The i-motif is a high-order DNA structure formed by hemiprotonated cytosine-cytosine base pairs under acidic conditions. It is less well studied than other high-order DNA structures, such as G-quadruplexes. However, increasing numbers of i-motif-binding ligands are being reported, and they are being used as tools to investigate the i-motif's structure and biological functions. It has become clear that the i-motif has a functional role in the regulation of gene expression. In this review, we provide an overview of i-motif ligands so far reported, and we summarize their effects on the structure and their use as tools to investigate its biological functions.
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Genetic causes of vitamin D-related hypercalcemia are known to involve mutation of 25-hydroxyvitamin D-24-hydroxylase CYP24A1 or the sodium phosphate co-transporter SLC34A1, which result in excessive 1,25-(OH) 2 D hormonal action. However, at least 20% of idiopathic hypercalcemia (IH) cases remain unresolved. In this case-control study, we used precision vitamin D metabolite profiling based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) of an expanded range of vitamin D metabolites to screen German and French cohorts of hypercalcemia patients, to identify patients with altered vitamin D metabolism where involvement of CYP24A1 or SLC34A1 mutation had been ruled out and who possessed normal 25-OH-D 3 :24,25-(OH) 2 D 3 ratios. Profiles were compared to those of hypercalcemia patients with hypervitaminosis D, Williams-Beuren syndrome (WBS), CYP24A1 mutation, and normal subjects with a range of 25-OH-D levels. We observed that certain IH and WBS patients exhibited a unique profile comprising eightfold to 10-fold higher serum 23,25,26-(OH) 3 D 3 and 25-OH-D 3 -26,23-lactone than normals, as well as very low serum 1,25-(OH) 2 D 3 (2-5 pg/ml) and elevated 1,24,25-(OH) 3 D 3 , which we interpret implies hypersensitive expression of vitamin D-dependent genes, including CYP24A1, as a general underlying mechanism of hypercalcemia in these patients. Because serum 25-OH-D 3 and 24,25-(OH) 2 D 3 remained normal, we excluded the possibility that the aberrant profile was caused by hypervitaminosis D, but instead points to an underlying genetic cause that parallels the effect of Williams syndrome transcription factor deficiency in WBS. Furthermore, we observed normalization of serum calcium and vitamin D metabolite profiles at follow-up of an IH patient where 25-OH-D was reduced to 9 ng/ml, suggesting that symptomatic IH may depend on vitamin D nutritional status. Other hypercalcemic patients with complex conditions exhibited distinct vitamin D metabolite profiles. Our work points to the importance of serum vitamin D metabolite profiling in the differential diagnosis of vitamin D-related hypercalcemia that can rationalize expensive genetic testing, and assist healthcare providers in selecting appropriate treatment.
23S,25R)-Calcitriol lactone is a major metabolite of vitamin D 3 , but its synthesis has been far less well investigated than that of 1α,25(OH) 2 vitamin D 3 , the active form of vitamin D 3 , even though the lactone is present at a significant level in serum. This paper describes stereoselective syntheses of natural calcitriol lactone and its diastereomers at C23 and C25. This work features (i) the diastereoselective Reformatsky-type crotylation of aldehyde 25 in the presence of chiral ligand L2 to construct the stereochemistry at C23 and (ii) the diastereoselective epoxidation of homoallylic-allylic alcohol 31 to control the stereochemistry at C25. These key reactions allowed us to synthesize CD-ring synthon 30 with all four stereoisomers, and these were further converted into calcitriol lactones 3a−3d by reaction with ene-yne-type A-rings 33 in the presence of a palladium (0) catalyst.
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