Bioorg Chem
January 2025
The landscape of cancer treatment has been transformed by the emergence of immunotherapy, especially through the use of antibodies that target the PD-1/PD-L1 pathway. Recently, there has been a notable increase in interest surrounding immune checkpoint inhibitors for cancer therapy. While antibody-based approaches have drawbacks like high costs and prolonged activity, the approval of monoclonal antibodies such as pembrolizumab and nivolumab has paved the way for a range of alternative therapies, including peptides, peptidomimetics, and small-molecule inhibitors.
View Article and Find Full Text PDFThe physiological Src proto-oncogene is a protein tyrosine kinase receptor that served as the essential signaling pathway in different types of cancer. Src kinase receptor is divided into different domains: a unique domain, an SH3 domain, an SH2 domain, a protein tyrosine kinase domain, and a regulatory tail, which runs from the N-terminus to the C-terminus. Src kinase inhibitors bind in the kinase domain and are activated by phosphorylation.
View Article and Find Full Text PDFBRAF is the most common serine-threonine protein kinase and regulates signal transduction from RAS to MEK inside the cell. The BRAF is a highly active isoform of RAF kinase. BRAF has two domains such as regulatory and kinase domains.
View Article and Find Full Text PDFACS Omega
February 2023
Herein, we rationally designed and developed two novel glitazones (G1 and G2) to target peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) signaling through peroxisome proliferator-activated receptors (PPAR)-γ agonism as a therapeutic for Parkinson's disease (PD). The synthesized molecules were analyzed by mass spectrometry and NMR spectroscopy. The neuroprotective functionality of the synthesized molecules was assessed by a cell viability assay in lipopolysaccharide-intoxicated SHSY5Y neuroblastoma cell lines.
View Article and Find Full Text PDFPPARα and PPARγ are isoforms of the nuclear receptor superfamily which regulate glucose and lipid metabolism. Activation of PPARα and PPARγ receptors by exogenous ligands could transactivate the expression of PPARα and PPARγ-dependent genes, and thereby, metabolic pathways get triggered, which are helpful to ameliorate treatment for the type 2 diabetes mellitus, and related metabolic complications. Herein, by understanding the structural requirements for ligands to activate PPARα and PPARγ proteins, we developed a multilevel in silico-based virtual screening protocol to identify novel chemical scaffolds and further design and synthesize two distinct series of glitazone derivatives with advantages over the classical PPARα and PPARγ agonists.
View Article and Find Full Text PDFBioorg Chem
January 2023
Discoidin domain receptors (DDRs) are one of the less explored targets for the treatment of cancer which belong to receptor tyrosine kinases family. Discoidin domain receptors (DDRs) are a collagen-activated receptor tyrosine kinase and essential for controlling cellular functions like proliferation, morphogenesis, adhesion, differentiation, invasion, matrix remodeling, and migration. Although there are many targets and their inhibitors are reported which treat cancer.
View Article and Find Full Text PDFB-Raf protein is a serine-threonine kinase and an important signal transduction molecule of the MAPK signaling pathway that mediates signals from RAS to MEK, ultimately promoting various essential cellular functions. The B-Raf kinase domain is divided into two subdomains: a small N-terminal lobe and a large C-terminal lobe, with a deep catalytic cleft between them. The N-terminal lobe contains a phosphate-binding loop (P-loop) and nucleotide-binding pocket, while the C-terminal lobe binds the protein substrates and contains the catalytic loop.
View Article and Find Full Text PDFCurrent treatment for Rheumatoid arthritis (RA) utilizes Disease-modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs or its combination, to decrease joint inflammation. In the present study, naproxen (NAP) and sulfapyridine (SULF) ethosomes were prepared by a thin-film hydration technique using PL90G and cholesterol, later crosslinked with carbopol®934. The ethosomes and ethosomal hydrogel were evaluated for rheological properties, physico-chemical analysis, and study.
View Article and Find Full Text PDFCurr Neuropharmacol
May 2022
Peroxisome proliferator-activated receptors (PPARs) activity has significant implications for the development of novel therapeutic modalities against neurodegenerative diseases. Although PPAR-α, PPAR-β/δ, and PPAR-γ nuclear receptor expressions are significantly reported in the brain, their implications in brain physiology and other neurodegenerative diseases still require extensive studies. PPAR signaling can modulate various cell signaling mechanisms involved in the cells contributing to on- and off-target actions selectively to promote therapeutic effects as well as the adverse effects of PPAR ligands.
View Article and Find Full Text PDFHeat shock protein (HSP)90 is the most abundant HSPs, which are chaperone molecules whose major roles are cell protection and maintenance by means of aiding the folding, the stabilization and the remodeling of a wide range of proteins. A few hundreds of proteins depend on HSP90 chaperone activity, including kinases and transcriptional factors that play essential roles in cancer and inflammation, so that HSP90-targeted therapies have been considered as a potential strategy for the treatment of cancer and inflammatory-associated diseases. HSP90 inhibition by natural, semi-synthetic and synthetic compounds have yield promising results in pre-clinical studies and clinical trials for different types of cancers and inflammation.
View Article and Find Full Text PDFHsp90, as a key molecular chaperone, plays an important role in modulating the activity of many cell signaling proteins and is an attractive target for anticancer therapeutics. Herein, we report the discovery of N-pyridoyl-Δ -pyrazoline analogs as novel Hsp90 inhibitors by integrated approaches of drug design, organic synthesis, cell biology, and qualitative proteomic analysis. Novel chemical compounds were designed and optimized in the adenosine triphosphate-binding site of Hsp90; lead optimized compounds were found to have significant interactions with Asp93 and other amino acids crucial for Hsp90 inhibition.
View Article and Find Full Text PDFBackground: Heat shock protein 90 (Hsp90) is an encouraging anticancer target for the development of clinically significant molecules. Schiff bases play a crucial role in anticancer research because of their ease of synthesis and excellent antiproliferative effect against multiple cancer cell lines. Therefore, we started our research work with the discovery of resorcinol/4-chloro resorcinol derived Schiff bases as Hsp90 inhibitors, which resulted in the discovery of a viable anticancer lead molecule.
View Article and Find Full Text PDFDual-targeting/Multi-targeting of oncoproteins by a single drug molecule represents an efficient, logical and alternative approach to drug combinations. An increasing interest in this approach is indicated by a steady upsurge in the number of articles on targeting dual/multi proteins published in the last 5 years. Combining different inhibitors that destiny specific single target is the standard treatment for cancer.
View Article and Find Full Text PDFBackground: Heat shock protein 90 is a molecular chaperone required for the stability and function of several client proteins that promote cancer cell growth and/or survival. Discovery of Hsp90 inhibitors has emerged as an attractive target of research in cancer therapeutics. Natural products like geldanamycin and radicicol are established Hsp90 inhibitors, but face limitations with toxicity and inactivity, by in vivo studies respectively.
View Article and Find Full Text PDFPharmacol Res
January 2017
Activation of toll-like receptors (TLRs) by pathogen-associated molecular patterns (PAMPs) triggers an innate immune response, via cytokine production and inflammasome activation. Herein, we have investigated the modulatory effect of the natural limonoid gedunin on TLR activation in vitro and in vivo. Intraperitoneal (i.
View Article and Find Full Text PDFWe report on the synthesis of novel Ru(II) compounds (Ru-1 to Ru-8) bearing R-pdc, 4-Cl-pbinh ligands (where R=4-CF3, 4-F, 4-OH pdc=3-phenyl-5-(1H-pyrrol-2-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide, pbinh=phenoxybenzylidene isonicotinyl hydrazides) and their in vitro antitumor activity toward the cell lines murine leukemia L1210, human lymphocyte CEM, human epithelial cervical carcinoma HeLa, BEL-7402 and Molt4/C8. Some of the complexes exhibited more potent antiproliferative activity against cell lines than the standard drug cisplatin. Ruthenium complex Ru-2 displayed potent cytotoxicity with than that of cisplatin.
View Article and Find Full Text PDFThe ubiquitously expressed heat shock protein 90 is an encouraging target for the development of novel anticancer agents. In a program directed towards uncovering novel chemical scaffolds against Hsp90, we performed molecular docking studies using Tripos-Sybyl drug designing software by including the required conserved water molecules. The results of the docking studies predicted Mannich bases derived from 2,4-dihydroxy acetophenone/5-chloro 2,4-dihydroxy acetophenone as potential Hsp90 inhibitors.
View Article and Find Full Text PDFA series of novel substituted 2-amino-5-(1-(4-isobutylphenyl)ethyl)-1,3,4-thiadiazoles were designed, synthesized and evaluated as anti-inflammatory and analgesic agents. Compounds were characterized by elemental and spectroscopic analysis. Compounds possessing significant activities were screened for ulcerogenic activity.
View Article and Find Full Text PDFA series of substituted 2-(6-methoxynapthalen-2-yl) propanoic acid (naproxen) analogs were synthesized. (S)- naproxen (1) was treated with thionyl chloride to yield acid chloride (2) which was then reacted with different heterocyclic moieties and aryl acids to yield the (S)-naproxen analogs (3a-k). All the compounds were screened for antiinflammatory activity using in vivo rat paw oedema model and most of the active ones were investigated for their ulcerogenic potential.
View Article and Find Full Text PDFThe existing NSAIDs having number of toxicities emphasises the need for discovery of new non-toxic anti-inflammatory agents. In this Letter, we present the simple two step chemical synthesis, in vivo pharmacological screening and docking study of few N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs. Different amino benzothiazoles were chloroacetylated and further reacted with substituted piperazines in presence of a base to get N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs (A1-C4).
View Article and Find Full Text PDFBreast cancer is the second most common type of cancer after lung cancer and the fifth most common cause of cancer death. Several structural classes of compounds were discovered against tumor, but many of the existing antitumor agents exhibit severe side effects. Hence there is a need to identify a novel chemical entity having a broad range of therapeutic activity with fewer side effects.
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