6731-11-9Relevant academic research and scientific papers
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
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.
, p. 1 - 59 (2021/03/16)
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.
Visible Light-Catalyzed Benzylic C-H Bond Chlorination by a Combination of Organic Dye (Acr+-Mes) and N-Chlorosuccinimide
Xiang, Ming,Zhou, Chao,Yang, Xiu-Long,Chen, Bin,Tung, Chen-Ho,Wu, Li-Zhu
, p. 9080 - 9087 (2020/08/14)
By combining "N-chlorosuccinimide (NCS)"as the safe chlorine source with "Acr+-Mes"as the photocatalyst, we successfully achieved benzylic C-H bond chlorination under visible light irradiation. Furthermore, benzylic chlorides could be converted to benzylic ethers smoothly in a one-pot manner by adding sodium methoxide. This mild and scalable chlorination method worked effectively for diverse toluene derivatives, especially for electron-deficient substrates. Careful mechanistic studies supported that NCS provided a hydrogen abstractor "N-centered succinimidyl radical,"which was responsible for the cleavage of the benzylic C-H bond, relying on the reducing ability of Acr?-Mes.
Photogeneration of benzhydryl cations by near-UV laser flash photolysis of pyridinium salts
Nigst, Tobias A.,Ammer, Johannes,Mayr, Herbert
, p. 8494 - 8499 (2013/01/14)
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).
Ionizing power of aprotic solvents
Streidl, Nicolas,Mayr, Herbert
supporting information; experimental part, p. 2498 - 2506 (2011/06/10)
Rate constants for the heterolysis reactions (SN1) of a series of chloro-diarylmethanes in aprotic solvents (dimethyl sulfoxide (DMSO), acetonitrile, carboxamides, etc.) have been determined conductometrically in the presence of amines or triphenylphosphane, which trap the intermediate ion-pairs and suppress ion recombination. The operation of SN2 mechanisms can be excluded because the observed first-order rate constants become almost independent of the nature of the nucleophilic additive when a certain concentration of nucleophile is exceeded. The heterolysis rate constants are used to calculate nucleofugality parameters Nf and sf for chloride in aprotic solvents according to the linear free-energy relationship lgak (25 °C) = sf(Nf + Ef). Ionizing powers YBnCl of these solvents were calculated according to the Winstein-Grunwald equation. Because the heterolysis rate constants in aprotic solvents correlate only poorly with dielectric constants or empirical solvent parameters such as Gutmann's acceptor numbers or ETN values, the most common solvent polarity parameters do not reliably predict ionization rates in aprotic solvents. The kinetics of the heterolyses of chloro-diarylmethanes in aprotic solvents have been studied conductometrically by suppressing ion recombination with amine additives. In this way it became possible to determine the ionizing power of aprotic solvents and compare them to those of protic solvents. Copyright
Structure-activity relationships of diphenylpiperazine N-type calcium channel inhibitors
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.
scheme or table, p. 1378 - 1383 (2010/07/06)
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.
Suppression of common-ion return by amines: A method to measure rates of fast SN1 reactions
Streidl, Nicolas,Antipova, Anna,Mayr, Herbert
supporting information; experimental part, p. 7328 - 7334 (2010/01/16)
(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.
Kinetics of the solvolyses of benzhydryl derivatives: Basis for the construction of a comprehensive nucleofugality scale
Denegri, Bernard,Streiter, Andre,Juric, Sandra,Ofial, Armin R.,Kronja, Olga,Mayr, Herbert
, p. 1648 - 1656 (2007/10/03)
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.
Kinetics of the reactions of halide anions with carbocations: Quantitative energy profiles for SN1 reactions
Minegishi, Shinya,Loos, Robert,Kobayashi, Shinjiro,Mayr, Herbert
, p. 2641 - 2649 (2007/10/03)
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.
Kinetic studies on the reactivity of triphenylmethyl cations adsorbed on silica, alumina, and aluminosilicate
Spange, Stefan,Adolph, Simone,Walther, Ralph,Zimmermann, Yvonne
, p. 298 - 305 (2007/10/03)
The apparent rate constants ka?2 of different surface-mediated reactions of three nucleophiles 1,4-cyclohexadiene, triethylsilane, and isobutylvinyl ether with triphenylmethylium ions have been determined for three different solid acid catalysts and various triphenylmethylium precursors (R1R2R3C-X, X = SCN, OH, Cl, or Br). Generation of triphenylmethylium ions [R1R2R3C+] was used for kinetic measurements when R1R2R3C-X derivates are chemisorbed to the solid acid catalysts. The catalysis of those surface-mediated reactions by a silica, an alumina, and an aluminosilicate has been studied in a slurry of dichloromethane at ambient temperature. The value of ka?2 increases in the order OH- - - - and silica s of the corresponding HX from R1R2R3C-X or the acidity of the solid acid (Adolph, S.; Spange, S.; Zimmermann, Y. J. Phys. Chem. B 2000, 104, 6429-6438) indicating the importance of the effective surface concentration of [R1R2R3C+] on the apparent rate constant. It is also shown that the specific rate constant of the surface-mediated reaction can be interpreted in terms of Mayr's nucleophilicity parameters of the ??-nucleophile (N) and the pKR+ values of the carbenium ion derived from polar reactions in homogeneous solution.
Reactions between nitrile oxides and carbenium ions: Synthesis of benzoxazines, oximes, and amides through intramolecular ortho or ipso attack
Auricchio, Sergio,Magnani, Caterina,Truscello, Ada M.
, p. 2411 - 2416 (2007/10/03)
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.
