Studies on the Synthesis of Vitamin D Analogs with Aromatic D-Ring

Herein, we describe our studies on the synthesis of 1α,25-dihydroxyvitamin D3 analogs possessing a benzene ring replacing the natural 5-membered D-ring by the Wittig-Horner and dienyne approaches. A key feature is the synthesis of a Cr(CO)3-complexed previtamin D derivative that enables the construction of vitamin D analogs with aromatic D-ring through a thermal [1,7]-H sigmatropic shift. This study establishes the basis for the design of new vitamin D analogs containing aromatic D-ring, complexed or uncomplexed to Cr(CO)3 type moieties for specific molecular recognition and drug research and developmentWe thank Xunta de Galicia (project GPC2014/001) and for financial support. Silvina Eduardo thanks the Spanish MEC for a fellowship. Rita Sigüeiro thanks Xunta de Galicia for a post-doctoral fellowship (Axudas posdoutorais, plan I2C, mod B)S

Novel Vitamin D Analogs for Prostate Cancer Therapy

Prostate cells contain specific receptors for 1α,25-dihydroxyvitamin D [1α,25(OH)2D] or calcitriol, the active form of vitamin D. 1α,25(OH)2D is known to inhibit the proliferation and invasiveness of prostate cancer cells. These findings support the use of 1α,25(OH)2D for prostate cancer therapy. However, 1α,25(OH)2D can cause hypercalcemia, analogs of 1α,25(OH)2D that are less calcemic but exhibit potent antiproliferative activity would be attractive as therapeutic agents. To accomplish these goals, different strategies, based on metabolism, molecular mechanism of actions, and structural modeling, have been taken to modify the structure of vitamin D molecule with the aims to improve the efficacy and decrease the toxicity of vitamin D to treat different diseases. During the past four decades, over 3,000 analogs have been synthesized. In this paper, we discuss the development and the biological analysis of a unique class of vitamin D analogs with a substitution at the carbon 2 of 19-nor-1α,25(OH)2D3 molecule for potential application to the prevention and treatment of prostate cancer as well as other cancers

Experimental secondary hyperparathyroidism and the therapeutic application of vitamin D analogs

The two major pathophysiologic mechanisms responsible for the development of secondary hyperparathyroidism (SHPT) in advanced renal insufficiency are phosphorus retention and low levels of 1,25-dihydroxyvitamin D[subscript]3 (1,25-(OH)[subscript]2D[subscript]3].;The actions of the hormonal form of vitamin D extend beyond its role in mineral homeostasis. Recently, analogs of vitamin D that are less calcemic, but retain the therapeutically useful properties of 1,25-(OH)[subscript]2D have been developed;This study was designed to determine if a high phosphorus diet could be the main contributor for increasing plasma phosphate and parathyroid hormone (PTH) and reducing the production of renal 1,25-(OH)[subscript]2D[subscript]3 in renal failure (reduced renal cell mass). Another objective was to determine if vitamin D analogs could be used as an effective drug in lowering plasma PTH and increase calcium during SHPT;One hundred twelve 60-day-old male rats of Harlan-Sprague-Dawley (weighing 400-450 gm) were divided into 7 groups: SLP, SHP, NLP, NHP, NHP-A, NHP-B and NHP-C. SLP and SHP were sham (S) operated groups whereas the rest were unilaterally nephrectomized (N). The rats were fed two synthetic diets with low (LP) or high (HP) phosphorus levels. Three groups of rats: NHP-A, NHP-B, and NHP-C were simultaneously given an oral administration of 18 ng/day of 1,25-(OH)[subscript]2D[subscript]3 (A), 18 ng/day of 1,25-(OH)[subscript]2D[subscript]2 (B) or 2 [mu]g/day of 1,25,28-(OH)[subscript]3D[subscript]2 (C), respectively, every day for 30 days;After 30 days all rats were made unconscious with CO[subscript]2-O[subscript]2 (50%:50% vol/vol) and decapitated. Blood samples were collected and plasma was analyzed for inorganic phosphorus, calcium, 1,25-(OH)[subscript]2D[subscript]3, PTH and creatinine;The results of this study indicate that sham and nephrectomized rats fed high dietary phosphorus lost 9.50 and 24.72%, respectively, of their initial body weights. Plasma phosphate increased significantly as dietary phosphorus increased. The treatment with vitamin D analogs lowered plasma phosphate, PTH and raised plasma calcium and 1,25-(OH)[subscript]2D[subscript]3. Among the vitamin D analogs, 1,25-(OH)[subscript]2D[subscript]3 was found to be superior. These changes indicate that vitamin D analogs may be effective in SHPT

Pink verrucous plaque in a man with systemic mastocytosis

Porokeratosis ptychotropica is a rare and commonly misdiagnosed subtype of porokeratosis involving the body folds. We present a 53-year-old man with systemic mastocytosis who presented with a pruritic, verrucous plaque in the gluteal fold that showed multiple cornoid lamellae on histopathologic evaluation, diagnostic of porokeratosis ptychotropica. Various treatments have been reported, including topical corticosteroids, retinoids, vitamin D analogs, calcineurin inhibitors, imiquimod, phototherapy, cryotherapy, or ablative laser therapy, but recurrences are common

2-methylene-(20S,25S)-19,27-dinor-(22E)-vitamin D analogs

This invention discloses 2-methylene-(20S,25S)-19,27-dinor-(22E)-vitamin D analogs, and specifically 2-methylene-(20S,25S)-19,27-dinor-(22E)-1.alpha.,25-dihydroxyvitamin D.sub.3, and pharmaceutical uses therefor. This compound exhibits pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as an anti-cancer agent and for the treatment of skin diseases such as psoriasis as well as skin conditions such as wrinkles, slack skin, dry skin and insufficient sebum secretion. This compound also has little, if any, calcemic activity and therefore may be used to treat autoimmune disorders or inflammatory diseases in humans as well as renal osteodystrophy. This compound may also be used for the treatment or prevention of obesity

Caso clínico dermatológico

The case of a teenager with guttate psoriasis secondary to trauma and upper airway infection is reported. Guttate psoriasis is the second most common psoriasis variant in pediatric age. Infection and trauma (leading to Koebner phenomenon) seem to be major triggers of the condition. The diagnosis is clinical. Most cases with no previous history of psoriasis spontaneously remit. Topical corticosteroids and vitamin D analogs, as well as phototherapy, are the first-line treatments.info:eu-repo/semantics/publishedVersio

Anabolic Vitamin D Analogs as Countermeasures to Bone Loss

We demonstrated for the first time that vitamin D3 influences the effect of PTH on bone cell calcium ion levels. This is a rapid effect, taking place within seconds/minutes. This may prove to be a critical contribution to our understanding of bone physiology in that these two hormones are among the most potent regulators of bone calcium content and of systemic calcium homeostasis. Together with the data gathered from the study of astronauts exposed to microgravity for extended periods, these observations suggest the interaction of vitamin D3 and PTH as a possible therapeutic target in the treatment of bone loss disorders such as osteoporosis and disuse atrophy. Chronic exposure of cultured osteoblasts to vitamin D, altered the number of voltage-sensitive Ca(+2) channels expressed. Estrogen treatment yielded a similar result, suggesting that there is overlap in the mechanism by which these hormones elicit long-term effects on bone cell calcium homeostasis

Effects of etelcalcetide on fibroblast growth factor 23 in patients with secondary hyperparathyroidism receiving hemodialysis

Background: Etelcalcetide is an intravenous calcimimetic approved for treatment of secondary hyperparathyroidism (sHPT) in patients receiving hemodialysis. Besides lowering parathyroid hormone (PTH), etelcalcetide also significantly reduces fibroblast growth factor 23 (FGF23), but the mechanisms are unknown. Methods: To investigate potential mediators of etelcalcetide-induced FGF23 reduction, we performed secondary analyses of the 26-week randomized trials that compared the effects on PTH of etelcalcetide (n = 509) versus placebo (n = 514) and etelcalcetide (n = 340) versus cinacalcet (n = 343) in adults with sHPT receiving hemodialysis. We analyzed changes in FGF23 in relation to changes in PTH, calcium, phosphate and bone turnover markers. We also investigated how concomitant treatments aimed at mitigating hypocalcemia altered the FGF23-lowering effects of etelcalcetide. Results: Etelcalcetide reduced FGF23 [median % change (quartile 1-quartile 3)] from baseline to the end of the trial significantly more than placebo [-56% (-85 to -7) versus +2% (-40 to +65); P < 0.001] and cinacalcet [-68% (-87 to -26) versus -41% (-76 to +25); P < 0.001]. Reductions in FGF23 correlated strongly with reductions in calcium and phosphate, but not with PTH; correlations with bone turnover markers were inconsistent and of borderline significance. Increases in concomitant vitamin D administration partially attenuated the FGF23-lowering effect of etelcalcetide, but increased dialysate calcium concentration versus no increase and increased dose of calcium supplementation versus no increase did not attenuate the FGF23-lowering effects of etelcalcetide. Conclusion: These data suggest that etelcalcetide potently lowers FGF23 in patients with sHPT receiving hemodialysis and that the effect remains detectable among patients who receive concomitant treatments aimed at mitigating treatment-associated decreases in serum calcium

N-Cyclopropyl-(20R)-2-Methylene-19,26,27-trinor-25-aza-Vitamin D analogs and their uses

This invention discloses N-cyclopropyl-(20R)-2-methylene-19,26,27-trinor-25-aza-vitamin D analogs, and specifically N-cyclopropyl-(20R)-2-methylene-19,26,27-trinor-25-aza-1.alpha.-hydroxyvi- tamin D.sub.3 and pharmaceutical uses therefor. This compound exhibits relatively high binding activity and pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as an anti-cancer agent especially for the treatment or prevention of leukemia, colon cancer, breast cancer, skin cancer or prostate cancer