[Show abstract][Hide abstract] ABSTRACT: Imatinib mesylate is the leading compound to treat chronic myeloid leukemia (CML) and other cancers, through its inhibition of Bcr-Abl tyrosine kinases. However, resistance to imatinib develops frequently, particularly in late-stage disease and has necessitated the development of new Bcr-Abl inhibitors. The synthesis of a new series of phenylaminopyrimidines, structurally related to imatinib, showed large interest since the introduction of nilotinib. Here, we compare the protein levels in K562 cells treated with either imatinib or with novel imatinib derivates. Our results revealed that among the 986 quantified proteins, 35 had significantly altered levels of expression by imatinib or its derivates. In a second series of experiments, we directly compared the proteomes of imatinib treated K562 cells with those K562 cells treated with any of the four imatinib derivates. More than 1029 protein were quantified, 80 of which had altered levels of expression. Both experiments pointed to changes in the expression of the ATP-dependent RNA helicase DDX3X and of two mitochondrial coiled-coil-helix-coiled-coil-helix domain-containing proteins.
[Show abstract][Hide abstract] ABSTRACT: The diol host compound 2 featuring a structure with two 9-fluorenol moieties attached in 3,3′-position to a biphenyl core unit has been synthesized and is shown to form crystalline inclusion complexes with organic guest molecules. Aside from the single-crystal X-ray structures of unsolvated 2 in two polymorphous forms (2A, 2B), structures of five inclusion compounds with 1,4-dioxane (2a), DMSO (2b), diethylamine (2c), acetic acid (2d), and ethyl acetate (2e) are described and comparatively discussed in the interaction behavior including corresponding host compounds with different attachment mode of the biphenyl unit and the diphenylhydroxymethyl-substituted equivalent.
[Show abstract][Hide abstract] ABSTRACT: The asymmetric unit of the title compound, C44H30O2, contains two independent mol-ecules in which the terminal rings of the terphenyl element are inclined at angles of 36.3 (1) and 22.5 (1)° with respect to the central ring and the dihedral angles between the fluorenyl units are 72.3 (1) and 62.8 (1)°. In the crystal, pairs of O-H⋯O hydrogen bonds link the mol-ecules into inversion dimers. The hy-droxy H atoms not involved in these hydrogen bonds form O-H⋯π inter-actions in which the central terphenyl rings act as acceptors. Weak C-H⋯O contacts and π-π [centroid-centroid distance = 4.088 (2) Å] stacking inter-actions also occur. Taking into account directed non-covalent bonding between the molecules, the crystal is constructed of supramolecular strands extending along the a-axis direction.
[Show abstract][Hide abstract] ABSTRACT: The formation of crystalline host–guest complexes of three constitutionally isomeric host compounds 1–3 featuring two diphenylhydroxymethyl groups attached in different positions to a biphenylylene central moiety is studied. Dependent on the connection mode (2,2′-, 3,3′-, or 4,4′-) with reference to the biphenylylene unit, a distinctly different complex behavior of the host compounds is observed. X-ray crystal structures of the solvent-free hosts are reported including a third polymorph with respect to already known polymorphous structures. The crystal structures of eight host–guest complexes of 1–3, including a pair of complexes differing only in the host/guest stoichiometry, are described and comparatively discussed covering the structures of known complex species of the isomeric hosts. Correlations between the constitutional isomerism of the host molecules and their conformational as well as packing structures in the crystalline state, both in unsolvated and solvent complexed form, are demonstrated providing potential usefulness in the future design of crystalline host–guest complexes.
[Show abstract][Hide abstract] ABSTRACT: α,β-Unsaturated acids, through their acid chlorides, react with tritylamine in the presence of triethylamine under mild conditions, to afford in high yield and high regioselectivity the corresponding β,γ-unsaturated tritylamides. Detritylation with TFA generates quantitatively β,γ-unsaturated primary amides. An investigation of this deconjugative isomerization was performed.
[Show abstract][Hide abstract] ABSTRACT: The X-ray crystallographic structures of four new inclusion compounds of the versatile clathrate host 2,2′-bis(9-hydroxy-9-fluorenyl)biphenyl (1) as well as the crystal structure of the unsolvated host are reported and comparatively discussed with regard to the molecular conformation and the modes of interactions the molecules make use of in the crystal packing. While the inclusion crystals demonstrate full saturation of the hydrogen bond capacity of the host molecule, 1 is only involved in weak intermolecular π-contacts in the solvent-free structure. We draw the conclusion that the well-tried strategy of coordinato-clathration, underlying the present inclusion compounds, should not be regarded as a strict rule with reference to the formation of inclusion crystals but a helpful framework in the search of new efficient clathrate hosts.
[Show abstract][Hide abstract] ABSTRACT: Imatinib is a clinically important ATP analogue inhibitor that targets the tyrosine kinase domain of the intracellular Abl kinase and the PDGF receptor family. Imatinib has revolutionised the treatment of chronic myeloid leukaemia, which is caused by the oncogene Bcr-Abl and certain solid tumours that harbor oncogenic mutations of the PDGF receptor family. As a leading kinase inhibitor, imatinib also provides an excellent model system to investigate how changes in drug design impact biological activity, which is an important consideration for rational drug design. Herein we report a new series of imatinib derivatives that in general have greater activity against the family of PDGF receptors and poorer activity against Abl, as a result of modifications of the phenyl and N-methylpiperazine rings. These new compounds provide a platform for further drug development against the therapeutically important PDGF receptor family and they also provide insight into the engineering of drugs with altered biological activity.
[Show abstract][Hide abstract] ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
[Show abstract][Hide abstract] ABSTRACT: An unexpected compound, the aniline derived benzophenone imine, was isolated when tritylamine was treated with n-BuLi and alkyl halides, during the formation of N-alkyl tritylamines, in the process of preparing primary amines. A nucleophilic attack of the nitrogen anion of tritylamide on the adjacent C-bonded phenyl, either substituted or not, involving a bridging anionic intermediate, is proposed for this base-induced tritylamine rearrangement to produce the corresponding imine. Electron-withdrawing groups in the aromatic ring, favoring the negative charge development, affect the relative migratory tendencies.
[Show abstract][Hide abstract] ABSTRACT: A very mild and rapid procedure for the efficient alkaline hydrolysis of esters in non-aqueous conditions has been developed, by the use of dichloromethane/methanol (9:1) as solvent. This method conveniently provides both carboxylic acids and alcohols from the corresponding esters and sodium hydroxide in a few minutes at room temperature. A plausible reaction mechanism is proposed.
Tetrahedron Letters - TETRAHEDRON LETT. 01/2007; 48(46):8230-8233.
[Show abstract][Hide abstract] ABSTRACT: The simple triarylmethanol hosts, 2 and 4, and their silicon analogues, 1 and 3, have been studied for comparison of the formation of crystalline inclusion compounds. Clathrate formation experiments showed
that replacement of the carbinol C atoms in 2 and 4 by Si atoms to give 1 and 3 resulted in a distinct increase of the capability to form inclusion compounds with organic guests, in particular with alcohols.
Moreover, the naphthyl derivatives are much more efficient than the phenyl species, irrespective of the carbinol and silanol
features. In order to investigate and compare the guest recognition modes and packing relations of hosts 1–4 in their crystalline inclusion compounds, 11 selected co-crystals, namely 1·DMSO (2:1), 3·EtOH (1:1), 3·
i-PrOH (1:1), 3·acetone (1:1), 3·DMSO (1:1), 3·THF (1:1), 3·piperidine (1:1), 4·acetone (1:1), 4·DMSO (1:1), 4·1,4-dioxane (1:1) and 4·benzene (1:1), were studied by X-ray diffraction from single crystals. The survey contains additional 11 crystal structures
from the literature and provides a detailed discussion of isostructurality relationships.
Journal of Inclusion Phenomena 05/2006; 55(1):131-149. · 1.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A series of new clathrate host molecules 1 – 8 containing two bis(diarylhydroxymethyl) groups attached to different positions (2,2′ or 8,8′) of a 1,1′-binaphthyl frame have been synthesized. Their clathrate formation properties with organic guests including alcohols, amines, ketones, and other dipolar aprotic compounds or aromatic hydrocarbons are reported (74 examples of clathrates) together with the results of solvent competition experiments for the parent host compound. The inclusion formation and the clathrate stoichiometries depend on the structure of the host molecules in a systematic manner. The crystal structures of the free parent host 1 and its pyridine clathrate (1 : 3) have been determined by X-ray diffraction. The molecular structure of the host is similar in the two species involving an intramolecular hydrogen bond between the host hydroxyls. No other hydrogen bond is involved in the free host case while in the pyridine inclusion compound the second host hydroxyl forms a hydrogen bond with the nitrogen of one pyridine guest which is surrounded by two unbound pyridine species such as to form clusters of three pyridine guests enclosed in the cavities between the host molecules. Thermal analysis corresponds with the two binding states of the pyridine molecules in the clathrate.
Berichte der deutschen chemischen Gesellschaft 01/2006; 126(5):1141 - 1148. · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An efficient and facile air oxidation of benzoins in the presence of the heterogeneous catalyst aluminum oxide, avoiding the use of noxious metal compounds as oxidizing agents has been developed. It thus constitutes a very simple, environmentally friendly, clean, economical and selective method for the aerobic preparation of benzils from the corresponding benzoins.
[Show abstract][Hide abstract] ABSTRACT: The crystal structures of the inclusion compounds of 4,4‘-bis(diphenylhydroxymethyl)diphenyl with 3- and 4-picolines were elucidated. The selectivity of enclathration is concentration dependent. The 4-picoline inclusion compound undergoes a phase transition between 235 and 240 K. The transition is second order with no change in volume and is accompanied by a small change in the host conformation.
[Show abstract][Hide abstract] ABSTRACT: A variety of triarylmethanol compounds including benzo condensed and laterally substituted derivatives 1–10 have been prepared and shown to act as crystallinehosts for the inclusion of organic solvents involving protic polar, aprotic dipolar and apolar molecules. The inclusion ability is ratherhigh for aprotic dipolar solvents while protic polarcompounds are only rarely enclathrated. Host 9 is an exception, being also efficient with alcohols and amines. Compound3 displays no inclusion formation under theexperimental conditions. X-ray crystal structures of the inclusion compound 1·acetone (2:1) and of two amineinclusion compounds of host 9 [9· n-propylamine(1:1), 9·di-n-propylamine (1:1)] are reported showing the formation of H-bondedhost-guest associates as the common feature of supramolecular association.
Journal of Inclusion Phenomena 01/1997; 28(2):163-179. · 1.40 Impact Factor