Diabetic foot ulcers (DFUs) are significant complications of diabetes and an unmet medical need. Matrix metalloproteinases (MMPs) play important roles in the pathology of wounds and in the wound healing process. However, because of the challenge in distinguishing active MMPs from the two catalytically inactive forms of MMPs and the clinical failure of broad-spectrum MMP inhibitors in cancer, MMPs have not been a target for treatment of DFUs until recently. This review covers the discovery of active MMP-9 as the biochemical culprit in the recalcitrance of diabetic wounds to healing and targeting this proteinase as a novel approach for the treatment of DFUs. Active MMP-8 and MMP-9 were observed in mouse and human diabetic wounds using a batimastat affinity resin and proteomics. MMP-9 was shown to play a detrimental role in diabetic wound healing, whereas MMP-8 was beneficial. A new class of selective MMP-9 inhibitors shows clinical promise for the treatment of DFUs.
The reactions of 1,3-dichloro-1,1,3,3-tetrabutyldistannoxane and dialkyltin dihalides with silver perfluorooctanesulfonate provided the corresponding sulfonates as hydrates. The number of water molecules (n) of hydration was dependent on the conditions. The distannoxane derivative was identified as n from 0.5 to 6, while in the hydrated mononuclear species and DMSO complexes n varied widely from 4 to 13. 119Sn NMR spectroscopy and conductivity measurements indicated the ionic dissociation of these compounds in solution. These compounds exhibited unusually high solubility in polar organic solvents. The ionic dissociation together with facile hydration probably causes the unusual solubility. The Lewis acidity of these compounds was found to be high among organotin derivatives on the basis of ESR spectra of superoxide/metal-ion complexes. In contrast to well-known organotin triflates, these compounds suffered no hydrolysis upon storage in open air. The high catalytic activity of the distannoxane 1 was exemplified for various carbon-carbon bond-forming reactions, such as Mukaiyama-aldol as well as -Michael reactions and allylation of aldehydes.
A novel protocol towards N-aroylated sulfoximines from NH-sulfoximines and methyl arenes was herein demonstrated. The reaction took place in the presence of elemental iodine, requiring no external organic solvents, transition metal-catalysts or ligands. The aroylated products were obtained from the oxidative transformation in moderate to excellent yields (up to 94% yield) with a broad substrate scope (35 examples) through a radical pathway.
Diabetic
foot ulcers (DFUs) are a common complication of diabetes
that are recalcitrant to healing due to persistent inflammation. The
majority of DFUs have bacterial biofilms, with Staphylococcus
epidermidis as a predominant bacterium, requiring infection
control with antibiotics before treatment of the wound. Matrix metalloproteinases
(MMPs) play roles in the pathology and repair of DFUs. However, defining
the roles of the 24 human MMPs has been challenging due to the presence
of three forms for each MMP, of which only one is catalytically competent,
and the lack of convenient methods to distinguish among the three
forms of MMPs. Using an affinity resin that binds only to the active
forms of MMPs, with identification and quantification by mass spectrometry,
we found that infected wounds in mice had increased levels of active
MMP-9 compared to uninfected ones, paralleling infected human DFUs.
MMP-9 activity prevents diabetic wounds from healing. We evaluated
the efficacy of the selective small-molecule MMP-9 inhibitor, (R)-ND-336, in the infected diabetic mouse model of wound
healing and showed that (R)-ND-336 alone or in combination
with the antibiotic linezolid improves wound healing by inhibiting
the detrimental MMP-9, mitigating macrophage infiltration to diminish
inflammation, and increasing angiogenesis to restore the normal wound
healing process. An advantage of this strategy is the ability to administer
(R)-ND-336 concurrently with an antibiotic.
The results suggest that TIPS with embolotherapy cannot reduce the risk of rebleeding if PPG is less than 12 mm Hg after TIPS. PPG after TIPS is an independent predictor of rebleeding.
A series of unsymmetrical thiosulfonates were successfully prepared from sulfonyl hydrazides and disulfides with the assistance of H2O2 (7.0 equiv.) in PEG-400 at 100 °C, releasing N2 and H2O as byproducts. EPR analysis proved the protocol proceeded through a free radical pathway and a plausible mechanism was proposed.
A structure-activity relationship (SAR) for the oxadiazole class of antibacterials was evaluated by syntheses of 72 analogs and determination of the minimal-inhibitory concentrations (MICs) against the ESKAPE panel of bacteria. Selected compounds were further evaluated for in vitro toxicity, plasma protein binding, pharmacokinetics (PK), and a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) infection. Oxadiazole 72c showed potent in vitro antibacterial activity, exhibits low clearance, a high volume of distribution, 41% oral bioavailability, and shows efficacy in mouse models of MRSA infection.
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