ABSTRACT
There has been little innovation in identifying novel insulin sensitizers. Metformin, developed in the 1920s, is still used first for most Type 2 diabetes patients. Mice with genetic reduction of p52Shc protein have improved insulin sensitivity and glucose tolerance. By high-throughput screening, idebenone was isolated as the first small molecule 'Shc Blocker'. Idebenone blocks p52Shc's access to Insulin Receptor to increase insulin sensitivity. In this work the avidity of 34 novel idebenone analogs and 3 metabolites to bind p52Shc, and to block the interaction of p52Shc with the Insulin receptor was tested. Our hypothesis was that if an idebenone analog bound and blocked p52Shc's access to insulin receptor better than idebenone, it should be a more effective insulin sensitizing agent than idebenone itself. Of 34 analogs tested, only 2 both bound p52Shc more tightly and/or blocked the p52Shc-Insulin Receptor interaction more effectively than idebenone. Of those 2 only idebenone analog #11 was a superior insulin sensitizer to idebenone. Also, the long-lasting insulin-sensitizing potency of idebenone in rodents over many hours had been puzzling, as the parent molecule degrades to metabolites within 1 h. We observed that two of the idebenone's three metabolites are insulin sensitizing almost as potently as idebenone itself, explaining the persistent insulin sensitization of this rapidly metabolized molecule. These results help to identify key SAR = structure-activity relationship requirements for more potent small molecule Shc inhibitors as Shc-targeted insulin sensitizers for type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Receptor, Insulin/metabolism , Src Homology 2 Domain-Containing, Transforming Protein 1/genetics , Ubiquinone/analogs & derivatives , Animals , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/physiopathology , Insulin/metabolism , Insulin Resistance , Mice , Mice, Inbred C57BL , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Ubiquinone/chemistry , Ubiquinone/pharmacologyABSTRACT
In the decade since the discovery of englerin A (1) and its potent activity in cancer models, this natural product and its analogues have been the subject of numerous chemical, biological, and preclinical studies by many research groups. This review summarizes published findings and proposes further research directions required for entry of an englerin analogue into clinical trials for kidney cancer and other conditions.
Subject(s)
Antineoplastic Agents, Phytogenic , Kidney Neoplasms/drug therapy , Sesquiterpenes, Guaiane , Humans , Molecular StructureABSTRACT
Synthesis of analogues of englerin A with a reduced propensity for hydrolysis of the glycolate moiety led to a compound which possessed the renal cancer cell selectivity of the parent and was orally bioavailable in mice.
Subject(s)
Antineoplastic Agents/pharmacology , Sesquiterpenes, Guaiane/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Biological Availability , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Molecular Structure , Rats , Sesquiterpenes, Guaiane/administration & dosage , Sesquiterpenes, Guaiane/chemistry , Structure-Activity RelationshipABSTRACT
The effect of the alkyl side chain length of coenzyme Q10 on mitochondrial respiratory chain function has been investigated by the use of synthetic ubiquinone derivatives. Three analogues (3, 4 and 6) were identified that exhibited significantly improved effects on mitochondrial oxygen consumption and mitochondrial membrane potential, and also conferred significant cytoprotection on cultured mammalian cells in which glutathione had been depleted by treatment with diethyl maleate. The analogues also exhibited lesser inhibition of the electron transport chain than idebenone. The results obtained provide guidance for the design of CoQ10 analogues with improved activity compared to that of idebenone (1), the latter of which is undergoing evaluation in the clinic as a therapeutic agent.
Subject(s)
Electron Transport/drug effects , Mitochondria/drug effects , Ubiquinone/analogs & derivatives , Animals , Cattle , Cell Line , Cell Line, Tumor , Cytoprotection , Electron Transport/physiology , Humans , Leukemia/metabolism , Leukemia/pathology , Membrane Potential, Mitochondrial/drug effects , Mitochondria/metabolism , Oxygen Consumption/drug effects , Reactive Oxygen Species/metabolism , Retinal Ganglion Cells/cytology , Retinal Ganglion Cells/drug effects , Retinal Ganglion Cells/metabolism , Structure-Activity Relationship , Ubiquinone/chemistry , Ubiquinone/metabolism , Ubiquinone/pharmacologyABSTRACT
Two new aza analogues of the neuroprotective agent idebenone have been synthesized and characterized. Their antioxidant activity, and ability to augment ATP levels have been evaluated in several different cell lines having suboptimal mitochondrial function. Both compounds were found to be good ROS scavengers, and to protect the cells from oxidative stress induced by glutathione depletion. The compounds were more effective than idebenone in neurodegenerative disease cells. These novel pyrimidinol derivatives were also shown to augment ATP levels in coenzyme Q(10)-deficient human lymphocytes. The more lipophilic side chains attached to the pyrimidinol redox core in these compounds resulted in less inhibition of the electron transport chain and improved antioxidant activity.
Subject(s)
Antioxidants/chemistry , Mitochondria/metabolism , Neuroprotective Agents/chemistry , Pyrimidines/chemistry , Ubiquinone/analogs & derivatives , Adenosine Triphosphate/metabolism , Animals , Antioxidants/chemical synthesis , Antioxidants/toxicity , Cattle , Cell Line , Cell Survival/drug effects , Drug Design , Glutathione/metabolism , Humans , Lymphocytes/drug effects , Lymphocytes/metabolism , Mitochondria/enzymology , Multienzyme Complexes/antagonists & inhibitors , Multienzyme Complexes/metabolism , NADH, NADPH Oxidoreductases/antagonists & inhibitors , NADH, NADPH Oxidoreductases/metabolism , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/toxicity , Pyrimidines/chemical synthesis , Pyrimidines/toxicity , Reactive Oxygen Species/metabolism , Ubiquinone/chemical synthesis , Ubiquinone/chemistry , Ubiquinone/genetics , Ubiquinone/metabolism , Ubiquinone/toxicityABSTRACT
The number of renal cancers has increased over the last ten years and patient survival in advanced stages remains very poor. Therefore, new therapeutic approaches for renal cancer are essential. Englerin A is a natural product with a very potent and selective cytotoxicity against renal cancer cells. This makes it a promising drug candidate that may improve current treatment standards for patients with renal cancers in all stages. However, little is known about englerin A's mode of action in targeting specifically renal cancer cells. Our study is the first to investigate the biological mechanism of englerin A action in detail. We report that englerin A is specific for renal tumor cells and does not affect normal kidney cells. We find that englerin A treatment induces necrotic cell death in renal cancer cells but not in normal kidney cells. We further show that autophagic and pyroptotic proteins are unaffected by the compound and that necrotic signaling in these cells coincided with production of reactive oxygen species and calcium influx into the cytoplasm. As the first study to analyze the biological effects of englerin A, our work provides an important basis for the evaluation and validation of the compound's use as an anti-tumor drug. It also provides a context in which to identify the specific target or targets of englerin A in renal cancer cells.
Subject(s)
Antineoplastic Agents/pharmacology , Necrosis , Sesquiterpenes, Guaiane/pharmacology , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Autophagy/drug effects , Calcium/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Chloroquine/pharmacology , Cytoplasm/drug effects , Cytoplasm/metabolism , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Molecular Structure , Reactive Oxygen Species/metabolism , Sesquiterpenes, Guaiane/chemistry , Staurosporine/pharmacologyABSTRACT
Selected pyridinol analogues of the experimental neuroprotective drug idebenone have been synthesized and evaluated as antioxidants capable of preserving mitochondrial function. The compounds, having a different redox core but the same side chain as idebenone, exhibited a range of potencies, reflecting differences in their structures. The results obtained provide guidance in the design of such analogues with improved properties. Analogues were identified that have significantly improved antioxidant activity compared with idebenone in cultured lymphocytes, and which exhibit lesser inhibition of the electron transport chain.
