Synthesis of modified vitamin D precursors

Modified vitamin D precursors with oxygen-containing substituents at various positions in the side-chain were obtained using previously synthesized 20-isoxazolin-3-yl-and 20-isoxazolin-5-ylsteroids.Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 220141 Minsk, Belarus;Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 230–235, February, 2000.     

Dramatic enhancement of antagonistic activity on vitamin D receptor: a double functionalization of 1alpha-hydroxyvitamin D3 26,23-lactones

The synthesis of novel vitamin D receptor antagonists, 24-methyl-1alpha-hydroxyvitamin D(3) 26,23-lactones, is reported. We found that the biological activities of the vitamin D(3) lactones were affected by the structure of the lactone part. Furthermore, introduction of a 2alpha-methyl group into the 24-methylvitamin D(3) lactones dramatically enhanced their anti-vitamin D activity. [reaction: see text]     

Synthesis of C-19-functionalized 1alpha-hydroxyvitamin D(2) analogues via ring-closing metathesis

A heteroatom-tethered regioselective ring-closing metathesis reaction was used for the C-19 functionalization of 1alpha-hydroxy-5,6-trans-vitamin D(2) analogues. Applications of the reaction to form a range of analogues by manipulation of the tether using both organolithium reagents and Diels-Alder cycloadditions are described.     

Synthesis and pharmacokinetics of 1 alpha-hydroxyvitamin D3 tritiated at 22 and 23 positions showing high specific radioactivity

A novel synthesis of a radioactive compound of 1 alpha-hydroxyvitamin D3 (1 alpha OHD3) (1) and its pharmacokinetics are described. Radioactive 1 alpha OHD3 tritiated at 22 and 23 positions ([22,23-(3)H4]1 alpha OHD3) (5) was prepared via key reactions of the reduction of acetylenic side chain in the ketone (12) with tritium gas in the presence of palladium-charcoal and the subsequent Wittig reaction with the A-ring synthon (16). [22,23-(3)H4]1 alpha OHD3 (5) showed high specific radioactivity (111.5 Ci/mmol) and was used successfully in pharmacokinetics studies with rats. In the pharmacokinetics studies, the plasma concentration level of the active form of vitamin D3, 1 alpha,25-dihydroxy-vitamin D3 [1 alpha,25(OH)2D3], after oral or intravenous administration of [22,23-(3)H4]1 alpha OHD3 (5), showed longer half-life, lower maximum concentration, and lower area under the curve than those after treatment of 1 alpha,25(OH)2D3 tritiated at 26 and 27 positions (4). These results might suggest a beneficial therapeutic utility of 1 alpha OHD3 (1) over the treatment of 1 alpha,25(OH)2D3 (2).     

Synthesis of methylenedioxy-bearing 1-aryl-3-carboxylisoquinolines using a modified Ritter reaction procedure

This paper describes original approaches aimed at the preparation of electron-rich 1-aryl-3-carboxylisoquinolines. Our first attempt led to an efficient preparation of 1-hydroxyisoquinoline-3-carboxylic acid methyl ester starting from bromophthalide via a rearrangement of 2-acetylamino-2-(3-oxo-1,3-dihydroisobenzofuran-1-yl)-malonic acid dimethyl ester. However, as its eventual application to the synthesis of methylenedioxy-bearing substrates seemed rather long, a second approach involving an extension of the Ritter reaction to safrole was devised. We thus report that, under proper experimental settings, the use of 54% tetrafluoroboric acid in ether enables a Ritter reaction between safrole and 3,4,5-trimethoxybenzonitrile yielding 17% of 7-methyl-5-(3,4,5-trimethoxyphenyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline. This acidic reagent avoids the extensive decomposition seen when using the classical Ritter reaction conditions (i.e.: concentrated sulfuric acid). Further chemical transformations of this methyl-bearing dihydroisoquinoline led to the methylenedioxy-bearing 1-aryl-3-carboxylisoquinoline. These derivatives are related to the peripheral benzodiazepine receptor ligand PK 11195 as well as falcipain-2 inhibitors and other potential antitumor agents.     

Synthesis of gibbilimbols B and D by a modified Ramberg-Backlund reaction

Gibbilimbols B and D were synthesized from the facile rearrangement of sulfone in the presence of dibromodifluoromethane and alumina-supported KOH in dichloromethane,followed by refluxing the rearrangement products in conc.HC1 and methanol and then treating with thiophenol in the presence of AIBN.     

Application of ring-closing metathesis to the synthesis of 19-functionalized derivatives of 1alpha-hydroxyvitamin D3

[STRUCTURE: SEE TEXT] The synthesis of the 19-functionalized derivative of vitamin D3 based on ring-closing metathesis (RCM) is presented.     

Computational model for vitamin D deficiency using hair mineral analysis

Vitamin D deficiency is prevalent in the Arabian Gulf region, especially among women. Recent studies show that the vitamin D deficiency is associated with a mineral status of a patient. Therefore, it is important to assess the mineral status of the patient to reveal the hidden mineral imbalance associated with vitamin D deficiency. A well-known test such as the red blood cells is fairly expensive, invasive, and less informative. On the other hand, a hair mineral analysis can be considered an accurate, excellent, highly informative tool to measure mineral imbalance associated with vitamin D deficiency. In this study, 118 apparently healthy Kuwaiti women were assessed for their mineral levels and vitamin D status by a hair mineral analysis (HMA). This information was used to build a computerized model that would predict vitamin D deficiency based on its association with the levels and ratios of minerals. The first phase of the proposed model introduces a novel hybrid optimization algorithm, which can be considered as an improvement of Bat Algorithm (BA) to select the most discriminative features. The improvement includes using the mutation process of Genetic Algorithm (GA) to update the positions of bats with the aim of speeding up convergence; thus, making the algorithm more feasible for wider ranges of real-world applications. Due to the imbalanced class distribution in our dataset, in the second phase, different sampling methods such as Random Under-Sampling, Random Over-Sampling, and Synthetic Minority Oversampling Technique are used to solve the problem of imbalanced datasets. In the third phase, an AdaBoost ensemble classifier is used to predicting the vitamin D deficiency. The results showed that the proposed model achieved good results to detect the deficiency in vitamin D.     

Effects of wavelength and conformation on the photochemistry of vitamin D and related conjugated trienes

Irradiation experiments under various conditions establish that the photoreactions of conjugated trienes are governed by the ground state conformational equilibrium and the NEER principle, as well as by the wavelength dependent relaxation behaviour of the excited species.     

5-苄氧亚氨基-5-脱氧阿维菌素B1a的合成

以阿维菌素B1a为原料经过选择性氧化合成5-氧代-5-脱氧阿维菌素B1a, 再与O-取代羟胺盐酸盐反应合成了5个5-苄氧亚氨基-5-脱氧阿维菌素B1a (4a～4e), 通过¹H NMR, ¹³C NMR, MS, IR确证了它们的结构. 生测结果表明它们对于棉铃虫和甜菜夜蛾有一定的杀虫活性.     

Vector properties of the O(1D2) fragment produced from the photolysis of ozone in the wavelength range of 298 to 320 nm

The speed averaged translational anisotropy and electronic angular momentum polarization of the O(1D2) atomic fragment formed from the photodissociation of ozone in the atmospherically important long wavelength region of the Hartley band (298 to 320 nm) have been measured using resonance enhanced multiphoton ionization time of flight mass spectrometry. The translational anisotropy parameter, beta, is found to decline from 1.1 for photolysis at 300 nm to a minimum value of 0 at 310 nm which is the threshold for production of O(1D2) in conjunction with the O2(a 1Deltag v = 0) molecular cofragment. For photolysis wavelengths greater than 310 nm, O(1D2) is formed from the dissociation of internally excited ozone molecules. The corresponding beta parameters are markedly lower than for atomic fragments produced with the same speed from the photolysis of ground state ozone molecules. This result is consistent with two different pathways contributing to the photolysis of internally excited ozone at the longest wavelengths studied corresponding to initial internal excitation either in the symmetric or asymmetric stretching vibration. In addition, the polarization of the atomic angular momentum has been determined with the incoherent polarization parameters a0(2)(||) and a0(2)(_|) increasing from values of -0.53 and -0.62 at 300 nm to -0.37 and -0.19 at 317 nm, consistent with the increasing contribution from the photolysis of internally excited ozone as the dissociation wavelength lengthens. Evaluation of these alignment parameters allows the populations of the magnetic substrates, mj, to be determined. For example, for a photolysis wavelength of 303 nm the populations of mj = 0, +/- 1, +/- 2 are in the ratio of 0.36: 0.56: 0.08 and this ratio is essentially independent of the photolysis wavelength. The coherent contribution to the atomic polarization is quantified by the Re{a1(2)(||, _|)} and Im{a1(1)(||, _|)} parameters and these are found to vary from -0.21 and 0.21 at 300 nm to -0.04 and 0.24 at 313 nm, respectively.     

Synthesis of modified uracil and cytosine nucleobases using a microwave-assisted method

Modified nucleobases and nucleic acids have found many biological and pharmaceutical applications. Here we report a microwave-directed synthesis of a variety of modified uracil and cytosine nucleobases with high yields under solvent-free conditions. The reaction yields were further improved by addition of Lewis acid. The crystal structures of 5-isopropyl-6-methyluracil and 6-phenyluracil were also determined.     

Direct observation of spin-forbidden formation of O(D) in the near-UV photolysis of ozone

Time-of-flight measurements have been made of the O(¹D) fragment following the photolysis of ozone in the near-UV. At 321.9 nm fragments are seen with kinetic energies the values of which are those expected from spin-forbidden dissociation with ground state O₂(X³Σ_g⁻) molecules as the co-product. Spin-allowed dissociation of internally excited ozone molecules is also seen to produce translationally cold O(¹D) and O₂(a¹Δ_g) products. The implications for the dissociation of tropospheric ozone are briefly discussed.     

Synthesis of vitamin D(3) and calcitriol dimers as potential chemical inducers of vitamin D receptor dimerization

The design and synthesis of vitamin D(3) dimers 2 and 3 and 1 alpha, 25-dihydroxyvitamin D(3) (calcitriol) dimers 4 and 5 are described. The dimers were designed with a view to doubly binding the vitamin D receptor (VDR) and inducing the receptor homodimerization. In the dimers the units are linked through the C-11 position in ring C by an alkyl side chain of six or 10 carbon atoms, far from the hydroxy groups responsible for the VDR binding. The linker is formed by olefin metathesis of an olefinic side chain at the C-11 position introduced by stereoselective cuprate addition. The synthesis, which is both short and convergent, uses the Wittig-Horner approach to construct the vitamin D triene system and allows the preparation of dimers with a linker of modulated length with the purpose of optimizing the vitamin D(3)-VDR interaction.     

六氟磷酸/聚苯胺催化合成1,5-苯并二氮杂类化合物

以聚苯胺和六氟磷酸为原料制备了六氟磷酸/聚苯胺(HPF6/PANI)催化剂,研究了该催化剂在邻苯二胺与酮环化缩合反应合成1,5-苯并二氮杂化合物中的催化活性,考察了催化剂用量、温度、溶剂对反应的影响及催化剂的重复使用性.结果表明,该催化剂具有较高的催化活性及较好的重复使用性.     

Significance of water quality and radiation wavelength for UV photolysis of PhCs in simulated mixed solutions

Ultraviolet (UV) photolysis of sixteen pharmaceutical compounds (PhCs) in mixed solutions with four types of water and two sets of UV radiation was investigated. UVC (254 nm) photolysis was ineffective at eliminating a large number of PhCs while a big number of them were refractory. However, vacuum UV (VUV: 185 nm + 254 nm) photolysis in the same experimental conditions eliminated the PhCs almost completely. The eliminations in ultrapure water (UPW), tap water (TW) and Neya River water (NRW) and their organic/inorganic contents were inversely correlated, which was more evident in VUV photolysis. Natural organic matter (NOM) in NRW did not have an impact in indirect photolysis, but effluent organic matter (EfOM) in secondary-treated effluent (NWTPE) enhanced indirect photolysis, which was more evident in VUV photolysis underlining the point that radiation wavelength/intensity can be a limiting factor in organic-rich waters. Moreover, VUV photolysis was far superior (90% mineralization) to UVC photolysis (10% mineralization) for PhCs mineralization. The greatly enhanced elimination and mineralization efficiencies observed for VUV photolysis were attributed to accelerated direct photolysis with 185 nm wavelength and indirect photolysis involving ^·OH. The results demonstrated efficacy of VUV photolysis in wastewater treatment and its potential use as a tertiary treatment.