- Novel cis- and trans-configured bis(oxime)platinum(II) complexes: Synthesis, characterization, and cytotoxic activity
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Novel cis- and trans-configured bis(oxime)platinum(II) complexes have been synthesized and characterized by elemental analyses, IR, electrospray ionization mass spectrometry, multinuclear (1H, 13C, and 195Pt) NMR spectroscopy, and, in five cases, by X-ray diffraction. Their cytotoxicity was studied in the cisplatin-sensitive CH1 cell line as well as in inherently cisplatin-resistant SW480 cancer cells. Remarkably, every single dihalidobis(oxime)platinum(II) complex (with either a cis or trans configuration) shows a comparable cytotoxic potency in both cell lines, indicating a capacity of overcoming cisplatin resistance. Particularly strong cytotoxicities were observed in the case of trans-[PtCl2(R 2C=NOH)2] (R = Me, n-Pr, i-Pr) with IC50 values in the high nanomolar concentration range in both CH1 and SW480 cancer cells. These complexes are as potent as cisplatin in CH1 cells and up to 20 times more potent than cisplatin in SW480 cells. In comparison to transplatin, the novel compounds are up to 90 (CH1) and 120 times (SW480) more cytotoxic. The previously reported observation that the trans geometry yields a more active complex in the case of [PtCl2(Me2C=NOH)2] could be confirmed for at least two structural analogues.
- Scaffidi-Domianello, Yulia Yu.,Meelich, Kristof,Jakupec, Michael A.,Arion, Vladimir B.,Kukushkin, Vadim Yu.,Galanski, Markus,Keppler, Bernhard K.
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- Protein Modification at Tyrosine with Iminoxyl Radicals
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Post-translational modifications (PTMs) of proteins are a biological mechanism for reversibly controlling protein function. Synthetic protein modifications (SPMs) at specific canonical amino acids can mimic PTMs. However, reversible SPMs at hydrophobic amino acid residues in proteins are especially limited. Here, we report a tyrosine (Tyr)-selective SPM utilizing persistent iminoxyl radicals, which are readily generated from sterically hindered oximes via single-electron oxidation. The reactivity of iminoxyl radicals with Tyr was dependent on the steric and electronic demands of oximes; isopropyl methyl piperidinium oxime 1f formed stable adducts, whereas the reaction of tert-butyl methyl piperidinium oxime 1o was reversible. The difference in reversibility between 1f and 1o, differentiated only by one methyl group, is due to the stability of iminoxyl radicals, which is partly dictated by the bond dissociation energy of oxime O-H groups. The Tyr-selective modifications with 1f and 1o proceeded under physiologically relevant, mild conditions. Specifically, the stable Tyr-modification with 1f introduced functional small molecules, including an azobenzene photoswitch, to proteins. Moreover, masking critical Tyr residues by SPM with 1o, and subsequent deconjugation triggered by the treatment with a thiol, enabled on-demand control of protein functions. We applied this reversible Tyr modification with 1o to alter an enzymatic activity and the binding affinity of a monoclonal antibody with an antigen upon modification/deconjugation. The on-demand ON/OFF switch of protein functions through Tyr-selective and reversible covalent-bond formation will provide unique opportunities in biological research and therapeutics.
- Ishiyama, Takashi,Kanai, Motomu,Maruyama, Katsuya,Oisaki, Kounosuke,Sakai, Kentaro,Seki, Yohei,Togo, Takaya
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supporting information
p. 19844 - 19855
(2021/11/30)
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- Dehydrative Beckmann rearrangement and the following cascade reactions
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The Beckmann rearrangement has been predominantly studied for the synthesis of amide and lactam. By strategically using the in situ generated Appel's salt or Mitsunobu's zwitterionic adduct as the dehydrating agent, a series of Beckmann rearrangement and following cascade reactions have been developed herein. The protocol allows the conversion of various ketoximes into amide, thioamide, tetrazole and imide products in modular procedures. The generality and tolerance of functionalities of this method have been demonstrated.
- Liu, Yinghui,Wei, Yongjiao,Xie, Lan-Gui
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supporting information
(2021/11/16)
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- Scope and mechanism of a true organocatalytic beckmann rearrangement with a boronic acid/perfluoropinacol system under ambient conditions
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Catalytic activation of hydroxyl functionalities is of great interest for the production of pharmaceuticals and commodity chemicals. Here, 2-alkoxycarbonyl- and 2-phenoxycarbonyl-phenylboronic acid were identified as efficient catalysts for the direct and chemoselective activation of oxime N-OH bonds in the Beckmann rearrangement. This classical organic reaction provides a unique approach to prepare functionalized amide products that may be difficult to access using traditional amide coupling between carboxylic acids and amines. Using only 5 mol % of boronic acid catalyst and perfluoropinacol as an additive in a polar solvent mixture, the operationally simple protocol features mild conditions, a broad substrate scope, and a high functional group tolerance. A wide variety of diaryl, aryl-alkyl, heteroaryl-alkyl, and dialkyl oximes react under ambient conditions to afford high yields of amide products. Free alcohols, amides, carboxyesters, and many other functionalities are compatible with the reaction conditions. Investigations of the catalytic cycle revealed a novel boron-induced oxime transesterification providing an acyl oxime intermediate involved in a fully catalytic nonself-propagating Beckmann rearrangement mechanism. The acyl oxime intermediate was prepared independently and was subjected to the reaction conditions. It was found to be self-sufficient; it reacts rapidly, unimolecularly without the need for free oxime. A series of control experiments and 18O labeling studies support a true catalytic pathway involving an ionic transition structure with an active and essential role for the boronyl moiety in both steps of transesterification and rearrangement. According to 11B NMR spectroscopic studies, the additive perfluoropinacol provides a transient, electrophilic boronic ester that is thought to serve as an internal Lewis acid to activate the ortho-carboxyester and accelerate the initial, rate-limiting step of transesterification between the precatalyst and the oxime substrate.
- Mo, Xiaobin,Morgan, Timothy D. R.,Ang, Hwee Ting,Hall, Dennis G.
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supporting information
p. 5264 - 5271
(2018/04/24)
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- Copper-catalyzed synthesis of thiazol-2-yl ethers from oxime acetates and xanthates under redox-neutral conditions
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A novel copper-catalyzed annulation of oxime acetates and xanthates for the synthesis of thiazol-2-yl ethers with remarkable regioselectivity has been developed. Various oxime acetates, whether derived from aryl ketones or alkyl ketones, or natural product cores are suitable for this conversion. Unique dihydrothiazoles were also obtained when both reaction sites were methine. Mechanistic studies indicated that imino copper(iii) intermediates were involved. In addition, this protocol proceeded under redox-neutral conditions and did not require additives or ligands.
- Zhu, Zhongzhi,Tang, Xiaodong,Cen, Jinghe,Li, Jianxiao,Wu, Wanqing,Jiang, Huanfeng
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supporting information
p. 3767 - 3770
(2018/04/17)
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- ANTIVIRAL OXIME PHOSPHORAMIDE COMPOUNDS
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Compounds of Formula I: I and their pharmaceutically acceptable salts are useful for the inhibition of HIV reverse transcriptase. The compounds may also be useful for the prophylaxis or treatment of infection by HIV and in the prophylaxis, delay in the onset or progression, and treatment of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antiviral agents, immunomodulators, antibiotics or vaccines.
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Page/Page column 28
(2017/07/06)
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- Iminoxyl radical-based strategy for intermolecular C=O bond formation: Cross-dehydrogenative coupling of 1,3-dicarbonyl compounds with oximes
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Cross-dehydrogenative C=O coupling of 13-diketones and 1,3-keto esters with oximes was realized for the first time. The reaction proceeds in the presence of the oxidants [KMnO4, Mn(OAc)2/KMnO4, Mn(OAc)32 H2O, MnO2, Mn(acac)3, Fe(ClO4)3, Cu(ClO4)26 H 2O, Cu(NO3)22.5 H2O, and (NH 4)2Ce(NO3)6]. Twenty cross-coupling products were synthesized using potassium permanganate (KMnO4), manganese(II) acetate dihydrate [Mn(OAc)32 H2O], or the manganese(II) acetate/potassium permanganate [Mn(OAc)2/KMnO 4] system; yields are 27-92%. The synthesis can be easily scaled up to gram quantities of the target products. Apparently, the reaction proceeds via a radical mechanism in which the oxidizing agent serves to generate radicals from oximes and perform the one-electron oxidation of 1,3-dicarbonyl compounds. The formation of oxime radicals was confirmed quantitatively by electron spin resonance (ESR) spectroscopy. The coupling described in the present study is the first example of the selective intermolecular reaction involving unstable iminoxyl radicals generated in situ.
- Krylov, Igor B.,Terent'Ev, Alexander O.,Timofeev, Vladimir P.,Shelimov, Boris N.,Novikov, Roman A.,Merkulova, Valentina M.,Nikishin, Gennady I.
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supporting information
p. 2266 - 2280
(2014/07/21)
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- Chlorination of oximes with aqueous H2O2/HCl system: Facile synthesis of gem-chloronitroso- and gem-chloronitroalkanes, gem-chloronitroso- and gem-chloronitrocycloalkanes
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Chlorination of cyclic and linear ketone oximes with aqueous H 2O2/HCl in a two-phase dichloromethane-water system selectively affords gem-chloronitroso compounds in yields of up to 94%. One-pot oxidation of the resulting gem-chloronitroso compounds with peracetic acid, prepared in situ, gives gem-chloronitroalkanes and cycloalkanes in yields of up to 82%. The advantages of the method are that it is facile and environmentally benign and does not require gaseous chlorine. Georg Thieme Verlag Stuttgart.
- Terent'ev, Alexander O.,Krylov, Igor B.,Ogibin, Yuri N.,Nikishin, Gennady I.
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p. 3819 - 3824
(2008/02/09)
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- Cyanuric chloride as a mild and active Beckmann rearrangement catalyst
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The first general organocatalytic Beckmann rearrangement of ketoximes into amides has been realized by the catalytic use of cyanuric chloride. Furthermore, acids such as HCl and ZnCl2 are effective as cocatalysts with cyanuric chloride. For example, azacyclotridecan-2-one, which is synthetically useful as a starting material for nylon-12, was prepared in quantitative yield by the Beckmann rearrangement of cyclododecanone oxime (100 mmol scale) catalyzed by cyanuric chloride (0.5 mol %) and ZnCl2 (1 mol %). Copyright
- Furuya, Yoshiro,Ishihara, Kazuaki,Yamamoto, Hisashi
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p. 11240 - 11241
(2007/10/03)
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- Thermal decomposition of O-benzyl ketoximes; role of reverse radical disproportionation
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Thermolyses of seven dialkyl, two alkyl-aryl and two diaryl O-benzyl ketoxime ethers, R1R2C=NOCH2Ph, have been examined in three hydrogen donor solvents: tetralin, 9,10-dihydrophenanthrene, and 9,10-dihydroanthracene. All the oxime ethers gave the products expected from homolytic scission of both the O-C bond (viz., R1R2C=NOH and PhCH3) and N-O bond (viz., R1R2C=NH and PhCH2OH). The yields of these products depended on which solvent was used and the rates of decomposition of the O-benzyl oxime ethers were greater in 9,10-dihydrophenanthrene and 9,10-dihydroanthracene than in tetralin. These results indicated that a reverse radical disproportionation reaction in which a hydrogen atom was transferred from the solvent to the oxime ether, followed by β-scission of the resultant aminoalkyl radical, must be important in the latter two solvents. Benzaldehyde was found to be an additional product from thermolyses conducted in tetralin. This, and other evidence, indicated that another induced decomposition mode involving abstraction of a benzylic hydrogen atom, followed by β-scission of the resulting benzyl radical, became important for some substrates. Participation by minor amounts of enamine tautomers of the oxime ethers was shown to be negligible by comparison of thermolysis data for the O-benzyloxime of bicyclo[3.3.1]nonan-9-one, which cannot give an enamine tautomer, with that of the O-benzyloxime of cyclohexanone.
- Blake, Jessie A.,Ingold, Keith U.,Lin, Shuqiong,Mulder, Peter,Pratt, Derek A.,Sheeller, Brad,Walton, John C.
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p. 415 - 420
(2007/10/03)
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- ON THE FORMATION AND NITROGEN NUCLEAR MAGNETIC RESONANCE SPECTRA OF SOME NITRIMINES ('PERNITROSO-KETONES'), AND THE MECHANISM OF OXIME CLEAVAGE BY NITROUS ACID
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The formation of nitrimines, by the action of nitrous acid in oximes, is shown to proceed without scrambling of the nitrogen atoms, the oxime nitrogen forming the imine, and the nitrous acid generating the nitro group.Colorued intermediates in the reaction are proposed to be nitrosimines.The mechanism of nitrosative deoximation, and the nitrogen NMR spectra of nitrimines, are reported and discussed.
- Adamopoulos, Spiros,Boulton, A. J.,Tadayoni, Rahim,Webb, Graham A.
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p. 2073 - 2078
(2007/10/02)
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