Synthesis, biological profile and computational insights of new derivatives of benzo [B][1,4] diazepines as prospective anticancer agents for inhibiting the CDK-2 protein.

In the current work, a new series of benzo[b][1, 4] diazepines (A-1 to C-4) was synthesized and screened against three different human cancer cell lines, HepG2 (hepatocellular carcinoma), HeLa (cervical cancer) and MCF-7 (breast cancer), by employing MTT (MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay. The outcomes of in vitro screening revealed that all the compounds exhibited momentous anticancer activity, most notably against the MCF-7 cell line by B1-4 compounds. Further, network pharmacology, UALCAN analysis, molecular docking, molecular dynamics (MD) simulations and density functional theory calculations were conducted to explore expression analysis, pharmacokinetics, toxicity profiles and binding interactions of the B1-4 compounds. By UALCAN, we explored the expression analysis of CDK-2 in 19 cancers. Through UALCAN, Pan-cancer analysis revealed that the expression of CDK-2 in 19 cancers was statistically significant. Among the 19 cancers, the CDK-2 expression was significantly upregulated in breast cancer (BRCA), cervical cancer (CESC) and lung carcinoma (LUSC) than normal tissues. Enzyme-docking examination revealed that B1-4 compounds exhibited significant binding affinity against the CDK-2 (PDB ID: 5IEV) drug target protein. Furthermore, MD simulations supported the docking results, which confirmed that the ligand + protein complex was in a stable conformation throughout the simulation time of 100 nanoseconds. Therefore, the present study demonstrates the potential of these benzo [b][1,4] diazepines as promising drug candidates against cancer.Communicated by Ramaswamy H. Sarma.

A new series of benzodiazepine molecules were designed and synthesized as CDK-2 inhibitors.In vitro anticancer potential against HepG2, HeLa and MCF-7 cancer cells were assessed.Network pharmacology; expression analysis; in silico docking; molecular dynamics simulation; molecular mechanics­generalized Born and surface area; and absorption, distribution, metabolism, excretion and toxicity studies were carried out.This study overall revealed the anticancer activity of benzodiazepines by integrating network pharmacology, molecular modeling and in vitro experiments.

Therapeutic Potential of Medicinal Plant Proteins: Present Status and Future Perspectives.

Biologically active molecules obtained from plant sources, mostly including secondary metabolites, have been considered to be of immense value with respect to the treatment of various human diseases. However, some inevitable limitations associated with these secondary metabolites like high cytotoxicity, low bioavailability, poor absorption, low abundance, improper metabolism, etc., have forced the scientific community to explore medicinal plants for alternate biologically active molecules. In this context, therapeutically active proteins/peptides from medicinal plants have been promoted as a promising therapeutic intervention for various human diseases. A large number of proteins isolated from the medicinal plants have been shown to exhibit anti-microbial, anti-oxidant, anti-HIV, anticancerous, ribosome-inactivating and neuro-modulatory activities. Moreover, with advanced technological developments in the medicinal plant research, medicinal plant proteins such as Bowman-Birk protease inhibitor and Mistletoe Lectin-I are presently under clinical trials against prostate cancer, oral carcinomas and malignant melanoma. Despite these developments and proteins being potential drug candidates, to date, not a single systematic review article has documented the therapeutical potential of the available biologically active medicinal plant proteome. The present article was therefore designed to describe the current status of the therapeutically active medicinal plant proteins/peptides vis-à-vis their potential as future protein-based drugs for various human diseases. Future insights in this direction have also been highlighted.

An anti-cancerous protein fraction from Withania somnifera induces ROS-dependent mitochondria-mediated apoptosis in human MDA-MB-231 breast cancer cells.

Withania somnifera exhibits different pharmacological activities which mainly stem from its broad range of bioactive molecules. Majority of these bioactive molecules, fall into the groupings of alkaloids, steroidal lactones, phenolic compounds and glycoproteins. In this study, we evaluated a novel protein fraction, named here as WSPF, isolated from Withania somnifera roots for its cytotoxic properties against various human cancer cell lines. WSPF exhibited apoptotic activity for each cancer cell line tested, demonstrating significant activity against MDA-MB-231 human breast cancer cells with an IC50 value of 92 µg/mL. WSPF induced mitochondrial-mediated apoptosis of MDA-MB-231 cells via extensive reactive oxygen species generation, dysregulation of Bax/Bcl-2, loss of mitochondrial membrane potential and caspase-3 activation. Additionally, we observed G2/M-phase cell cycle arrest, cleavage of nuclear lamin A/C proteins, and nuclear morphological changes. The present results highlight the anti-cancer properties of WSPF, indicating that the proteins in this fraction can be potential therapeutic agents for triple negative breast cancer treatment.

Amelioration of hyperglycaemia and modulation of antioxidant status by Alcea rosea seeds in alloxan-induced diabetic rats.

CONTEXT: Alcea rosea L. (Malvaceae) has various medicinal uses including anticancer, anti-inflammatory and analgesic properties. However, there is no report on its antidiabetic activity. OBJECTIVE: Alcea rosea seed extracts were evaluated for antihyperglycaemic and antioxidative potential in diabetic rats. MATERIALS AND METHODS: Single intra-peritoneal injection of alloxan (130 mg/kg b.w.) was used for induction of diabetes in Albino Wistar rats. Antihyperglycaemic and antioxidant activities of methanol and aqueous extracts of Alcea rosea seed (100 and 300 mg/kg b.w.), administered orally on daily basis for 15 days, were assessed in vivo for fasting blood glucose level and antioxidant status of liver and pancreas. Metformin was used as a positive control. RESULTS: Aqueous and methanol extracts (300 mg/kg b.w.) decreased blood glucose level in diabetic rats by 24% and 46%, respectively. Administration of aqueous and methanol extracts at 300 mg/kg b.w. significantly (p < 0.01) modulated the antioxidant status of liver in diabetic rats by increasing levels of GR (22.5 ± 1.0, 24.4 ± 1.02 µg GSSG utilized/min/mg of protein), GPx (20.7 ± 1.2, 23.6 ± 2.04 µg GSH utilized/min/mg of protein), SOD (36.1 ± 1.7, 39.05 ± 1.5 units/mg of protein) and CAT (1744.5 ± 132.5, 1956.6 ± 125.2 nmol H2O2 decomposed/min/mg of protein), respectively. Similar results were observed for pancreas. DISCUSSION AND CONCLUSIONS: Antihyperglycaemic and antioxidative potentials of Alcea rosea seeds suggest its usefulness in management of diabetes and its complications. This is the first report on antidiabetic activity of this plant.

A Current Perspective on the Inhibition of Cholinesterase by Natural and Synthetic Inhibitors.

Majority of the observed cognitive and behavioral changes in Alzheimer's disease are postulated to be due to the deficiencies in cholinergic pathways of the brain. Enhancement of cholinergic transmission may thus stimulate the cholinergic receptors or prolong the availability of acetylcholine in synaptic cleft and hence improve the Alzheimer's disease associated symptoms. Of these two, the inhibition of cholinesterases (Acetylcholinesterase and Butyrylcholinesterase) by cholinesterase inhibitors is suggested to be a promising strategy. In this regard, various agents both natural and non-natural have been evaluated for the inhibition of cholinesterases. Phytochemical studies of some of the medicinal plants have shown the presence of many valuable compounds that show a wide range of pharmacological activity against cholinesterase enzymes. Interestingly, a good number of potent synthetic inhibitors of cholinesterase enzymes reported so far are natural-product based. This article aims to provide a comprehensive overview of both natural and synthetic cholinesterase inhibitors reported so far. Presenting a comparative overview of synthetic and natural cholinesterase inhibitors may provide some leads for the synthesis of new cholinesterase inhibitors from medicinal plants. Structural activity relationship of the active cholinesterase inhibitors is also discussed with some insights from simulation studies. Insights for possible future research have also been highlighted.

Unique Medicinal Properties of Withania somnifera: Phytochemical Constituents and Protein Component.

Withania somnifera is an important medicinal herb that has been widely used for the treatment of different clinical conditions. The overall medicinal properties of Withania somnifera make it a viable therapeutic agent for addressing anxiety, cancer, microbial infection, immunomodulation, and neurodegenerative disorders. Biochemical constituents of Withania somnifera like withanolideA, withanolide D, withaferin A and withaniamides play an important role in its pharmacological properties. Proteins like Withania somnifera glycoprotein and withania lectin like-protein possess potent therapeutic properties like antimicrobial, anti-snake venom poison and antimicrobial. In this review, we have tried to present different pharmacological properties associated with different extract preparations, phytochemical constituents and protein component of Withania somnifera. Future insights in this direction have also been highlighted.