protein interactions (PPIs) was generated by obtaining 877 target genes that overlapped gene symbols associated with isoxazole derivatives and BC. Molecular docking and MD modelling demonstrated a strong affinity between isoxazole derivatives and essential target genes. Further, the cell viability studies of isoxazole derivatives on the human breast carcinoma cell lines showed toxicity in all breast cancer cell lines. In summary, our study indicated that the isoxazole derivative showed the significant anticancer activity. The results highlight the prospective utility of isoxazole derivatives as new drug candidates for anticancer chemotherapy, suggesting route for the continued exploration and development of drugs suitable for clinical applications.

Kinetic and adsorption isotherm studies of Malachite Green dye onto surfactant-tailored alginate hydrogel beads: An influence of surfactant hydrophobicity.

This study details the synthesis and characterization of surfactant-modified sodium alginate hydrogel beads crosslinked with Ba2+ ions through ionotropic gelation. Cationic surfactants such as, dodecyltrimethylammonium bromide (DTAB), didodecyldimethylammonium bromide (DDAB), and butanediyl-α,ω-bis-(dimethyldodecylammonium bromide) (GEM), were employed in the modification process. The surfactant-modified ALG-DTAB, ALG-DDAB, and ALG-GEM beads were investigated for the removal of cationic dye Malachite Green (MG) to elucidate the impact of hydrophobicity of amphiphiles on the adsorption process. The characterizations were carried out using Rheometry, Field Emission Scanning Electron Microscopy (FESEM), Infrared Spectroscopy (IR), and Energy Dispersive X-ray Spectroscopy (EDX). Under optimized conditions, ALG-GEM and ALG-DDAB demonstrated highest maximum adsorption capacity (Qmax > 700 mgg-1). The adsorption data fitted well to pseudo-second order kinetic and Langmuir adsorption models, suggesting the involvement of chemisorption phenomena with notable contributions from pore diffusion. The effects of pH, initial dye concentration, adsorbent dose, temperature, and competing ions on the removal of MG were investigated. Interestingly, ALG-GEM beads exhibited an increase in adsorption capacity with rising pH and a subsequent decrease with increasing temperature, showcasing optimal adsorption at pH 7.0 and 25 °C. The study proposes that ALG beads modified with cationic surfactants with higher hydrophobicity could offer a promising avenue in wastewater treatment processes.

Synthesis, antioxidant, antiproliferative activity, molecular docking and DFT studies of novel isoxazole derivatives of diosgenin, a steroidal sapogenin from Dioscorea deltoidea.

Diosgenin [25R-spirost-5-en-3ß-ol], isolated from Dioscorea deltoidea was used as a starting material for synthesizing its various isoxazole derivatives. A library of fifteen isoxazole analogues (DG1-DG15) were synthesised via modification at the C-3 hydroxyl group. The resulting analogues were fully characterized by spectral techniques and evaluated for their antioxidant and anticancer activity against four breast cancer cell lines; MDA-MB-231, MDA-MB-468, MCF-7, and 4 T1, using MTT assay. Molecular docking studies were carried out for all analogues with EGFR protein (PDB id: 6LUD) to check their activity by inhibiting EGFR protein, which is an effective strategy for cancer cell death. Furthermore, DFT studies were carried out for four analogues. Among all analogues, compound DG6 and DG9 showed the highest scavenging activity and compound DG9 exhibited a maximum cytotoxic effect on the MDA-MB-468 and MCF-7 cell lines with an IC50 value of 6.25 µg/mL and 6.81 µg/mL, while compound DG5 was the least potent (IC50 25.89 µg/mL). Molecular docking results revealed that DG8 and DG9 afforded the highest binding energy of -14.33 and - 14.71 kcal/mol, respectively for the target EGFR protein. These results demonstrate the potential of diosgenin analogues as drug candidates for breast cancer therapy. Furthermore, DFT studies revealed that the molecules are more polarizable and have smaller energy gap between their HOMO and LUMO orbitals, the smallest being of DG9 (3.221 eV) and hence are more reactive.

Extraction of polysaccharide from Althea rosea and its physicochemical, anti-diabetic, anti-hypertensive and antioxidant properties.

The valorization of new polymer sources from underutilized plants as structuring, encapsulating, and texturizing agents for food and nutraceutical applications is gaining attention. This provides an opportunity where inexpensive plant-sourced biopolymers can play an impactful role, on both ecological and economic aspects performing equivalently effectual yet cost-effective substitutes to synthetic polymers. With this aim, we explored the use of mucilage from Althea rosea and reveal its physicochemical, in vitro antidiabetic and antihypertensive activity. Besides, structural, micrometric, crystallization, and anti-microbial properties was also seen. We determined the probable structure of the extracted mucilage by FTIR which confirmed the residues of saccharides as galactose and uronic acid with α and ß configurations. It consists of 78.26% carbohydrates, 3.51% ashes, and 3.72% proteins. Here, we show that the mucilage offered protection to DNA against the oxidative damage caused by (-OH) radicals and the morphology of the mucilage particles displayed a fibrillary material settled in a net-like, tangled structure. Our results demonstrate that the reconstituted mucilage powder exhibited good water holding capacity (2.89 g water/g mucilage), solubility (27.33%), and oil holding capacity (1.79 g oil/g mucilage). Moreover, high emulsifying property (95.83%) and foaming capacity (17.04%) was noted. Our results indicate that A.rosea mucilage can potentially serve as economical and eco-friendly hydrocolloid substitute for the food and nutraceutical industry owing to its functional, hypo-lipidemic, anti-hyperglycemic, antioxidant, and anti-bacterial properties.

Preparation and characterization of polyvinyl alcohol-piperic acid composite film for potential food packaging applications.

Piperic acid, a natural product-based derivative, has been used with polyvinyl alcohol for the first time to form polymer composite films for its suitable modification in physicochemical and antimicrobial properties. Initially, piperic acid was synthesized from piperine, a natural alkaloid extracted from black pepper (Piper nigrum). The solvent casting method was used for the synthesis of PVA-piperic acid composite films. The films were characterized by various spectral and microscopic techniques like UV-visible spectroscopy, FT-IR, SEM, XRD, and TGA. The antibacterial activity was shown by these polymer composites of piperic acid against Gram-positive Staphylococcus aureus (S. aureus-ATCC8738P) and Gram-negative Escherichia coli (E. coli-ATCC8739) was worthwhile. The antifungal activity of the composite films was evaluated by the food poisoning technique. Percentage mycelial growth inhibition was found maximum against Fusarium solani than Aspergillus and Penicillium. The water vapour and oxygen barrier properties are enhanced with the incorporation of increased content of piperic acid. Also, enhancement in the tensile strength of PVA/PA composite film was observed, while elongation at break shows decreased trend with the addition of piperic acid. The surface properties of polymer composite films were determined by contact angle measurements. Contact angle shows a considerable increase in these films when compared to virgin PVA film. It was increased by 56.1° in 15 mL composite film containing a higher concentration of piperic acid than virgin PVA.

Gas chromatographic-mass spectrometric analysis, antioxidant, antiproliferative and antibacterial activities of the essential oil of Prangospabularia.

The essential oil composition of the shoot parts of Prangos pabularia, growing in Drass area of Ladakh, India, along with its antioxidant, antibacterial and anticancer activity, is reported for the first time. Gas chromatography coupled with mass spectrometry (GC-MS) revealed the presence of 31 constituents, representing 97.342% of the total essential oil. The major constituents of essential oil were Durylaldehyde (62.161%), Bicyclo [3.1.1] hept-2-en-4-ol (8.846%), Chrysanthenyl acetate (5.120%) followed by unknown (3.420%), (-)-Spathulenol (3.028%), Mesityl aldehyde (2.402%) and Hexahydro farnesyl acetone (1.683%. Cytotoxic activity of the essential oil by MTT assay against human breast adenocarcinoma (MCF7), human breast (HBL-100), human cervical cancer (HELA) and human lung adenocarcinoma epithelial (A549) cells, at four different concentrations (20, 30, 50 & 100 µg/mL) revealed that the activity of 56.12% against A549 (human lung) cell line at 20 µg/mL concentration was the highest. The Essential oil displayed a significant free radical scavenging activity with DPPH. Antibacterial activity was carried out against 3 g positive and 2-g negative bacteria at four different concentrations using Agar Well Diffusion Method taking streptomycin sulphate as reference. The essential oil displayed significant and broad-spectrum antibacterial activity against different bacteria used. The MIC of the oil ranged from 2.06 to 5.00 µg/mL. The zones of inhibition were lesser for Micrococcus and Escherichia coli compared to other strains of bacteria.

Suitably Band-aligned MOF-Derived Ni2 P/MnO2 Heterostructure with Ni(I) Coordination Surface Sites for Self-Coupling of Aryl Halides to Biaryls.

An efficient photo-redox strategy for the aryl-aryl self-coupling of aryl halides through a heterogeneous catalysis route has been demonstrated. A coordinatively unsaturated Ni2 P surface with the enhanced photochemical property upon hetero-structuring with δ-MnO2 affects the organic transformation to biaryls with impressive yield and photo-conversion efficiency. The dual-role of the Ni2 P catalyst with its participation as the catalytic active surface and the photo-redox center distinguishes the organic transformation achieved herein with other catalytic and photocatalytic aryl-aryl self-coupling.

Synthesis, characterization, and antimicrobial evaluation of polyvinylalcohol-osthol composite films.

Although poly-vinyl alcohol (PVA) has certain mechanical drawbacks such as a weak barrier, it has widely been used in food packaging over the last many years. To increase the suitability of PVA (C2H4O)n and render it ideal for food packaging, a diversity of studies have already been carried out. In the below-mentioned script, we, for the first time, report the use of natural product osthol in making a new composite with PVA for enhancing thermal, physicochemical, and antimicrobial properties. The significant aim of the report is the insertion of osthol (C15H16O3) into PVA polymer, which is to be subsequently used for antimicrobial applications. The synthesis of the polymer composite film is done by solvent casting method and is characterized by SEM, XRD, FT-IR, and UV-Vis spectroscopy analysis. The manifestation of antimicrobial activity against (S. aureus) (ATCC8738P), E. coli (ATCC8739), Aspergillus niger, Alternaria alternata, and Fusarium solani by the film composite is remarkable. The addition of osthol molecule increases the tensile strength of PVA films from 18.73 ± 0.56 Mpa (PVA) to 24.58 ± 0.49 Mpa (15 mL). As a result, tensile strength increases by 23.79% in a film containing a higher concentration of osthol (15 mL). The barrier properties of PVA osthol composite films improve with the incorporation of osthol. OTR and WVTR decrease by 43.03% and 30.24%, respectively, on the addition of 15 mL osthol. Reduction in OTR and WVTR of the films could increase their applicability in the food sector. An increase in contact angle from 43° (pure PVA) to 66.7° increases the hydrophobic character of the composite films which is desirable for food packaging. This noticeable enhancement of the properties of the PVA film like hydrophobicity, mechanical, barrier, and antimicrobial is supporting the potential application of achieved material in packaging of easily perishable foods like fruits and vegetables by extending their shelf life.

Platanic Acid-Aryl Enones as Potential Anticancer Compounds: Synthesis and Biological Profiling against Breast, Prostate and Lung Cancer Cell Lines.

A series of rationally designed platanic acid-based compounds derived from naturally occurring betulinic acid were synthesized through a sequence of Lemieux-Johnson oxidation and Aldol condensation reaction. All the compounds were screened for cytotoxicity against a panel of human cancer and normal cell lines using MTT assay. From the biological data, it was observed that some of these semi-synthetic congeners exhibited potent biological profiles compared to platanic acid. One of the compounds with the p-tolyl substitution was found to be most active in this study, and its cytotoxicity against two of the cell lines, MDA-MB 231 and A-549 were in tune with the standard compound, 5-fluorouracil.

Gas Chromatographic-Mass Spectrometric Analysis, Antibacterial, Antioxidant and Antiproliferative Activities of the Needle Essential Oil of Abies pindrow growing wild in Kashmir, India.

The essential oil composition of the leaves of Abies pindrow, growing in Kashmir, India, along with its antioxidant, antibacterial and anticancer activity is reported for the first time. Gas chromatography coupled with mass spectrometry (GC-MS) revealed the presence of 12 constituents, representing 99.9% of the total oil. The major constituents of the oil were limonene (38.9%), α-pinene (36.5%), ß-pinene (6.9%), and α-selinene (4.4%). The essential oil was dominated by the presence of monoterpene hydrocarbons (90.2%), followed by sesquiterpene hydrocarbons (6.761%), oxygenated sesquiterpenes (2.096%) and oxygenated monoterpenes (0.942%). The monoterpene rich essential oil was subjected to antibacterial activity against 4 Gram negative bacteria and 2 Gram positive bacteria at three different concentrations using Agar Well Diffusion Method taking streptomycin sulphate as reference. The oil displayed significant and broad spectrum antibacterial activity against different bacteria used. The minimum inhibitory concentration (MIC) of the active essential oil was determined using Agar Dilution Method. Highest antibacterial activity was shown by the oil against E. Coli (25 mm), and the lowest by Bacillus subtilis (14 mm) and Pseudomonas aeruginosa (14 mm). The oil was subjected to cytotoxic activity by MTT assay against human mammary carcinoma (MCF), human ductal breast epithelial tumour (T47D), human lung adeno-carcinoma epithelial (A549) and rat glial (C6) cell lines at three different concentrations. The results revealed significant sensitization of the cell lines with highest inhibition against human ductal breast epithelial cell line (51%) and the lowest against rat glial cell line (33%) at a concentartion of 50 µg/mL. The oil displayed a significant free radical scavenging activity with DPPH.

Synthesis and Biological Evaluation of Novel Osthol Derivatives as Potent Cytotoxic Agents.

BACKGROUND: Natural product, osthol has been found to have important biological and pharmacological roles particularly having inhibitory effect on multiple types of cancer. OBJECTIVE: The unmet needs in cancer therapeutics make its derivatization an important and exciting field of research. Keeping this in view, a whole new series of diverse analogues of osthol (1) were synthesized. METHOD: All the newly synthesized compounds were made through modification in the lactone ring as well as in the side chain of the osthol molecule and were subjected to anti-proliferative screening through 3-(4,5-Dimethylthiazol-yl)-diphenyl tetrazoliumbromide (MTT) against four different human cancers of diverse origins viz. Colon (Colo-205), lung (A549), Leukemia (THP- 1) and breast (MCF-7) including SV40 transformed normal breast epithelial cell (fR-2). RESULTS: Interestingly, among the tested molecules, most of the analogs displayed better antiproliferative activity than the parent Osthol 1. However, among all the tested analogs, compound 28 exhibited the best results against leukemia (THP1) cell line with IC50 of 5µM.Compound 28 induced potent apoptotic effects and G1 phase arrest in leukemia cancer cells (THP1). The population of apoptotic cells increased from 13.8% in negative control to 26.9% at 8µM concentration of 28. Compound 28 also induced a remarkable decrease in mitochondrial membrane potential (ΛΨm) leading to apoptosis of the cancer cells. CONCLUSION: A novel series of molecules derived from natural product osthol were synthesized, wherein compound 28 was found to be most effective against leukemia and with 10 fold less toxicity against normal cells. The compound induced cancer inhibition mainly through apoptosis and thus has a potential in cancer therapeutics.

Synthesis, 17α-hydroxylase-C17,20-lyase Inhibitory and 5AR Reductase Activity of Novel Pregnenolone Derivatives.

BACKGROUND: The potential of steroids for development into lead pharmacological molecules lies in the regulation of a variety of biological processes by these molecules and also because of these being a fundamental class of signaling molecules. Steroid based scaffolds have been extensively used as active pharmaceutical agents for the treatment of various diseases including the deadly disease of cancer which despite the recent advances in the early diagnosis, prevention and therapy, remains a clinical challenge affecting millions of people world over and is one of the leading causes of death. It thus warrants the development of new drugs against this dreadful disease through exploitation of emerging molecularly defined targets. METHODS: The present study explores the effect of novel steroidal pyrazolines as presumed inhibitors of 5α- reductase (5AR) and 17α-hydroxylase-C17,20-lyase as a target for treatment of prostate cancer. A series of 1,5- diaryl pyrazoline pregnenolones were synthesized and screened for 5α-reductase inhibitory activities. Synthesis of the analogs is multistep and proceeds in good overall yields. The key step in the synthesis of 1,5- disubstituted pyrazolinyl pregnenolones is the heterocyclization of bezylidine derivatives (3) in presence of phenylhydrazines (4) through the initial formation of the phenylhydrazones, which undergo concomitant cyclization to generate the stable pyrazoline derivatives. RESULTS: All the synthesised D-ring 1,5-disubstituted pyrazolinyl pregnenolone derivatives (5a-l) were screened for prostate cancer cell inhibitory, 5α-reductase and 17α-hydroxylase-C17,20-lyase inhibitory activity. Amongst all the compounds screened for their 5α-reductase inhibitory activities, compound 5c, 5e, 5g and 5l were found to be the most active. Further, compounds 5g and 5h were found to have moderate 17α-hydroxylase-C17,20-lyase inhibitory activities. CONCLUSION: A series of D-ring 1,5-disubstituted pyrazolinyl pregnenolone derivatives (5a-l) were synthesized and screened for their prostate cancer cell inhibitory, 5a-reductase and 17α-hydroxylase-C17,20-lyase inhibitory activity. Amongst all the compounds screened for their 5α-reductase inhibitory activities, compound 5c, 5e, 5g and 5l were found to be the most active whereas compounds 5g and 5h were found to have moderate 17α- hydroxylase-C17,20-lyase inhibitory activities.

Synthesis and Fabrication of Collagen-Coated Ostholamide Electrospun Nanofiber Scaffold for Wound Healing.

A novel scaffold for effective wound healing treatment was developed utilizing natural product bearing collagen-based biocompatible electrospun nanofibers. Initially, ostholamide (OSA) was synthesized from osthole (a natural coumarin), characterized by 1H, 13C, DEPT-135 NMR, ESI-MS, and FT-IR spectroscopy analysis. OSA was incorporated into polyhydroxybutyrate (PHB) and gelatin (GEL), which serve as templates for electrospun nanofibers. The coating of OSA-PHB-GEL nanofibers with collagen resulted in PHB-GEL-OSA-COL nanofibrous scaffold which mimics extracellular matrix and serves as an effective biomaterial for tissue engineering applications, especially for wound healing. PHB-GEL-OSA-COL, along with PHB-GEL-OSA and collagen film (COLF), was characterized in vitro and in vivo to determine its efficacy. The developed PHB-GEL-OSA-COL nanofibers posed an impressive mechanical stability, an essential requirement for wound healing. The presence of OSA had contributed to antimicrobial efficacy. These scaffolds exhibited efficient antibacterial activity against common wound pathogens, Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus). The zones of inhibition were observed to be 14 ± 22 and 10 ± 2 mm, respectively. It was observed that nanofibrous scaffold had the ability to release OSA in a controlled manner, and hence, OSA would be present at the site of application and exhibit bioactivity in a sustained manner. PHB-GEL-OSA-COL nanofiber was determined to be stable against enzymatic degradation, which is the most important parameter for promoting proliferation of cells contributing to repair and remodeling of tissues during wound healing applications. As hypothesized, PHB-GEL-OSA-COL was observed to imbibe excellent cytocompatibility, which was determined using NIH 3T3 fibroblast cell proliferation studies. PHB-GEL-OSA-COL exhibited excellent wound healing efficacy which was confirmed using full thickness excision wound model in Wistar rats. The rats treated with PHB-GEL-OSA-COL nanofibrous scaffold displayed enhanced healing when compared to untreated control. Both in vitro and in vivo analysis of PHB-GEL-OSA-COL presents a strong case of therapeutic biomaterial suiting wound repair and regeneration.

Genicunolide A, B and C: three new triterpenoids from Euphorbia geniculata.

Three new triterpenoids, designated as genicunolide A (1), B (2) and C (3), along with friedelin (4) and friedelinol (5), were isolated from the aerial parts of Euphorbia geniculata. They were characterized as 1ß-acetoxy-3ß-hydroxy-11α,12α-oxidotaraxer-14-ene, 1ß,3ß-diacetoxy-21α-hydroxy-11α,12α-oxidotaraxer-14-ene and 3ß,9α,20α-trihydroxy-Ψ-taraxast-5-ene, respectively, by spectral and chemical methods.

Isolation, cytotoxicity evaluation and HPLC-quantification of the chemical constituents from Prangos pabularia.

Phytochemical analysis of the dichloromethane:methanol (1:1) extract of root parts of Prangos pabularia led to the isolation of twelve cytotoxic constituents, viz., 6-hydroxycoumarin (1), 7-hydroxycoumarin (2), heraclenol-glycoside (3), xanthotoxol (4), heraclenol (5), oxypeucedanin hydrate (6), 8-((3,3-dimethyloxiran-2-yl)methyl)-7-methoxy-2H-chromen-2-one (7), oxypeucedanin hydrate monoacetate (8), xanthotoxin (9), 4-((2-hydroxy-3-methylbut-3-en-1-yl)oxy)-7H-furo[3,2-g]chromen-7-one (10), imperatorin (11) and osthol (12). The isolates were identified using spectral techniques in the light of literature. 3-(4,5-dimethyl thiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity screening of the isolated constituents was carried out against six human cancer cell lines including lung (A549 and NCI-H322), epidermoid carcinoma (A431), melanoma (A375), prostate (PC-3) and Colon (HCT-116) cell lines. Osthol (12) exhibited the highest cytotoxicity with IC50 values of 3.2, 6.2, 10.9, 14.5, 24.8, and 30.2 µM against epidermoid carcinoma (A431), melanoma (A375), lung (NCI-H322), lung (A549), prostate (PC-3) and colon (HCT-116) cell lines respectively. Epidermoid carcinoma cell line A431 was sensitive to most of the compounds followed by lung (A549) cancer cell line. Finally a simple and reliable HPLC method was developed (RP-HPLC-DAD) and validated for the simultaneous quantification of these cytotoxic constituents in Prangos pabularia. The extract was analyzed using a reversed-phase Agilent ZORBAX eclipse plus column C18 (4.6×250 mm, 5 µm) at 250 nm wavelength using a gradient water-methanol solvent system at a flow rate of 0.8 ml/min. The RP-HPLC method is validated in terms of recovery, linearity, accuracy and precision (intra and inter-day validation). This method, because of shorter analysis time, makes it valuable for the commercial quality control of Prangos pabularia extracts and its future pharmaceutical preparations.

Conyzagenin-A and B, two new epimeric lanostane triterpenoids from Conyza canadensis.

Two new epimeric lanostane triterpenoids Conyzagenin-A and Conyzagenin-B were isolated from roots of Conyza canadensis, along with nine known compounds. The structures of these triterpenoids were elucidated by detailed spectral methods and chemical derivatisation.