Konstantinos Skobridis

Specific entrapment of methanol and dimethyl sulphoxide (DMSO) by a simple host compound (triphenylmethanol). Crystal structures of the Ph3COH·MeOH (1 : 1) and Ph3COH·DMSO (2 : 1) clathrate inclusion complexes

Triphenylmethanol (1) is shown to be a specific clathrate host for methanol and dimethyl sulphoxide; host–guest interaction schemes in the two crystalline inclusion complexes are discussed.

Novel Imatinib Derivatives with Altered Specificity between Bcr–Abl and FMS, KIT, and PDGF Receptors

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.

Complexation with diol host compounds. Part 11. Structures and thermal analyses of the inclusion compounds of 4,4′-bis(diphenylhydroxymethyl)biphenyl, C38H30O2, with acetone, acetophenone, 1,4-dioxane and p-xylene

Structures of the inclusion compounds of 4,4′-bis(diphenylhydroxymethyl)biphenyl with acetone (1), acetophenone (2), 1,4-dioxane (3) and p-xylene (4) have been determined. Crystal data: 1; C38H30O2·2C3H6O, Mr= 634.81 g mol–1, orthorhombic, Pna21, a= 29.169(6), b= 8.046(1), c= 15.235(2)A, V= 3576(1)A3, Z= 4, Dm= 1.17(3) g cm–3, Dc= 1.18 g cm–3, λ(Mo-Kα)= 0.710 69 A, µ= 0.39 cm–1, F(000)= 1316.2; C38H30O2·2C8H8O, triclinic, P, Mr= 758.95 g mol–1, a= 8.005(6), b= 11.464(3), c= 12.338(3)A, α= 85.14(2), β= 76.89(4), γ= 73.71(4)°, V= 1058(1)A3, Z= 1, Dm= 1.17(2) g cm–3, Dc= 1.19 g cm–3, λ(Mo-Kα)= 0.71069 A, µ= 0.40 cm–1, F(000)= 402. 3; C38H30O2·2C4H8O2, Mr= 654.80 g mol–1, monoclinic, P21/n, a= 9.434(2), b= 14.152(5), c= 14.503(1), β= 105.36(1)°, V= 1866(1)A3, Z= 2, Dm= 1.20(2) g cm–3, Dc= 1.22 g cm–3, λ(Mo-Kα)= 0.71069 A, µ= 0.44 cm–1, F(000)= 836. 4; C38H30O2·1.75C8H10, Mr= 1408.89 g mol–1, monoclinic, P21/n, a= 20.354(3), b= 21.142(4), c= 21.327(4)A, β= 117.92(1)°, V= 8109(3)A3, Z= 8, Dm= 1.15(2) g cm–3, Dc= 1.15 g cm–3, λ(Mo-Kα)= 0.710 69 A, µ= 0.71 cm–1, F(000)= 3004. Depending on the host–guest interaction, they are H-bonded coordinatoclathrates in the case of 1–3 and a true clathrate type of inclusion compound in the case of 4 with H-bonded tetramer clusters of host molecules forming the inclusions matrix. The thermal decompositions of the compounds have been studied. Compound 1 contains acetone molecules in two different binding states, one being more strongly bound than the other giving two individual endotherms. Phase transitions before the melting point occur in compounds 1,3 and 4. Compound 2 shows no melting point because of dissolution of the host compound in the released guest.

Factor-inhibiting HIF-1 (FIH-1) is required for human vascular endothelial cell survival

Factor‐inhibiting hypoxia‐inducible factor (HIF)‐1 (FIH‐1) is an asparaginyl β‐hydroxylase enzyme that was initially found to hydroxylate the HIF‐α, preventing its transcriptional activity and leading to adaptive responses to hypoxia. More recently, other substrates, such as neurogenic locus notch homolog (Notch), have been found to be alternative FIH targets, but the biologic relevance of this regulation was never investigated. Given the key function of Notch in angiogenesis, we here investigate the role of FIH/Notch signaling in endothelial cells. We report that FIH‐1 silencing in HUVECs results in reduced growth and increased apoptosis. The knockdown of FIH is associated with increased Notch2 activity, leading to enhanced expression of the Notch target hairy/enhancer‐of‐split related with YRPW motif protein 1 (Hey‐1). Consistent with recent findings showing that Notch2 suppresses survivin (a key inhibitor of apoptosis), FIH targeting in HUVECs leads to selective repression of survivin in endothelial cells, thus promoting cell apoptosis and growth arrest. Our data support the concept that FIH‐1 may interact with Notch2 and repress its activity, thereby playing a critical role in controlling the survival of vascular endothelial cells. These findings might pave the way toward novel, antiangiogenic strategies in disorders that are characterized by excessive vascular growth, such as cancer and rheumatoid arthritis.—Kiriakidis, S., Henze, A.‐T., Kruszynska‐Ziaja, I., Skobridis, K., Theodorou, V., Paleolog, E. M., Mazzone, M. Factor‐inhibiting HIF‐1 (FIH‐1) is required for human vascular endothelial cell survival. FASEB J. 29, 2814‐2827 (2015). www.fasebj.org

Synthetic methodologies in organic chemistry involving incorporation of [17O] and [18O] isotopes

This review is a critical survey of the literature that aims to highlight the most significant developments on synthetic strategies involving stable oxygen isotopes ([(17)O] and [(18)O]). The labeling methodologies are categorized in groups, according to the oxygen-containing functional group.

Triarylmethanol Host Compounds. Synthesis, Crystalline Complex Formation and X-Ray Crystal Structures of Three Inclusion Species

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.Supplementary data relating to this article have beendeposited with the British Library, No. SUP 82226 (10 pages).at Boston Spa, Wetherby, West Yorkshire, U.K., as Supplementary Publication.

Complexation with hydroxy host compounds. Part. 4. Structures and thermal stabilities of inclusion compounds with dioxane as the guest

Structures of the inclusion compounds of five hydroxy-containing hosts with dioxane have been solved. Crystal data: 1, monoclinic, C2/c, a= 8.648(1)A, b= 16.551(1)A, c= 17.038(4)A, β= 90°, V= 2398.64 A3, Z= 4; 2, triclinic, P, a= 8.441 (8)A, b= 10.544(2)A, c= 11.562(2)A, α=67.47(1)°, β= 83.96(5)°, γ= 89.08(5)°, V= 944.94 A3, Z= 2; 3, triclinic, P, a= 9.378(7)A, b= 11.851 (2)A, c= 14.891 (2)A, α= 87.85(1)°, β= 81.05(1)°, γ= 87.65(1)°, V= 1632.77 A3, Z= 1; 4, triclinic, P, a= 9.298(4)A, b= 12.577(9)A, c= 12.859(6)A, α= 115.63(5)°, β= 90.99(3)°, γ= 92.34(5)°, V= 1353.51 A3, Z= 2; 5, triclinic, P, a= 8.8337(1)A, b= 8.646(3)A, c= 11.700(3)A, α= 108.22(25)°, β= 94.22(2)°, γ=99.82(2)°, V= 781.52 A3, Z= 1. Host–guest hydrogen bonds are observed in all structures and a host–host hydrogen bond in structure 3. O ⋯ O distances are between 2.703 and 2.865 A. Thermal analysis revealed the strength of binding of the dioxane molecules. The energy of the guest molecules was evaluated using the method of atom–atom potentials. A correlation was observed between the minimum energy of the guest molecule and the enthalpy of the guest release reaction for 1–4.

Crystalline Complexes of 2,2'-Bis(9-hydroxy-9-fluorenyl)biphenyl Host with Oligofunctional and Conjugate Functional Group Guests

Four crystalline inclusion compounds of the 2,2′-bis(9-hydroxy-9-fluorenyl)biphenyl host 1, containing diethylene glycol (1:1) (1a), bis(2-aminoethyl)amine (1:1) (1b), methacrylic acid (1:1) (1c) and 2-cyclopenten-1-one (1:2) (1d), have been studied by X-ray diffraction analysis from single crystals. Departure from the expectation, the multifunctional and conjugate functional guest molecules, potentially being able to offer multiple H donor-/acceptorships or other modes of polar interaction due to the conjugation, do not result in the formation of infinitely connected networks in the crystal structures. Instead of this, discrete 2:2 host–guest aggregates (1a, 1b), guest dimers (1c) and rather conventional host–guest units (1d) are found. Hence, inherent shielding effects of the host molecule owing to the fluorenyl moieties and the presence of a strong intramolecular hydrogen bond, impeding multiple intermolecular association, are not overcome by the merits of the guest molecules, showing that the host compound 1 is superior by structural constancy in its crystalline inclusions.

Aspects of crystal engineering arising from packing behavior of functional mono para-substituted trityl compounds

Four trityl compounds differing both in the functional group (OH, OMe, NH2) at the specific trityl carbon and a para substituent, being bromine or phenyl at one of the phenyl groups, have been prepared and structurally studied by means of single crystal X-ray diffraction and making use of Hirshfeld surface analysis. Compared to the structures of corresponding prototypes and analogues, specific interaction modes and packing motifs including cluster aggregates as well as non-cluster type structures depending on the substitution and involving polymorphism were found, opening potential trend prediction with reference to crystal engineering being useful in this compound class.

Proteome Changes Induced by Imatinib and Novel Imatinib Derivatives in K562 Human Chronic Myeloid Leukemia Cells

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.