- Visible Light-Mediated Conversion of Alcohols to Bromides by a Benzothiadiazole-Containing Organic Photocatalyst
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The search for metal-free, stable and high effective photocatalysts with sufficient photo-redox potentials remains a key challenge for organic chemists. Here, we present a benzothiadiazole-containing molecular organic photocatalyst with redox potentials of ?1.30 V and +1.64 V vs. SCE. The singlet state lifetime is 13 ns. Direct conversion from aliphatic alcohols to bromides has been conducted with the designed organic photocatalyst under visible light irradiation with high efficiency and selectivity. The catalytic efficiency of the novel benzothiadiazole-based photocatalyst is comparable with the state-of-art metal and non-metal catalysts. Furthermore, advanced photophysical studies including time-resolved photoluminescence and transient absorption spectroscopy offer a powerful support for photo-induced electron transfer from photocatalyst to the reactive substrates. Lastly, no photo-bleaching effect is observed, demonstrating the high stability and recyclable of the designed organic photocatalyst. (Figure presented.).
- Li, Run,Gehrig, Dominik W.,Ramanan, Charusheela,Blom, Paul W. M.,Kohl, Fabien F.,Wagner, Manfred,Landfester, Katharina,Zhang, Kai A. I.
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p. 3852 - 3859
(2019/07/15)
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- Chemical modification-mediated optimisation of bronchodilatory activity of mepenzolate, a muscarinic receptor antagonist with anti-inflammatory activity
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The treatment for patients with chronic obstructive pulmonary disease (COPD) usually involves a combination of anti-inflammatory and bronchodilatory drugs. We recently found that mepenzolate bromide (1) and its derivative, 3-(2-hydroxy-2, 2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (5), have both anti-inflammatory and bronchodilatory activities. We chemically modified 5 with a view to obtain derivatives with both anti-inflammatory and longer-lasting bronchodilatory activities. Among the synthesized compounds, (R)-(–)-12 ((R)-3-(2-hydroxy-2,2-diphenylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide) showed the highest affinity in vitro for the human muscarinic M3 receptor (hM3R). Compared to 1 and 5, (R)-(–)-12 exhibited longer-lasting bronchodilatory activity and equivalent anti-inflammatory effect in mice. The long-term intratracheal administration of (R)-(–)-12 suppressed porcine pancreatic elastase-induced pulmonary emphysema in mice, whereas the same procedure with a long-acting muscarinic antagonist used clinically (tiotropium bromide) did not. These results suggest that (R)-(–)-12 might be therapeutically beneficial for use with COPD patients given the improved effects seen against both inflammatory pulmonary emphysema and airflow limitation in this animal model.
- Yamashita, Yasunobu,Tanaka, Ken-ichiro,Yamakawa,Asano,Kanda, Yuki,Takafuji,Kawahara, Masahiro,Takenaga, Mitsuko,Fukunishi, Yoshifumi,Mizushima
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supporting information
p. 3339 - 3346
(2019/06/18)
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- Inhibition of tyrosine phenol-lyase by tyrosine homologues
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We have designed, synthesized, and evaluated tyrosine homologues and their O-methyl derivatives as potential inhibitors for tyrosine phenol lyase (TPL, E.C. 4.1.99.2). Recently, we reported that homologues of tryptophan are potent inhibitors of tryptophan indole-lyase (tryptophanase, TIL, E.C. 4.1.99.1), with Ki values in the low μM range (Do et al. Arch Biochem Biophys 560:20–26, 2014). As the structure and mechanism for TPL is very similar to that of TIL, we postulated that tyrosine homologues could also be potent inhibitors of TPL. However, we have found that homotyrosine, bishomotyrosine, and their corresponding O-methyl derivatives are competitive inhibitors of TPL, which exhibit Ki values in the range of 0.8–1.5?mM. Thus, these compounds are not potent inhibitors, but instead bind with affinities similar to common amino acids, such as phenylalanine or methionine. Pre-steady-state kinetic data were very similar for all compounds tested and demonstrated the formation of an equilibrating mixture of aldimine and quinonoid intermediates upon binding. Interestingly, we also observed a blue-shift for the absorbance peak of external aldimine complexes of all tyrosine homologues, suggesting possible strain at the active site due to accommodating the elongated side chains.
- Do, Quang,Nguyen, Giang T.,Phillips, Robert S.
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p. 2243 - 2251
(2016/08/26)
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- Palladium-Catalyzed Alkoxycarbonylation of Unactivated Secondary Alkyl Bromides at Low Pressure
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Catalytic carbonylations of organohalides are important C-C bond formations in chemical synthesis. Carbonylations of unactivated alkyl halides remain a challenge and currently require the use of alkyl iodides under harsh conditions and high pressures of CO. Herein we report a palladium-catalyzed alkoxycarbonylation of secondary alkyl bromides that proceeds at low pressure (2 atm CO) under mild conditions. Preliminary mechanistic studies are consistent with a hybrid organometallic-radical process. These reactions efficiently deliver esters from unactivated alkyl bromides across a diverse range of substrates and represent the first catalytic carbonylations of alkyl bromides with carbon monoxide.
- Sargent, Brendon T.,Alexanian, Erik J.
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supporting information
p. 7520 - 7523
(2016/07/06)
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- Isoprenoid Biosynthesis Inhibitors Targeting Bacterial Cell Growth
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We synthesized potential inhibitors of farnesyl diphosphate synthase (FPPS), undecaprenyl diphosphate synthase (UPPS), or undecaprenyl diphosphate phosphatase (UPPP), and tested them in bacterial cell growth and enzyme inhibition assays. The most active compounds were found to be bisphosphonates with electron-withdrawing aryl-alkyl side chains which inhibited the growth of Gram-negative bacteria (Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa) at ~1–4 μg mL?1levels. They were found to be potent inhibitors of FPPS; cell growth was partially “rescued” by the addition of farnesol or overexpression of FPPS, and there was synergistic activity with known isoprenoid biosynthesis pathway inhibitors. Lipophilic hydroxyalkyl phosphonic acids inhibited UPPS and UPPP at micromolar levels; they were active (~2–6 μg mL?1) against Gram-positive but not Gram-negative organisms, and again exhibited synergistic activity with cell wall biosynthesis inhibitors, but only indifferent effects with other inhibitors. The results are of interest because they describe novel inhibitors of FPPS, UPPS, and UPPP with cell growth inhibitory activities as low as ~1–2 μg mL?1.
- Desai, Janish,Wang, Yang,Wang, Ke,Malwal, Satish R.,Oldfield, Eric
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p. 2205 - 2215
(2016/10/22)
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- Scalable anti-Markovnikov hydrobromination of aliphatic and aromatic olefins
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To improve access to a key synthetic intermediate we targeted a direct hydrobromination-Negishi route. Unsurprisingly, the anti-Markovnikov addition of HBr to estragole in the presence of AIBN proved successful. However, even in the absence of an added initiator, anti-Markovnikov addition was observed. Re-examination of early reports revealed that selective Markovnikov addition, often simply termed "normal" addition, is not always observed with HBr unless air is excluded, leading to the rediscovery of a reproducible and scalable initiator-free protocol.
- Galli, Marzia,Fletcher, Catherine J.,Del Pozo, Marc,Goldup, Stephen M.
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supporting information
p. 5622 - 5626
(2016/07/06)
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- Cyclohexanones by Rh-mediated intramolecular C-H insertion
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Some long chain α-aryl α-diazo ketones under Rh catalysis cyclize efficiently to the corresponding cyclohexanones. This is in marked contrast to the cyclizations of α-diazo β-ketoesters, which consistently deliver cyclopentanone products.
- Taber, Douglass F.,Paquette, Craig M.,Gu, Peiming,Tian, Weiwei
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p. 9772 - 9780
(2013/10/22)
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- Visible-light-mediated conversion of alcohols to halides
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The development of new means of activating molecules and bonds for chemical reactions is a fundamental objective for chemists. In this regard, visible-light photoredox catalysis has emerged as a powerful technique for chemoselective activation of chemical bonds under mild reaction conditions. Here, we report a visible-light-mediated photocatalytic alcohol activation, which we use to convert alcohols to the corresponding bromides and iodides in good yields, with exceptional functional group tolerance. In this fundamentally useful reaction, the design and operation of the process is simple, the reaction is highly efficient, and the formation of stoichiometric waste products is minimized.
- Dai, Chunhui,Narayanam, Jagan M.R.,Stephenson, Corey R.J.
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experimental part
p. 140 - 145
(2012/02/06)
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- AMINE COMPOUND AND PHARMACEUTICAL USE THEREOF
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Provided is a novel amine compound represented by the following formula (I) having a superior peripheral blood lymphocyte decreasing action and superior in the immunosuppressive action, rejection suppressive action and the like, which shows decreased side effects of, for example, bradycardia and the like, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, or a solvate thereof. wherein each symbol is as defined in the specification.
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Page/Page column 46
(2010/04/25)
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- COMPOUNDS
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The present invention provides the use of a compound of the Formula: (I) wherein R1 is C1-5 alkoxy, OCOC1-3Alkyl, O(CH2)2O(CH2)2O(CH2)2OMe, O(CH2)2O(CH2)2O(CH2)2OH or OH; R2 is H, (CH2)nOH, OCH3, Hal or (II) or (III) R3 is H or (CH2)nOH; and R4 is C1-6 alkyl, optionally substituted by one or more of Hal, OH, COCH3, NH2, NHCH3, NHMe, NMe2, OCOCH3, CO2H or esters or amides thereof where n is 1-5; and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for use in modulating PKB activity.
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Page/Page column 14
(2009/09/08)
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- N-linked sulfonamide of heterocyclic thioesters for vision and memory disorders
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This invention relates to pharmaceutical compositions and methods for treating a vision disorder, improving vision, treating memory impairment, or enhancing memory performance using N-linked sulfonamides of heterocyclic thioesters.
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Page/Page column 25
(2008/12/07)
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- Method for treating nerve injury caused as a result of surgery
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The present invention relates generally to methods for treating or preventing nerve injury in a warm-blooded animal caused as a consequence of surgery by administering neurotrophic compounds described below. The invention relates more specifically to methods for treating or preventing nerve injury caused as a consequence of prostate surgery as well as erectile dysfunction.
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- Synthesis of N-glyoxyl prolyl and pipecolyl amides and thioesters and evaluation of their in vitro and in vivo nerve regenerative effects
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The recent discovery that small molecule ligands for the peptidyl-prolyl isomerase (PPIase) FKBP12 possess powerful neuroprotective and neuroregenerative properties in vitro and in vivo suggests therapeutic utility for such compounds in neurodegenerative disease. The neurotrophic effects of these compounds are independent of the immunosuppressive pathways by which drugs such as FK506 and rapamycin operate. Previous work by ourselves and other groups exploring the structure-activity relationships (SAR) of small molecules that mimic only the FKBP binding domain portion of FK506 has focused on esters of proline and pipecolic acid. We have explored amide and thioester analogues of these earlier structures and found that they too are extremely potent in promoting recovery of lesioned dopaminergic pathways in a mouse model of Parkinson's disease. Several compounds were shown to be highly effective upon oral administration after lesioning of the dopaminergic pathway, providing further evidence of the potential clinical utility of a variety of structural classes of FKBP12 ligands.
- Hamilton, Gregory S.,Wu, Yong-Qian,Limburg, David C.,Wilkinson, Douglas E.,Vaal, Mark J.,Li, Jia-He,Thomas, Christine,Huang, Wei,Sauer, Hansjorg,Ross, Douglas T.,Soni, Raj,Chen, Yi,Guo, Hongshi,Howorth, Pamela,Valentine, Heather,Liang, Shi,Spicer, Dawn,Fuller, Mike,Steiner, Joseph P.
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p. 3549 - 3557
(2007/10/03)
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- N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses
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This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using an N-oxide of a heterocyclic ester, amide, thioester, or ketone.
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- N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses
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This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using an N-oxide of a heterocyclic ester, amide, thioester, or ketone.
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- Pyrrolidine derivative hair growth compositions and uses
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This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using pyrrolidine derivatives.
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- N-linked sulfonamides of heterocyclic thioesters
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This invention relates to neurotrophic low molecular weight, small molecule N-linked sulfonamides of heterocyclic thioesters having an affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin pr
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- Structure-activity relationship for a series of 2-substituted 1,2,3,4- tetrahydro-9H-pyrido[3,4-b]indoles: Potent subtype-selective inhibitors of N- methyl-D-aspartate (NMDA) receptors
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A series of 2-substituted 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indoles was synthesized as potential antagonists for the NR1(A)/2B subtype of N-methyl- D-aspartate (NMDA) receptors. Assayed by electrical recording under steady- state conditions, 7-hydroxy-2-(4-phenylbutyl)-1,2,3,4-tetrahydropyrido-[3,4- b]indole (30) was the most potent compound in the series having an IC50 value of 50 nM at the NR1(A)/2B receptors.
- Tamiz, Amir P.,Whittemore, Edward R.,Woodward, Richard M.,Upasani, Ravindra B.,Keana, John F.W.
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p. 1619 - 1624
(2007/10/03)
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- N-linked sulfonamides of heterocyclic thioesters
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This invention relates to neurotrophic low molecular weight, small molecule N-linked sulfonamides of heterocyclic thioesters having an affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.
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- N-linked sulfonamide of heterocyclic thioester hair growth compounds and uses
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This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using N-linked sulfonamides of heterocyclic thioesters.
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- β-Phenylselenoalanine as a dehydroalanine precursor-efficient synthesis of alternariolide (AM-toxin I)
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Alternariolide (AM-toxin) is synthesized in 44% overall yield from L-2-amino-5-(4-methoxyphenyl)pentanoic acid; D-β-phenylselenoalanine is used as the dehydroalanine precursor.
- Hashimoto, Kimiko,Sakai, Mitsuru,Okuno, Toshikatsu,Shirahama, Haruhisa
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p. 1139 - 1140
(2007/10/03)
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- Search for the pharmacophore of bispyridinium-type allosteric modulators of muscarinic receptors
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The bis(dichlorobenzyl) ether of the bispyridinium oxime TMB 4 stabilizes antagonist binding to M2-cholinoceptors which is indicative of an allosteric action. More than 10 derivatives of the lead compound were synthesized to investigate structu
- Cid,Holzgrabe,Kostenis,Mohr,Trankle
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p. 1439 - 1445
(2007/10/02)
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- Alpha-(phenylalkyl) pyridinealkanol derivatives
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This invention relates to novel α-(phenylalkyl) pyridinealkanol derivatives useful in the treatment of diseases or disorders mediated by platelet-activating factor. This invention further relates to pharmaceutical compositions of such α-(phenylalkyl)pyridinealkanol derivatives.
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- Synthesis of meta,meta-Bridged Biaryls (-Metacyclophanes) via Aryl-Aryl Coupling: Factors affecting the Cyclisation
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Two bis(iodoaryl)heptanoids (28) and (33), the iodoarylbutyl iodoarylpropyl sulphide (39), and the corresponding sulphone (40) have been prepared, and each treated with tetrakis(triphenylphosphine)nikel(0).Two new m,m-bridged biaryls (29) (31percent) and (34) (49percent) were obtained; the sulphur compounds were deiodinated in preference to coupling.These reactions are compared with those used previously in myricanol synthesis and the factors affecting ring closure are discussed.Steric effects at the coupling sites appear more important in determining product yield than torsional strain in the products.
- Mohamed, Salah E.N.,Whiting, Donald A.
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p. 2577 - 2582
(2007/10/02)
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