ABSTRACT
Optimisation of a series of benzazepine sulfonamide hit compounds identified from high throughput screening led to the discovery of a new series of tractable, potent motilin receptor agonists.
Subject(s)
Receptors, Gastrointestinal Hormone/agonists , Receptors, Neuropeptide/agonists , Sulfonamides/pharmacology , Sulfones/pharmacology , Animals , Binding Sites , CHO Cells , Chemistry, Pharmaceutical , Cricetinae , Cricetulus , Drug Design , Drug Discovery , Models, Chemical , Molecular Structure , Structure-Activity RelationshipABSTRACT
A wide range of biologically active compounds contain the quinazoline ring system. A new free-radical-based method of making functionalized quinazolines is described, which relies on microwave-promoted reactions of O-phenyl oximes with aldehydes. A small set of 2-aminoaryl alkanone O-phenyl oximes was prepared and shown to produce dihydroquinazolines when mixed with an aldehyde in toluene and subjected to microwave heating. When ZnCl(2) was included in the reaction mixture, fully aromatic quinazolines were produced in high yields by a rapid and convenient process. The method worked well with alkyl, aryl, and heterocyclic aldehydes and for a variety of substituents in the benzenic part of the molecule. Similar reactions employing ketones instead of aldehydes were less efficient. Although some dihydroquinazolines did form, they were accompanied by several byproducts. Surprisingly, in each case, one of the byproducts was a quinoline derivative, and a plausible mechanism to account for this rearrangement is proposed.
Subject(s)
Alkanes/chemistry , Ketones/chemistry , Microwaves , Oximes/chemistry , Oxygen/chemistry , Quinazolines/chemical synthesis , Amination , Chemistry, Pharmaceutical , Molecular Structure , Quinazolines/chemistryABSTRACT
Dioxime oxalates are useful precursors for the clean generation of iminyl radicals by sensitised UV photolysis and can be adapted for serviceable preparations of 3,4-dihydro-2H-pyrroles and phenanthridines.
Subject(s)
Imines/chemistry , Oxalates/chemistry , Phenanthridines/chemistry , Pyrroles/chemistry , Electron Spin Resonance Spectroscopy , Free RadicalsABSTRACT
This research aimed to provide a new and "clean" synthetic method that would enable both known and novel N-heterocycles to be prepared efficiently. O-Phenyl oximes were found to be excellent precursors for iminyl radicals with a variety of acceptor side chains. Dihyropyrroles were made in good yields from O-phenyl oximes containing pent-4-ene acceptors. The analogous process with a hex-5-enyl acceptor did not yield a dihydropyridine, probably because the 6-exo-trig ring closure of the iminyl radical was too slow to compete with H-atom abstraction. The iminyl radical from a precursor with a pent-4-yne type side chain underwent ring closure followed by rearrangement to afford a pyrrole derivative. Suitably substituted iminyl radicals ring closed readily onto aromatic acceptors, thus enabling several polycyclic systems to be accessed. Quinolines were made from 3-phenylpropanones via their O-phenyl oximes. Syntheses of phenanthridines starting from 2-formylbiphenyls were particularly efficient, and this approach enabled the natural product trisphaeridine to be made. Starting from 2-phenylnicotinaldehyde derivatives, ring closures of the derived iminyl radicals onto the phenyl rings yielded benzo[h][1,6]naphthyridines. Similarly, ring closure onto a phenyl ring from a benzothiophene-based iminyl yielded a benzo[b]thieno[2,3-c]quinoline. By way of contrast, iminyl radical ring closure onto pyridine rings was not observed. However, iminyl radicals did cyclize onto indoles, enabling indolopyridines to be prepared. The latter route was exploited in a short formal synthesis of neocryptolepine starting from 2-((1H-indol-3-yl)methyl)cyclohexanone.
Subject(s)
Alkaloids/chemical synthesis , Alkanes/chemistry , Heterocyclic Compounds/chemistry , Microwaves , Oximes/chemistry , Quinolines/chemical synthesis , Alkaloids/chemistry , Cyclization , Molecular Structure , Quinolines/chemistry , TemperatureABSTRACT
Microwave irradiations of 2-(aminoaryl)alkanone O-phenyl oximes and carbonyl compounds generate iminyl radicals in company with imines; iminyl on imine ring closure yields dihydroquinazolines or quinazolines when ZnCl2 is included in the mixture.
Subject(s)
Alkanes/chemistry , Oximes/chemical synthesis , Quinazolines/chemical synthesis , Amination , Chlorides/chemistry , Indicators and Reagents , Molecular Structure , Oximes/chemistry , Quinazolines/chemistry , Zinc Compounds/chemistryABSTRACT
High throughput screening combined with efficient datamining and parallel synthesis led to the discovery of a novel series of indolines showing potent in vitro ghrelin receptor agonist activity and acceleration of gastric emptying in rats.
Subject(s)
Indoles/chemistry , Receptors, Ghrelin/agonists , Animals , Gastric Emptying/drug effects , Gastric Emptying/physiology , Human Growth Hormone/agonists , Humans , Indoles/pharmacology , Rats , Receptors, Ghrelin/physiology , StereoisomerismABSTRACT
Microwave irradiation of alkenone O-phenyl oximes produces iminyl radicals that ring close to yield dihydropyrrole derivatives; pyrroles and pyridines can be obtained from related precursors.
Subject(s)
Alkanes/chemistry , Hydrogen/chemistry , Microwaves , Oximes/chemistry , Pyrroles/chemical synthesis , Free Radicals/chemistry , Molecular Structure , Pyrroles/chemistryABSTRACT
The detection of leukemia cells on newborn genetic screening cards ("Guthrie cards") of a small group of patients and several sets of identical twins developing acute lymphoblastic leukemia (ALL) with identical phenotypic and chromosomal markers has provided evidence that childhood ALL cases may arise in utero. We conducted a retrospective study of a randomly selected group of childhood B-precursor ALL patients to determine the frequency of the presence of "leukemic" clones prenatally in ALL cases by testing newborn screening cards. The 17 ALL patients analyzed had a median age of 46 months (range, 18 months to 13 years) and had median presenting white blood cell (WBC) counts of 10 950/microL (range, 2900-70 300/microL) at diagnosis. A clonal rearrangement of the immunoglobulin heavy chain (IgH) gene was identified in diagnostic lymphoblasts and sequenced and patient-specific primers were used to amplify DNA from blood samples on the patient's newborn screening cards. Twelve of the 17 (71%) analyzed newborn cards had detectable IgH rearrangements amplified by seminested polymerase chain reaction. DNA sequencing confirmed that the IgH rearrangements detected matched the IgH sequences identified from diagnostic leukemia cells, indicating the presence of a "leukemic" clone at birth. There were no differences in age or presenting WBC counts between the cases with or without positive newborn screening cards. All 6 patients with hyperdiploid ALL had detectable "leukemic" clones on their cards. The results of our study support the notion that a high proportion of childhood B-precursor ALL cases arise in utero, although postnatal events are also important factors in leukemogenesis.
