- Niacin-ligated platinum(iv)-ruthenium(ii) chimeric complexes synergistically suppress tumor metastasis and growth with potentially reduced toxicity: In vivo
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Niacin-ligated platinum(iv)-ruthenium(ii) chimeric complexes (PtRu 1-4) have been synthesized and evaluated for their antitumor performance. Using the optimal complex, PtRu-1, we show that this water-soluble chimeric prodrug not only potently inhibits the metastasis and proliferation of tumor cells but also has an unexpectedly higher safety margin in animals compared with the traditionally-used, clinically approved drug cisplatin.
- Chen, Chao,Fang, Tao,Han, Weidong,Ren, Lulu,Shu, Liwei,Wang, Hangxiang,Wang, Yuchen,Ye, Zhijian
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- Conformational Studies of N,N-Disubstituted Nicotinamides. NMR Peak Assignments and Utilization of Shift Reagents with 2,6-Dichloronicotinamides
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Europium-induced shift studies are reported for numerous substituted nicotinamides.Without ring substituents, the europium ion interacts with both the pyridine nitrogen and the amide oxygen; however, with 2,6 ring substituents interaction with the amide oxygen is favored.Simple correlations for the induced shifts of the pyridine ring hydrogens are presented and are useful in the conformational analysis of nicotinamides.A combination of variable-temperature nuclear magnetic resonance (VTNMR) studies and europium shift reagents is used to ascertain the preferred conformation in solution of both simple and complex, substituted nicotinamides.
- Newkome, George R.,Kawato, Toshio
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- Syntheses of diacyltanshinol derivatives and their suppressive effects on macrophage foam cell formation by reducing oxidized LDL uptake
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A series of diacyltanshinol derivatives were synthesized by esterifying the corresponding o-hydroquinones of tanshinones. The suppressive effects of the synthesized compounds on oxidized low-density lipoprotein (oxLDL) uptake and oxLDL-induced macrophage-derived foam cell formation were evaluated. Our results indicated that the nicotinate derivatives 1a and 2a, modified from tanshinone IIA and cryptotanshinone, showed stronger suppressive activity on oxLDL uptake and the resultant foam cell formation relative to tanshinone IIA. Western Blot analysis indicated that derivatives 1a and 2a could dose-dependently inhibit the expression of oxLDL-induced LOX-1, implying that the suppressive effects of 1a and 2a on oxLDL uptake and foam cell formation could be at least partially attributed to the inhibition of LOX-1 expression in macrophages.
- Cheng, Xi,Zhang, Da-Li,Li, Xiao-Bing,Ye, Jian-Tao,Shi, Lei,Huang, Zhi-Shu,Gu, Lian-Quan,An, Lin-Kun
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- Isothiourea-Catalysed Regioselective Acylative Kinetic Resolution of Axially Chiral Biaryl Diols
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An operationally simple isothiourea-catalysed acylative kinetic resolution of unprotected 1,1′-biaryl-2,2′-diol derivatives has been developed to allow access to axially chiral compounds in highly enantioenriched form (s values up to 190). Investigation of the reaction scope and limitations provided three key observations: i) the diol motif of the substrate was essential for good conversion and high s values; ii) the use of an α,α-disubstituted mixed anhydride (2,2-diphenylacetic pivalic anhydride) was critical to minimize diacylation and give high selectivity; iii) the presence of substituents in the 3,3′-positions of the diol hindered effective acylation. This final observation was exploited for the highly regioselective acylative kinetic resolution of unsymmetrical biaryl diol substrates bearing a single 3-substituent. Based on the key observations identified, acylation transition state models have been proposed to explain the atropselectivity of this kinetic resolution.
- Qu, Shen,Greenhalgh, Mark D.,Smith, Andrew D.
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supporting information
p. 2816 - 2823
(2019/02/05)
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- Optimization by Molecular Fine Tuning of Dihydro-β-agarofuran Sesquiterpenoids as Reversers of P-Glycoprotein-Mediated Multidrug Resistance
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P-glycoprotein (P-gp) plays a crucial role in the development of multidrug resistance (MDR), a major obstacle for successful chemotherapy in cancer. Herein, we report on the development of a natural-product-based library of 81 dihydro-β-agarofuran sesquiterpenes (2-82) by optimization of the lead compound 1. The compound library was evaluated for its ability to inhibit P-gp-mediated daunomycin efflux in MDR cells. Selected analogues were further analyzed for their P-gp inhibition constant, intrinsic toxicity, and potency to reverse daunomycin and vinblastine resistances. Analogues 6, 24, 28, 59, and 66 were identified as having higher potency than compound 1 and verapamil, a first-generation P-gp modulator. SAR analysis revealed the size of the aliphatic chains and presence of nitrogen atoms are important structural characteristics to modulate reversal activity. The present study highlights the potential of these analogues as modulators of P-gp mediated MDR in cancer cells.
- Callies, Oliver,Sánchez-Ca?ete, María P.,Gamarro, Francisco,Jiménez, Ignacio A.,Castanys, Santiago,Bazzocchi, Isabel L.
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supporting information
p. 1880 - 1890
(2016/03/22)
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- Magnetic nano-Fe3O4-supported 1-benzyl-1,4- dihydronicotinamide (BNAH): Synthesis and application in the catalytic reduction of α,β-epoxy ketones
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A novel magnetically recoverable organic hydride compound was successfully constructed by using silica-coated magnetic nanoparticles as a support. An as-prepared magnetic organic hydride compound, BNAH (1-benzyl-1,4- dihydronicotinamide), showed efficient activity in the catalytic reduction of α,β-epoxy ketones. After reaction, the magnetic nanoparticle- supported BNAH can be separated by simple magnetic separation which made the separation of the product easier.
- Xu, Hua-Jian,Wan, Xin,Shen, Yong-Ya,Xu, Song,Feng, Yi-Si
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supporting information; experimental part
p. 1210 - 1213
(2012/04/18)
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- A versatile, practical, and inexpensive reagent, pyridine-3-carboxylic anhydride (3-PCA), for condensation reactions
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A highly useful method for the preparation of carboxylic esters and carboxamides from various carboxylic acids was established by using a novel condensing reagent, pyridine-3-carboxylic anhydride (3-PCA), in the presence of 4-(dimethylamino)pyridine as an activator. The reactions of various carboxylic acids with nucleophiles, such as alcohols or amines, afforded the corresponding carboxylic acids or carboxamides in good to high yields under mild conditions by using simple experimental procedure. In addition, it was confirmed that this protocol was applicable to a gram-scale synthesis and the by-products, including pyridine-3-carboxylic acid and pyridine-3-carboxylate (or pyridine-3- carboxamide) produced in situ, were easily removed by using a simple aqueous workup.
- Funasaka, Setsuo,Mukaiyama, Teruaki
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experimental part
p. 148 - 159
(2009/04/06)
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- Pyridine-3-carboxylic anhydride (3-PCA): A versatile, practical, and inexpensive reagent for condensation reaction between carboxylic acids and alcohols
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A synthesis of carboxylic esters from various carboxylic acids and alcohols is successfully carried out by using a condensation reagent, pyridine-3-carboxylic anhydride (3-PCA). This reaction materialized synthesis of various carboxylic esters to be carried out under mild conditions by simple experimental procedure. Copyright
- Mukaiyama, Teruaki,Funasaka, Setsuo
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p. 326 - 327
(2008/02/04)
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- Substrate activity screening: A fragment-based method for the rapid identification of nonpeptidic protease inhibitors
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A new fragment-based method for the rapid development of novel and distinct classes of nonpeptidic protease inhibitors, Substrate Activity Screening (SAS), is described. This method consists of three steps: (1) a library of N-acyl aminocoumarins with diverse, low molecular weight N-acyl groups is screened to identify protease substrates using a simple fluorescence-based assay, (2) the identified N-acyl aminocoumarin substrates are optimized by rapid analogue synthesis and evaluation, and (3) the optimized substrates are converted to inhibitors by direct replacement of the aminocoumarin with known mechanism-based pharmacophores. The SAS method was successfully applied to the cysteine protease cathepsin S, which is implicated in autoimmune diseases. Multiple distinct classes of nonpeptidic substrates were identified upon screening an N-acyl aminocoumarin library. Two of the nonpeptidic substrate classes were optimized to substrates with >8000-fold improvements in cleavage efficiency for each class. Select nonpeptidic substrates were then directly converted to low molecular weight, novel aldehyde inhibitors with nanomolar affinity to cathepsin S. This study demonstrates the unique characteristics and merits of this first substrate-based method for the rapid identification and optimization of weak fragments and provides the framework for the development of completely nonpeptidic inhibitors to many different proteases.
- Wood, Warren J. L.,Patterson, Andrew W.,Tsuruoka, Hiroyuki,Jain, Rishi K.,Ellman, Jonathan A.
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p. 15521 - 15527
(2007/10/03)
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- Polysiloxane-supported NAD(P)H model 1-benzyl-1,4-dihydronicotinamide: Synthesis and application in the reduction of activated olefins
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A new polysiloxane-supported NAD(P)H model, 1-benzyl-1,4-dihydronicotinamide, was designed and synthesized, which can efficiently reduce many activated olefins under mild conditions. The most advantageous features of this new polysiloxane-supported reductant are (i) easy workup and separation of the reaction products and (ii) good potential for recycling use of the reductant, which makes this new polysiloxane-supported NAD(P)H model a promising alternative both in research laboratories and in industrial processes.
- Zhang, Baolian,Zhu, Xiao-Qing,Lu, Jin-Yong,He, Jiaqi,Wang, Peng G.,Cheng, Jin-Pei
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p. 3295 - 3298
(2007/10/03)
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- Combinatorial modification of natural products: Preparation of unencoded and encoded libraries of Rauwolfia alkaloids
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We report the preparation of combinatorial libraries which consist of derivatives of the stereoisomeric alkaloids yohimbine and rauwolscine- members of the Rauwolfia genus. The chemistry was performed on solid support using the divide-and-pool method, and involved the derivatization of the E- ring carboxylates and hydroxyls of these alkaloids with 36 amino acids and 22 carboxylic acids, respectively, to afford 792 bifunctionalized derivatives. The rauwolscine library was prepared using an encoding strategy in which the identity of each incorporated amino acid was recorded by cosynthesizing chemically inert tags prior to the pooling step. The general strategy for library synthesis exploits existing functionality present on the natural products, and should be applicable to other families of secondary metabolites.
- Atuegbu, Andy,Maclean, Derek,Nguyen, Cindy,Gordon, Eric M.,Jacobs, Jeffrey W.
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p. 1097 - 1106
(2007/10/03)
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- Hydroxy protection groups
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The present invention concerns a method for preparing unprotected hydroxy compounds or acylated derivatives thereof by conversion of silyl alkyl-protected hydroxy compounds. The invention also relates to novel intermediates useful in the method and for other purposes.
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