Anilino Group Research Articles

Discovery of a Potent Retinoid X Receptor Antagonist Structurally Closely Related to RXR Agonist NEt-3IB.

We discovered a potent retinoid X receptor (RXR) antagonist, 6-[N-ethyl-N-(5-isobutoxy-4-isopropyl-2-(E)-styrylphenyl)amino]nicotinic acid (13e), that is structurally closely related to the RXR full agonist 6-[N-ethyl-N-(3-isobutoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IB) (4). Compound 13e was synthesized via a simple route from 11, a methyl ester precursor of 4. Because 11 possesses high electrophilic reactivity because of the amino and alkoxy groups, it was readily transformed to 12 by iodization, and the iodine atom of 12 was converted to a C-C or C-N bond by means of palladium-catalyzed reaction to afford 13. Transcriptional activation assay revealed that 13g (in which the iodine atom was replaced with an amino group) is a weak RXR agonist, while 13d (a phenyl group), 13e (a styryl group), and 13f (an anilino group) are RXR antagonists. Among them, 13e was found to be more potent than the known RXR antagonist PA452 (9).

2-Isopropyl-5-methylcyclohexyl diphenylphosphonamidate

In the title compound, C22H30NO2P, the P atom has an irregular tetra­hedral geometry. In the crystal, mol­ecules are connected by N—H⋯O hydrogen-bonding inter­actions, giving rise to a chain along the b axis. The phenyl ring of the anilino group is twisted by 77.40 (16)° relative to the other phenyl ring. The absolute configuration of phospho­rus is S p.

Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2)

The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(E-oct-4-en-4-yl)-1-phenylamino-2-phenyl-cis-bicyclo[3.3.0]oct-2-ene 5 is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or 1-ethenyl group were designed, synthesized, and tested for activity in a peptide recruitment assay. Both new classes gave very active compounds, particularly against SF-1. Structure-activity studies led to excellent dual-LRH-1/SF-1 agonists (e.g., RJW100) as well as compounds selective for LRH-1 (RJW101) and SF-1 (RJW102 and RJW103). The series based on 1-ethenyl substitution was acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on the regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes.

Correlations among molecular structures, solubilities in fluorinated media, thermal properties and absorption spectra of anthraquinone dichroic dyes with phenylthio and/or anilino groups

Attractive correlations among molecular structures, solubilities in fluorinated media, thermal properties and absorption spectra of several anthraquinone dichroic dyes with phenylthio and/or anilino groups were investigated. These dyes are classifiable into three types from the viewpoint of correlations between thermal properties and solubilities. The first group consists of hardly soluble anthraquinone dyes with the same phenylthio groups at positions 1 and 5. They have large enthalpy of fusions (94–127 kg/kJ) which induce strong interactions among dye molecules. The second group consists of dyes with two different phenylthio groups at positions 1 and 5. They have smaller enthalpy of fusions (around 60 kg/kJ) and can be solved in the cases of some combinations of phenylthio groups. The third group consists of dyes with two different phenylthio groups and one of them has a trifluoromethyl group at a meta position. They have very low enthalpy of fusions (2.8–22.8 kg/kJ) and their solubilities are very large even at low temperatures. The difference between the solubility in fluorinated liquid crystals and in fluorinated solvents suggests that dyes in liquid crystal phase have specific solvation forms that are different from those in isotropic phase.

Metal Cation Induced Modulation of the Photophysical Properties of a Platinum(II) Complex Featuring a Dipicolylanilino–Acetylide Ligand

AbstractWe report the synthesis of a new, luminescent, cyclometalated platinum complex 1 incorporating a bis(2‐picolyl)anilino (DPA) group. The complex has the form LPt–C≡C–C6H4–N(CH2py)2, where L is a CNN‐coordinating ligand based on phenylbipyridine. The ground‐state absorption and excited‐state luminescence of complex 1 are modulated by the binding of selected divalent metal ions (Zn2+, Cd2+, Ni2+, and Pb2+) to the DPA unit; the extent of the observed changes are dependent upon the identity of the metal ion. In particular, binding of Zn2+ leads to a substantial enhancement in the emission intensity.

Gaining Control: Direct Suzuki Arylation of Dihydroazulenes and Tuning of Photo‐ and Thermochromism

AbstractA protocol for functionalizing the seven‐membered ring of the DHA/VHF photochromic system via a Suzuki cross‐coupling was developed. Kinetic studies reveal that direct attachment of an aromatic moiety on the seven‐membered ring strongly affects the thermal back reaction. By the introduction of an anilino group, pH control of both the photochromic and thermochromic properties was obtained. Furthermore, it was possible to switch between three different states: two photochromic and one thermochromic.

Controlled-Access Hollow Mechanized Silica Nanocontainers

A new category of mechanized nanoparticles, consisting of a hollow mesoporous silica spherical framework controlled by a supramolecular system containing the alpha-cyclodextrin (alpha-CD) ring on a stalk that is tethered to the pore openings on the nanosphere, is synthesized and tested. Construction of the nanovalve relies on the hydrogen-bonding interaction between alpha-CD and the stalk. The stalk is bonded to the nanoparticle chemically and contains an anilino group that is located on the end of the linker molecule that is closest to the pore entrance. When the alpha-CD ring is complexed with the stalk at neutral pH, the bulky cyclic component is located near the pore openings, thereby blocking departure of cargo molecules that were loaded in the nanopores and hollow interior of the particle. Protonation of the nitrogen atoms at lower pH causes the binding affinity to decrease, releasing the alpha-CD and allowing the cargo molecules to escape. The properties of this newly designed pH-responsive nanovalve are compared to those of conventional mesoporous silica nanoparticles. The on-command pH-activated release is measured using luminescence spectroscopy. The effect of different stalk lengths and pH conditions on the release of fluorescent dye cargo molecules is measured.

Discovery of substituted 4-anilino-2-arylpyrimidines as a new series of apoptosis inducers using a cell- and caspase-based high throughput screening assay. 2. Structure–activity relationships of the 2-aryl group

As a continuation of our efforts to discover and develop the apoptosis inducing 4-anilino-2-(2-pyridyl)pyrimidines as potential anticancer agents, we explored replacing the 2-pyridyl group by other aryl groups. SAR studies showed that the 2-pyridyl group can be replaced by a 3-pyridyl, 4-pyridyl and 2-pyrazinyl group, and that the SAR for the anilino group was similar to that of the 2-pyridyl series. However, replacement of the 2-pyridyl group by a phenyl group, a 3,5-dichloro-4-pyridyl group, or a saturated ring led to inactive compounds. Several potent compounds, including 2f, 3d, 3j and 4a, with EC 50 values of 0.048–0.024 μM in the apoptosis induction assay against T47D cells, were identified through the SAR studies. In a tubulin polymerization assay, compound 2f, which was active against all the three cell lines tested (T47D, HTC116 and SNU398), inhibited tubulin polymerization with an IC 50 value of 0.5 μM, while compound 2a, which was active against T47D cells but not active against HTC116 and SNU398 cells, was not active in the tubulin assay at up to 50 μM.

Squaraines as Reporter Units: Insights into their Photophysics, Protonation, and Metal‐Ion Coordination Behaviour

The synthesis, photophysical properties, protonation, and metal-ion coordination features of a family of nine aniline-based symmetrical squaraine derivatives are reported. The squaraine scaffold displays very attractive photophysical properties for a signalling unit. These dyes show absorption and weakly Stokes-shifted, mirror-image-shaped emission bands in the visible spectral range and there are no hints of multiple emission bands. The mono-exponential fluorescence decay kinetics observed for all the derivatives indicate that only one excited state is involved in the emission. These data stress the interpretation that squaraines can be regarded as polymethine-type dyes. From a coordination chemistry point of view, the squaraines possess four potential binding sites; that is, two nitrogen atoms from the anilino groups and two oxygen atoms from the central C(4)O(2) four-membered ring. These coordination sites are part of a cross-conjugated pi-system and coordination events with protons or certain metal ions affect the electronic properties of the delocalised pi-system dramatically, resulting in a rich modulation of the colour of the squaraines. The absorption band at around 640 nm is blue-shifted when coordination at the anilino nitrogen atoms occurs, whereas coordination to the C(2)O(4) oxygen atoms results in the development of red-shifted bands. Addition of more than one equivalent of protons or metal cations could additionally entail mixed N,O- or N,N-coordinated complexes, manifested in the development of a broad band at 480 nm or complete bleaching in the visible range, respectively. Analysis of the spectrophotometric titration data with HYPERQUAD yielded the macroscopic and microscopic stability constants of the complexes. Theoretical modelling of the various protonated species by molecular mechanics methods and consideration of some of the title dyes within the framework of molecular chemosensing and molecular-scale "logic gates" complement this contribution.

Characterization of the binding of 8-anilinonaphthalene sulfonate to rat class Mu GST M1-1

Molecular docking and ANS-displacement experiments indicated that 8-anilinonaphthalene sulfonate (ANS) binds the hydrophobic site (H-site) in the active site of dimeric class Mu rGST M1-1. The naphthalene moiety provides most of the van der Waals contacts at the ANS-binding interface while the anilino group is able to sample different rotamers. The energetics of ANS binding were studied by isothermal titration calorimetry (ITC) over the temperature range of 5–30 °C. Binding is both enthalpically and entropically driven and displays a stoichiometry of one ANS molecule per subunit (or H-site). ANS binding is linked to the uptake of 0.5 protons at pH 6.5. Enthalpy of binding depends linearly upon temperature yielding a Δ C p of − 80 ± 4 cal K − 1 mol − 1 indicating the burial of solvent-exposed nonpolar surface area upon ANS-protein complex formation. While ion-pair interactions between the sulfonate moiety of ANS and protein cationic groups may be significant for other ANS-binding proteins, the binding of ANS to rGST M1-1 is primarily hydrophobic in origin. The binding properties are compared with those of other GSTs and ANS-binding proteins.

Ditopic N-Crowned 4-(p-Aminophenyl)-2,6-diphenylpyridines: Implications of Macrocycle Topology on the Spectroscopic Properties, Cation Complexation, and Differential Anion Responses

A family of N-crowned 4-p-(aminophenyl)-2,6-diphenylpyridines DA (1-6) has been synthezised, characterized, and studied as potential hosts for the signaling of cationic and anionic guests. The ditopic probes contain two coordination sites, a monodentate 2,6-diphenylpyridine and an anilino group with macrocycles of different ring size, denticity, and type of secondary heteroatom (O and/or S). X-ray structure analysis of aza-oxa-thia-crowned 5 indicated a largely planar chromophore. Optical spectroscopic and electrochemical studies revealed that the anilino-type donor (D) and the 2,6-diphenylpyridine acceptor (A) are strongly pi-conjugated, entailing intense intramolecular charge-transfer absorption bands at 340 nm. Binding studies with protons and metal ions (M = Cu2+, Zn2+, Hg2+, Fe3+, Pb2+, Ni2+, Cd2+) showed shifts of the band to the visible (440 nm) when coordination at the pyridine group occurs, strengthening its acceptor character. In contrast, no band in the visible is formed if binding takes place at the anilino group. Three different responses were found for various pairs of DA and M: selective metal coordination to D or A as well as coordination at both sites. A selective response was found for 5 and Hg2+. Because of the multitude of coordination-induced effects, the DA-M ensembles were further employed for differential anion sensing. In this protocol, the addition of an anion X to a certain, weakly coordinated DA-M can (i) lead to the formation of a ternary ion pair complex (DA-M-X), (ii) change the preference for A or D coordination, (iii) induce dissociation of the complex, or (iv) can have no effect. Various patterns of absorption changes were obtained as a result of different responses (i)-(iv) of the DA-M's in the presence of various X's. Data analysis yielded recognition patterns for acetate, F- and CN-, demonstrating the potential of simple chromogenic host-guest pairs for differential anion signaling.

Electronic excitations in anti-aromatic dehydro[12]- and aromatic dehydro[18]annulenes: a time-dependent density functional theory study

The excited states of 12 and 18 dehydroannulenes have been studied using time-dependent density functional theory (TD-DFT). These compounds undergo intense intramolecular charge transfer between the terminal anilino groups and the central all-carbon core. The main geometric changes taking place on excitation are an increase in the C=C bond length and an increase in the adjacent C–C single bond. Protonation of the anilino groups causes only localized changes in the geometry but extensive changes in the excitation energies. The calculated transition energies and the shift in the absorption spectra upon protonation show a good qualitative agreement with the absorption spectra. The greater intensity of the absorption band in the aromatic 18annulene can be attributed to contributions from two degenerate excited electronic states rather than aromatic/anti-aromatic effects.

Synthesis and antitumor evaluation of novel 5-substituted-4-hydroxy-8-nitroquinazolines as EGFR signaling-targeted inhibitors

The synthesis and biological activity of a series of novel 5-substituted-4-hydroxy-8-nitroquinazolines that may function as inhibitors of EGFR- and/or ErbB-2-related oncogenic signaling are described. These compounds were prepared by S NAr reaction of 5-chloro-4-hydroxy-8-nitroquinazoline with alkyl or aryl amines, or alkyl alcohol as nucleophiles. Although the enzyme assay showed a weak inhibition effect against both EGFR and ErbB-2 tyrosine kinases, the cell-based antitumor activity turned out promising. Compounds having 5-anilino substituent exhibit high potency with 5-(4-methoxy)anilino-4-hydroxy-8-nitroquinazoline ( 1h) being the best dual EGFR/ErbB-2 inhibitors, which effectively inhibited the growth of both EGFR (MDA-MB-468, IC 50 < 0.01 μM) and ErbB-2 (SK-BR-3, IC 50 = 13 μM) overexpressing human tumor cell lines in vitro. More interestingly, the variation of the substituent(s) at the 3- and/or 4-position of the 5-anilino portion was found to modulate the selectivity and potency dramatically. However, compounds having an alkylamino or alkyloxy group at the 5-position of 4-hydroxy-8-nitroquinazolines are essentially inactive. These results are consistent with molecular modeling observations. This study was the first attempt to identify new structural types of dual EGFR/ErbB-2-related signaling inhibitors by incorporation of the anilino group at the 5-position of 4-hydroxy-8-nitroquinazolines’ core structure, providing promising new templates for further development of potent inhibitors targeting both EGFR and ErbB-2 tyrosine kinases.

Efficient Unimolecular Deprotonation of Aniline Radical Cations

[reaction: see text] Deprotonation of the radical cations of aromatic amines, such as anilines, generally occurs much more slowly than other fragmentation reactions. Here we report a stereoelectronic effect involving twisting of the anilino group out of the plane of the benzene ring that results in a significantly increased rate of reactivity toward deprotonation. Quantitative studies of the rate constants for deprotonation as a function of aniline radical cation pKa (Brønsted plots) demonstrate that the effect is not simply due to a change in the reaction thermodynamics. By combining this stereoelectronic effect with covalent attachment of carboxylate as a base, aniline radical cations that undergo unimolecular deprotonation with rate constants as high as 10(8) s(-1), even in unfavorable protic media, are described.

Photochemistry of Kynurenine, a Tryptophan Metabolite: Properties of the Triplet State

Photolysis of aqueous kynurenine (KN) solutions results in the formation of triplet kynurenine TKN. In low pH solutions, triplet formation occurs with almost 100% efficiency, while in neutral solutions the triplet quantum yield is PhiT = 0.018 +/- 0.004. The dissociation constant of TKN, which is attributed to deprotonation of the anilino group, has a pKa value of 4.7. Similar triplet absorption spectra were obtained under direct and acetone-sensitized photolysis. The large difference in quantum yields as a function of pH is attributed to excited-state properties of the first excited singlet state of KN. The rate constant quenching for TKN by oxygen is kq = 2 x 10(9) M(-1) s(-1).

Semi-empirical infrared spectra simulations of metal complexes of sulfanilamide

The infrared spectra for Co and Cd complexes of sulfanilamide are studied by PM3 method. It has been found that the proposed structures for these compounds derived from IR spectra and X-ray powder diffraction patterns are consistent with the IR spectra simulated by PM3 method. The band assignments on the basis of the 3D dynamic image of the vibrations corresponding to significant modes have also given. Coordination effects on vibrational modes of anilino and sulfonamido groups of sulfanilamide are in close agreement with the observed results.

Bis-4-aminoquinolines: novel triple-helix DNA intercalators and antagonists of immunostimulatory CpG-oligodeoxynucleotides

Six dimeric 2-(2-naphthyl)quinolin-4-amines with a linker between the amino groups and eight dimeric 2-(4-anilino)quinolin-4-amines linked between the anilino groups were synthesized and evaluated for their interaction with duplex/triplex DNA's and as antagonists of immunostimulatory oligodeoxynucleotides with a CpG-motif (CpG-ODN). The most powerful triple-helix DNA intercalator known to date, with high affinity toward T·A·T triplets and triplex/duplex selectivity, was found. The potent antagonism of immunostimulatory CpG-ODN by several bis-4-aminoquinolines is not related to their DNA interactions.

Dual Fluorescence and Excited-State Structural Relaxations in Donor−Acceptor Stilbenes

The time-resolved fluorescence behavior of two derivatives of 4-(dimethylamino)-4‘-cyanostilbene (DCS) bearing a more voluminous (JCS) and less voluminous anilino group (ACS) was investigated in ethanol by reconstructing the emission spectra using picosecond time-resolved single-photon-counting technique. For JCS, these spectra exhibit a temporary isosbestic point, a clear indication of level dynamics between two emitting excited singlet states (LE and CT). Kinetic evaluation yielded a precursor−successor relationship between LE and CT and CT formation time constants of 4 ps for ACS and 8 ps for JCS. This slowing of the reaction for the compound with the larger volume of the donor moiety supports the assumption of a twisting mechanism being a major component of the reaction coordinate. An additional transient red shift of the CT band is observed for both compounds and follows the relatively slow solvation dynamics (ethanol).

Reversal of the Intramolecular Charge Transfer in p-Dimethylaminobenzanilides by Amido Anilino Substitution

p-Dimethylaminobenzanilides with a para or meta substituent at the amido anilino moiety were designed to generate a series of dual fluorescent molecules of variable electron acceptors. Ab initio calculations indicated that the anilino substitution did not lead to an obvious change in the ground-state structures of the fluorophores, and the 1H NMR signal of the amido −NH proton was found to experience a linear downfield shift with increasing σ of the substitutent, supporting the fact that the amido anilino moiety was indeed varied comparably by the substitution. The intramolecular charge transfer dual fluorescence was indeed observed in solvents over a large polarity range from the nonpolar cyclohexane (CHX) through diethyl ether (DEE) and tetrahydrofuran (THF) to highly polar acetonitrile (ACN). It was found that the CT emission shifted to the blue with increasing electron-withdrawing ability of the amido anilino substituent up to a Hammett constant σ of ca. +0.39 and to the red at higher σ. The solvent polarity variation did not change the σ value at which the CT emission shift direction reverses. Similar variation profiles were also observed with the CT to LE emission intensity ratio and the total fluorescence quantum yield. It was concluded that the CT direction in p-dimethylaminobenzanilides was reversed by the amido anilino substitution, and the CT occurs from amido anilino to benzoyl moiety at low σ, whereas at high σ, the CT switches to that from dimethylamino to the benzanilide moiety, which was also supported from the Hartree−Fock calculations. This finding provides an alternative method based on substitutent effect for identifying the charge-transfer direction in multiple charge-transfer systems. The results suggested that the anilino group could be a much stronger electron donor than an aliphatic amino group, which would be of use in designing electron donor substituted molecules. In both cases the dependences of the CT emission energy against σ of the substituent at the amido aniline phenyl ring were found to be much stronger than that in the ester counterparts of p-dimethylaminobenzanilides. This interesting σ dependence in the CT emission would be of significance in developing new fluorescent sensors based on electron donor/acceptor variations in p-dimethylaminobenzanilides.

Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor.

Aberrant control of cyclin-dependent kinases (CDKs) is a central feature of the molecular pathology of cancer. Iterative structure-based design was used to optimize the ATP- competitive inhibition of CDK1 and CDK2 by O(6)-cyclohexylmethylguanines, resulting in O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino)purine. The new inhibitor is 1,000-fold more potent than the parent compound (K(i) values for CDK1 = 9 nM and CDK2 = 6 nM versus 5,000 nM and 12,000 nM, respectively, for O(6)-cyclohexylmethylguanine). The increased potency arises primarily from the formation of two additional hydrogen bonds between the inhibitor and Asp 86 of CDK2, which facilitate optimum hydrophobic packing of the anilino group with the specificity surface of CDK2. Cellular studies with O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino) purine demonstrated inhibition of MCF-7 cell growth and target protein phosphorylation, consistent with CDK1 and CDK2 inhibition. The work represents the first successful iterative synthesis of a potent CDK inhibitor based on the structure of fully activated CDK2-cyclin A. Furthermore, the potency of O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino)purine was both predicted and fully rationalized on the basis of protein-ligand interactions.