ABSTRACT
A new series of N'-(substituted phenyl)-5-chloro/iodo-3-phenyl-1H-indole-2-carbohydrazide (5, 6) and N-[2-(substituted phenyl)-4-oxo-1,3-thiazolidin-3-yl]-5-iodo/chloro-3-phenyl-1H-indole-2-carboxamide (7, 8) derivatives were synthesized and evaluated for their anticancer properties. Compounds 5a and 6b, selected as prototypes by the National Cancer Institute for screening against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions, demonstrated remarkable antiproliferative activity against leukemia, non-small cell lung cancer, colon cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, renal cancer, and breast cancer (MCF-7) cell lines with GI50 values < 0.4 µM. A subset of the compounds was then tested for their potential to inhibit tubulin polymerization. Compounds 6f and 6g showed significant cytotoxicity at the nM level on MCF-7 cells and exhibited significant inhibitory activity on tubulin assembly and colchicine binding at about the same level as combretastatin A-4. Finally, docking calculations were performed to identify the binding mode of these compounds. Group 5 and 6 compounds interacted with the colchicine binding site through hydrophobic interactions similar to those of colchicine. These compounds with antiproliferative activity at high nanomolar concentration can serve as scaffolds for the design of novel microtubule targeting agents.
Subject(s)
Antineoplastic Agents/pharmacology , Hydrazines/pharmacology , Indoles/pharmacology , Thiazolidines/pharmacology , Tubulin Modulators/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Binding Sites , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Hydrazines/chemical synthesis , Hydrazines/chemistry , Hydrazines/metabolism , Indoles/chemical synthesis , Indoles/chemistry , Indoles/metabolism , MCF-7 Cells , Molecular Docking Simulation , Protein Binding , Thiazolidines/chemical synthesis , Thiazolidines/chemistry , Thiazolidines/metabolism , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Tubulin Modulators/metabolismABSTRACT
Lysosome is the organelle responsible for breaking down macromolecules to maintain homeostasis and to fight infection. The disruption of normal lysosomal function due to mutations in the sphingolipid metabolism proteins leads to a class of lysosomal storage diseases (LSDs). Defective autophagy and activation of inflammation are observed in most LSDs. The crosstalk between these key metabolic pathways suggests that therapeutic approaches used in the treatment of LSDs may provide anti-inflammatory therapies against chronic inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease. Here, we review the role of sphingolipids in the inflammatory response and build a protein-protein interaction network for proteins related with sphingolipid metabolism and inflammation to identify key interaction partners for the crosstalk between sphingolipids and inflammation. In addition, we present an overview of LSDs in relation with sphingolipids and inflammation, and review the pharmacological chaperones identified for these diseases.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Inflammation/drug therapy , Molecular Chaperones/pharmacology , Rare Diseases/drug therapy , Sphingolipids/antagonists & inhibitors , Sphingolipids/metabolism , Animals , Humans , Inflammation/metabolism , Rare Diseases/metabolismABSTRACT
Beta-Glucocerebrosidase (GBA) is a lysosomal protein that is responsible for the hydrolysis of glycosylceramide into glucose and ceramide. Mutations in GBA lead to the accumulation of glycosylceramide in the lysosome causing an enlargement of the spleen and the liver and skeletal deformations. This disease is called Gaucher Disease. Enzyme replacement therapies and substrate reduction methods that are used to treat Gaucher Disease fail when the disease is neuropathic because they fail to pass the blood brain barrier. In this work, QSAR, virtual screening, docking and molecular dynamics simulations were performed to obtain a set of compounds that might be pharmacological chaperones for GBA. ZINC Database was screened using ligand-based and structure-based pharmacophore hypotheses. After docking of these molecules and filtration based on druglikeness, top ranking ligands were identified and their binding stabilities were examined using MD simulations. As a result, seven new compounds that can potentially cross the blood brain barrier were proposed as GBA inhibitors. Three of the seven compounds have a tricyclic pyrido-thieno-pyrimidine scaffold and one has the dioxino quinolone scaffold. Derivatives of these scaffolds have been reported as antiallergic agents, antibiotic and anticancer compounds. These results offer a new approach for the development of new drugs against neuropathic Gaucher Disease Type 2 and Type 3.
