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Distinguishing Rate-Limiting Electron versus H-Atom Transfers in Cu 2(O2)-Mediated Oxidative N-Dealkylations: Application of Inter- versus Intramolecular Kinetic Isotope Effects

Copper-dioxygen adducts are important biological oxidants. To gain a better understanding of the underlying chemistries of such species, we report on a series of Cu2II-O2 complexes, [{CuII(MePY2)R-}2(O2)](B(C6F5)4)2 (1R-) (where (MePY2)R- is a 4-pyridyl substituted bis[2-(2-(4-R-pyridyl)ethyl]methylamine; R- = H, MeO, Me2N; Zhang, C. X.; et al. J. Am. Chem. Soc. 2003, 125, 634-635), which readily oxidize exogenous substrates. In this study, we explore the mechanism by which 1R- facilitates the oxidative N-dealkylation of para-substituted N,N-dimethylanilines (R-DMA; R = MeO, Me, H, CN). In the case of 1H, the linear free-energy correlation plot (rho = -2.1) and intramolecular deuterium kinetic isotope effect (KIEintra, using p-R-(C6H4)-N(CH3)(CD3)) profile suggest that R-DMA oxidation occurs through rate-limiting electron transfer (ET). This mechanism was further enforced by comparison of KIEintra versus the intermolecular KIE (KIEinter, using p-R-(C6H4)-N(CH3)2 versus p-R-(C6H4)-N(CD3)2). It was found that KIEinter < KIEintra, suggesting an ET process. In the case of both 1MeO and 1Me2N, the KIEintra profile and linear free-energy correlation plots (rho = -0.49 and -0.99 for 1Me2N and 1MeO with especially poor fitting for the latter) are inconclusive in distinguishing between a rate-limiting ET or hydrogen atom transfer (HAT) pathway. Comparisons of KIEinter versus KIEintra demonstrate a switch in mechanism from ET to HAT for 1Me2N and 1MeO oxidation of R-DMA as R-DMA is made less reducing. In the case of 1Me2N, MeO-DMA and Me-DMA are oxidized via a rate-limiting ET (KIEinter < KIEintra), while H-DMA and CN-DMA are oxidized through a HAT pathway (KIEinter ? KIEintra). For 1MeO, oxidation occurs through an ET pathway for MeO-, Me-, and H-DMA (KIEinter < KIEintra), while CN-DMA is oxidized though a HAT process (KIEinter ? KIEintra). Copper complex attributes, which may contribute to the mechanistic observations, are suggested. Copyright Balanced chemical reaction does not necessarily reveal either the individual elementary reactions by which a reaction occurs or its rate law.Application of 33282-15-4. In my other articles, you can also check out more blogs about 33282-15-4

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BASICITY OF NITROGEN-SULPHUR(VI) COMPOUNDS. PART 5. IONIZATION OF TRISUBSTITUTED SULPHAMIDES

The ionization equilibria in base of 27 trisubstituted sulphamides, mainly represented by the following series: X-C6H4NHSO2NR2R1, where NR2R1=piperidyl, morpholinyl, and NnPr2, and RHNSO2NR2R1, where R,R1, and R2 are cyclo-C6H11, Ac, and X-C6H4 and X-C6H4, Ac and X-C6H4, have been studied in 60percent v/v ethanol-water using the potentiometric method.In a few cases pKa values have been determined by u.v. method.The effect of substituents has been correlated in Hammett plots and values are generally ca. 2.6 (as an for aryl linked nitrogen in sulphonanilide ionizations).The acid-strengthening effect of the acetyl group and the acid-weakening effect of the methyl group are seen in some series.

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Phosphoramidate tantalum complexes for room-temperature C-H functionalization: Hydroaminoalkylation catalysis

A cooled reaction: Phosphoramidate-ClTaMe3 complexes promote the first example of room-temperature hydroaminoalkylation catalysis. This reaction can be realized under solvent-free conditions and with challenging substrates such as styrenes and dialkyl amines. When using a vinylsilane substrate, for the first time the linear regioisomer is obtained preferentially using a Group5 metal. TBS=tert-butyldimethylsilyl, TMS=trimethylsilyl. Copyright

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Rhodium(iii)-catalyzed indole synthesis at room temperature using the transient oxidizing directing group strategy

Rh-catalyzed reactions of N-alkyl anilines with internal alkynes at room temperature have been developed using an in situ generated N-nitroso group as a transient oxidizing directing group. Due to mild reaction conditions, this method enabled synthesis of a broad range of N-alkyl indoles, including even two indole-based medicinal compounds. Our work disclosed the feasibility of the transient oxidizing directing group strategy in C-H functionalization reactions, which possesses the potential to enhance overall step-economy and impart new reactivity patterns to substrates.

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Reaction of functionalized anilines with dimethyl carbonate over NaY faujasite. 3. Chemoselectivity toward mono-N-methylation

In the presence of NaY faujasite, dimethyl carbonate (MeOCO2Me, DMC) is a highly chemoselective methylating agent of functionalized anilines such as aminophenols (1), aminobenzyl alcohols (2), aminobenzoic acids (3), and aminobenzamides (4). The reaction proceeds with the exclusive formation of N-methylanilines without any concurrent O-methylation or N-/O-methoxy carbonylation side processes. Particularly, only mono-N-methyl derivatives [XC6H4NHMe, X = o-, m-, and p-OH; o- and p-CH 2OH; o- and P-CO2H; o- and p-CONH2] are obtained with selectivity up to 99% and isolated yields of 74-99%. DMC, which usually promotes methylations only at T > 120 C, is activated by the zeolite catalyst and it reacts with compounds 1, 2, and 4, at 90 C. Aminobenzoic acids (3) require a higher reaction temperature (?130 C).

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Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple-acting angiokinase inhibition as antitumor agents

The utility of cytostatic antiangiogenic agents (AA) in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of AA with microtubule targeting agents (MTAs) have been particularly successful. The discovery, synthesis and biological evaluations of a series of 7-benzyl-N-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds which inhibit proangiogenic receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor-beta (PDGFR-beta) and epidermal growth factor receptor (EGFR), along with microtubule targeting in single molecules are described. These compounds also inhibited blood vessel formation in the chicken chorioallantoic membrane (CAM) assay, and some potently inhibited tubulin assembly (with activity comparable to that of combretastatin A-4 (CA)). In addition, some of the analogs circumvent the most clinically relevant tumor resistance mechanisms (P-glycoprotein and beta-III tubulin expression) to microtubule targeting agents (MTA). These MTAs bind at the colchicine site on tubulin. Two analogs displayed two to three digit nanomolar GI50values across the entire NCI 60 tumor cell panel and one of these, compound 7, freely water soluble as its HCl salt, afforded excellent in vivo antitumor activity against an orthotopic triple negative 4T1 breast cancer model and was superior to doxorubicin.

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Synthesis and in vitro cancer cell growth inhibition evaluation of 11-amino-modified 5-Me-indolo[2,3-b]quinolines and their COMPARE analyses

A plant-derived neocryptolepine core, the 5-Me-indolo[2,3-b]quinoline skeleton, was emblazoned with substituents at C11 and C2 and then tested against various cancer cell lines to find potent anticancer agents. In the in vitro antiproliferative activity assay against the breast cancer MDA-MB-453 cell line, the attachment of alkylamino substituents at C11 of the 5-Me-indolo[2,3-b]quinoline induced improved activities. Specifically, 11-(3-aminopropylamino) and 11-(4-aminobutylamino) derivatives indicated the highest activity and selectivity against MDA-MB-453 (IC50 = 0.3-0.5 muM) and also exhibited a higher cytotoxicity against the colon adenocarcinoma (WiDr) and ovarian cancer (SKOv3) cell lines. A synergistic effect by attachment of substituents at C2 was favorably observed with an electron-donating group, such as CH3O, and unfavorably observed with an electron-withdrawing one, such as F and CF3. Further modification of the terminal free amino group of the lariat attachment at C11 into the corresponding acylamides and 2,3-dihydrobenzo[e][1,3]thiazin-4-ones was not effective for the antiproliferative activity. The computer-assisted database analysis, COMPARE, suggested that 14e and 13b have a mode of action similar to actinomycin D and 13c has a mode of actions similar to vindesine sulfate or aclarubicin hydrochloride. However, the new compounds may have other unique mode of actions since the correlation coefficients (r) were in relatively low levels.

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Chemical profiling of HIV-1 capsid-targeting antiviral PF74

The capsid protein (CA) of HIV-1 plays essential roles in multiple steps of the viral replication cycle by assembling into functional capsid core, controlling the kinetics of uncoating and nuclear entry, and interacting with various host factors. Targeting CA represents an attractive yet underexplored antiviral approach. Of all known CA-targeting small molecule chemotypes, the peptidomimetic PF74 is particularly interesting because it binds to the same pocket used by a few important host factors, resulting in highly desirable antiviral phenotypes. However, further development of PF74 entails understanding its pharmacophore and mitigating its poor metabolic stability. We report herein the design, synthesis, and evaluation of a large number of PF74 analogs aiming to provide a comprehensive chemical profiling of PF74 and advance the understanding on its detailed binding mechanism and pharmacophore. The analogs, containing structural variations mainly in the aniline domain and/or the indole domain, were assayed for their effect on stability of CA hexamers, antiviral activity, and cytotoxicity. Selected analogs were also tested for metabolic stability in liver microsomes, alone or in the presence of a CYP3A inhibitor. Collectively, our studies identified important pharmacophore elements and revealed additional binding features of PF74, which could aid in future design of improved ligands to better probe the molecular basis of CA-host factor interactions, design strategies to disrupt them, and ultimately identify viable CA-targeting antiviral leads.

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Tungsten-catalyzed regio- and enantioselective aminolysis of trans-2,3-epoxy alcohols: An entry to virtually enantiopure amino alcohols

The first catalytic enantioselective aminolysis of trans-2,3-epoxy alcohols has been accomplished. This stereo-specific ring-opening process was efficiently promoted by a tungsten/bis(hydroxamic acid) catalytic system, furnishing various anti-3-amino-1,2-diols with excellent regiocontrol and high enantioselectivities (up to 95% ee). Moreover, virtually enantiopure 3-amino-1,2-diols could be obtained by the sequential combination of two reactions that both involve the use of a chiral catalyst.

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Dirhodium-catalyzed C-H arene amination using hydroxylamines

Primary and N-alkyl arylamine motifs are key functional groups in pharmaceuticals, agrochemicals, and functional materials, as well as in bioactive natural products. However, there is a dearth of generally applicablemethods for the direct replacement of aryl hydrogens with NH2/NH(alkyl) moieties. Here, we present a mild dirhodium-catalyzed C-H amination for conversion of structurally diverse monocyclic and fused aromatics to the corresponding primary and N-alkyl arylamines using NH2/NH(alkyl)-O-(sulfonyl)hydroxylamines as aminating agents; the relatively weak RSO2O-N bond functions as an internal oxidant. The methodology is operationally simple, scalable, and fast at or below ambient temperature, furnishing arylamines in moderate-to-good yields and with good regioselectivity. It can be readily extended to the synthesis of fused N-heterocycles.

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