光化学合成维生素D2和D3

综述了光化学法合成维生素Ｄ２和Ｄ３的研究进展。     

国内维生素D2研究与产业化现状

简介维生素D2的调节钙磷代谢、抑制癌细胞增殖、调节血压和免疫系统等功能,广泛应用于医药、食品、饲料等领域。重点论述国内维生素D2研究与产业化开发现状,详细介绍了维生素D2的光化学法生产工艺,展望了维生素D2广阔的市场前景。     

控制紫外波长合成维生素D3的研究

在合成维生素D3的过程中有多种光异构化产物．光异构产物取决于激发的紫外波长。束用一步光异构法。加入两种滤光液窄化禹压汞灯紫外波长在270hm-320hm．授维生素D3的转化率达到67％。     

维生素D2生产新工艺

经预处理、萃取、浓缩、结晶等过程从富含麦角固醇的菌丝体中提取麦角固醇,并用自制紫外光源和反应器将其转化为维生素D_2。此新工艺成本低,麦角固醇转化率高,具有良好的经济效益,得到的麦角固醇和维生素D_2分别符合SIGMA公司试剂标准和国家药典标准。     

国内维生素D2研究与产业化现状

合成VD的方法有热化学和光化学方法。热化学反应合成维生素D要经过20余步，光化学方法合成VD则简单得多。20世纪30年代初，科学家们就已经提出了从麦角固醇出发，利用光化学方法合成VD2的路线，麦角固醇光照得到VD2的过程相对简单，但产生多个复杂的副产物，给VD2的分离提纯造成极大困难。另外，VD2以及中间体对光、热、空气都很敏感，因此在合成过程中对控制反应与后处理的条件要求极为苛刻。     

麦角固醇光解生产维生素D2新工艺

本工艺采用紫外光照法用麦角固醇生产维生素D2(简称VD2)，并对其生产的条件进行了优化和比较，进行了工业化实验，得到了较好的结果。最终麦角固醇转化率为50％以上，维生素D2选择性得率为40％以上．达到了工业化的要求。     

维生素D衍生物的临床应用及合成方法

维生素D及其衍生物不仅可以作为治疗疾病的药物,而且也可以成为化学合成的原料。现在有些维生素D及其衍生物已经作为商品投放在市场上,并对临床研究和工业合成做出了巨大的贡献。对目前临床做出贡献的维生素D衍生物马沙骨化醇、度骨化醇、帕立骨化醇、骨化三醇、卡泊三醇和他卡西醇在临床方面的应用及合成路线进行了介绍,对药物的开发提供参考,并进一步提出未来药物开发的前景。     

天然甾体合成1α，25—二羟基维生素D3的研究进展

讨论了近年来天然甾体俣成1a,25-二羟基维生素D3的研究进展状况。     

维生素D3合成新工艺的初步设想

维生素D3在医药及临床上有许多重要的应用，其目前都是由7-脱氢胆固醇通过光照反应而得。综述了7-脱氢胆固醇的制备方法，包括两种化学法——溴化／脱溴化氢法和氧化还原消除法。由胆固醇的生物合成全过程，综述采用生物化学法合成7-脱氢胆固醇的研究，提出几种生物法合成7-脱氢胆固醇的构想：①角鲨烯或是羊毛甾醇酶法转化；②麦角固醇生产菌的改造或是采用基因工程的方法；③胆固醇经脱氢酶脱氢转化；④动物细胞培养。     

高效液相色谱法测定化妆品中VD2及VD3

采用高效液相色谱法对VD2及VD3进行测定,以甲醇/乙腈(90∶10)为流动相,流速为1.0 mL/min,DAD检测器,C18柱,检测波长260 nm,得到在0.50～50.0 mg/L浓度范围内有较好的线性关系,相关系数分别为rVD2=0.999 4和rVD3=0.999 5,回收率为96.9%～100.6%,方法检出限VD2为0.13 mg/L,VD3为0.06 mg/L。该方法快速方便,可用于化妆品VD2及VD3的检测。     

Investigation of Vitamin D2 and Vitamin D3 Hydroxylation by Kutzneria albida

The active vitamin D metabolites 25-OH−D and 1α,25-(OH)₂−D play an essential role in controlling several cellular processes in the human body and are potentially effective in the treatment of several diseases, such as autoimmune diseases, cardiovascular diseases and cancer. The microbial synthesis of vitamin D₂ (VD₂) and vitamin D₃ (VD₃) metabolites has emerged as a suitable alternative to established complex chemical syntheses. In this study, a novel strain, Kutzneria albida, with the ability to form 25-OH−D₂ and 25-OH−D₃ was identified. To further improve the conversion of the poorly soluble substrates, several solubilizers were tested. 100-fold higher product concentrations of 25-OH−D₃ and tenfold higher concentrations of 25-OH−D₂ after addition of 5 % (w/v) 2-hydroxypropyl β-cyclodextrin (2-HPβCD) were reached. Besides the single-hydroxylation products, the human double-hydroxylation products 1,25-(OH)₂−D₂ and 1,25-(OH)₂−D₃ and various other potential single- and double-hydroxylation products were detected. Thus, K. albida represents a promising strain for the biotechnological production of VD₂ and VD₃ metabolites.     

Vitamin D Analogs Regulate the Vitamin D System and Cell Viability in Ovarian Cancer Cells

Background: Ovarian cancer (OC) is one of the most lethal cancers in women. The active form of vitamin D₃, 1,25-dihydroxyvitamin D₃ (1,25D₃, calcitriol) has anticancer activity in several cancers, including ovarian cancer, but the required pharmacological doses may cause hypercalcemia. We hypothesized that newly developed, low calcemic, vitamin D analogs (an1,25Ds) may be used as anticancer agents instead of calcitriol in ovarian cancer cells. Methods: We used two patient-derived high-grade serous ovarian cancer (HGSOC) cell lines with low (13781) and high (14433) mRNA expression levels of the gene encoding 1,25-dihydroxyvitamin D₃ 24-hydroxylase CYP24A1, one of the main target genes of calcitriol. We tested the effect of calcitriol and four structurally related series of an1,25Ds (PRI-1906, PRI-1907, PRI-5201, PRI-5202) on cell number, viability, the expression of CYP24A1, and the vitamin D receptor (VDR). Results: CYP24A1 mRNA expression increased in a concentration-dependent manner after treatment with all compounds. In both cell lines, after 4 h, PRI-5202 was the most potent analog (in 13781 cells: EC₅₀ = 2.98 ± 1.10 nmol/L, in 14433 cells: EC₅₀ = 0.92 ± 0.20 nmol/L), while PRI-1907 was the least active one (in 13781 cells: EC₅₀ = n/d, in 14433 cells: EC₅₀ = n/d). This difference among the analogs disappeared after 5 days of treatment. The 13781 cells were more sensitive to the an1,25Ds compared with 14433 cells. The an1,25Ds increased nuclear VDR levels and reduced cell viability, but only in the 13781 cell line. Conclusions: The an1,25Ds had different potencies in the HGSOC cell lines and their efficacy in increasing CYP24A1 expression was cell line- and chemical structure-dependent. Therefore, choosing sensitive cancer cell lines and further optimization of the analogs’ structure might lead to new treatment options against ovarian cancer.     

The Role of Vitamin D and Vitamin D Binding Protein in Chronic Liver Diseases

Vitamin D (calciferol) is a fat-soluble vitamin that has a significant role in phospho-calcium metabolism, maintaining normal calcium levels and bone health development. The most important compounds of vitamin D are cholecalciferol (vitamin D3, or VD3) and ergocalciferol (vitamin D2, or VD2). Besides its major role in maintaining an adequate level of calcium and phosphate concentrations, vitamin D is involved in cell growth and differentiation and immune function. Recently, the association between vitamin D deficiency and the progression of fibrosis in chronic liver disease (CLD) was confirmed, given the hepatic activation process and high prevalence of vitamin D deficiency in these diseases. There are reports of vitamin D deficiency in CLD regardless of the etiology (chronic viral hepatitis, alcoholic cirrhosis, non-alcoholic fatty liver disease, primary biliary cirrhosis, or autoimmune hepatitis). Vitamin D binding protein (VDBP) is synthesized by the liver and has the role of binding and transporting vitamin D and its metabolites to the target organs. VDBP also plays an important role in inflammatory response secondary to tissue damage, being involved in the degradation of actin. As intense research during the last decades revealed the possible role of vitamin D in liver diseases, a deeper understanding of the vitamin D, vitamin D receptors (VDRs), and VDBP involvement in liver inflammation and fibrogenesis could represent the basis for the development of new strategies for diagnosis, prognosis, and treatment of liver diseases. This narrative review presents an overview of the evidence of the role of vitamin D and VDBP in CLD, both at the experimental and clinical levels.     

维生素B6的合成研究进展

维生素B6是一种重要的水溶性维生素,为人体和动物生长所必需,因此被广泛用于医药、食品及饲料添加剂等领域。本文综述了近年来维生素B6的合成研究进展,分别介绍了化学合成方法及微生物法在维生素B6合成中的应用,比较了各法的优缺点,并对研究前景进行了展望。     

Chemical Synthesis of Side-Chain-Hydroxylated Vitamin D3 Derivatives and Their Metabolism by CYP27B1

1α,25-Dihydroxyvitamin D₃ (abbreviated here as 1,25D₃) is a hormonally active form of vitamin D₃ (D₃), and is produced from D₃ by CYP27 A1-mediated hydroxylation at C25, followed by CYP27B1-mediated hydroxylation at C1. Further hydroxylation of 25D₃ and 1,25D₃ occurs at C23, C24 and C26 to generate corresponding metabolites, except for 1,25R,26D₃. Since the capability of CYP27B1 to hydroxylate C1 of side-chain-hydroxylated metabolites other than 23S,25D₃ and 24R,25D₃ has not been examined, we have here explored the role of CYP27B1 in the C1 hydroxylation of a series of side-chain-hydroxylated D₃ derivatives. We found that CYP27B1 hydroxylates the R diastereomers of 24,25D₃ and 25,26D₃ more effectively than the S diastereomers, but shows almost no activity towards either diastereomer of 23,25D₃. This is the first report to show that CYP27B1 metabolizes 25,26D₃ to the corresponding 1α-hydroxylated derivative, 1,25,26D₃. It will be interesting to examine the physiological relevance of this finding.     

维生素B6合成中的Diels-Alder反应及重排机理研究

4-甲基-5-乙氧基噁唑与2-正丙基-4,7-二氢-1,3-二氧七环之间的Diels-Alder反应是合成维生素B6传统工艺的关键反应,加成物经过重排即生成维生素B6的前体,经水解脱保护后再成盐即制得维生素B6相关酸加成盐。文章通过分离纯化并鉴定加成反应产物及后续重排反应的中间体,对加成反应的exo/endo选择性及重排反应的机理过程进行了讨论,这些结果将被用于对exo/endo选择性和反应体系收率影响进行研究。     

Vitamin D-Binding Protein and the Free Hormone Hypothesis for Vitamin D in Bio-Naïve Patients with Psoriasis

High levels of vitamin D-binding protein (DBP) have been reported in patients with psoriasis and the possibility of DBP as a marker of inflammation has been discussed. Furthermore, high DBP levels might negatively affect free 25(OH)D concentrations. According to the free hormone hypothesis, only the free fraction of a steroid hormone is capable of exerting biological action. Thus, free 25(OH)D level could be a better biomarker of vitamin D status than total 25(OH)D level. The objectives of this study were to identify the strongest determinants for DBP levels and to test the free hormone hypothesis for vitamin D in psoriasis. Additionally, we also aimed to investigate correlations between directly measured free 25(OH)D levels in serum and psoriasis disease severity compared to total 25(OH)D levels. This was a retrospective cross-sectional study including 40 bio-naïve patients with mild to severe plaque psoriasis. Psoriasis disease severity was evaluated using high sensitivity C-reactive protein (hsCRP), Psoriasis Area Severity Index (PASI) and visual analogue scale (VAS). Vitamin D metabolites including directly measured free 25(OH)D and serum DBP levels were measured. DBP levels were higher in patients with self-reported arthropathy than those without irrespective of confounding factors like sex, age and body weight. Total and free 25(OH)D levels correlated well (ρ = 0.77, p < 0.0001) and both were inversely correlated to intact parathyroid hormone (iPTH) (ρ = −0.33, p = 0.038 for total 25(OH)D and ρ = −0.40, p = 0.010 for free 25(OH)D). Only total 25(OH)D correlated to serum calcium levels (ρ = 0.32, p = 0.047). No correlations between any of the vitamin D metabolites and psoriasis disease severity were observed. In conclusion, DBP might be a new inflammatory biomarker in psoriasis, especially in psoriatic arthritis. Total 25(OH)D was a reliable measure for vitamin D status in this psoriasis cohort. However, evaluation of free 25(OH)D in patients with psoriatic disease and multiple co-morbidities and/or ongoing biologic treatment should be considered.