scholarly journals Convergent Total Synthesis of (+)-Calcipotriol: A Scalable, Modular Approach to Vitamin D Analogs

2021 ◽  
Author(s):  
Jieyu Gu ◽  
Kevin Rodriguez ◽  
yuzuru kanda ◽  
Shenghua Yang ◽  
Michal Ociepa ◽  
...  
Keyword(s):  
Vitamin D ◽  
Total Synthesis ◽  
Hydrogen Atom Transfer ◽  
Vitamin D Analogs ◽  
Novel Approach ◽  
Vitamin D Analog ◽  
Coupling Approach ◽  
The Rich ◽  
Convergent Approach ◽  
Intramolecular Hydrogen

Vitamin D is a group of seco-steroids with diverse bioactivities. An enormous amount of effort was expended by medicinal chemists to search for Vitamin D analogs that could exhibit pro-differentiating and antiproliferative effects on normal and cancer cells as well as immunomodulatory effects without causing hypercalcemia. A convergent approach for the total synthesis of calcipotriol (brand name: Dovonex), a proven Vitamin D analog used for the treatment of psoriasis, and medicinally relevant synthetic analogs is described. Given the rich synthetic history of the Vitamin D family, a complete novel approach towards both the A-ring and CD-ring is reported. From a retrosynthetic standpoint, hidden symmetry within the decorated A-ring is disclosed, which allowed for scalable quantities of this advanced intermediate. In addition, a radical retrosynthetic approach is described, which highlights an electrochemical reductive coupling as well as an intramolecular hydrogen atom transfer (HAT)-Giese addition to establish the 6,5-trans-carbon skeleton found in the Vitamin D family. Lastly, a late-stage decarboxylative cross-coupling approach allowed for the facile preparation of various C20-arylated derivatives which show promising biological activity in an early bioassay.

scholarly journals Conversion from Intravenous Vitamin D Analogs to Oral Calcitriol in Patients Receiving Maintenance Hemodialysis

2020 ◽  
Vol 15 (3) ◽  
pp. 384-391
Author(s):  
Ravi I. Thadhani ◽  
Sophia Rosen ◽  
Norma J. Ofsthun ◽  
Len A. Usvyat ◽  
Lorien S. Dalrymple ◽  
...  
Keyword(s):  
United States ◽  
Vitamin D ◽  
Hospital Admissions ◽  
The United States ◽  
Target Range ◽  
Maintenance Hemodialysis ◽  
Laboratory Parameters ◽  
Vitamin D Analogs ◽  
Vitamin D Analog ◽  
Intravenous Vitamin

Background and objectivesIn the United States, intravenous vitamin D analogs are the first-line therapy for management of secondary hyperparathyroidism in hemodialysis patients. Outside the United States, oral calcitriol (1,25-dihydroxyvitamin D3) is routinely used. We examined standard laboratory parameters of patients on in-center hemodialysis receiving intravenous vitamin D who switched to oral calcitriol.Design, setting, participants, & measurementsWe conducted a retrospective cohort study of adult patients treated within Fresenius Kidney Care clinics. During a 6-month period (December 2013 to May 2014), we identified patients on an intravenous vitamin D analog (doxercalciferol or paricalcitol) who switched to oral calcitriol and matched them to patients receiving an intravenous vitamin D analog. Mean serum calcium, phosphate, and intact parathyroid hormone (iPTH) concentrations were examined for up to 12 months of follow-up. We used Poisson and Cox proportional hazards regression models to examine hospitalization and survival rates. The primary analysis was conducted as intention-to-treat; secondary analyses included an as-treated evaluation.ResultsA total of 2280 patients who switched to oral calcitriol were matched to 2280 patients receiving intravenous vitamin D. Compared with patients on intravenous vitamin D, mean calcium and phosphate levels in the oral calcitriol group were lower after the change to oral calcitriol. In contrast, iPTH levels were higher in the oral calcitriol group. At 12 months, the percentage of patients with composite laboratories in target range (calcium <10 mg/dl, phosphate 3.0–5.5 mg/dl, and iPTH 150–600 pg/ml) were comparable between groups (45% versus 45%; P=0.96). Hospital admissions, length of hospital stay, and survival were comparable between groups. An as-treated analysis and excluding those receiving cinacalcet did not reveal significant between-group differences.ConclusionsAmong patients receiving in-center hemodialysis who were switched to oral calcitriol versus those on an intravenous vitamin D analog, the aggregate of all mineral and bone laboratory parameters in range was largely similar between groups.

Tackling the Challenge of the Total Synthesis of Periploside A

Synlett ◽  
2018 ◽  
Vol 29 (13) ◽  
pp. 1683-1692
Author(s):  
Biao Yu ◽  
Xiaheng Zhang
Keyword(s):  
Hydrogen Atom ◽  
Medicinal Plant ◽  
Total Synthesis ◽  
Hydrogen Atom Transfer ◽  
Atom Transfer ◽  
Final Solution ◽  
Anomeric Configuration ◽  
Periploca Sepium ◽  
Intramolecular Hydrogen ◽  
Chinese Medicinal Plant

Periploside A is the prototypical congener of the pregnane glycosides occurring in the Chinese medicinal plant Periploca sepium, featuring a unique seven-membered formyl acetal bridged spiro-­orthoester (FABO) sugar linkage and potent immunosuppressive activities. This account details our efforts on the stereoselective construction of the FABO motif that has led to a successful total synthesis of peri­ploside A.1 Introduction2 Attempts at Construction of the FABO Motif2.1 Intermolecular Condensation and Transacetalation2.2 Intramolecular Hydrogen Atom Transfer (HAT) Reaction3 Synthesis of the FABO Motif Bearing the Unnatural Anomeric Configuration4 Synthesis of the FABO Motif Bearing the Natural Anomeric ­Configuration4.1 Unsuccessful Attempts4.2 Final Solution5 Conclusion

scholarly journals Simultaneous Synthesis of Vitamins D2, D4, D5, D6, and D7 from Commercially Available Phytosterol, β-Sitosterol, and Identification of Each Vitamin D by HSQC NMR

Metabolites ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. 107
Author(s):  
Shiro Komba ◽  
Eiichi Kotake-Nara ◽  
Wakako Tsuzuki
Keyword(s):  
Vitamin D ◽  
Vitamin D3 ◽  
Chemical Industry ◽  
Chemical Shifts ◽  
Vitamin D Analogs ◽  
Vitamin D Analog ◽  
Simultaneous Synthesis ◽  
The Difference ◽  
Pure Cholesterol ◽  
Tokyo Chemical Industry

We succeeded in simultaneously synthesizing the vitamin D family, vitamins D2, D4, D5, D6, and D7, from β-sitosterol, which is sold as a commercially available reagent from Tokyo Chemical Industry Co., Ltd. It is officially sold as a mixture of four phytosterols {β-sitosterol (40–45%), campesterol (20–30%), stigmasterol, and brassicasterol}. Owing to this, we anticipated that, using this reagent, various vitamin D analogs could be synthesized simultaneously. We also synthesized vitamin D3 from pure cholesterol and analyzed and compared all vitamin D analogs (D2, D3, D4, D5, D6, and D7) by HSQC NMR. We succeeded in clearly demonstrating the difference in the NMR chemical shifts for each vitamin D analog.

Oxidative Stress and Inflammation in Chronic Kidney Disease: Role of Intravenous Iron and Vitamin D

2008 ◽  
Vol 21 (3) ◽  
pp. 214-224
Author(s):  
Amy Barton Pai ◽  
Todd A. Conner
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Vitamin D ◽  
Kidney Disease ◽  
Iron Supplementation ◽  
Intravenous Iron ◽  
Current Data ◽  
Vitamin D Analogs ◽  
Vitamin D Analog ◽  
Intravenous Iron Supplementation

Cardiovascular disease (CVD) is the leading cause of death among chronic kidney disease patients (CKD). The etiology of CVD in CKD is multifactorial and increasing evidence points to the important contribution of “nontraditional” risk factors including oxidative stress and inflammation. CKD is associated with a chronic imbalance of prooxidant and antioxidant factors that results in a state of chronic inflammation. Intravenous iron supplementation has been shown to induce oxidative stress and has been associated with lipid peroxidation and DNA damage. Conversely, treatment with vitamin D analogs has been associated with improved mortality in hemodialysis patients in 2 recent large cohort studies. These data suggest that vitamin D analogs may exert effects beyond their pharmacologic role in parathyroid hormone suppression. This article addresses the current data regarding the relative contributions of intravenous iron supplementation and vitamin D analog therapy on oxidative stress and inflammation in CKD patients.

scholarly journals Selective Interaction of Vitamin D Receptor with Transcriptional Coactivators by a Vitamin D Analog

1999 ◽  
Vol 19 (2) ◽  
pp. 1049-1055 ◽  
Author(s):  
Ken-Ichi Takeyama ◽  
Yoshikazu Masuhiro ◽  
Hiroaki Fuse ◽  
Hideki Endoh ◽  
Akiko Murayama ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Target Gene ◽  
Biological Action ◽  
Gene Promoters ◽  
Vitamin D Analogs ◽  
Dihydroxyvitamin D ◽  
Vitamin D Analog ◽  
Selective Interaction ◽  
Selective Interactions

ABSTRACT The nuclear vitamin D receptor (VDR) is a member of a nuclear receptor superfamily and acts as a ligand-dependent transcription factor. A family of cotranscriptional activators (SRC-1, TIF2, and AIB-1) interacts with and activates the transactivation function of nuclear receptors in a ligand-dependent way. We examined interaction of VDR with these coactivators that was induced by several vitamin D analogs, since they exert differential subsets of the biological action of vitamin D through unknown mechanisms. Unlike other vitamin D analogs tested, OCT (22-oxa-1α,25-dihydroxyvitamin D3) induced interaction of VDR with TIF2 but not with SRC-1 or AIB-1. Consistent with these interactions, only TIF2 was able to potentiate the transactivation function of VDR bound to OCT. Thus, the present findings suggest that the structure of VDR is altered in a vitamin D analog-specific way, resulting in selective interactions of VDR with coactivators. Such selective interaction of coactivators with VDR may specify the array of biological actions of a vitamin D analog like OCT, possibly through activating a particular set of target gene promoters.

190: BXL-628, a Vitamin D Analog, Decreases RHOA/ROK Signalling in Rat and Human Bladder

2006 ◽  
Vol 175 (4S) ◽  
pp. 62-62
Author(s):  
Annamaria Morelli ◽  
Sandra Filippi ◽  
Rosa Mancina ◽  
Linda Vignozzi ◽  
Gabriella B. Vannelli ◽  
...  
Keyword(s):  
Vitamin D ◽  
Human Bladder ◽  
Vitamin D Analog

Association between calcitriol and paricalcitol with oxidative stress in patients with hemodialysis

2020 ◽  
pp. 1-8
Author(s):  
Hasan Haci Yeter ◽  
Berfu Korucu ◽  
Elif Burcu Bali ◽  
Ulver Derici
Keyword(s):  
Oxidative Stress ◽  
Vitamin D ◽  
Antioxidant Status ◽  
Total Antioxidant Status ◽  
Stress Index ◽  
Total Oxidant Status ◽  
Vitamin D Analog ◽  
Total Antioxidant ◽  
Oxidant Status ◽  
And Oxidative Stress

Abstract. Background: The pathophysiological basis of chronic kidney disease and its complications, including cardiovascular disease, are associated with chronic inflammation and oxidative stress. We investigated the effects of active vitamin D (calcitriol) and synthetic vitamin D analog (paricalcitol) on oxidative stress in hemodialysis patients. Methods: This cross-sectional study was composed of 83 patients with a minimum hemodialysis vintage of one year. Patients with a history of any infection, malignancy, and chronic inflammatory disease were excluded. Oxidative markers (total oxidant and antioxidant status) and inflammation markers (C-reactive protein and interleukin-6) were analyzed. Results: A total of 47% (39/83) patients were using active or analog vitamin D. Total antioxidant status was significantly higher in patients with using active or analog vitamin D than those who did not use (p = 0.006). Whereas, total oxidant status and oxidative stress index were significantly higher in patients with not using vitamin D when compared with the patients who were using vitamin D preparation (p = 0.005 and p = 0.004, respectively). On the other hand, total antioxidant status, total oxidant status, and oxidative stress index were similar between patients who used active vitamin D or vitamin D analog (p = 0.6; p = 0.4 and p = 0.7, respectively). Conclusion: The use of active or selective vitamin D analog in these patients decreases total oxidant status and increases total antioxidant status. Also, paricalcitol is as effective as calcitriol in decreasing total oxidant status and increasing total antioxidant status in patients with chronic kidney disease.

Synthesis of Spongidine A, D and Petrosaspongiolide L Methyl Ester Using Pyridine C-H Functionalization

2019 ◽  
Author(s):  
Florian Bartels ◽  
Manuela Weber ◽  
Mathias Christmann
Keyword(s):  
Natural Products ◽  
Methyl Ester ◽  
Hydrogen Atom ◽  
Phospholipase A2 ◽  
Late Stage ◽  
Hydrogen Atom Transfer ◽  
Ring System ◽  
Tetracyclic Core ◽  
Intramolecular Hydrogen ◽  
Phospholipase A2 Inhibitors

<div>An efficient strategy for the synthesis of the potent phospholipase A2 inhibitors spongidine A and D is presented. The tetracyclic core of the natural products was assembled via an intramolecular hydrogen atom transfer‐initiated Minisci reaction. A divergent late‐stage functionalization of the tetracyclic ring system was also used to achieve a concise synthesis of petrosaspongiolide L methyl ester.</div>

Convergent Total Synthesis of Principinol D, a Rearranged Kaurane Diterpenoid

2019 ◽  
Author(s):  
Timothy Newhouse ◽  
Aneta Turlik ◽  
Yifeng Chen ◽  
Anthony Scruse
Keyword(s):  
Total Synthesis ◽  
Natural Product ◽  
Late Stage ◽  
Membered Ring ◽  
Entry Point ◽  
Ketone Reduction ◽  
Coupling Approach

<div> <p>The total synthesis of principinol D, a rearranged kaurane diterpenoid, is reported. This grayanane natural product is constructed via a convergent fragment coupling approach, wherein the central 7-membered ring is synthesized at a late stage. The bicyclo[3.2.1]octane fragment is accessed by a Ni-catalyzed α-vinylation reaction. Strategic reductions include a diastereoselective SmI<sub>2</sub>-mediated ketone reduction with PhSH and a new protocol for selective ester reduction in the presence of ketones. The convergent strategy reported herein may be an entry point to the larger class of kaurane diterpenoids.</p> </div>

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