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1.
Ono K Yoshida A Saito N Fujishima T Honzawa S Suhara Y Kishimoto S Sugiura T Waku K Takayama H Kittaka A 《The Journal of organic chemistry》2003,68(19):7407-7415
Six novel 2-substituted analogues of 1alpha,25-dihydroxy-19-norvitamin D(3), 6a,b-8a,b, were efficiently synthesized utilizing (-)-quinic acid as the A-ring precursor. The C2-modified A-rings were prepared as 4-alkylated (3R,5R)-3,5-dihydroxycyclohexanones 12-15 from (-)-quinic acid based on radical allylation at the C4 position of methyl (-)-quinicate. The new type of the CD-ring coupling partner 23 was synthesized from 25-hydroxy Grundmann's ketone 19 to apply to the modified Julia olefination to construct a diene unit between the A-ring and the CD-ring. The coupling yields, including a deprotection step, were 47-62%. After the separation of the diastereomers based on C2 stereochemistry, the structure (2alpha or 2beta) was determined by (1)H NMR experiments and compared to DeLuca's 2-methyl- and 2-ethyl-1alpha,25-dihydroxy-19-norvitamin D(3). Thus, the synthesized 2alpha-(3-hydroxypropyl)-1alpha,25-dihydroxy-19-norvitamin D(3) (8a) showed almost the same potency in binding to the bovine thymus vitamin D receptor (VDR) as the natural hormone 1, while its beta-isomer 8b had only a 3% affinity. Both 2alpha-allyl- and 2alpha-propyl-1alpha,25-dihydroxy-19-norvitamin D(3) (6a and 7a) and their 2beta-analogues (6b and 7b) possessed a weak affinity for the VDR. The strong VDR ligand 8a was ca. 36-fold more potent in induction of HL-60 cell differentiation than 1, and interestingly, even the weaker ligand 8b showed a 6.7-fold higher potency in the cell differentiation activity than that of 1. 相似文献
2.
A highly efficient synthesis of the vitamin D(3) system on solid support is described. Two synthetic strategies for the solid-phase synthesis of vitamin D(3) were developed. One is for 11-hydroxy analogues, and the other is for most other synthetic analogues. In the latter strategy, the sulfonate-linked CD-ring 58 was initially immobilized on PS-DES resin to give solid-supported CD-ring 63 (Scheme 10). Similarly, solid-supported CD-ring 63 was prepared by attachment of the CD-ring 10 to the chlorosulfonate resin 64. The vitamin D(3) system was synthesized by Horner-Wadsworth-Emmons reaction of the A-ring phosphine oxide to a solid-supported CD-ring, followed by simultaneous introduction of the side chain and cleavage from resin with a Cu(I)-catalyzed Grignard reagent. Parallel synthesis of the vitamin D(3) analogues was accomplished by a split and pool methodology utilizing radio frequency encoded combinatorial chemistry, and a manual parallel synthesizer for side chain diversification and deprotection. Additionally, we demonstrated the synthesis of various A-rings in a similar protocol for efficient preparation of building blocks. 相似文献
3.
Saitoh H Chida T Takagi K Horie K Sawai Y Nakamura Y Harada Y Takenouchi K Kittaka A 《Organic & biomolecular chemistry》2011,9(10):3954-3964
In order to obtain vitamin D derivatives, which have strong activity for enhancing bone growth, we designed vitamin D derivatives with various substitutions at the C-2 position. Novel 2 α-substituted vitamin D derivatives were synthesized starting from d-glucose as a chiral template of the A-ring with a CD-ring bromoolefin unit using the Trost coupling method. We evaluated these compounds by two in vitro assays, affinity to VDR and transactivation assays, using human osteosarcoma (Hos) cells, and demonstrated the SAR of the C-2 position of VD(3). Furthermore, by using the OVX model, we found that compound 5c, which has a hydroxypropoxy side chain at C-2 and 2,2-dimethyl cyclopentanone in the CD-ring side chain, has a strong activity for enhancing bone growth, same as the reported compound, 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D(3)1d, and this derivative shows a possibility that calcemic activity is less than 1d in vivo. 相似文献
4.
Efficient syntheses of A-ring synthons 24 and 32 are described from hydroxy ester 16, which is easily available on a preparative scale from (-)-quinic acid. Key features of the syntheses were (a) the ability to selectively perform desilylations in the presence of p-nitrobenzoate esters and (b) the excellent yield and complete stereospecificity with which the configuration of alcohols 16, 18, and 26 could be inverted under Mitsunobu conditions. Thus, A-ring synthons 24 and 32 were both prepared in 35-38% yield (eight steps) from the common precursor 16. The coupling of A-ring synthons 24 and 32 with the appropriate CD-ring/side chain fragment 7 provides access to novel 6-s-cis locked analogues of steroid hormone 1alpha, 25-dihydroxyvitamin D(3): 1alpha, 25-dihydroxy-3-epi-19-nor-previtamin D(3) (37) and 1beta, 25-dihydroxy-3-epi-19-nor-previtamin D(3) (38), which are unable to undergo rearrangement to the respective vitamin D form by virtue of the absence of the C-19 methyl group. Compounds 37 and 38 can be used as tools for studying the genomic and nongenomic mechanisms of action of the previtamin form of the hormone 1alpha, 25-dihydroxyvitamin D(3). 相似文献
5.
Gabriëls S Van Haver D Vandewalle M De Clercq P Verstuyf A Bouillon R 《Chemistry (Weinheim an der Bergstrasse, Germany)》2001,7(2):520-532
The discovery that 1alpha,25-dihydroxyvitamin D3 is effective in the inhibition of cellular proliferation and in the induction of cellular differentiation has led to a search for analogues in which these activities and the classical calcemic activity of this hormone are separated. In this context, the synthesis and biological evaluation are reported of the three stereoisomeric CD-ring modified structural analogues in order to enforce a particular and different orientation of the 25-hydroxylated side chain. Comparison of the results of the biological evaluation and conformational analysis of the side chain suggests one defined and "active" geometry. 相似文献
6.
Toshie Fujishima Takuro Komatsu Yuri Takao Wataru Yonamine Tsutomu Suenaga Hiroaki Isono Masayuki Morikawa Keisuke Takaguchi 《Tetrahedron》2019,75(8):1098-1106
Five novel vitamin D analogues (2a, 2b, 3a, 3b and 4) bearing an aromatic side chain have been designed and synthesized in a convergent manner. The requisite CD-ring synthons (10a–c) were prepared from C22 aldehyde (5) using four- or five-step procedures. Using turbo-Grignard reagents allowed aromatic side chains with a polar functional moiety to be installed in a single step with excellent yields. A preliminary biological evaluation using bovine thymus vitamin D receptor (VDR) suggested that incorporating a carboxylic acid instead of the C25-hydroxy group had a positive effect on the VDR affinity compared with the corresponding esters. 相似文献
7.
An example of the Julia-Lythgoe attachment of the vitamin D side chain to a solid-phase linked Inhoffen-Lythgoe diol derived CD-ring fragment is reported. 相似文献
8.
9.
A synthesis of enantiopure 19-nor-Vitamin D(3) and its C-2 substituted cyclic phosphate analogs is achieved via in situ trapping of an α-sulfonyl anion with a CD-ring allyl chloride and 1,2-eliminative desulfonylation exploiting the basic properties of TBAF. The A-ring is prepared via anti-selective dithiane addition to vinyl sulfone and LiBH(4) mediated sequential bis reduction of an epoxy vinyl sulfone. 相似文献
10.
In search of analogs of 1α,25-dihydroxyvitamin D3 featuring a dissociation of calcemic and other activities, a series of stereoisomeric 19-nor-22-oxa derivatives, characterized by a spiro[4.5]decane cyclic system instead of the classical CD-ring system, have been synthesized in an enantioselective way. 相似文献
11.
Chen YJ Gao LJ Murad I Verstuyf A Verlinden L Verboven C Bouillon R Viterbo D Milanesio M Van Haver D Vandewalle M De Clercq PJ 《Organic & biomolecular chemistry》2003,1(2):257-267
A novel series of analogs of 1,25-dihydroxyvitamin D3, the hormonally active metabolite of vitamin D3, characterised by the presence of a trans-fused decalin CD-ring system, possesses surprising biological activities in combination with specific structural modifications in the flexible parts of the molecule, when compared with the natural hydrindane derivatives. (1) A large difference in biological activity is observed between the 20-epimeric trans-decalin analogs that follows a pattern opposite to what is usually observed for the natural ring size. (2) Several trans-decalin analogs that are modified in the seco-B-ring region, including previtamin derivatives, possess a pronounced vitamin D-like activity, whereas the corresponding hydrindane derivatives are inactive. The molecular origin of this behavior is still under study. 相似文献
12.
Five new cyclolanostane triterpene glycosides, 12-deacetyloxy-15alpha-hydroxy-23-epi-26-deoxyactein, 12-deacetyloxy-23-epi-26-deoxyactein, 24-O-acetyldahurinol-3-O-beta-D-xylopyranoside, 12beta-hydroxycimigenol-3-O-beta-D-xylopyranosyl-(1-->3)-beta-D-xylopyranoside, 25-anhydrocimicigenol-3-O-beta-D-(2'-O-acetyl)xylopyranoside, were isolated from the rhizome of Souliea vaginata collected in China. Their structures were elucidated by spectroscopic techniques, including 2D NMR spectra, and in the case of 5, by chemical correlation. 相似文献
13.
Sydorenko N Zificsak CA Gerasyuto AI Hsung RP 《Organic & biomolecular chemistry》2005,3(11):2140-2144
Total syntheses of indoloquinolizidine alkaloid (+/-)-, R-(+)-, and S-(-)-deplancheine are described here. The synthesis features an enantioselective intramolecular formal aza-[3 + 3] cycloaddition for the construction of the quinolizidine CD-ring. This application serves to introduce a new synthetic strategy for the synthesis of indoloquinolizidine alkaloids. 相似文献
14.
[reaction; see text] Asymmetric synthesis of the spirocyclic CD-ring moiety of (+)-ophiobolin A is described. Fragment A, which was prepared via pig liver esterase (PLE)-mediated kinetic resolution, and fragment B, which was prepared via diastereoselective allylation and subsequent kinetic iodolactonization, were coupled to afford the allylsilane 2, which was successfully cyclized to the desired spirocyclic CD-ring moiety 1a in the presence of a Lewis acid. 相似文献
15.
An atomistic molecular dynamics simulation of the protein villin headpiece subdomain or HP-36 has been carried out with explicit water to explore the microscopic inhomogeneity of local density reorganization of the hydration layers of the three alpha-helical segments of the protein. The density reorganization of the hydration layer of helix-3 is found to occur faster than that for the hydration layers of the other two helices. It is noticed that such inhomogeneous density reorganization at the surface of different secondary structures exhibits excellent correlation with the microscopic dynamics of hydrogen bonds between the protein residues and the hydration water. Further, it is observed that the reorientation of water molecules involved in the formation and breaking of protein-water or water-water hydrogen bonds plays an important role in determining the dynamics of local density of the hydration layer. The faster density reorganization of the hydration layer of helix-3 is also consistent with the functionality of HP-36, as helix-3 contains several active site residues. 相似文献
16.
建立了一种高通量液相色谱-串联质谱技术检测干血点(DBS)样本中25-羟基维生素D2[25(OH)D2]和25-羟基维生素D3[25(OH)D3]的方法.以DBS为样本,以4-苯基-1,2,4-三唑啉-3,5-二酮(PTAD)为试剂进行分析物衍生化,所需样本量仅约相当于6μL全血当量的DBS样本;使用甲醇直接超声提取分析物,避开了通常情况下DBS样本前处理中的全血复溶和蛋白质沉淀等繁琐步骤;整个前处理过程使用自动化液体处理平台实现自动化操作和高检测通量;以25(OH)D2-D6和25(OH)D3-D3为同位素内标,消除基质效应的影响.前处理后的样本进行LC-MS/MS分析,使用C18柱进行分离,流动相为甲醇(含5 mmol/L甲酸铵)-水(含5 mmol/L甲酸铵)(75:25,V/V),洗脱时间为4 min,使用多反应监测模式(MRM)定量.结果表明:25(OH)D2和25(OH)D3的检出限为0.12 ng/mL(S/N=3),定量限为0.94 ng/mL(S/N=10).25(OH)D2和25(OH)D3在0.94~120.00 ng/mL范围内线性关系良好,日内相对标准偏差(RSD)分别为1.4%~8.6%和3.7%~15.5%,日间RSD分别为4.0%~5.3%和3.8%~14.9%,平均回收率分别为91.7%±7.9%~108.5%±6.5%和94.8%±6.8%~101.3%±2.9%.DBS样本在不同温度(-20℃,22℃,37℃)下储存不同时间(0,1,2,3,5,7,14天)后的稳定性实验显示样本总体RSD°15%.以25(OH)D参考物质NIST SRM 972a中的Level 3制备标准DBS样本,25(OH)D2和25(OH)D3的回收率分别为110.3%和103.0%. 相似文献
17.
Differences in agonist responses of the novel estrogen receptor ligands (17alpha,20Z)-(p-methoxyphenyl)vinyl estradiol (1), (17alpha, 20Z)-(o-alpha,alpha,alpha-trifluoromethylphenyl)vinyl estradiol (2), and (17alpha,20Z)-(o-hydroxymethylphenyl)vinyl estradiol (3) led us to investigate their solution conformation. In competitive binding assay studies, we observed that several phenyl-substituted (17alpha, 20E/Z)-(X-phenyl)vinyl estradiols exhibited significant estrogen receptor binding, but with variation (RBA (1) = 20; RBA (2) = 23; RBA (3) = 140 where estradiol RBA = 100) depending on the phenyl substitution pattern. Because the 17alpha-phenylvinyl substituent interacts with the key helix-12 of the ligand binding domain, we considered that differences in the preferred conformation of 1-3 could account for their varying binding affinity. 2D NMR experiments at 500 MHz allowed the complete assignment of the (13)C and (1)H spectra of 1-3. The conformations of these compounds in solution were established by 2D and 1D NOESY spectroscopy. A statistical approach of evaluating contributing conformers of 1-3 from predicted (13)C shifts correlated quite well with the NOE data. The 17alpha substituents of 1 and 2 exist in similar conformational equilibria with some differences in relative populations of conformers. In contrast, the 17alpha substituent of 3 exists in a different conformational equilibrium. The similarity in solution conformations of 1 and 2 suggests they occupy a similar receptor volume, consistent with similar RBA values of 20 and 23. Conversely, the different conformational equilibria of 3 may contribute to the significant binding affinity (RBA = 140) of this ligand. 相似文献
18.
T Eguchi N Ikekawa K Sumitani M Kumegawa S Higuchi S Otomo 《Chemical & pharmaceutical bulletin》1990,38(5):1246-1249
A series of analogs of 1 alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3 (1)] with alkyl substitutions in 26- and 27-positions have been tested for their activity 1) in competing with 1,25-(OH)2D3 for binding to chick intestinal cytosol receptor, 2) in ability for formation of multinucleated cells (MNC) with various osteoclastic cell characteristics from blast cells, and 3) in stimulating bone calcium mobilization in vitamin D-deficient rats. The relative potencies of 1,25-(OH)2D3, 1 alpha,25-dihydroxy-26,27-dimethylvitamin D3 (2), 1 alpha,25-dihydroxy-26,27-diethylvitamin D3 (3), and 1 alpha,25-dihydroxy-26,27-dipropylvitamin D3 (4) in competing for intestinal cytosolic binding were 1:1.1:0.25:0.05. The similar order of the abilities on formation of the multinucleated cells in the same series was observed. In a bone calcium mobilization test with vitamin D-deficient rats, 1 alpha,25-dihydroxy-26,27-dimethylvitamin D3 showed slightly less activity than 1,25-(OH)2D3 at 12 h after administration, but long lasting activity was observed during time course experiments. 1 alpha,25-Dihydroxy-26,27-diethylvitamin D3, and 1 alpha,25-dihydroxy-26,27-dipropylvitamin D3 were found to be much less active than 1,25-(OH)2D3 in a bone calcium mobilization test. 相似文献
19.
Bandyopadhyay S Chakraborty S Bagchi B 《Journal of the American Chemical Society》2005,127(47):16660-16667
The heterogeneous nature of a protein surface plays an essential role in its biological activity and molecular recognition, and this role is mediated at least partly through the surrounding water molecules. We have performed atomistic molecular dynamics simulations of an aqueous solution of HP-36 to investigate the correlation between the dynamics of the hydration layer water molecules and the lifetimes of protein-water hydrogen bonds. The nonexponential hydrogen bond lifetime correlation functions have been analyzed by using the formalism of Luzar and Chandler, which allowed identification of the quasi-bound states in the surface and quantification of the dynamic equilibrium between quasi-bound and free water molecules in terms of time-dependent rate of interconversion. It is noticed that, irrespective of the structural heterogeneity of different segments of the protein, namely the three alpha-helices, the positively charged amino acid residues form longer-lived hydrogen bonds with water. The overall relaxation behavior of protein-water hydrogen bonds is found to differ significantly among the three helices of the protein. Study of water number density fluctuation reveals that the hydration layer of helix-3 is much less rigid, which can be correlated with faster structural relaxation of the hydrogen bonds between its residues and water. This also agrees excellently with faster translational and rotational motions of water near helix-3, and hence the lower rigidity of its hydration layer. The lower rigidity of the helix-3 hydration layer also correlates well with the biological activity of the protein, as several of the active-site residues of HP-36 are located in helix-3. 相似文献
20.
The first synthesis of analogues of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (1a) with substituents at C-12 is reported. The following are the relative affinities of the novel compounds for the vitamin D receptor (VDR) compared to that of 1a (100%): 1alpha,12alpha,25-(OH)(3)-D(3) (1b, 1%), 1alpha,25-(OH)(2)-12-methylene-D(3) (1c, 50%), and 1alpha,25-(OH)(2)-12beta-methyl-D(3) (1d, 440%). [structure: see text] 相似文献