共查询到20条相似文献,搜索用时 15 毫秒
1.
《Bioorganic & medicinal chemistry》2014,22(21):5891-5901
Non-secosteroidal vitamin D receptor (VDR) ligands are promising candidates for many clinical applications. We recently developed novel non-secosteroidal VDR agonists based on p-carborane (an icosahedral carbon-containing boron cluster) as a hydrophobic core structure. Here, we report the design, synthesis and biological evaluation of carborane-based vitamin D analogs bearing various substituents at the diol moiety. Among the synthesized compounds, methylene derivative 31 exhibited the most potent vitamin D activity, which was comparable to that of the natural hormone, 1α,25(OH)2D3. This compound is one of the most potent non-secosteroidal VDR agonists reported to date, and is a promising lead for development of novel drug candidates. 相似文献
2.
Takashi Misawa Genichiro Tsuji Takeo Takahashi Eiji Ochiai Ken-ichiro Takagi Kyohei Horie Shinji Kakuda Midori Takimoto-Kamimura Masaaki Kurihara Yosuke Demizu 《Bioorganic & medicinal chemistry》2018,26(23-24):6146-6152
Non-secosteroidal VDR ligands without any assymmetric carbon were designed and synthesized based on the structure of the previously reported non-secosteroidal VDR agonist LG190178. The VDR-agonistic activity of all synthesized compounds was evaluated, and 7b emerged as a potent agonist activity with an EC50 value of 9.26?nM. Moreover, a docking simulation analysis was also performed to determine the binding mode of 7b with VDR-LBD. 相似文献
3.
《Bioorganic & medicinal chemistry》2014,22(4):1227-1235
1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3: 1] is a specific modulator of nuclear vitamin D receptor (VDR), and novel vitamin D analogs are therapeutic candidates for multiple clinical applications. We recently developed non-secosteroidal VDR agonists bearing a p-carborane cage (a carbon-containing boron cluster) as a hydrophobic core structure. These carborane derivatives are structurally quite different from classical secosteroidal vitamin D analogs. Here, we report systematic synthesis and activity evaluation of carborane-based non-secosteroidal vitamin D analogs. The structure–activity relationships of carborane derivatives are different from those of secosteroidal vitamin D derivatives, and in particular, the length and the substituent position of the dihydroxylated side chain are rather flexible in carborane derivatives. The structure–activity relationships presented here should be helpful in development of non-secosteroidal vitamin D analogs for clinical applications. 相似文献
4.
Cho K Uneuchi F Kato-Nakamura Y Namekawa J Ishizuka S Takenouchi K Nagasawa K 《Bioorganic & medicinal chemistry letters》2008,18(15):4287-4290
Structure–activity relationship studies on 1α,25-dihydroxyvitamin D3-26,23-lactams (DLAMs), antagonists of vitamin D, were conducted, focusing on the substituents of the phenyl group. One of the derivatives (23S,25S)-DLAM-1P-3,5(OEt)2, showed potent antagonistic activity with an IC50 of 90 nM. 相似文献
5.
6.
Hiroyuki Masuno Yuko Kazui Aya Tanatani Shinya Fujii Emiko Kawachi Teikichi Ikura Nobutoshi Ito Keiko Yamamoto Hiroyuki Kagechika 《Bioorganic & medicinal chemistry》2019,27(16):3674-3681
Lithocholic acid (2) was identified as the second endogenous ligand of vitamin D receptor (VDR), though its binding affinity to VDR and its vitamin D activity are very weak compared to those of the active metabolite of vitamin D3, 1α,25-dihydroxyvitamin D3 (1). 3-Acylated lithocholic acids were reported to be slightly more potent than lithocholic acid (2) as VDR agonists. Here, aiming to develop more potent lithocholic acid derivatives, we synthesized several derivatives bearing a 3-sulfonate/carbonate or 3-amino/amide substituent, and examined their differentiation-inducing activity toward human promyelocytic leukemia HL-60 cells. Introduction of a nitrogen atom at the 3-position of lithocholic acid (2) decreased the activity, but compound 6 bearing a 3-methylsulfonate group showed more potent activity than lithocholic acid (2) or its acylated derivatives. The binding of 6 to VDR was confirmed by competitive binding assay and X-ray crystallographic analysis of the complex of VDR ligand-binding domain (LBD) with 6. 相似文献
7.
8.
9.
10.
11.
12.
Jehan F d'Alésio A Garabédian M 《The Journal of steroid biochemistry and molecular biology》2007,103(3-5):361-367
The human vitamin D receptor (hVDR) gene encompasses eight exons (2–9) in the so-called coding region and six more exons (1a–1f) in the so-called regulatory region, which contains several reported promoters. Evolutionary comparison performed on the VDR promoter sequences of a dozen of mammalian species shows a very high conservation of numerous regions around and in the 1a promoter, including exons 1e, 1a and 1d, and the Sp1 site region. This suggests that the so-called 1a promoter is well conserved among mammals. Homology among mammals also concerns three functional SNP site regions of the hVDR 1a promoter, the 1e-G-1739A SNP region (a Cdx-2 binding site), and both 1a-G-1521C and 1a-A-1012G sites, the 1a-1012A being located within a GATA site. Interestingly, the 1521G and 1012A nucleotides are being evolutionary conserved, suggesting that the 1521C/1012G haplotype, which is found in human chromosomes (43% of Caucasians), is a human specificity. 相似文献
13.
Barbara Chen Megumi Kawai J. Ruth Wu-Wong 《Bioorganic & medicinal chemistry letters》2013,23(21):5949-5952
We have synthesized a novel vitamin D receptor agonist VS-105 ((1R,3R)-5-((E)-2-((3αS,7αS)-1-((R)-1-((S)-3-hydroxy-2,3-dimethylbutoxy)ethyl)-7α-methyldihydro-1H-inden-4(2H,5H,6H,7H,7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol). Preparation of a-ring phenylphosphine oxide 11, followed by Wittig–Horner coupling of 11 with the protected 25-hydroxy Grundmann’s ketone 22 generated the precursor 12. Deprotection of the TBDMS groups of 12 produced the target compound VS-105. The biological profiles of VS-105 were evaluated using in vitro assays (VDR receptor binding, VDR reporter gene and HL-60 differentiation) in comparison to calcitriol (the endogenous hormone) or paricalcitol. Furthermore, the PTH suppressing potency and hypercalcemic side effects of VS-105 were evaluated in the 5/6 nephrectomized uremic rats in comparison to paricalcitol. Combining various changes at 20-epi, 22-oxa, 24-methyl, and 2-methylene yielded VS-105 that not only is highly potent in inducing functional responses in vitro, but also effectively suppresses PTH in a dose range that does not affect serum calcium in the 5/6 nephrectomized uremic rats. 相似文献
14.
Premature aging in vitamin D receptor mutant mice 总被引:1,自引:0,他引:1
Tiina Keisala Anna Minasyan Yan-Ru Lou Jing Zou Allan V. Kalueff Ilmari Pyykk Pentti Tuohimaa 《The Journal of steroid biochemistry and molecular biology》2009,115(3-5):91-97
Hypervitaminosis vitamin D3 has been recently implicated in premature aging through the regulation of 1alpha hydroxylase expression by klotho and fibroblast growth factor-23 (Fgf-23). Here we examined whether the lack of hormonal function of vitamin D3 in mice is linked to aging phenomena. For this, we used vitamin D3 receptor (VDR) “Tokyo” knockout (KO) mice (fed with a special rescue diet) and analyzed their growth, skin and cerebellar morphology, as well as overall motor performance. We also studied the expression of aging-related genes, such as Fgf-23, nuclear factor kappaB (NF-kappaB), p53, insulin like growth factor 1 (IGF1) and IGF1 receptor (IGF1R), in liver, as well as klotho in liver, kidney and prostate tissues. Overall, VDR KO mice showed several aging related phenotypes, including poorer survival, early alopecia, thickened skin, enlarged sebaceous glands and development of epidermal cysts. There was no difference either in the structure of cerebellum or in the number of Purkinje cells. Unlike the wildtype controls, VDR KO mice lose their ability to swim after 6 months of age. Expression of all the genes was lower in old VDR KO mice, but only NF-kappaB, Fgf-23, p53 and IGF1R were significantly lower. Since the phenotype of aged VDR knockout mice is similar to mouse models with hypervitaminosis D3, our study suggests that VDR genetic ablation promotes premature aging in mice, and that vitamin D3 homeostasis regulates physiological aging. 相似文献
15.
Wong KE Kong J Zhang W Szeto FL Ye H Deb DK Brady MJ Li YC 《The Journal of biological chemistry》2011,286(39):33804-33810
Our previous studies demonstrated a high fat diet-resistant lean phenotype of vitamin D receptor (VDR)-null mutant mice mainly due to increased energy expenditure, suggesting an involvement of the VDR in energy metabolism. Here, we took a transgenic approach to further define the role of VDR in adipocyte biology. We used the aP2 gene promoter to target the expression of the human (h) VDR in adipocytes in mice. In contrast to the VDR-null mice, the aP2-hVDR Tg mice developed obesity compared with the wild-type counterparts without changes in food intake. The increase in fat mass was mainly due to markedly reduced energy expenditure, which was correlated with decreased locomotive activity and reduced fatty acid β-oxidation and lipolysis in the adipose tissue in the transgenic mice. Consistently, the expression of genes involved in the regulation of fatty acid transport, thermogenesis, and lipolysis were suppressed in the transgenic mice. Taken together, these data confirm an important role of the VDR in the regulation of energy metabolism. 相似文献
16.
Toshie Fujishima Takato Nozaki Tsutomu Suenaga 《Bioorganic & medicinal chemistry》2013,21(17):5209-5217
Four structurally novel stereoisomeric analogues of 1,25-dihydroxyvitamin D3 (3a–d) bearing a spiro-oxetane fused at the C2 position of the A-ring have been designed and synthesised in a convergent manner. The requisite A-ring enyne precursors (13a,b) for the vitamin D analogues (3a,b) and (3c,d), respectively, were synthesised from pentaerythritol according to an eleven-step procedure. Preliminary biological evaluation of the analogues using the bovine thymus vitamin D receptor (VDR) suggested that the incorporation of the spiro-oxetane moiety instead of a gem-dimethyl group at the C2 position had a beneficial effect on the VDR affinity. 相似文献
17.
Peräkylä M 《European biophysics journal : EBJ》2009,38(2):185-198
Molecular dynamics simulation techniques have been used to study the unbinding pathways of 1α,25-dihydroxyvitamin D3 from the ligand-binding pocket of the vitamin D receptor (VDR). The pathways observed in a large number of relatively short
(<200 ps) random acceleration molecular dynamics (RAMD) trajectories were found to be in fair agreement, both in terms of
pathway locations and deduced relative preferences, compared to targeted molecular dynamics (TMD) and streered molecular dynamics
simulations (SMD). However, the high-velocity ligand expulsions of RAMD tend to favor straight expulsion trajectories and
the observed relative frequencies of different pathways were biased towards the probability of entering a particular exit
channel. Simulations indicated that for VDR the unbinding pathway between the H1–H2 loop and the β-sheet between H5 and H6
is more favorable than the pathway located between the H1–H2 loop and H3. The latter pathway has been suggested to be the
most likely unbinding path for thyroid hormone receptors (TRs) and a likely path for retinoic acid receptor. Ligand entry/exit
through these two pathways would not require displacement of H12 from its agonistic position. Differences in the packing of
the H1, H2, H3 and β-sheet region explain the changed relative preference of the two unbinding pathways in VDR and TRs. Based
on the crystal structures of the ligand binding domains of class 2 nuclear receptors, whose members are VDR and TRs, this
receptor class can be divided in two groups according to the packing of the H1, H2, H3 and β-sheet region.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
18.
19.
Yasmine Asaad Mansour El-Sayed M.M. Mosallam Shaymaa Hussein Ebtihal M.M. Elleithy Ihab M. Moussa Ayman S. Mubarak Turki M. Dawoud Roua A. Alsubki Jwaher H. Alhaji Hassan A. Hemeg Gehad A.H. EL-Bargeesy 《Saudi Journal of Biological Sciences》2021,28(1):217-223
This study illustrated the immunohistochemical distribution of androgen and vitamin D receptors of epididymis in 20 sexually mature ram (Rahmani breed) with average age ranged from (2_4) years and average weight ranged from (50_65kg). Androgen receptor was localized in the cytoplasm of both ciliated and non ciliated cells of efferent ductules, besides the principal cells via the entire epididymal duct. The principal cells of both corpus and proximal cauda epididymis showed the highest immunoreactivity to androgen receptors. Furthermore, vitamin D receptor was localized in the cytoplasm of all epithelium of the efferent ductules besides principal cells of all epididymal regions, however the immunoreaction was significantly higher in the efferent ductules, distal caput and distal cauda epididymis. In conclusion, these results suggest that the function of ram epididymis is regulated by both androgen and Vitamin D. 相似文献
20.
Yongji Wang 《Archives of biochemistry and biophysics》2010,494(2):166-76
The active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) is critical for regulation of serum calcium and phosphorus levels and for proper maintenance of bone mineralization and neuromuscular function. Biological effects of 1,25(OH)2D3 are mediated through a nuclear steroid hormone receptor, known as the vitamin D receptor (VDR). The discovery of VDR in a number of different cell and tissue types, suggests that the physiological role of vitamin D may extend beyond the regulation of calcium homeostasis and bone function. Unfortunately, identification of tissues expressing VDR has been controversial due to low abundance of the receptor and quality of the antibodies used. Therefore, we elected to characterize a panel of commercially available VDR antibodies in order to identify antibodies with high specificity and sensitivity. To address these objectives, we have used multiple immunoassays to determine VDR expression in tissues from several organs from multiple species employing tissues from VDR knockout mice as critical negative controls. Many of the antibodies tested showed nonspecific binding that can account for divergent reports. However, one antibody, identified as D-6, is highly specific and extremely sensitive. The specificity, sensitivity, and versatility of this antibody make it the preferred antibody for identifying VDR expression in target tissues using immunological methods. 相似文献