Palladium-Catalyzed Synthesis of Aromatic Carboxylic Acids with Silacarboxylic Acids

Aryl iodides and bromides were easily converted to their corresponding aromatic carboxylic acids via a Pd-catalyzed carbonylation reaction using silacarboxylic acids as an <i>in situ</i> source of carbon monoxide. The reaction conditions were compatible with a wide range of functional groups, and with the aryl iodides, the carbonylation was complete within minutes. The method was adapted to the double and selective isotope labeling of tamibarotene

Synthesis and Evaluation of Silanediols as Highly Selective Uncompetitive Inhibitors of Human Neutrophil Elastase

Chronic obstructive pulmonary disease (COPD) is an increasing health problem and is estimated to be the fifth leading cause of death in 2020 according to the World Health Organization. Current treatments are only palliative, and therefore the development of new medicine for the treatment of COPD is urgent. Human Neutrophil Elastase (HNE) is a serine protease that is heavily involved in the progression of COPD through inflammatory breakdown of lung tissue. Consequently, inhibitors of HNE are of great interest as therapeutics. In this article, the development of silanediol peptide isosters as inhibitors of HNE is presented. Kinetic studies revealed that incorporation of a silanediol isoster in the inhibitor structure resulted in an uncompetitive mechanism of inhibition, which further resulted in excellent selectivity. The peculiar mechanism of inhibition and the resulting selectivity makes the presented inhibitors promising leads for the development of new HNE-inhibitor-based therapeutics for the treatment of COPD

General Method for the Preparation of Active Esters by Palladium-Catalyzed Alkoxycarbonylation of Aryl Bromides

A useful method was developed for the synthesis of active esters by palladium-catalyzed alkoxycarbonylation of (hetero)­aromatic bromides. The protocol was general for a range of oxygen nucleophiles including <i>N</i>-hydroxysuccinimide (NHS), pentafluorophenol (PFP), hexafluoroisopropyl alcohol (HFP), 4-nitrophenol, and <i>N</i>-hydroxyphthalimide. A high functional group tolerance was displayed, and several active esters were prepared with good to excellent isolated yields. The protocol was extended to access an important synthetic precursor to the HIV-protease inhibitor, saquinavir, by formation of an NHS ester followed by acyl substitution

PTH levels as a function of the number of surfaces with canopy coverage in patients with renal osteodystrophy.

<p>Lines represent median values; bars represent interquartile ranges.</p

Immunostaining for PTHR1 and RANKL in trabecular bone from a patient treated with maintenance dialysis.

<p>A-C: PTHR1 immunoreactivity (red) was observed in both thin and thick canopies above eroded surface (ES) and osteoid surface (OS). On the eroded surface the reversal cells, but not the osteoclasts (OC), demonstrated PTHR1 immunoreactivity (A). No osteoblasts on the osteoid surface showed PTHR1 immunoreactivity (B-C). D-F: RANKL immunoreactivity was also observed in both thin and thick canopies above eroded and osteoid surfaces. Only the reversal cells and not the osteoclasts on the eroded surface demonstrated RANKL immunoreactivity (D). No osteoblasts on the osteoid surface demonstrated RANKL immunoreactivity (E-F). Thin canopies are marked with green arrowheads and diamonds while the thick canopies are framed by two green dotted lines.</p

PTH levels (A) and the number of surfaces with canopy coverage (B) as a function of ROD diagnosis in dialysis patients.

<p>Lines represent median values; bars represent interquartile ranges. Low: lone bone turnover; normal: normal bone turnover; mild: mildly increased bone turnover; 2°HPT: severe high bone turnover/secondary hyperparathyroidism; mixed: mixed uremic osteodystrophy.</p

Light microscopic features of canopies in patients treated with maintenance dialysis.

<p>Toluidine blue staining of a 5 μm undecalcified section of iliac crest trabecular bone from patients treated with maintenance dialysis demonstrating osteoid surfaces (OS) colonized by osteoblasts (A-B) and eroded surfaces (ES) colonized by osteoclasts (OC) and reversal cells (C-D), which are separated from the bone marrow by either a thin (A, C) or thick (B, D) canopy. The thin canopies are marked with cyan arrowheads and diamonds, while the thick canopies are framed by two cyan dotted lines.</p

Multiple linear regression model considering the contributions of PTH levels, and extent of osteoid and osteoclast surfaces in the prediction of the canopy coverage.

<p>Multiple linear regression model considering the contributions of PTH levels, and extent of osteoid and osteoclast surfaces in the prediction of the canopy coverage.</p

Bone histomorphometric parameters of bone formation and resorption as a function of canopy coverage observed by histology.

<p>A) osteoid surfaces/bone surface (OS/BS); B) eroded surface/bone surface (ES/BS). C) osteoclast surface/bone surface (Oc.S/BS); D) reversal surface/bone surface (Rv.S/BS). Lines represent median values; bars represent interquartile ranges.</p

Bone histomorphometry, PTHR1 expression, and canopy coverage in bone specimens from pre-dialysis CKD and from dialysis patients.

<p>Bone histomorphometry, PTHR1 expression, and canopy coverage in bone specimens from pre-dialysis CKD and from dialysis patients.</p