- Synthesis of Novel Iminosugar Derivatives Based on a 2-Azabi-ccyclo[41.0]heptane Skeleton
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Iminosugars are good starting points for the development of different kinds of drugs. Many are polyhydroxylated piperidines that behave as biomimetics of their corresponding pyranoses analogues. In the interaction with carbohydrate processing enzymes, sel
- López-Rodríguez, Alberto,Domínguez, Gema,Pérez-Castells, Javier
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- Design and synthesis of benzylidenecyclohexenones as TrxR inhibitors displaying high anticancer activity and inducing ROS, apoptosis, and autophagy
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Oxidative therapy, a strategy that specifically increases reactive oxygen species (ROS) levels in tumor cells by disrupting the redox homeostasis has gained increasing interest. The antitumor effects of the natural product piperlongumine (PL) appear to result from its ability to increase intracellular ROS levels via inhibition of antioxidative thioredoxin reductase (TrxR). Twenty-seven benzylidenecyclohexenone-based PL analogues (2a-v and 15a-e) were designed, synthesized and evaluated for their pharmacological properties. Most of the compounds exhibited potent antiproliferative activities against five human cancer cell lines, especially against breast tumor cells. One of the most promising analogueues 2c showed 12-fold higher inhibitory activity against the thioredoxin reductase (TrxR) than PL and surpressed the expression of TrxR1 protein in breast cancer cells and inhibited TrxR enzymatic activity. In addition, 2c increased ROS levels and resulted in marked apoptosis by regulating apoptosis-related proteins expressed in the breast cancer cells. Compound 2c also triggered the formation of autophagosomes and autolysosomes by promoting the expression of LC3-II and Beclin-1 and diminishing the expression of LC3-I and p62 proteins. Finally, 2c displayed low acute toxicity and good inhibitory potency to tumors in mice. Overall, 2c is a promising anti-breast cancer candidate warranting further investigation.
- Hsu, Pei-Ling,Lee, Kuo-Hsiung,Li, Yangyang,Ling, Yong,Liu, Ji,Meng, Chi,Morris-Natschke, Susan L.,Qian, Jianqiang,Xu, Zhongyuan,Yang, Yumin,Zhang, Yanan,Zhu, Weizhong
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- An efficient synthesis of cis-4-hydroxyphosphonic and cis-4-hydroxyphosphinic analogs of pipecolic acid from cyclic enaminones
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An expedient synthetic entry to cis-4-hydroxyphosphonic and cis-4-hydroxyphosphinic analogs of cis-4-hydroxypipecolic acid is presented in this paper. The main feature of this methodology is the highly regioselective addition of silyl phosphites or phosph
- Argüello-Velasco, Rubén Oswaldo,Morales-Solís, Juan Carlos,Mu?oz-Vidales, Misael,Ordó?ez, Mario,Romero-Estudillo, Ivan,Viveros-Ceballos, José Luis
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- Site-Selective Acceptorless Dehydrogenation of Aliphatics Enabled by Organophotoredox/Cobalt Dual Catalysis
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The value of catalytic dehydrogenation of aliphatics (CDA) in organic synthesis has remained largely underexplored. Known homogeneous CDA systems often require the use of sacrificial hydrogen acceptors (or oxidants), precious metal catalysts, and harsh reaction conditions, thus limiting most existing methods to dehydrogenation of non- or low-functionalized alkanes. Here we describe a visible-light-driven, dual-catalyst system consisting of inexpensive organophotoredox and base-metal catalysts for room-temperature, acceptorless-CDA (Al-CDA). Initiated by photoexited 2-chloroanthraquinone, the process involves H atom transfer (HAT) of aliphatics to form alkyl radicals, which then react with cobaloxime to produce olefins and H2. This operationally simple method enables direct dehydrogenation of readily available chemical feedstocks to diversely functionalized olefins. For example, we demonstrate, for the first time, the oxidant-free desaturation of thioethers and amides to alkenyl sulfides and enamides, respectively. Moreover, the system's exceptional site selectivity and functional group tolerance are illustrated by late-stage dehydrogenation and synthesis of 14 biologically relevant molecules and pharmaceutical ingredients. Mechanistic studies have revealed a dual HAT process and provided insights into the origin of reactivity and site selectivity.
- Zhou, Min-Jie,Zhang, Lei,Liu, Guixia,Xu, Chen,Huang, Zheng
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supporting information
p. 16470 - 16485
(2021/10/20)
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- CHEMICAL PROCESS FOR PREPARING PHENYLPIPERIDINYL INDOLE DERIVATIVES
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The present invention relates to a method of synthesizing a compound of formula (I) also referred to as 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid, or a pharmaceutically acceptable salt thereof, and/or intermediates thereof, their use as pharmaceuticals and pharmaceutical compositions and the use of intermediates for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof.
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Page/Page column 43-44
(2020/02/14)
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- FXR (farnesol X receptor) agonist
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The invention belongs to the technical field of medicine and particularly relates to a compound shown as formula (I) that is shown in the description, and its pharmaceutically acceptable salts, estersor stereoisomers, with R1, R2, R3, M1, M2, Q, L, ring A
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Paragraph 0231; 0233; 0234; 0235
(2019/04/17)
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- Highly Enantioselective Catalytic Addition of Grignard Reagents to N-Heterocyclic Acceptors
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General methods to prepare chiral N-heterocyclic molecular scaffolds are greatly sought after because of their significance in medicinal chemistry. Described here is the first general catalytic methodology to access a wide variety of chiral 2- and 4-substituted tetrahydro-quinolones, dihydro-4-pyridones, and piperidones with excellent yields and enantioselectivities, utilizing a single catalyst system.
- Guo, Yafei,Harutyunyan, Syuzanna R.
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supporting information
p. 12950 - 12954
(2019/08/07)
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- A consecutive process for C-C and C-N bond formation with high enantio-and diastereo-control: Direct reductive amination of chiral ketones using hydrogenation catalysts
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High diastereoselectivity was observed in the Rh-catalysed reductive amination of 3-arylcyclohexanones to form tertiary amines. This was incorporated into a one-pot enantioselective conjugate addition and diastereoselective reductive amination, including an example of assisted tandem catalysis.
- Gilbert, Sophie H.,Viseur, Virginie,Clarke, Matthew L.
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supporting information
p. 6409 - 6412
(2019/06/07)
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- Catalytic Allylic Oxidation of Cyclic Enamides and 3,4-Dihydro-2H-Pyrans by TBHP
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Allylic oxidation of heteroatom substituted cyclic alkenes by tert-butyl hydroperoxide (70% TBHP in water) using catalytic dirhodium caprolactamate [Rh2(cap)4] forms enone products with a variety of 2-substituted cyclic enamides and 3,4-dihyro-2H-pyrans. These reactions occur under mild reaction conditions, are operationally convenient to execute, and are effective for product formation with as low as 0.25 mol% catalyst loading. With heteroatom stabilization of the intermediate allylic free radical two sites for oxidative product formation are possible, and the selectivity of the oxidative process varies with the heteroatom when R = H. Cyclic enamides produce 4-piperidones in good yields when R = alkyl or aryl, but oxidation of 2H-pyrans also gives alkyl cleavage products. Alternative catalysts for TBHP oxidations show comparable selectivities but give lower product yields.
- Yu, Yang,Humeidi, Ranad,Alleyn, James R.,Doyle, Michael P.
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p. 8506 - 8513
(2017/08/23)
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- Design and synthesis of cenocladamide analogues and their evaluation against breast cancer cell lines
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This work describes the total synthesis of the alkaloid cenocladamide and a concise library of nine structural analogues aiming at their evaluation against the breast cancer cell line MDA-MB-231. The most promising compound (3; IC50 = 6.6 μM) was also evaluated in a panel of seven breast cancer cell lines and two non-tumorigenic cell lines. We further conducted an initial investigation on the mechanism of action of analogue 3, which lacks the endocyclic double bond when compared to cenocladamide. The present study presents the discovery of a cenocladamide analogue with interesting cytotoxic activity, which could be useful for further optimization towards new chemotherapeutic agents for breast cancer treatment.
- Santos, Carla C. F.,Paradela, Luciana S.,Novaes, Luiz F. T.,Dias, Sandra M. G.,Pastre, Julio C.
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p. 755 - 766
(2017/04/27)
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- Highly enantioselective organocatalytic oxidative kinetic resolution of secondary alcohols using chiral alkoxyamines as precatalysts: Catalyst structure, active species, and substrate scope
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The development and characterization of enantioselective organocatalytic oxidative kinetic resolution (OKR) of racemic secondary alcohols using chiral alkoxyamines as precatalysts are described. A number of chiral alkoxyamines have been synthesized, and their structure-enantioselectivity correlation study in OKR has led us to identify a promising precatalyst, namely, 7-benzyl-3-n-butyl-4-oxa-5-azahomoadamantane, which affords various chiral aliphatic secondary alcohols (ee up to >99%, krel up to 296). In a mechanistic study, chlorine-containing oxoammonium species were identified as the active species generated in situ from the alkoxyamine precatalyst, and it was revealed that the chlorine atom is crucial for high reactivity and enantioselectivity. The present OKR is the first successful example applicable to various unactivated aliphatic secondary alcohols, including heterocyclic alcohols with high enantioselectivity, the synthetic application of which is demonstrated by the synthesis of a bioactive compound.
- Murakami, Keiichi,Sasano, Yusuke,Tomizawa, Masaki,Shibuya, Masatoshi,Kwon, Eunsang,Iwabuchi, Yoshiharu
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p. 17591 - 17600
(2015/02/19)
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- Copper-catalyzed asymmetric 1,4-addition of alkenyl alanes to N-substituted-2-3-dehydro-4-piperidones
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Readily available vinyl alanes are used in the Cu-catalyzed asymmetric conjugate addition reaction to N-substituted-2-3-dehydro-4-piperidones. The enhanced reactivity of recently developed and easily prepared phosphine amine ligands in combination with inexpensive Cu(II)naphtenate (CuNp) allows the introduction of a great variety of alkenyl, alkyl, and aryl aluminums in high enantioselectivity.
- Mueller, Daniel,Alexakis, Alexandre
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supporting information; experimental part
p. 1842 - 1845
(2012/06/18)
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- Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and Efficacious γ-Secretase Inhibitors
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Discovery of a series of pyrazolopiperidine sulfonamide based γ-secretase inhibitors and its SAR evolution is described. Significant increases in APP potency on the pyrazolopiperidine scaffold over the original N-bicyclic sulfonamide scaffold were achieved and this potency increase translated in an improved in vivo efficacy.
- Ye, Xiaocong M.,Konradi, Andrei W.,Smith, Jenifer,Xu, Ying-Zi,Dressen, Darren,Garofalo, Albert W.,Marugg, Jennifer,Sham, Hing L.,Truong, Anh P.,Jagodzinski, Jacek,Pleiss, Michael,Zhang, Hongbin,Goldbach, Erich,Sauer, John-Michael,Brigham, Elizabeth,Bova, Michael,Basi, Guriqbal S.
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scheme or table
p. 2195 - 2199
(2010/07/05)
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- 5-(ARYLSULFONYL)-PYRAZOLOPIPERIDINES
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The invention provides N-cyclic sulfonamido compounds of Formula (I) wherein A, B, R1, R1a, R2, R2a, R3 and R3a are as described in the specification. Compounds of Formula (I) are useful in treating or preventing cognitive disorders, such as Alzheimer 's disease. The invention also encompasses pharmaceutical compositions comprising compounds of Formula (I), methods of preparing compounds of formula (I), and methods of treating cognitive disorders, such as Alzheimer's disease.
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Page/Page column 111
(2010/11/27)
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- Synthesis and kinetic analysis of the N-acetylhexosaminidase inhibitor XylNAc-isofagomine
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An efficient 10-step preparation from 4-methoxypyridine of (2R,3R,4R)-2-acetamido-3,4-dihydroxy-piperidine ("XylNAc-isofagomine") in optically active form is described. Key steps include an enantioselective reduction with catecholborane/(S)-2-methyl-CBS-o
- Knapp, Spencer,Yang, Chunhua,Pabbaraja, Srihari,Rempel, Brian,Reid, Steven,Withers, Stephen G.
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p. 7715 - 7720
(2007/10/03)
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- Catalytic enantioselective conjugate addition of dialkylzinc reagents to N-substituted-2,3-dehydro-4-piperidones
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The first, highly enantioselective, copper/phosphoramidite-catalyzed conjugate addition of dialkylzinc reagents to N-substituted 2,3-dehydro-4- piperidones is described. The Royal Society of Chemistry 2005.
- Sebesta, Radovan,Pizzuti, Maria Gabriella,Boersma, Arnold J.,Minnaard, Adriaan J.,Feringa, Ben L.
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p. 1711 - 1713
(2007/10/03)
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- Exploitation of palladium-catalyzed reductive enyne cyclization in the synthesis of (-)-4a,5-dihydrostreptazolin
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Hydroxyl-promoted reductive cyclization of enyne compounds catalyzed by Pd(OAc)2-BBEDA was explored and found to effect constructing the pyrindine framework with the alkylidene appendage. This methodology was applied to the stereoselective synthesis of (-)-4a,5-dihydrostreptazolin.
- Yamada, Hironari,Aoyagi, Sakae,Kibayashi, Chihiro
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p. 8787 - 8790
(2007/10/03)
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