Diphenylamine Series Research Articles

Synthesis and Evaluation of a Novel Series of Diphenylamine and Diphenylether Derivatives with Osteoblastogenic and Osteogenic Effects via CDK8 Inhibition.

Osteoporosis is induced by an imbalance between osteogenesis and bone resorption, and is treated with osteogenic drugs and/or resorption inhibitors. Resorption inhibitors, such as bisphosphonates, are orally used; however, orally active small molecules with osteogenic activity are not clinically available. We synthesized various types of small molecules and identified a series of diphenylamine and diphenylether derivatives that promoted osteoblast differentiation. Among them, diphenylether derivatives 13a, 13g, and 13h potently promoted osteoblast differentiation (EC200 for increasing alkaline phosphatase activity = 11.3, 31.1, and 12.3 nM, respectively) and inhibited cyclin-dependent kinase 8 (CDK8) activity (IC50 = 2.5, 7.8, and 3.9 nM, respectively), suggesting that their osteoblastgenic effects are mediated by the inhibition of CDK8. The ratio of the maximal plasma concentration after oral administration at 10 mg/kg in female rats and EC200 for osteoblastogenesis was 148.1 for compound 13a, 53.4 for 13g, and 101.8 for 13h, indicating possible in vivo osteoblastogenic and osteogenic effects. In ovariectomized female rats, 13g and 13h at 10 mg/kg/d for 8 weeks increased plasma bone-type alkaline phosphatase activity, indicating enhanced in vivo osteoblastogenesis. Furthermore, micro-computed tomography (micro-CT) showed that both compounds increased femoral cortical bone volume and mineral contents, which were unaffected by ovariectomy, while having negligible effects on trabecular bone volume and mineral contents, which were markedly reduced by ovariectomy. In conclusion, diphenylamine and diphenylether structures are novel scaffolds for osteoblastogenesis enhancers via the inhibition of CDK8. Among them, 13g and 13h are candidates for anti-osteoporotic drugs with cortical bone-selective osteogenic effects.

Design, synthesis and photoelectrical properties of diphenylamine-containing triphenylamine-based D-D-π-A-type fluorescence dyes

Available online A series of diphenylamine (DPA)-containing triarylamine-based D-D-π-A organic fluorescence dyes were designed under the guidance of theoretical calculations and then synthesized (cyanoacrylic acid, methylene malononitrile or isophorone served as the electron acceptor while ethylene served as the π-bridge). The results of theoretical calculations, electrochemical properties and optical properties tests indicated that the new dyes possessed high thermal stability, desirable HOMO levels and intramolecular charge transfer property. Some of them possessed high fluorescence quantum yields and performed very well as luminescent material as expected..

Abstract 4204: Structure-activity relationship of diphenylamine derivatives to target epithelial to mesenchymal transition in triple negative breast cancer

Abstract Triple negative breast cancer (TNBC) is characterized by the loss of hormone receptors and high invasive potential. TNBC cells express high levels of the mesenchymal markers vimentin, fibronectin, N-cadherin, and cadherin11, which are involved in cell invasion and metastasis, and low levels of the epithelial markers E-cadherin, occludins and cytokeratins, which are involved in cellular contact and stability of the cell membrane. Mitogen activated protein kinases, including ERK5 and ERK1/2 are important pro-survival proteins and are known to be upregulated in most cancers. Of these pathways, the MEK5-ERK5 pathway is understudied in triple negative breast cancer, and there are few research tools available to selectively inhibit this pathway. The diphenylamine moiety was derived from the parent molecule Trametinib, a FDA approved MEK1/2 inhibitor for melanoma. Structural modifications were made on the lead molecule to gain selectivity towards MEK. SC-1-151, one of the compounds from this diphenylamine series was identified as a dual MEK1/2 (98.6% inhibition) and MEK5 (59% inhibition) inhibitor. Additionally, we have shown that SC-1-151 attenuates tumor growth in severe combined immunodeficient (SCID) xenograft mice and causes a mesenchymal to epithelial transition (MET) in MDA-MB-231 TNBC cells. The goal of this research is to determine the structural features of diphenylamines that are responsible for MET. E-cadherin and cadherin-11 protein expression and cell morphology were examined to study MET after the treatment of MDA-MB-231 cells with different structural analogs of SC-1-151 for 5 days. Alkyl or N-Methyl piperazine substituents on the amide of ring 1 produced similar result as SC-1-151, and substituting the amide group with acid or ester also induced MET. In contrast, ortho-fluoro, para-iodo functional groups of the arene ring 2, when replaced with a meta-bromo substituent did not induce MET. Therefore, our data suggest the necessary functional groups for inducing MET include the hydrogen atom on the amine linkage, and the iodine atom on the arene ring 2. Future studies will be performed to determine the specific protein interactions of the promising compounds. Citation Format: Akshita B. Bhatt, Thomas D. Wright, Katie Anna, Mohit Gupta, Patrick Flaherty, Van Hoang, Matthew Burow, Jane E. Cavanaugh. Structure-activity relationship of diphenylamine derivatives to target epithelial to mesenchymal transition in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4204.

DFT studies of the effectiveness of p-substituted diphenyl amine antioxidants in styrene-butadiene rubber through their Cu(II) coordination ability

Structures of a series of diphenyl amine (DPA) antioxidants and of their complexes with Cu2+ were optimized at B3LYP level of theory. DPAs may be divided into two groups according to their molar antioxidant effectiveness (AEM). The effectiveness of high-AEM DPA antioxidants at 130°C rises with decreasing spin densities at Cu atoms and with the increasing electron density Laplacian at Cu–N bond critical points in the 2[DPA…Cu]2+ complexes similarly as in the case of p-phenylene diamine antioxidants. No such trends are observed at 25°C and for low- AEM DPA antioxidants.

Estimation of the main characteristics of reagents of the diphenylamine series using quantum chemistry and chemometrical methods

The possibility of using quantum chemistry and chemometrical methods for the a priori estimation of the major analytical characteristics of analytical reagents has been demonstrated by the example of compounds of the diphenylamine series. The employed methods for the estimation of the characteristics of compounds are simple and rapid and are equal to the known experimental approaches in terms of precision.

Self-Assembly, Dynamics, and Phase Transformation Kinetics of Donor−Acceptor Substituted Perylene Derivatives

The role of alkyl chain substitution on the phase formation and core dynamics is studied in a series of diphenylamine functionalized perylenemonoimides (PMIs), by X-ray scattering, calorimetry and site-specific solid-state NMR techniques. In addition, the strong dipole associated with the donor-acceptor character of the molecules allow an investigation of the dynamics with dielectric spectroscopy. The self-assembly revealed an ordered phase only in PMIs with branched alkyl chains. This phase comprises a helical stacking of molecules with a molecular twist angle of 60 degrees. Results from solid-state NMR further pointed out the importance of intramolecular hydrogen bonding in stabilizing the intracolumnar packing within the ordered phase. Moreover, the core dynamics are frozen as revealed by the value of the dynamic order parameters and the reduced strength of dipolar relaxation. The kinetics of phase transformation from the isotropic to the ordered phase proceeds via a nucleation and growth mechanism, and the rates are dominated by the nucleation barrier. Within the isotropic phase the core dynamics display strong temperature dependence with rates that depend on the number of methylene units in the alkyl chains.

Physicochemical and Analytical Properties of Surfactant-Modified Redox Reagents of the Diphenylamine Series

The effect of the nature and concentration of aqueous solutions of surfactants (ions and micelles) on the spectrochemical, acid-base and redox properties of organic reagents of the diphenylamine series bearing different substituents in phenyl rings and at the bridging nitrogen atom was studied by potentiometric titration and absorption and photoluminescence spectroscopy. The surfactant micelle–reagent binding constants were determined, and the correlation between the binding constants and the above-mentioned properties was analyzed.

The influence of surfactants on the acid—base and redox properties of reagents of the diphenylamine series

The influence of aqueous solutions of surfactants on the redox and acid—base properties of diphenylamine redox reagents was studied by potentiometric titration and UV spectroscopy. The formal redox potentials, the pKa values of the reagents in aqueous solutions and in the presence of surfactants, and the constants of binding of the reagents by micellar solutions of surfactants were estimated.

Semiempirical quantum chemical PM3 computations and evaluations of redox potentials, basicities, and dipole moments of the diphenylamine series as analytical reagents

By evaluating the obtained results of PM3 computations, the following correlations were found: (i) the diarylamines redox potentials (E) with the first ionization potentials (I); (ii) the pKa values characterizing both the amines nitrogen protonation and the carboxy substituted reagents dissociation via the COOH group, with the proton affinities of the corresponding diphenylamines and COO--containing anions; (iii) the experimental values of the molecules dipole moments (μ) with the theoretical ones. The feasibility of the simple semiempirical quantum chemical evaluation of E, pKa, and μ of the diphenylamine series as redox reagents was determined.Key words: diphenylamine series, redox potential, pKa, dipole moment, semiempirical quantum chemical evaluation

Semiempirical quantum chemical PM3 computations and evaluations of redox potentials, basicities, and dipole moments of the diphenylamine series as analytical reagents

Semiempirical quantum chemical PM3 computations and evaluations of redox potentials, basicities, and dipole moments of the diphenylamine series as analytical reagents

Halogenations in the diphenylamine series

The preparation of substituted dibenz[b.f]azepin required several substituted diphenylamines, especially 2,2′-dichloro-diphenylamine ( I) and its derivatives. The observations made in this investigation are believed to be of some general interest.