Multicentric Carpotarsal Osteolysis Syndrome Associated Nephropathy: Novel Variants of MAFB Gene and Literature Review.

Multicentric carpo-tarsal osteolysis (MCTO) is a rare osteolysis syndrome mainly involving carpal and tarsal bones usually presenting in early childhood. MCTO has autosomal dominant inheritance with heterozygous mutation in the MAFB gene. The skeletal disorder is often associated with chronic kidney disease. Data on clinical characterization and best treatment option of MCTO-associated nephropathy are scarce and mostly limited to case reports. With the aim to better define the phenotype and long-term outcomes of MCTO-associated nephropathy, we launched an online survey through the Workgroup for hereditary glomerulopathies of the European Rare Kidney Disease Network (ERKNet). Overall, we collected clinical and genetic data of 54 MCTO patients, of which 42 previously described and 12 new patients. We observed a high rate of kidney involvement (70%), early age of kidney disease onset, nephrotic-range proteinuria, and a kidney survival around of 40% at long-term follow-up. Our finding confirmed the heterogeneity of clinical manifestations and widen the spectrum of phenotypes resulting from MCTO-associated nephropathy. Furthermore, we report the first case of complete remission after treatment with cyclosporine A. We demonstrated that multidisciplinary care is essential for MCTO patients and early referral to nephrologists is therefore warranted to facilitate prompt treatment.

Modification of estrone at the 6, 16, and 17 positions: novel potent inhibitors of 17beta-hydroxysteroid dehydrogenase type 1.

The 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) catalyze the interconversion between the oxidized and reduced forms of androgens and estrogens at the 17 position. The 17beta-HSD type 1 enzyme (17beta-HSD1) catalyzes the reduction of estrone to estradiol and is expressed in malignant breast cells. Inhibitors of this enzyme thus have potential as treatments for hormone dependent breast cancer. Here we report the syntheses and biological evaluation of novel inhibitors based on the estrone or estradiol template. These have been investigated by modification at the 6, 16 or 17 positions or combinations of these in order to gain information about structure-activity relationships by probing different areas in the enzyme active site. Activity data have been incorporated into a QSAR with predictive power, and the X-ray crystal structures of compounds 15 and 16c have been determined. Compound 15 has an IC50 of 320 nM for 17beta-HSD1 and is selective for 17beta-HSD1 over 17beta-HSD2. Three libraries of amides are also reported that led to the identification of inhibitors 19e and 20a, which have IC50 values of 510 and 380 nM respectively, and 20 h which, having an IC50 value of 37 nM, is the most potent inhibitor of 17beta-HSD1 reported to date. These amides are also selective for 17beta-HSD1 over 17beta-HSD2.

Metalation of 4-oxazolinyloxazole derivatives. A convenient route to 2,4-bifunctionalized oxazoles.

The synthesis of an array of 5-phenyloxazole derivatives bearing a variety of hydroxyalkyl groups at the C-2 position of the heterocyclic nucleus and possessing a formyl or a carboxyl function at C-4 is reported. These bifunctionalized compounds have been efficiently prepared by addition of carbonylated electrophiles to the 2-lithio derivative of 5-phenyloxazole preliminarily equipped with an oxazoline unit at the 4-position of the oxazole nucleus. It is demonstrated that this protocol offers a double advantage since it suppresses the troublesome electrocyclic ring-opening reaction and allows access to the target compounds by simple chemical transformation of the oxazoline ring system.

Synthesis and activity of a new methoxytetrahydropyran derivative as dual cyclooxygenase-2/5-lipoxygenase inhibitor.

Dual COX-2/5-LO inhibitors are described as potential new therapeutic agents for inflammatory diseases. A surprisingly potent effect of a 5-LO pharmacophoric group on the COX-2 inhibition is presented as well as pharmacological in vitro and in vivo results.