Local production of active vitamin D3 metabolites in breast cancer cells by CYP24A1 and CYP27B1.

The role of vitamin D3 and its metabolites in cancer and especially as a treatment option has been widely disputed. Clinicians noting low serum 25-hydroxyvitamin D3 [25(OH)D3] levels in their patients, recommend vitamin D3 supplementation as a method of reducing the risk of cancer; however, data supporting this are inconsistent. These studies rely on systemic 25(OH)D3 as an indicator of hormone status, but 25(OH)D3 is further metabolized in the kidney and other tissues under regulation by several factors. This study examined if breast cancer cells also possess the ability to metabolize 25(OH)D3, and if so, whether the resulting metabolites are secreted locally; if this ability reflects ERα66 status; and if they possess vitamin D receptors (VDR). To address this question, estrogen receptor alpha (ERα) positive (MCF-7) and ERα negative (HCC38 and MDA-MB-231) breast cancer cell lines were examined for expression of ERα66, ERα36, CYP24A1, CYP27B1, and VDR as well as for local production of 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] after treatment with 25(OH)D3. The results showed that independent of ER status, breast cancer cells express the enzymes CYP24A1 and CYP27B1, which are responsible for converting 25(OH)D3 into its dihydroxylated forms. Moreover, these metabolites are produced at levels comparable to the levels observed in blood. They are positive for VDR, indicating that they can respond to 1α,25(OH)2D3, which can upregulate CYP24A1. These findings suggest that vitamin D metabolites may contribute to the tumorigenicity of breast cancer via autocrine and/or paracrine mechanisms.

Ionic Hydrogen and Halogen Bonding in the Gas Phase Association of Acetonitrile and Acetone with Halogenated Benzene Cations.

We report on the gas phase association of the small polar and aprotic solvent molecules acetonitrile (CH3CN) and acetone (CH3COCH3) with the halogenated benzene radical cations (C6H5X•+, X = F, Cl, Br, and I) using the mass-selected ion mobility technique and density functional theory calculations. The association energies (-Δ H°) of CH3CN (CH3COCH3) with C6H5F•+ and C6H5I•+ are similar [13.0 (13.3) and 13.2 (14.1) kcal/mol, respectively] but higher than those of CH3CN (CH3COCH3) with C6H5Cl•+ and C6H5Br•+ [10.5 (11.5) and 10.9 (10.6) kcal/mol, respectively]. However, the electrostatic potentials of the lowest energy structures of C6H5Br•+(CH3CN) and C6H5Br•+(CH3COCH3) or C6H5I•+(CH3CN) and C6H5I•+(CH3COCH3) complexes clearly show the formation of the ionic halogen bonds (IXBs) C-Brδ+- -NCCH3 and C-Brδ+- -OC(CH3)2 or C-Iδ+- -NCCH3 and C-Iδ+- -OC(CH3)2 driven by positively charged σ-holes on the external sides of the C-Br and C-I bond axes of the bromobenzene and iodobenzene radical cations, respectively. For the C6H5F•+(CH3CN) complex, the dominant interaction involves a T-shaped structure between the N atom of CH3CN and the C atom of the C-F bond of C6H5F•+. The structure of the C6H5Cl•+(CH3CN) complex shows the formation of unconventional ionic hydrogen bonds (uIHBs) between the N atom of CH3CN and the C-H bonds of the C6H5Cl•+ cation. Similar results are obtained for the association of acetone with the halogenated benzene radical cations. The formation of IXBs of the iodobenzene cation with acetonitrile or acetone involves a significant entropy loss (-Δ S° = 25-27 cal /(mol K)) resulting from the formation of more ordered and highly directional structures between the nitrogen or oxygen lone pair of electrons of acetonitrile or acetone, respectively, and the electropositive region around the iodine atom of the iodobenzene cation. In comparison, for the association of acetonitrile or acetone with the fluorobenzene, chlorobenzene, and bromobenzene cations, -Δ S° = 16-23 cal/(mol K), consistent with the formation of less ordered structures and loose interactions. The lowest energy structures of the C6H5Br•+(CH3COCH3)2 and C6H5I•+(CH3COCH3)2 clusters show a novel combination of ionic halogen bonding and hydrogen bonding where the oxygen atom of one acetone molecule forms the halogen bond while the oxygen atom of the second acetone molecule becomes the hydrogen acceptor from the methyl group of the first acetone molecule.

Gas phase hydration of halogenated benzene cations. Is it hydrogen or halogen bonding?

Halogen bonding (XB) non-covalent interactions can be observed in compounds containing chlorine, bromine, or iodine which can form directed close contacts of the type R1-XY-R2, where the halogen X acts as a Lewis acid and Y can be any electron donor moiety including electron lone pairs on hetero atoms such as O and N, or π electrons in olefin double bonds and aromatic conjugated systems. In this work, we present the first evidence for the formation of ionic halogen bonds (IXBs) in the hydration of bromobenzene and iodobenzene radical cations in the gas phase. We present a combined thermochemical investigation using the mass-selected ion mobility (MSIM) technique and density functional theory (DFT) calculations of the stepwise hydration of the fluoro, chloro, bromo, and iodobenzene radical cations. The binding energy associated with the formation of an IXB in the hydration of the iodobenzene cation (11.2 kcal mol-1) is about 20% higher than the typical unconventional ionic hydrogen bond (IHB) of the CHδ+OH2 interaction. The formation of an IXB in the hydration of the iodobenzene cation involves a significant entropy loss (29 cal mol-1 K-1) resulting from the formation of a more ordered structure and a highly directional interaction between the oxygen lone pair of electrons of water and the electropositive region around the iodine atom of the iodobenzene cation. In comparison, the hydration of the fluorobenzene and chlorobenzene cations where IHBs are formed, -ΔS° = 18-21 cal mol-1 K-1 consistent with the formation of less ordered structures and loose interactions. The electrostatic potentials on the lowest energy structures of the hydrated halogenated benzene radical cations show clearly that the formation of an IXB is driven by a positively charged σ-hole on the external side of the halogen atom X along the C-X bond axis. The size of the σ-hole increases significantly in bromobenzene and iodobenzene radical cations which results in strong interaction potentials with the electron lone pairs of the oxygen atom of the water molecules and thus IXBs provide the most stable hydrated structures of the bromobenzene and iodobenzene radical cations. The results clearly distinguish the hydration behaviors resulting from the ionic hydrogen and halogen bonding interactions of fluorobenzene and iodobenzene cations, respectively, and establish the different bonding and structural features of the two interactions.