193966-77-7Relevant articles and documents
Structurally Divergent Lithium Catalyzed Friedel–Crafts Reactions on Oxetan-3-ols: Synthesis of 3,3-Diaryloxetanes and 2,3-Dihydrobenzofurans
Croft, Rosemary A.,Mousseau, James J.,Choi, Chulho,Bull, James A.
supporting information, p. 16271 - 16276 (2016/10/30)
The first examples of 3,3-diaryloxetanes are prepared in a lithium-catalyzed and substrate dependent divergent Friedel–Crafts reaction. para-Selective Friedel–Crafts reactions of phenols using oxetan-3-ols afford 3,3-diaryloxetanes by displacement of the hydroxy group. These constitute new isosteres for benzophenones and diarylmethanes. Conversely, ortho-selective Friedel–Crafts reactions of phenols afford 3-aryl-3-hydroxymethyl-dihydrobenzofurans by tandem alkylation–ring-opening reactions; the outcome of the reaction diverging to structurally distinct products dependent on the substrate regioselectivity. Further reactivity of the oxetane products is demonstrated, suitable for incorporation into drug discovery efforts.
Biomimetic deiodination of thyroid hormones and iodothyronamines-a structure-activity relationship study
Mondal, Santanu,Mugesh, Govindasamy
supporting information, p. 9490 - 9500 (2016/10/22)
Mammalian selenoenzymes, iodothyronine deiodinases (DIOs), catalyze the tyrosyl and phenolic ring deiodination of thyroid hormones (THs) and play an important role in maintaining the TH concentration throughout the body. These enzymes also accept the decarboxylated thyroid hormone metabolites, iodothyronamines (TAMs), as substrates for deiodination. Naphthalene-based selenium and/or sulphur-containing small molecules have been shown to mediate the regioselective tyrosyl ring deiodination of thyroid hormones and their metabolites. Herein, we report on the structure-activity relationship studies of a series of peri-substituted selenium-containing naphthalene derivatives for the deiodination of thyroid hormones and iodothyronamines. Single crystal X-ray crystallographic and 77Se NMR spectroscopic studies indicated that the intramolecular Se?X (X = N, O and S) interactions play an important role in the deiodinase activity of the synthetic mimics. Furthermore, the decarboxylated metabolites, TAMs, have been observed to undergo slower tyrosyl ring deiodination than THs by naphthyl-based selenium and/or sulphur-containing synthetic deiodinase mimics and this has been explained on the basis of the strength of Se?I halogen bonding formed by THs and TAMs.
New strategy for the synthesis of proaporphine and homoproaporphine-type alkaloids from a common intermediate
Magnus, Philip,Marks, Kyle D.,Meis, Alan
, p. 3872 - 3877 (2015/06/02)
Starting with 3-bromo-4,5-dimethoxybenzaldehyde 14, it was coupled with the boronic anhydride 15 using standard Suzuki reaction conditions to give 16 (91%). The aldehyde 16 was exposed to classical nitro-aldol reaction conditions to give 17 (88%), and conjugatively reduced with DIBAL-H to give 18 (91%). Protection of the amine 18 as its N-carbamate derivative 19, followed by condensation with glycol aldehyde dimer under acidic reaction conditions gave 20 (78%). Subsequent conversion of 20 into its mesylate derivative 21, and exposure to CsF under aprotic reaction conditions gave 22 (81%). Deprotection of 22 gave (±)-stepharine 10 in 29% overall yield though 8 steps. A similar sequence of reaction conditions converted the amine 18 into the -NTs protected homoproaporphine adduct 28.
Regioselective deiodination of iodothyronamines, endogenous thyroid hormone derivatives, by deiodinase mimics
Mondal, Santanu,Mugesh, Govindasamy
supporting information, p. 11120 - 11128,9 (2014/11/27)
Iodothyronine deiodinases (IDs) are mammalian selenoenzymes that play an important role in the activation and inactivation￡ of thyroid hormones. It is known that iodothyronamines (TnAMs), produced by the decarboxylation of thyroid hormones, act as substrates for deiodinases. To understand whether decarboxylation alters the rate and/or regioselectivity of deiodination by using synthetic deiodinase mimics, we studied the deiodination of different iodothyronamines. The triiodo derivative 3,3,5-triiodothyronamine (T3 AM) is deiodinated at the inner ring by naphthyl-based deiodinase mimics, which is similar to the deiodination of 3,3,5-triiodothyronine (T3). However, T3 AM undergoes much slower deiodination than T3. Detailed experimental and theoretical investigations suggest that T3 AM forms a weaker halogen bond with selenium donors than T3. Kinetic studies and single-crystal X-ray structures of T3 and T3 AM reveal that intermolecular I...I interactions may play an important role in deiodination. The formation of hydrogen- and halogen-bonding assemblies, which leads to the formation of a dimeric species of T3 in solution, facilitates the interactions between the selenium and iodine atoms. In contrast, T3 AM, which does not have I...I interactions, undergoes much slower deiodination.
Boronic acid catalysis as a mild and versatile strategy for direct carbo- and heterocyclizations of free allylic alcohols
Zheng, Hongchao,Ghanbari, Sina,Nakamura, Shinji,Hall, Dennis G.
supporting information; experimental part, p. 6187 - 6190 (2012/08/13)
BAC to the future: Boronic acid catalysis (BAC) was applied to the direct activation of alcohols leading to the preparation of carbocycles (see scheme), benzofurans, tetrahydrofurans, pyrrolidines, pyrans, piperidines, and various polycyclic compounds. The reactions proceed under mild conditions that circumvent the use of reactive leaving groups like halides. Copyright
Discovery and SAR exploration of a novel series of imidazo[4,5-b]pyrazin-2- ones as potent and selective mTOR kinase inhibitors
Mortensen, Deborah S.,Perrin-Ninkovic, Sophie M.,Harris, Roy,Lee, Branden G.S.,Shevlin, Graziella,Hickman, Matt,Khambatta, Gody,Bisonette, Rene R.,Fultz, Kimberly E.,Sankar, Sabita
supporting information; experimental part, p. 6793 - 6799 (2012/01/03)
We report here the discovery of a novel series of selective mTOR kinase inhibitors. A series of imidazo[4,5-b]pyrazin-2-ones, represented by screening hit 1, was developed into lead compounds with excellent mTOR potency and exquisite kinase selectivity. Potent compounds from this series show >1000-fold selectivity over the related PI3Kα lipid kinase. Further, compounds such as 2 achieve mTOR pathway inhibition, blocking both mTORC1 and mTORC2 signaling, in PC3 cancer cells as measured by inhibition of pS6 and pAkt (S473).
SYNTHESIS OF MORPHINE AND RELATED DERIVATIVES
-
Page/Page column 67, (2010/12/17)
The present invention relates to methods for the synthesis of galanthamine, morphine, intermediates, salts and derivatives thereof, wherein the starting compound is biphenyl.
PHENOXYALKANOIC ACID COMPOUND
-
Page/Page column 35, (2008/06/13)
The present invention provides a compound represented by the formula: wherein each symbol is as defined in the specification. Since the compound of the present invention has superior hypoglycemic action and superior hypolipidemic action, it is useful as an agent for the prophylaxis or treatment of diabetes, hyperlipidemia, impaired glucose tolerance and the like.
HETEROARYL COMPOUNDS, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH
-
Page/Page column 109, (2008/12/05)
Provided herein are Heteroaryl Compounds having the following structure: (I) wherein R1, R2, L, X, Y, Z, Q, A and B are as defined herein, compositions comprising an effective amount of a Heteroaryl Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions treatable or preventable by inhibition of a kinase pathway comprising administering an effective amount of a Heteroaryl Compound to a patient in need thereof.
Trace amine-associated receptor agonists: Synthesis and evaluation of thyronamines and related analogues
Hart, Matthew E.,Suchland, Katherine L.,Miyakawa, Motonori,Bunzow, James R.,Grandy, David K.,Scanlan, Thomas S.
, p. 1101 - 1112 (2007/10/03)
We have previously shown that several thyronamines, decarboxylated and deiodinated metabolites of the thyroid hormone, potently activate an orphan G protein-coupled receptor in vitro (TAAR1) and induced hypothermia in vivo on a rapid time scale [Scanlan, T. S.; Suchland, K. L.; Hart, M. E.; Chiellini, G.; Huang, Y.; Kruzich, P. J.; Frascarelli, S.; Crossley, D. A.; Bunzow, J. R.; Ronca-Testoni, S.; Lin, E. T.; Hatton, D.; Zucchi, R.; Grandy, D. K. 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat. Med. 2004, 10 (6), 638-642]. Herein, we report the synthesis of these thyronamines. Additionally, a large number of thyroamine derivatives were synthesized in an effort to understand the molecular basis of TAAR1 activation and hypothermia induction. Several derivatives were found to potently activate both rTAAR1 and mTAAR1 in vitro (compounds 77, 85, 91, and 92). When administered to mice at a 50 mg/kg dose, these derivatives all induced significant hypothermia within 60 min and exhibited a hypothermic induction profile analogous to 3-iodothyronamine (1, T1AM) except 91, which proved to be more efficacious. On the basis of this result, a dose-dependent profile for 91 was generated and an ED50 of 30 μmol/kg was calculated. Compound 91 proved to be more potent than T1AM for TAAR1 activation and exhibits increased potency and efficacy for hypothermia induction. These data further strengthen the pharmacological correlation linking TAAR1 activation by thyronamines and hypothermia induction in mice.
