ABSTRACT
CL285032 is an anxiolytic compound currently under investigation as a possible treatment for canine noise phobia associated anxiety. A robust scale-up and manufacturing process is essential for the development and marketability of the drug. The current synthetic route, although reliable, requires seven steps and has a low overall yield (18%), leaving opportunity for improvement. We are presenting an efficient alternative approach toward the synthesis of CL285032 and the results thereof.
Subject(s)
Anti-Anxiety Agents/chemical synthesis , Pyridazines/chemical synthesis , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/therapeutic use , Dogs , Phobic Disorders/drug therapy , Pyridazines/chemistry , Pyridazines/therapeutic useABSTRACT
Wnt/ß-catenin signaling is critically involved in metazoan development, stem cell maintenance and human disease. Using Xenopus laevis egg extract to screen for compounds that both stabilize Axin and promote ß-catenin turnover, we identified an FDA-approved drug, pyrvinium, as a potent inhibitor of Wnt signaling (EC(50) of â¼10 nM). We show pyrvinium binds all casein kinase 1 (CK1) family members in vitro at low nanomolar concentrations and pyrvinium selectively potentiates casein kinase 1α (CK1α) kinase activity. CK1α knockdown abrogates the effects of pyrvinium on the Wnt pathway. In addition to its effects on Axin and ß-catenin levels, pyrvinium promotes degradation of Pygopus, a Wnt transcriptional component. Pyrvinium treatment of colon cancer cells with mutation of the gene for adenomatous polyposis coli (APC) or ß-catenin inhibits both Wnt signaling and proliferation. Our findings reveal allosteric activation of CK1α as an effective mechanism to inhibit Wnt signaling and highlight a new strategy for targeted therapeutics directed against the Wnt pathway.
Subject(s)
Casein Kinase Ialpha/metabolism , Cell Proliferation/drug effects , Enzyme Inhibitors/pharmacology , Pyrvinium Compounds/pharmacology , Signal Transduction/drug effects , Wnt Proteins/antagonists & inhibitors , Adaptor Proteins, Signal Transducing , Adenomatous Polyposis Coli/genetics , Adenomatous Polyposis Coli/metabolism , Animals , Axin Protein , Casein Kinase I/genetics , Casein Kinase I/metabolism , Cell Extracts , Cell Line, Tumor , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Oocytes/cytology , Oocytes/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolism , Wnt Proteins/chemistry , Wnt Proteins/genetics , Wnt Proteins/metabolism , Xenopus Proteins , Xenopus laevis , beta Catenin/genetics , beta Catenin/metabolismABSTRACT
The isolation, characterization, and cytotoxicity against H292 cells of apoptolidin G are reported. Apoptolidin G is shown to be derived by a light-induced isomerization of the C2-C3 carbon-carbon double bond of apoptolidin A.
Subject(s)
Macrolides/chemistry , Pyrones/chemistry , Ultraviolet Rays , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Macrolides/isolation & purification , Macrolides/pharmacology , Molecular Conformation , Pyrones/isolation & purification , Pyrones/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Glycosylation of a synthetic aglycone using precursor-directed biosynthesis is facilitated by a chemical ketosynthase "knockdown" of the apoptolidin producer Nocardiopsis sp. This synthetic approach facilitated the preparation of an unnatural disaccharide derivative of apoptolidin D that substantially restores cytotoxicity against H292 cells and deconvolutes the role of the decorating sugars in apoptolidin bioactivity.
Subject(s)
Actinomyces/chemistry , Antineoplastic Agents/chemical synthesis , Macrolides/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , Glycosylation , Humans , Macrolides/chemistry , Macrolides/pharmacology , Molecular Structure , Structure-Activity RelationshipABSTRACT
Apoptolidins A-D are microbial secondary metabolites shown to be selectively cytotoxic against several cancer cell lines and noncytotoxic against normal cells. Total syntheses of apoptolidinones A and D are reported. The efficient synthetic strategy leading to the apoptolidinones features construction of the common 20-membered macrolactone by an intramolecular Suzuki reaction and stereocontrolled aldol reactions establishing the C19/C20 and C22/C23 stereocenters. In contrast to apoptolidin A, the aglycones apoptolidinone A and D were shown to be noncytotoxic when evaluated against human lung cancer cells (H292).
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Macrolides/chemical synthesis , Macrolides/pharmacology , Pyrones/chemical synthesis , Pyrones/pharmacology , Cell Line, Tumor , Humans , Molecular StructureABSTRACT
A new example is provided of completely diastereoselective polycyclization, affording the octahydrophenanthrene framework. Generation of an iron tricarbonyl stabilized pentadienyl carbocation is the triggering event of the cascade reaction. The carbocation is generated by anchimerically assisted regiospecific protonation of a double bond adjacent to the iron tricarbonyl diene moiety. Tetrafluoroboric acid ether complex appears to be the optimum reagent, affording good yields, even under catalytic conditions.
ABSTRACT
A new example of stereospecific cationic cyclization of iron tricarbonyl diene complexes with pendant alkenes and arenes is provided. Protonation of a double bond vicinal to the iron tricarbonyl diene moiety is employed to trigger the cyclization, rather than the previously reported Lewis/protic acid dehydroxylation of diastereomeric alcohols, eliminating one step of separation and avoiding some reactivity problems previously encountered for one of the alcohol diastereoisomers. [reaction: see text]
