- Synthesis and biological evaluation of 1‐(Diarylmethyl)‐1h‐1,2,4‐triazoles and 1‐(diarylmethyl)‐1h‐imidazoles as a novel class of anti‐mitotic agent for activity in breast cancer
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We report the synthesis and biochemical evaluation of compounds that are designed as hybrids of the microtubule targeting benzophenone phenstatin and the aromatase inhibitor letrozole. A preliminary screening in estrogen receptor (ER)‐positive MCF‐7 breast cancer cells identified 5‐((2H‐1,2,3‐triazol‐1‐yl)(3,4,5‐trimethoxyphenyl)methyl)‐2‐methoxyphenol 24 as a potent antiproliferative compound with an IC50 value of 52 nM in MCF‐7 breast cancer cells (ER+/PR+) and 74 nM in triple‐negative MDA‐MB‐231 breast cancer cells. The compounds demonstrated significant G2/M phase cell cycle arrest and induction of apoptosis in the MCF‐7 cell line, inhibited tubulin polymerisation, and were selective for cancer cells when evaluated in non-tumorigenic MCF‐10A breast cells. The immunofluorescence staining of MCF‐7 cells confirmed that the compounds targeted tubulin and induced multinucleation, which is a recognised sign of mitotic catastrophe. Computational docking studies of compounds 19e, 21l, and 24 in the colchicine binding site of tubulin indicated potential binding conformations for the compounds. Compounds 19e and 21l were also shown to selectively inhibit aromatase. These compounds are promising candidates for development as antiproliferative, aromatase inhibitory, and microtubule‐disrupting agents for breast cancer.
- Ana, Gloria,Kelly, Patrick M.,Malebari, Azizah M.,Noorani, Sara,Nathwani, Seema M.,Twamley, Brendan,Fayne, Darren,O’boyle, Niamh M.,Zisterer, Daniela M.,Pimentel, Elisangela Flavia,Endringer, Denise Coutinho,Meegan, Mary J.
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- Direct halogenation of alcohols with halosilanes under catalyst- and organic solvent-free reaction conditions
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A chemoselective method for the direct halogenation of different types of alcohols with halosilanes under catalyst- and solvent-free reaction conditions (SFRC) is reported. Various primary, secondary and tertiary benzyl alcohols and tertiary alkyl alcohols were directly transformed to the corresponding benzyl and alkyl halides, respectively, using chlorotrimethylsilane (TMSCl) and bromotrimethylsilane (TMSBr).
- Ajvazi, Njomza,Stavber, Stojan
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supporting information
p. 2430 - 2433
(2016/05/19)
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- Photogeneration of benzhydryl cations by near-UV laser flash photolysis of pyridinium salts
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Laser flash irradiation of substituted N-benzhydryl pyridinium salts yields benzhydryl cations (diarylcarbenium ions) and/or benzhydryl radicals (diarylmethyl radicals). The use of 3,4,5-triamino-substituted pyridines as photoleaving groups allowed us to employ the third harmonic of a Nd/YAG laser (355 nm) for the photogeneration of benzhydryl cations. In this way, benzhydryl cations can also be photogenerated in the presence of aromatic compounds and in solvents which are opaque at the wavelength of the quadrupled Nd/YAG laser (266 nm). To demonstrate the scope and limitations of this method, the rate constants for the bimolecular reactions of benzhydryl cations with several substituted pyridines were determined in acetonitrile and with water in acetone. The obtained data agree with results obtained by stopped-flow UV-vis spectroscopic measurements. The rate constants for the reaction of the 4,4'-bis[methyl(2,2,2- trifluoroethyl)amino]benzhydrylium ion with 4- (dimethylamino)pyridine were also determined in dimethyl sulfoxide, N,N-dimethylformamide, and acetone. From the secondorder rate constants, we derived the nucleophilicity parameters N and sN for the substituted pyridines, as defined by the linear free energy relationship, log k2 = sN(N + E).
- Nigst, Tobias A.,Ammer, Johannes,Mayr, Herbert
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p. 8494 - 8499
(2013/01/14)
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- Structure-activity relationships of diphenylpiperazine N-type calcium channel inhibitors
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A novel series of compounds derived from the previously reported N-type calcium channel blocker NP118809 (1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one) is described. Extensive SAR studies resulted in compounds with IC50 values in the range of 10-150 nM and selectivity over the L-type channels up to nearly 1200-fold. Orally administered compounds 5 and 21 exhibited both anti-allodynic and anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain.
- Pajouhesh, Hassan,Feng, Zhong-Ping,Ding, Yanbing,Zhang, Lingyun,Pajouhesh, Hossein,Morrison, Jerrie-Lynn,Belardetti, Francesco,Tringham, Elizabeth,Simonson, Eric,Vanderah, Todd W.,Porreca, Frank,Zamponi, Gerald W.,Mitscher, Lester A.,Snutch, Terrance P.
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scheme or table
p. 1378 - 1383
(2010/07/06)
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- Suppression of common-ion return by amines: A method to measure rates of fast SN1 reactions
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(Chemical Equation Presented) Rate constants for solvolyses of benzhydryl chlorides, which take place on the 10 ms to minute time scale, have been determined in aqueous acetone and acetonitrile by conductometry, using conventional conductometers as well as stopped-flow techniques. Secondary and tertiary amines were used to suppress ion recombination (common-ion return) thus giving access to the ionization rate constants k1. The observed common-ion rate depressions can be rationalized by the correlation equation for electrophile-nucleophile combinations, log k(20 °C) = s(E + N), where electrophiles (here: carbocations) are characterized by the parameter Eand nucleophiles (here: chloride anions and solvents) are characterized by N and s. 2009 American Chemical Society.
- Streidl, Nicolas,Antipova, Anna,Mayr, Herbert
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supporting information; experimental part
p. 7328 - 7334
(2010/01/16)
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- Kinetics of the solvolyses of benzhydryl derivatives: Basis for the construction of a comprehensive nucleofugality scale
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A series of 21 benzhydrylium ions (diarylmethylium ions) are proposed as reference electrofuges for the development of a general nucleofugality scale, where nucleofugality refers to a combination of leaving group and solvent. A total of 167 solvolysis rate constants of benzhydrylium tosylates, bromides, chlorides, trifluoroacetates, 3,5-dinitrobenzoates, and 4-nitroben-zoates, two-thirds of which have been determined during this work, were subjected to a least-squares fit according to the correlation equation log k 25°C = Sf(Nf + Ef), where s f and Nf are nucleofuge-specific parameters and E f is an electrofuge-specific parameter. Although nucleofuges and electrofuges characterized in this way cover more than 12 orders of magnitude, a single set of the parameters, namely sf, Nf, and E f, is sufficient to calculate the solvolysis rate constants at 25°C with an accuracy of ± 16%. Because sf ≈ 1 for all nucleofuges, that is, leaving group/ solvent combinations, studied so far, qualitative discussions of nucleofugality can be based on Nf.
- Denegri, Bernard,Streiter, Andre,Juric, Sandra,Ofial, Armin R.,Kronja, Olga,Mayr, Herbert
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p. 1648 - 1656
(2007/10/03)
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- Kinetics of the reactions of halide anions with carbocations: Quantitative energy profiles for SN1 reactions
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Rate constants for the reactions of Laser flash photolytically generated benzhydrylium ions (diarylcarbenium ions) with halide ions have been determined in various solvents, including neat and aqueous acetonitrile as well as some alcohols. Substitution of the rate constants into the correlation equation log k = s(N + E) yields the nucleophilicity parameters N for the halide ions in different solvents. Linear correlations with negative slopes are found between the nucleophilicity parameters N for Cl- and Br- in different solvents and the solvent ionizing powers Y of the corresponding solvents. Increasing halide solvation reduces the rates of carbocation/chloride combinations by approximately half as much as it increases the rates of ionizations of benzhydryl chlorides. Comparison of the solvent dependent nucleophilicity parameters N of halide anions and the nucleophilicity parameters N1 for solvents yields a quantitative prediction of common ion rate depression, as demonstrated by the analysis of a variety of literature reported mass-law constants α. Combination of the rate constants for the reactions of benzhydrylium ions with halide ions (k-1) reported in this work with the ionization constants of benzhydryl halides (k1) and the recently reported rate constants for the reactions of benzhydrylium ions with solvents (k2) yields complete quantitative free energy profiles for solvolysis reactions. The applicability of Hammond's postulate for interpreting solvolysis reactions can thus be examined quantitatively.
- Minegishi, Shinya,Loos, Robert,Kobayashi, Shinjiro,Mayr, Herbert
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p. 2641 - 2649
(2007/10/03)
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- Reactions between nitrile oxides and carbenium ions: Synthesis of benzoxazines, oximes, and amides through intramolecular ortho or ipso attack
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Reactions between nitrile oxides and benzylic carbocations are described. Different results were obtained when the carbocations were generated from the corresponding chlorides with different Lewis acids, with addition products such as benzoxazines, oximes, and amides being produced. Primary, secondary, and tertiary carbocations showed different reactivities. The product ratios strongly depended on the substituents on the aromatic ring of the benzylic carbocations. Evidence for the proposed mechanism is reported. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.
- Auricchio, Sergio,Magnani, Caterina,Truscello, Ada M.
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p. 2411 - 2416
(2007/10/03)
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- Solvolysis of benzylic chlorides with extended charge delocalization. α-tert-Butyl(2-naphthyl)methyl, 9-fluorenyl and monosubstituted benzhydryl chlorides
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Rate constants of solvolysis of α-tert-butyl(2-naphthyl)methyl chloride (1), 9-fluorenyl chloride (2) and a series of monosubstituted benzhydryl chlorides (3) in a wide range of solvents were measured. Grunwald-Winstein-type correlation analysis of log k for 2 and 3 against YBnCl, with or without nucleophilicity N, yielded less satisfactory linear correlations than that against log k(l). A new scale of solvent ionizing power, YxBnCl for the correlation of solvolytic reactivities of benzylic chlorides with extended charge delocalization based on log k(1) was developed. Application to the mechanistic study suggested the solvolysis of 2 and 4-nitrobenzhydryl chloride were non-limiting. Hammett plots against α+ constants exhibited more negative ρ values in less nucleophilic solvents. In a benzhydryl chloride containing a strong deactivating substituent, such as 4-nitro, the positive charge delocalizes mainly over the unsubstituted ring in the cationic transition state. The uneven charge distribution was also confirmed by Mulliken population analysis at the level of the RHF/6-31G*//RHF/3-21G(*) basis set for cations. Comparison of the results of correlation analysis using the equation log(k/k0) = mY vs the equation log(k/k0) = mY + hI, and using the equation log(k/k0) = mY +IN vs the equation log(k/ko) = mY + IN + hI indicated the use of YBnCl or YxBncl could give a better understanding of solvolytic mechanisms than the combinatorial use of YCl and I.
- Liu, Kwang-Ting,Lin, Yen-Shyi,Tsao, Meng-Lin
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p. 223 - 229
(2007/10/03)
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- Novel 4'-Substituted and 4',4"-Disubstituted 3α-(Diphenylmethoxy)tropane Analogs as Potent and Selective Dopamine Uptake Inhibitors
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A series of 4'-substituted and 4',4"-disubstituted 3α-(diphenylmethoxy)tropane analogs were prepared as novel probes for the dopamine transporter.These compounds were evaluated in radiolabeled binding assays for the dopamine, norepinephrine, and serotonin transporters.All of these compounds monophasically displaced WIN 35,428 binding in rat caudate putamen with Ki values ranging from 11.8 to 2000 nM.The most potent compound in this series was 4',4"-difluoro 3α-(diphenylmethoxy)tropane 7c with Ki=11.8 nM.All of the compounds inhibited dopamine uptake in rat caudate putamen (IC50 = 24-4456 nM) which correlated significantly (r = 0.907; p > 0.0001) with binding affinities at the dopamine transporter.None of the compounds demonstrated high-affinity binding at the norepinephrine (Ki > 4800 nM) or serotonin (Ki > 690 nM)transporters.Therefore, the most potent dopamine uptake inhibitors in this series were highly selective for the dopamine transporter.Preliminary behavioral studies of several of these analogs (7a-e) suggested that the compounds did not display a cocaine-like behavioral profile, despite their ability to inhibit dopamine uptake.The present data coupled with the 3α-(diphenylmethoxy)tropane analogs may be interacting at a different active site than cocaine on the dopamine transporter and that an additional binding domain might be exploited for the identification of potential therapeutics for the treatment of cocaine abuse.
- Newman, Amy Hauck,Kline, Richard H.,Allen, Andrew C.,Izenwasser, Sari,George, Clifford,Katz, Jonathan L.
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p. 3933 - 3940
(2007/10/03)
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- Ionisation and Dissociation of Diarylmethyl Chlorides in BCl3/CH2Cl2 Solution: Spectroscopic Evidence for Carbenium Ion Pairs
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The ionisation equilibria of diarylmethyl chlorides Ar2CHCl (Ar = p-CH3O-C6H4, p-PhO-C6H4, p-CH3-C6H4) reacting with BCl3 in CH2Cl2 to give ion-pairs Ar2CH(+)BCl4(-) (KI), and the dissociation of these (KD) were studied by conductimetry and spectro-photometry.The molar conductivities are almost independent of the nature of the aryl group (ca. 3.5E-3 Sm2/mol at -70 deg C).The ionisation constants KI increase strongly with increasing electron releasing ability of the p-substituents.The standard ionisation enthalpies and entropies for (p-CH3-C6H4)2CHCl and (p-PhO-C6H4)(Ph)CHCl, calculated from the KI at different temperatures are negative.The dissociation constants KD do not show a systematic dependence on the electron donating abilities of the substituents in the aryl groups.Small differences between the UV-vis absorption spectra of unpaired and paired ions were used to confirm the conductimetrically determined values of KD. - Key words: Carbocations / Electrochemistry / Ionisation / Spectroscopy, Visible / Thermodynamics
- Schneider, Reinhard,Mayr, Herbert,Plesch, Peter H.
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p. 1369 - 1374
(2007/10/02)
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- Stabilities of Carbonium Ions. IV. Steric Effects in the Solvolysis of Substituted Diphenylmethyl Chlorides
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The replacement of ortho-hydrogen atoms by methyl groups in diphenylmethyl chloride has three distinguishable results upon the rate of solvolysis.Firstly, the alkyl group activates by its electronic effect; secondly, steric interactions diminish all obsse
- Bolton, Roger,Burley, Rita E.,Williams, Nigel J.
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p. 625 - 634
(2007/10/02)
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- Synthesis and quantitative structure-activity relationships of antibacterial 1-(substituted benzhydryl)-4-(5-nitro-2- furfurylideneamino)piperazines
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1-Benzhydryl-4-(5-nitro-2-furfurylideneamino)piperazine and 11 substituted analogs were prepared and examined for in vitro antimicrobial activity. The compounds were active against Bacillus cereus 7, Bacillus megaterium 122, Bacillus subtilis 104, Clostridium perfringens 13, and the tetracycline-resistant Clostridium perfringens 37. Regression analyses on the antibacterial activity data based on the Hansch approach, using π, π2, and σ parameters, yielded several statistically significant correlation equations. 1-Benzhydryl-4-(5-nitro-2-furfurylideneamino)piperazine stopped the protein and DNA syntheses in C. perfringens 13, as indicated by precipitable radioactivity. The compound, however, showed no effect on the cell wall synthesis in the bacteria.
- Yung,Gilroy,Mahony
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p. 900 - 905
(2007/10/04)
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