- Synthesis and Biological Studies of Pyrazolyl-Diamine PtII Complexes Containing Polyaromatic DNA-Binding Groups
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New [PtCl(pzNN)]n+ complexes anchored by pyrazolyl-diamine (pzNN) ligands incorporating anthracenyl or acridine orange DNA-binding groups have been synthesized so as to obtain compounds that would display synergistic effects between platination and intercalation of DNA. Study of their interaction with supercoiled DNA indicated that the anthracenyl-containing complex L2Pt displays a covalent type of binding, whereas the acridine orange counterpart L3Pt shows a combination of intercalative and covalent binding modes with a strong contribution from the former. L2Pt showed a very strong cytotoxic effect on ovarian carcinoma cell lines A2780 and A2780cisR, which are, respectively, sensitive to and resistant to cisplatin. In these cell lines, L2Pt is nine to 27 times more cytotoxic than cisplatin. In the sensitive cell line, L3Pt showed a cytotoxic activity similar to that of cisplatin, but like L2Pt was able significantly to overcome cisplatin cross-resistance. Cell-uptake studies showed that L2Pt accumulates preferentially in the cytoplasm, whereas L3Pt reaches the cell nucleus more easily, as clearly visualized by time-lapse confocal imaging of live A2870 cells. Altogether, these findings seem to indicate that interaction with biological targets other than DNA might be involved in the mechanism of action of L2Pt because this compound, despite having a weaker ability to target the cell nucleus than L3Pt, as well as an inferior DNA affinity, is nevertheless more cytotoxic. Furthermore, ultrastructural studies of A2870 cells exposed to L2Pt and L3Pt revealed that these complexes induce different alterations in cell morphology, thus indicating the involvement of different modes of action in cell death.
- Gama, Sofia,Mendes, Filipa,Esteves, Teresa,Marques, Fernanda,Matos, Antonio,Rino, Jose,Coimbra, Joana,Ravera, Mauro,Gabano, Elisabetta,Santos, Isabel,Paulo, Antonio
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- Nickel-catalyzed reductive monofluoroakylation of alkyl tosylate with bromofluoromethane to primary alkyl fluoride
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A nickel-catalysed direct terminal monofluoromethlyation between alkyl tosylates and a low-cost, industrial raw material bromofluoromethane has been developed. This transformation has demonstrated high efficiency, mild conditions, and good functional-grou
- Cui, Ru,Sheng, Jie,Wu, Bing-Bing,Hu, Duo-Duo,Zheng, Hong-Qian,Wang, Xi-Sheng
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supporting information
p. 9084 - 9087
(2021/09/14)
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- Copper-Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds
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The engagement of unactivated alkyl halides in copper-catalyzed cross-coupling reactions has been historically challenging, due to their low reduction potential and the slow oxidative addition of copper(I) catalysts. In this work, we report a novel strategy that leverages the halogen abstraction ability of aryl radicals, thereby engaging a diverse range of alkyl iodides in copper-catalyzed Negishi-type cross-coupling reactions at room temperature. Specifically, aryl radicals generated via copper catalysis efficiently initiate the cleavage of the carbon–iodide bonds of alkyl iodides. The alkyl radicals thus generated enter the copper catalytic cycles to couple with a difluoromethyl zinc reagent, thus furnishing the alkyl difluoromethane products. This unprecedented Negishi-type difluoromethylation approach has been applied to the late-stage modification of densely functionalized pharmaceutical agents and natural products.
- Cai, Aijie,Liu, Wei,Wang, Chao,Yan, Wenhao
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supporting information
p. 27070 - 27077
(2021/11/18)
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- Benzil compound as well as preparation method and application thereof
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The invention provides a benzil compound as well as a preparation method and application thereof, the structure of the benzil compound is shown as a formula I, wherein R1 is -(CH2) n-N (CX1Y1Z1) (CX2Y2Z2), n is an integer from 1 to 6, and X1, X2, Y1, Y2, Z1 and Z2 are independently selected from hydrogen or deuterium. The benzil compound provided by the invention is applied to detection of guanidine compounds, can remarkably improve the sensitivity, accuracy and stability of detection, can be used for identifying potential guanidine compounds in a to-be-detected sample, and is low in cost.
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Paragraph 0058; 0063
(2021/06/09)
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- Chiral Alkyl Amine Synthesis via Catalytic Enantioselective Hydroalkylation of Enecarbamates
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Chiral alkyl amines are omnipresent as bioactive molecules and synthetic intermediates. The catalytic and enantioselective synthesis of alkyl amines from readily accessible precursors is challenging. Here we develop a nickel-catalyzed hydroalkylation method to assemble a wide range of chiral alkyl amines from enecarbamates (N-Cbz-protected enamines) and alkyl halides with high regio- and enantioselectivity. The method works for both nonactivated and activated alkyl halides and is able to produce enantiomerically enriched amines with two minimally differentiated α-alkyl substituents. The mild conditions lead to high functional group tolerance, which is demonstrated in the postproduct functionalization of many natural products and drug molecules, as well as the synthesis of chiral building blocks and key intermediates to bioactive compounds.
- Qian, Deyun,Bera, Srikrishna,Hu, Xile
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supporting information
p. 1959 - 1967
(2021/02/06)
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- Multiplexed Analysis of Endogenous Guanidino Compounds via Isotope-Coded Doubly Charged Labeling: Application to Lung Cancer Tissues as a Case
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Endogenous guanidino compounds (GCs), nitrogen-containing metabolites, have very important physiological activities and participate in biochemical processes. Therefore, accurately characterizing the distribution of endogenous GCs and monitoring their concentration variations are of great significance. In this work, a new derivatization reagent, 4,4′-bis[3-(dimethylamino)propyl]benzyl (BDMAPB), with isotope-coded reagents was designed and synthesized for doubly charged labeling of GCs. BDMAPB-derivatized GCs not only promote the MS signal but also form multicharged quasimolecular ions and abundant fragment ions. With this reagent, an isotope-coded doubly charged labeling (ICDCL) strategy was developed for endogenous GCs with high-resolution liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF MS). The core of this methodology is a 4-fold multiplexed set of [d0]-/[d4]-/[d8]-/[d12]-BDMAPB that yields isotope-coded derivatized GCs. Following a methodological assessment, good linear responses in the range of 25 nM to 1 μM with correlation coefficients over 0.99 were achieved. The limit of detection and the limit of quantitation were below 5 and 25 nM, respectively. The intra- and interday precisions were less than 18%, and the accuracy was in the range of 77.3–122.0%. The percentage recovery in tissues was in the range of 85.1–113.7%. The results indicate that the developed method facilitates long-term testing and ensures accuracy and reliability. Finally, the method was applied for the simultaneous analysis of endogenous GCs in four types of lung tissues (solid adenocarcinoma, solid squamous-cell carcinoma, ground-glass carcinoma, and paracancerous tissues) for absolute quantification, nontargeted screening, and metabolic difference analysis. It is strongly believed that ICDCL combined with isotope-coded BDMAPB will benefit the analysis and study of endogenous GCs.
- Liu, Li,Chen, Yan-Zhen,Zhang, Shu-Sheng,Chen, Xiu-Ping,Lin, Guo-Qiang,Yin, Hang,Feng, Chen-Guo,Zhang, Fang
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p. 16862 - 16872
(2021/12/27)
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- Isolable Pyridinium Trifluoromethoxide Salt for Nucleophilic Trifluoromethoxylation
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An isolable pyridinium trifluoromethoxide salt is prepared from the reaction of 4-dimethylaminopyridine with the commercially available liquid 2,4-dinitro(trifluoromethoxy)benzene. The salt is an effective trifluoromethoxide source for SN2 reactions to form trifluoromethyl ethers.
- Duran-Camacho, Geraldo,Ferguson, Devin M.,Kampf, Jeff W.,Bland, Douglas C.,Sanford, Melanie S.
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supporting information
p. 5138 - 5142
(2021/07/19)
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- Fluorination Triggers Fluoroalkylation: Nucleophilic Perfluoro-tert-butylation with 1,1-Dibromo-2,2-bis(trifluoromethyl)ethylene (DBBF) and CsF
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Perfluoro-tert-butylation reaction has long remained a challenging task. We now report the use of 1,1-dibromo-2,2-bis(trifluoromethyl)ethylene (DBBF) as a practical reagent for perfluoro-tert-butylation reactions for the first time. Through a consecutive triple-fluorination process with DBBF and CsF, the (CF3)3C? species can be liberated and observed, which is able to serve as a robust nucleophilic perfluoro-tert-butylating agent for various electrophiles. The power of this synthetic protocol is evidenced by the efficient synthesis of structurally diverse perfluoro-tert-butylated molecules. Multiple applications demonstrate the practicability of this method, as well as the superiority of perfluoro-tert-butylated compounds as sensitive probes. The perfluoro-tert-butylated product was successfully applied in 1H- and 19F-magnetic resonance imaging (MRI) experiment with an ultra-low field (ULF) MRI system.
- Dong, Hui,Hu, Jinbo,Ni, Chuanfa,Tao, Quan,Wang, Qian,Xie, Xiaoming
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supporting information
p. 27318 - 27323
(2021/11/22)
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- Quaternary Ammonium Trifluoromethoxide Salts as Stable Sources of Nucleophilic OCF3
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The reaction of nucleophilic tertiary amines with trifluoromethyl and pentafluoroethyl methyl ethers provides quaternary ammonium trifluoromethoxide (NR4OCF3) and pentafluoroethoxide (NR4OCF2CF3) salts, respectively, in good yields. The new trifluoromethoxide salts disclosed herein are uniquely stable for extended periods of time in both the solid state and in solution, which complements contemporary reagents. Here we describe the preparation of a range of NR4OCF3 salts, their long-term stability, and utility in substitution reactions.
- Britton, Robert,Friesen, Chadron M.,Jelier, Benson J.,Martin, Rainer E.,Meanwell, Michael,Newton, Josiah J.
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p. 1785 - 1790
(2020/03/24)
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- Copper-Catalyzed Reductive Trifluoromethylation of Alkyl Iodides with Togni's Reagent
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This work illustrates a reductive cross-electrophile coupling protocol for trifluoromethylation of alkyl iodides under Cu-catalyzed/Ni-promoted reaction conditions. The use of diboron esters as the terminal reductant allows the effective generation of the alkyl-CF3 products with excellent functional group tolerance and broad substrate scope. A mechanism involving a reaction of alkyl-Cu with Togni's reagent was proposed.
- Chen, Yanchi,Ma, Guobin,Gong, Hegui
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supporting information
p. 4677 - 4680
(2018/08/07)
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- Selective Reductive Elimination at Alkyl Palladium(IV) by Dissociative Ligand Ionization: Catalytic C(sp3)?H Amination to Azetidines
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A palladium(II)-catalyzed γ-C?H amination of cyclic alkyl amines to deliver highly substituted azetidines is reported. The use of a benziodoxole tosylate oxidant in combination with AgOAc was found to be crucial for controlling a selective reductive elimination pathway to the azetidines. The process is tolerant of a range of functional groups, including structural features derived from chiral α-amino alcohols, and leads to the diastereoselective formation of enantiopure azetidines.
- Nappi, Manuel,He, Chuan,Whitehurst, William G.,Chappell, Ben G. N.,Gaunt, Matthew J.
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supporting information
p. 3178 - 3182
(2018/02/28)
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- PELLET COMPOSITION CONTAINING REPAIR CELLS
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This disclosure describes compositions and methods for delivering and localizing repair cells, such as mesenchymal stem cells (MSCs) to the sites of tissue injuries, including cartilage injuries. This disclosure also describes methods for chondrogenic differentiation of MSCs in pellet compositions.
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Paragraph 993
(2017/02/24)
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- METHODS AND COMPOSITIONS FOR TARGETED THERAPEUTICS
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This disclosure describes compositions and methods for delivering and localizing repair cells to therapeutic targets.
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Paragraph 970
(2017/02/24)
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- METHODS AND COMPOSITIONS FOR TARGETED THERAPEUTICS
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This disclosure describes compositions and methods for delivering and localizing repair cells to therapeutic targets.
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Paragraph 968; 969
(2017/02/24)
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- METHODS AND COMPOSITIONS USING REPAIR CELLS AND CATIONIC DYES
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This disclosure describes compositions and methods for delivering and localizing repair cells to therapeutic targets.
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Paragraph 1222
(2017/05/11)
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- COMPOSITIONS CONTAINING REPAIR CELLS AND CATIONIC DYES
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This disclosure describes compositions and methods for delivering and localizing repair cells, such as mesenchymal stem cells (MSCs) to the sites of tissue injuries, including cartilage injuries. This disclosure also describes methods for chondrogenic differentiation of MSCs in pellet compositions.
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Paragraph 1207
(2017/06/12)
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- TARGETED THERAPEUTICS
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This disclosure describes compositions and methods for delivering and localizing therapeutic agents to therapeutic targets. This disclosure also provides multivalent forms of cationic dyes ("cationic dye multimers") and methods by which these compounds can be used to treat joint injuries.
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Paragraph 1194
(2015/11/02)
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- Ligand-Enabled Meta-C-H Alkylation and Arylation Using a Modified Norbornene
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2-Carbomethoxynorbornene is identified as a more effective transient mediator to promote a Pd(II)-catalyzed meta-C(sp2)-H alkylation of amides with various alkyl iodides as well as arylation with previously incompatible aryl iodides. The use of a tailor-made quinoline ligand is also crucial for this reaction to proceed.
- Shen, Peng-Xiang,Wang, Xiao-Chen,Wang, Peng,Zhu, Ru-Yi,Yu, Jin-Quan
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supporting information
p. 11574 - 11577
(2015/09/28)
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- Reactions of difluorocarbene with organozinc reagents
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Reactions of difluorocarbene with benzyl and alkylzinc halides leading to fluorinated organozinc species have been described. The generated α-difluorinated organozinc reagents are reasonably stable in solution and can be quenched with external electrophiles (iodine, bromine, proton), affording compounds containing the CF2 fragment.
- Levin, Vitalij V.,Zemtsov, Artem A.,Struchkova, Marina I.,Dilman, Alexander D.
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supporting information
p. 917 - 919
(2013/03/28)
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- Chiral lithium amides on polymer support - Synthesis and use in deprotonation of ketones
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A number of chiral secondary amines attached to Merrifield resin or to noncrosslinked (soluble) polystyrene support were synthesized. The corresponding lithium amides, generated from these amines by treatment with BuLi, react with tropinone, a model symme
- Majewski, Marek,Ulaczyk-Lesanko, Agnieszka,Wang, Fan
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p. 257 - 268
(2007/10/03)
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- Palladium-catalyzed negishi cross-coupling reactions of unactivated alkyl iodides, bromides, chlorides, and tosylates
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A single method (2% Pd2(dba)3/8% PCyp 3/NMI in THF/NMP at 80°C; Cyp = cyclopentyl) achieves the cross-coupling of a range of β-hydrogen-containing primary alkyl iodides, bromides, chlorides, and tosylates with an array of alkyl-, alkenyl-, and arylzinc halides. The process is compatible with a variety of functional groups, including esters, amides, imides, nitriles, and heterocycles.
- Zhou, Jianrong,Fu, Gregory C.
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p. 12527 - 12530
(2007/10/03)
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- A novel approach for the formation of carbon-nitrogen bonds: Azidation of alkyl radicals with sulfonyl azides
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Two preparatively attractive methods for the azidation of alkyl radicals are described. Secondary and tertiary alkyl iodides and dithiocarbonates are easily converted into the corresponding azides, either by reaction with ethanesulfonyl azide in the prese
- Ollivier,Renaud
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p. 4717 - 4727
(2007/10/03)
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- Immunoassay for LSD and 2-oxo-3-hydroxy-LSD
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The present invention provides hapten derivatives useful for the preparation of antigens, antibodies and reagents for use in immunoassays for the detection of LSD and 2-oxo-3-hydroxy LSD. In the present invention, the 2-oxy LSD nucleus is derivatized out of the indole nitrogen to form an aminoalkyl derivative. The resulting haptens can then be further modified at this functionalized position for linking to appropriate immunogenic or labeling groups to provide reagents for immunoassays having substantially equal specificity for both LSD and 2-oxo-3-hydroxy-LSD.
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- Reagents for lysergic acid diethylamide immunoassay
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The present invention provides hapten derivatives that are useful for the preparation of antigens, antibodies and reagents having superior performance characteristics for use in immunoassays for the detection of LSD and nor-LSD. In the present invention the LSD nucleus is derivatized out of the indole nitrogen to form an aminoalkyl derivative. Derivatives have also been synthesized out of the piperidine nitrogen of the LSD nucleus. The resulting haptens can then be further modified at these functionalized positions for linking to appropriate antigenic or labelling groups to provide reagents for LSD immunoassays having excellent sensitivity and selectivity for both LSD and nor-LSD.
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- Bicyclic nitrogen heterocycles
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Amino-substituted dihydropyrimido[4,5-d]pyrimidinones of the formula in which R1 represents hydrogen, lower alkyl, aryl, aryl-lower alkyl, heteroaryl, heteroaryl-lower alkyl, lower cycloalkyl or lower cycloalkyl-lower alkyl, R2 represents lower alkyl, aryl, aryl-lower alkyl, heteroaryl, heteroaryl-lower alkyl, lower cycloalkyl or lower cycloalkyl-lower alkyl, and R3 represents hydrogen, lower alkyl, aryl, aryl-lower alkyl, heteroaryl, heteroaryl-lower alkyl, lower cycloalkyl, lower cycloalkenyl or lower cycloalkyl-lower alkyl, and pharmaceutically acceptable salts thereof are protein kinase inhibitors. They can be used in the treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular disorders, in the treatment of asthma, central nervous system disorders or diabetic complications or for the prevention of graft rejection following transplant surgery.
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- Process research and development of melatonin
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A short, simple, and industrially feasible process for the preparation of melatonin (N-acetyl-5-methoxy tryptamine), starting from phthalimide and 1-bromo-3-chloropropane, in essentially four steps is discussed. The present article elucidates the preparative process along with the impurity profile of each intermediate.
- Prabhakar,Kumar, N. Vasanth,Reddy, M. Ravikanth,Sarma,Reddy, G. Om
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p. 155 - 160
(2013/09/08)
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- Reductive cyclization of N-iodoalkyl cyclic imides to nitrogen-fused polycyclic amides induced by samarium diiodide
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SmI2-promoted cyclizations of cyclic imides having 3-iodopropyl or 4-iodobutyl groups on the imide nitrogen have been studied for construction of nitrogen-fused polycyclic amides.
- Ha, Deok-Chan,Yun, Chang-Soo,Yu, Eunsun
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p. 2577 - 2580
(2007/10/03)
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- Biosynthesis of blasticidin S from L-α-arginine. Stereochemistry in the arginine-2,3-aminomutase reaction
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A series of labeled α-arginines have been fed to fermentations of Streptomyces griseochromogenes in order to examine the mechanism of L-β-arginine formation in the biosynthesis of the antibiotic blasticidin S. [3-13C,2-15N]Arginine was synthesized and fed; analysis of the derived antibiotic by 13C NMR spectroscopy revealed the retention of the original α-nitrogen and its intramolecular migration to the β-position, revealing the presence of an arginine-2,3-aminomutase. Feedings of [2,3,3-2H3]-, [3,3-2H2]-, and [2-2H]arginines revealed the complete retention of the original β-hydrogens with migration of one to the α-position, as well as partial loss of the original α-hydrogen presumably due to arginine racemase activity. (3R)-[3-2H]- and (3S)-[3-2H]arginines were synthesized unambiguously and used to determine that the pro-3R hydrogen of α-arginine migrates to the α-position (C-2). δ-N-[13CH3]Methylarginine was synthesized, mixed with [guanidino-14C]arginine, and fed to S. griseochromogenes. A 42% incorporation of radioactivity from arginine was obtained, but no 13C enrichment was observed in the blasticidin S sample, indicating that arginine, itself, is the aminomutase substrate.
- Prabhakaran,Woo,Yorgey,Gould
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p. 5785 - 5791
(2007/10/02)
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- The biosynthesis of the streptolidine moiety in streptothricin F
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A series of arginines specifically labeled either with 13C and 15N or with 2H were synthesized and fed to Streptomyces L-1689-23. The streptothricin F isolated in each case was analyzed by either 13C or 2H NMR, respectively, in order to determine the labeling pattern obtained. From these results, it appears that arginine is metabolized to a β-ketoarginine, possibly via a pyridoxal phosphate adduct, and then via cyclization, reduction, rearrangement, and hydroxylation to the streptolidine moiety. The pathway described can also account for the formation of other known antibiotics, and for β-hydroxy-γ-amino acids, generally.
- Martinkus,Tann,Gould
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p. 3493 - 3505
(2007/10/02)
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