1-azakenpaullone and Neoplasms

The search for new lead compounds of simple structure, displaying highest quality anti-tumor potency with new mechanisms of action and least adverse effects is the major intention of cancer drug discovery now a days. For the time being, indole-fused azepines emerged as a simple class of compounds prolifically designed with strong pharmacological significances in particular of cancer protecting ability. In the recent years from the efforts of our research group, indole-fused heteroazepines, a simple structural class achieved by fusion of indole with oxygen, sulphur and nitrogen containing heteroazepine rings, have known for its superior outcomes in cancer treatment. Surprisingly, the chemistry and biology of these unique families with an amazing role in cancer drug discovery has remained broadly unexplored. This short review is consequently an endeavor to highlight the preliminary ideas over this structural class and to draw the medical attention towards future development of indole-fused azepines and analogues for their promising function in cancer drug discovery.

Topics: Animals; Antineoplastic Agents; Azepines; Chemistry Techniques, Synthetic; Drug Design; Humans; Indoles; Neoplasms; Structure-Activity Relationship

Three closely related forms of glycogen synthase kinase 3 (GSK-3alpha, GSK-3beta and GSK-3beta2) have a major role in Wnt and Hedgehog signaling pathways and regulate the cell-division cycle, stem-cell renewal and differentiation, apoptosis, circadian rhythm, transcription and insulin action. A large body of evidence supports speculation that pharmacological inhibitors of GSK-3 could be used to treat several diseases, including Alzheimer's disease and other neurodegenerative diseases, bipolar affective disorder, diabetes, and diseases caused by unicellular parasites that express GSK-3 homologues. The toxicity, associated side-effects and concerns regarding the absorption, distribution, metabolism and excretion of these inhibitors affect their clinical potential. More than 30 inhibitors of GSK-3 have been identified. Seven of these have been co-crystallized with GSK-3beta and all localize within the ATP-binding pocket of the enzyme. GSK-3, as part of a multi-protein complex that contains proteins such as axin, presenilin and beta-catenin, contains many additional target sites for specific modulation of its activity.

Topics: Animals; Cell Differentiation; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Humans; Neoplasms; Nervous System Diseases; Parasitic Diseases; Signal Transduction; Stem Cells; Structure-Activity Relationship