ABSTRACT
An intramolecular, gold-catalyzed alkyne hydroarylation results in the formation of the core pyrroloazepinone framework of the hymenin group of oroidin alkaloids. Elaboration of the cyclic adduct via C2-azidation, bromination of the pyrrole, and deprotection set the stage for global reduction with Mo(CO)6 resulting in the formation 2-debromohymenin.
Subject(s)
Alkynes/chemistry , Hydrocarbons, Brominated/chemical synthesis , Sesquiterpenes/chemical synthesis , Azepines/chemical synthesis , Azepines/chemistry , Carbon Monoxide/chemistry , Catalysis , Chemistry Techniques, Synthetic/methods , Cyclization , Gold/chemistry , Hydrocarbons, Brominated/chemistry , Molybdenum/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Sesquiterpenes/chemistryABSTRACT
Constitutive WNT activity drives the growth of various human tumors, including nearly all colorectal cancers (CRCs). Despite this prominence in cancer, no WNT inhibitor is currently approved for use in the clinic largely due to the small number of druggable signaling components in the WNT pathway and the substantial toxicity to normal gastrointestinal tissue. We have shown that pyrvinium, which activates casein kinase 1α (CK1α), is a potent inhibitor of WNT signaling. However, its poor bioavailability limited the ability to test this first-in-class WNT inhibitor in vivo. We characterized a novel small-molecule CK1α activator called SSTC3, which has better pharmacokinetic properties than pyrvinium, and found that it inhibited the growth of CRC xenografts in mice. SSTC3 also attenuated the growth of a patient-derived metastatic CRC xenograft, for which few therapies exist. SSTC3 exhibited minimal gastrointestinal toxicity compared to other classes of WNT inhibitors. Consistent with this observation, we showed that the abundance of the SSTC3 target, CK1α, was decreased in WNT-driven tumors relative to normal gastrointestinal tissue, and knocking down CK1α increased cellular sensitivity to SSTC3. Thus, we propose that distinct CK1α abundance provides an enhanced therapeutic index for pharmacological CK1α activators to target WNT-driven tumors.
Subject(s)
Antineoplastic Agents/pharmacology , Benzoates/pharmacology , Casein Kinase Ialpha/metabolism , Enzyme Activators/pharmacology , Neoplasms/drug therapy , Wnt Proteins/metabolism , Animals , Enzyme Activation , Gene Expression Regulation, Neoplastic , HCT116 Cells , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Nude , Neoplasm Metastasis , Organ Culture Techniques , Phosphorylation , Pyrvinium Compounds/chemistry , Signal Transduction , Surface Plasmon Resonance , Wnt Signaling Pathway , Xenograft Model Antitumor Assays , Xenopus laevisABSTRACT
High performance liquid chromatography (HPLC) and capillary electrophoresis (CE) were used to examine the enantiomeric separation of a series of 17 racemic tetrahydrobenzimidazole analytes. These compounds were prepared as part of a synthetic program directed towards a select group of pyrrole-imidazole alkaloids. This group of natural products has a unique framework of pyrrole- and guanidine-containing fused rings which can be constructed through the intermediacy of a tetrahydrobenzimidazole scaffold. Several bonded cyclodextrin- (both native and derivatized) and derivatized cyclofructan-based chiral stationary phases were evaluated for their ability to separate these racemates via HPLC. Similarly, several cyclodextrin derivatives and derivatized cyclofructan were evaluated for their ability to separate this set of chiral compounds via CE. Enantiomeric selectivity was observed for the entire set of racemic compounds using HPLC with resolution values up to 3.0. Among the 12 different CSPs, enantiomeric recognition was most frequently observed with the Cyclobond RN and LARIHC CF6-P, while the Cyclobond DMP yielded the greatest number of baseline separations. Fifteen of the analytes showed enantiomeric recognition in CE with resolution values as high as 5.0 and hydroxypropyl-γ-cyclodextrin was the most effective chiral additive.
Subject(s)
Benzimidazoles/chemistry , Cyclodextrins/chemistry , Cyclodextrins/isolation & purification , Fructans/chemistry , Fructans/isolation & purification , Chromatography, High Pressure Liquid , Electrophoresis, Capillary , StereoisomerismABSTRACT
Based upon observations from our initial findings, additional myxopyronin B analogs have been prepared and tested for in vitro inhibitory activity against DNA-dependent RNA polymerase and antibacterial activity against Escherichia coli and Staphylococcus aureus.
Subject(s)
DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Lactones/chemistry , Lactones/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , DNA-Directed RNA Polymerases/metabolism , Enzyme Inhibitors/chemistry , Escherichia coli/drug effects , Escherichia coli/enzymology , Inhibitory Concentration 50 , Lactones/chemical synthesis , Methylation , Molecular Structure , Staphylococcus aureus/drug effects , Staphylococcus aureus/enzymologyABSTRACT
Hemiasterlin is a potent antimitotic peptide that interferes with microtubule dynamics at picomolar concentrations in cell culture. The molecule largely eludes P glycoprotein-mediated drug efflux, and an analog is currently being evaluated in clinical trials as cancer chemotherapy. From a nonclonal genetic screen in Caenorhabditis elegans we isolated eight independent mutants resistant to a synthetic hemiasterlin analog. In one recessive mutant, phb-2(ad2154), a point mutation in prohibitin 2 (E130K) protects worms from drug-induced injury. Data indicate that direct binding of hemiasterlin to prohibitin 2 is unlikely. In fact, C. elegans phb-2(ad2154) was also found to be resistant to numerous other drugs that bind tubulin and to camptothecin, yet this mutant was sensitive to nocodazole and phalloidin. Thus, prohibitin 2 is implicated in a previously uncharacterized pathway of multidrug resistance.
Subject(s)
Antinematodal Agents/pharmacology , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Mutation, Missense , Oligopeptides/pharmacology , Repressor Proteins/genetics , Tubulin Modulators/pharmacology , Animals , Caenorhabditis elegans/physiology , Caenorhabditis elegans Proteins , Cell Line , Drug Resistance, Multiple/physiology , Genetic Complementation Test , Humans , Molecular Structure , Nocodazole/pharmacology , Oligopeptides/chemistry , Phalloidine/pharmacology , Prohibitins , Protein Isoforms/genetics , Protein Isoforms/metabolism , Repressor Proteins/metabolism , Tubulin/metabolism , Tubulin Modulators/chemistrySubject(s)
Alkaloids/chemistry , Guanidines/chemistry , Spiro Compounds/chemistry , Cyclization , Isomerism , Models, MolecularABSTRACT
A series of myxopyronin B analogs has been prepared via a convergent synthetic route and were tested for in vitro inhibitory activity against DNA-dependent RNA polymerase and antibacterial activity against E. coli and S. aureus. The parent lead compound proved to be very sensitive to even small changes. Only the achiral desmethyl myxopyronin B (1a) provided enhanced potency.
