Diverse strategies for the preparation of mixed-metal three-dimensional porous solids abound, although many of them lend themselves only moderate levels of tunability. Herein, we report the design ...and synthesis of surface functionalized permanently microporous coordination cages and their use in the isolation of mixed metal solids. Judicious alkoxide-based ligand functionalization was utilized to tune the solubility of starting copper(
ii
)-based cages and their resulting compatibility with the mixed-cage approach described here. We further prepared a family of isostructural molybdenum(
ii
) cages for a subset of the ligands. The preparation of mixed-metal cage solids proceeds under facile conditions where solutions of parent cages are mixed and product phases isolated. A suite of spectroscopic and characterization tools confirm the starting cages are intact in the amorphous product. Finally, we show that utilization of precise ligand functional groups can be used to prepare mixed cage solids that can be easily and cleanly separated into their constituent components through simple solvent washing or solvent extraction techniques.
Surface-functionalized porous coordination cages can be used to create homogeneous mixed-cage alloys with high levels of tunability and processability.
Coordination assemblies containing transition-metal cations with coordinatively unsaturated sites remain a challenging target in the synthesis of porous molecules. Herein, we report the design, ...synthesis, and characterization of three porous hybrid inorganic/organic porous molecular assemblies based on cobalt(II) and nickel(II). Precise tuning of ligand functionalization allows for the isolation of molecular species in addition to two- and three-dimensional metal–organic frameworks. The cobaltous and nickelous cage compounds display excellent thermal stabilities in excess of 473 K and Brunauer–Emmett–Teller surface areas on the order of 200 m2/g. The precise ligand functionalization utilized here to control phases between discrete molecules and higher-dimensional solids can potentially further be tuned to optimize the porosity and solubility in future molecular systems.
An iron(II)-based metal–organic framework featuring coordinatively unsaturated redox-active metal cation sites, Fe2(dobdc) (dobdc4– = 2,5-dioxido-1,4-benzenedicarboxylate), is shown to strongly bind ...nitric oxide at 298 K. Adsorption isotherms indicate an adsorption capacity greater than 16 wt %, corresponding to the adsorption of one NO molecule per iron center. Infrared, UV–vis, and Mössbauer spectroscopies, together with magnetic susceptibility data, confirm the strong binding is a result of electron transfer from the FeII sites to form FeIII–NO– adducts. Consistent with these results, powder neutron diffraction experiments indicate that NO is bound to the iron centers of the framework with an Fe–NO separation of 1.77(1) Å and an Fe–N–O angle of 150.9(5)°. The nitric oxide-containing material, Fe2(NO)2(dobdc), steadily releases bound NO under humid conditions over the course of more than 10 days, suggesting it, and potential future iron(II)-based metal–organic frameworks, are good candidates for certain biomedical applications.
.
A structure–activity relationship study of dorsomorphin, a previously identified inhibitor of SMAD 1/5/8 phosphorylation by bone morphogenetic protein (BMP) type 1 receptors ALK2, 3, and 6, ...revealed that increased inhibitory activity could be accomplished by replacing the pendent 4-pyridine ring with 4-quinoline. The activity contributions of various nitrogen atoms in the core pyrazolo1,5-
apyrimidine ring were also examined by preparing and evaluating pyrrolo1,2-
apyrimidine and pyrazolo1,5-
apyridine derivatives. In addition, increased mouse liver microsome stability was achieved by replacing the ether substituent on the pendent phenyl ring with piperazine. Finally, an optimized compound
13 (LDN-193189 or DM-3189) demonstrated moderate pharmacokinetic characteristics (e.g., plasma
t
1/2
=
1.6
h) following intraperitoneal administration in mice. These studies provide useful molecular probes for examining the in vivo pharmacology of BMP signaling inhibition.
Sudden cardiac arrest (CA) is one of the leading causes of death worldwide. We sought to evaluate the impact of hydrogen sulfide (H(2)S) on the outcome after CA and cardiopulmonary resuscitation ...(CPR) in mouse.
Mice were subjected to 8 minutes of normothermic CA and resuscitated with chest compression and mechanical ventilation. Seven minutes after the onset of CA (1 minute before CPR), mice received sodium sulfide (Na(2)S) (0.55 mg/kg IV) or vehicle 1 minute before CPR. There was no difference in the rate of return of spontaneous circulation, CPR time to return of spontaneous circulation, and left ventricular function at return of spontaneous circulation between groups. Administration of Na(2)S 1 minute before CPR markedly improved survival rate at 24 hours after CPR (15/15) compared with vehicle (10/26; P=0.0001 versus Na(2)S). Administration of Na(2)S prevented CA/CPR-induced oxidative stress and ameliorated left ventricular and neurological dysfunction 24 hours after CPR. Delayed administration of Na(2)S at 10 minutes after CPR did not improve outcomes after CA/CPR. Cardioprotective effects of Na(2)S were confirmed in isolated-perfused mouse hearts subjected to global ischemia and reperfusion. Cardiomyocyte-specific overexpression of cystathionine gamma-lyase (an enzyme that produces H(2)S) markedly improved outcomes of CA/CPR. Na(2)S increased phosphorylation of nitric oxide synthase 3 in left ventricle and brain cortex, increased serum nitrite/nitrate levels, and attenuated CA-induced mitochondrial injury and cell death. Nitric oxide synthase 3 deficiency abrogated the protective effects of Na(2)S on the outcome of CA/CPR.
These results suggest that administration of Na(2)S at the time of CPR improves outcome after CA possibly via a nitric oxide synthase 3-dependent signaling pathway.
A Mn(iv) complex featuring a terminal oxo ligand, Mn
(O)(ditox)
K(15-C-5)
(
; ditox =
Bu
MeCO
, 15-C-5 = 15-crown-5-ether) has been isolated and structurally characterized. Treatment of the ...colorless precursor Mn
(ditox)
K(15-C-5)
(
) with iodosobenzene affords
as a green free-flowing powder in high yields. The X-ray crystal structure of
reveals a pseudotetrahedral geometry about the central Mn, which features a terminal oxo (
(Mn-O
= 1.628(2) Å)). EPR spectroscopy, SQUID magnetometry, and Evans method magnetic susceptibility indicate that
consists of a high-spin
= 3/2 Mn(iv) metal center.
promotes C-H bond activation by a hydrogen atom abstraction. The Mn
(O)(ditox)
furnishes a model for the proposed terminal oxo of the unique manganese of the oxygen evolving complex of photosystem II.
A subset of coordination cages have garnered considerable recent attention for their potential permanent porosity in the solid state. Herein, we report a series of functionalized carbazole-based ...cages of the structure type M
12
(R-cdc)
12
(M = Cr, Cu, Mo) where the functional groups include a range of aromatic substituents. Single-crystal X-ray structure determinations reveal a variety of intercage interactions in these materials, largely governed by pi-pi stacking. Density functional theory for a subset of these cages was used to confirm that the nature of the increased stability of aryl-functionalized cages is a result of inter-cage ligand interactions.
Straightforward coupling reactions give access to aryl-functionalized ligands for the synthesis of porous coordination cages with tunable properties and increased stability.
Non-alcoholic fatty liver disease (NAFLD) affects over 30% of adults in the United States. Bone morphogenetic protein (BMP) signaling is known to contribute to hepatic fibrosis, but the role of BMP ...signaling in the development of NAFLD is unclear. In this study, treatment with either of two BMP inhibitors reduced hepatic triglyceride content in diabetic (db/db) mice. BMP inhibitor-induced decrease in hepatic triglyceride levels was associated with decreased mRNA encoding Dgat2, an enzyme integral to triglyceride synthesis. Treatment of hepatoma cells with BMP2 induced DGAT2 expression and activity via intracellular SMAD signaling. In humans we identified a rare missense single nucleotide polymorphism in the BMP type 1 receptor ALK6 (rs34970181;R371Q) associated with a 2.1-fold increase in the prevalence of NAFLD. In vitro analyses revealed R371Q:ALK6 is a previously unknown constitutively active receptor. These data show that BMP signaling is an important determinant of NAFLD in a murine model and is associated with NAFLD in humans.
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