ABSTRACT
Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.
Subject(s)
Acetylcholinesterase/metabolism , Carbazoles/chemistry , Carbazoles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Acetylcholinesterase/chemistry , Acetylcholinesterase/pharmacokinetics , Acetylcholinesterase/therapeutic use , Animals , Aza Compounds/chemistry , Aza Compounds/pharmacokinetics , Aza Compounds/pharmacology , Aza Compounds/therapeutic use , Cell Line, Tumor , Checkpoint Kinase 1 , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacokinetics , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Crystallography, X-Ray , Dogs , Humans , Mice , Mice, Nude , Models, Molecular , Neoplasms/drug therapy , Neoplasms/enzymology , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein Kinases/chemistry , RatsABSTRACT
A series of dual-targeting, alcohol-containing benzothiazoles has been identified with superior antibacterial activity and drug-like properties. Early lead benzothiazoles containing carboxylic acid moieties showed efficacy in a well-established in vivo model, but inferior drug-like properties demanded modifications of functionality capable of demonstrating superior efficacy. Eliminating the acid group in favor of hydrophilic alcohol moieties at C(5), as well as incorporating solubilizing groups at the C(7) position of the core ring provided potent, broad-spectrum Gram-positive antibacterial activity, lower protein binding, and markedly improved efficacy in vivo.
Subject(s)
Anti-Bacterial Agents/pharmacology , Benzothiazoles/chemistry , Benzothiazoles/pharmacology , DNA, Bacterial/chemistry , DNA, Bacterial/drug effects , DNA, Superhelical/drug effects , Haemophilus influenzae/drug effects , Alcohols/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Benzothiazoles/chemical synthesis , Dose-Response Relationship, Drug , Drug Discovery , Microbial Sensitivity Tests , Molecular Structure , Staphylococcus , Structure-Activity RelationshipABSTRACT
The discovery and optimisation of a new class of benzothiazole small molecules that inhibit bacterial DNA gyrase and topoisomerase IV are described. Antibacterial properties have been demonstrated by activity against DNA gyrase ATPase and potent activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes and Haemophilus influenzae. Further refinements to the scaffold designed to enhance drug-likeness included analogues bearing an α-substituent to the carboxylic acid group, resulting in excellent solubility and favourable pharmacokinetic properties.
Subject(s)
Benzothiazoles/chemistry , Benzothiazoles/pharmacology , DNA Topoisomerase IV/antagonists & inhibitors , Drug Design , Isonipecotic Acids/chemistry , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Benzothiazoles/chemical synthesis , DNA Gyrase/chemistry , DNA Gyrase/metabolism , DNA Topoisomerase IV/metabolism , Enterococcus faecalis/drug effects , Enterococcus faecalis/enzymology , Enzyme Activation/drug effects , Haemophilus influenzae/drug effects , Haemophilus influenzae/enzymology , Half-Life , Mice , Microbial Sensitivity Tests , Rats , Staphylococcus aureus/drug effects , Staphylococcus aureus/enzymology , Streptococcus pyogenes/drug effects , Streptococcus pyogenes/enzymology , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/pharmacokineticsABSTRACT
The total syntheses of the 3,6-dihydroxydecanolide from Cordyceps militaris and the novel C-3 epimer are reported using a diastereoselective Nozaki-Hiyama-Kishi reaction in the key cyclization to generate the 6R stereocenter.
Subject(s)
Biological Products/chemical synthesis , Cordyceps/chemistry , Lactones/chemical synthesis , Biological Products/chemistry , Biological Products/isolation & purification , Cyclization , Lactones/chemistry , Lactones/isolation & purification , Molecular Structure , StereoisomerismSubject(s)
Lactones/isolation & purification , Multienzyme Complexes/chemistry , Polymerase Chain Reaction/methods , Antifungal Agents/chemistry , Ascomycota/enzymology , Fungal Proteins/chemistry , Fungal Proteins/genetics , Fungal Proteins/isolation & purification , Fungal Proteins/metabolism , Magnetic Resonance Spectroscopy , Models, Chemical , Multienzyme Complexes/genetics , Multienzyme Complexes/isolation & purification , Multienzyme Complexes/metabolismABSTRACT
A series of substituted naphthyl containing chiral [2.2.1] bicycloheptanes were prepared utilizing asymmetric Diels-Alder chemistry. This paper describes structure-activity relationships in this series. The N-methyl 2-naphthyl analogue (16d) and its des-methyl analogue (17d) are active triple re-uptake inhibitors both in vivo and in vitro.
