IDENTIFICATION AND USE: Psoralen is a solid. Psoralen photochemotherapy (PUVA) is the combined treatment of skin disorders with a photosensitizing drug (Psoralen) and UltraViolet A radiation. The introduction of PUVA therapy has arguably been the most important development in dermatology over the past 30 years. HUMAN STUDIES: Exposure to more than 350 PUVA treatments greatly increases the risk of squamous cell carcinoma. Exposure to fewer than 150 PUVA treatments has, at most, modest effects on squamous cell carcinoma risk. Even high-dose exposure to PUVA does not greatly increase basal cell carcinomaa risk. The risks of squamous cell carcinom in long-term PUVA-treated patients should be considered in determining the risk of this therapy relative to other treatments for severe psoriasis. Psoralen ultraviolet B radiation (PUVB) can contribute to blue vitiligo. Psoralen can generate a very unique type of DNA damage, namely ICL (interstrand cross-link). An ICL can severely block DNA replication and transcription and cause programmed cell death. It is proposed that PUVA therapy conditions are more favorable for the formation of immunosuppressive rather than membrane-damaging psoralen photooxidation products. Psoralen inhibited the viability of normal human liver L02 cells in vitro by inducing S-phase arrest. In addition, psoralen upregulated cyclin E1 and p27 protein levels in these cells. ANIMAL STUDIES: Mice were administered psoralen intragastrically at doses of 400 mg/kg or 800 mg/kg, and were sacrificed 24 hr after treatment. Changes in various hepatotoxicity indicators demonstrated that psoralen can cause mild liver injury in mice. In addition, psoralen upregulated cyclin E1 and p27 protein levels in mouse livers. In rats, the liver was the target of toxicity of psoralen. Multivariate analysis identified 7 metabolites in serum samples and 15 in liver samples as potential biomarkers in liver injury induced by psoralen. In addition, psoralen can cause a disturbance in amino acid metabolism, especially valine, leucine, and isoleucine biosynthesis in both serum and liver samples. Mutagenic activity of psoralen was studied in the HGPRT system on V79 Chinese hamster cells in culture. When activated by near-ultraviolet (NUV) light, were effective in inducing HGPRT mutants. Albino guinea pigs were treated with furocoumarin derivatives plus 320-400 NM UV radiation, and DNA was extracted from their epidermis. The electron microscopic assay was sensitive enough to put an upper limit of 1 crosslink/10X6 nucleotide pairs (80 cross-links/chromosome) for the low dose studies. Psoralen was demonstrated to exhibit in vitro inhibitory actions on monoamine oxidase (MAO) activities in rat brain mitochondria, preferentially inhibiting MAO-A activity over MAO-B activity. ECOTOXICITY STUDIES: The rRNA genes from fungi, plants, and animals give distinctly bimodal distributions of psoralen crosslinking, which has led to the suggestion that these genes might be largely devoid of nucleosomes when transcriptionally active. Chromatin structure of the multicopy rRNA and histone genes was studied during sea urchin early embryogenesis. The rRNA genes, which are weakly expressed, give a unimodal distribution of weak psoralen crosslinking, in contrast to the situation in all other organisms studied. The early histone genes were more accessible to psoralen crosslinking when active than inactive.
The mechanism of action many furocoumarins is based on their ability to form photoadducts with DNA and other cellular components such as RNA, proteins, and several proteins found in the membrane such as phospholipases A2 and C, Ca-dependent and cAMPdependent protein-kinase and epidermal growth factor. Furocoumarins intercalate between base pairs of DNA and after ultraviolet-A irradiation, giving cycloadducts. (L579).
来源:Toxin and Toxin Target Database (T3DB)
毒理性
肝毒性
在开放标签试验中，接受甲氧沙林和紫外线光疗的受试者中，血清ALT或AST升高的情况发生在2%到12%之间。这些升高通常是轻到中度的严重程度，无症状且在过程中自我限制。临床上明显的急性肝损伤也有报道出现在口服甲氧沙林治疗中，但仅在孤立的病例报告中，包括一例归因于外用甲氧沙林治疗的情况。发病时间从1个月到5个月不等，典型潜伏期为6到8周。发病通常是隐匿的，出现恶心和腹痛，随后出现黄疸。在某些情况下会出现发热，但皮疹和嗜酸性粒细胞增多并不常见。典型的损伤模式是肝细胞损伤。已发表的补骨脂肝毒性的病例大多数是轻到中度的严重程度，但在患有预先存在肝硬化的患者中，由于甲氧沙林引起的进一步急性肝损伤，已经描述了严重的黄疸和肝衰竭导致的死亡。大多数病例在6到8周内解决。
补骨脂还存在于许多用于治疗各种疾病（包括银屑病和白斑病）的草药产品中。在使用补骨脂种籽、粉末和茶剂的病例报告中，已经报道了急性肝损伤，这些产品在中国有不同的名称，如Boh Gol Zhee、Xin Cu Hei Su和Qu Bai Ba Bu Gi Pian。化学分析显示这些产品中存在补骨脂素。这些病例的临床特征与甲氧沙林引起的特征相似，潜伏期为1到2个月，肝细胞损伤模式，无免疫过敏或自身免疫特征，自我限制过程，6到8周内恢复。
可能性评分：C（可能是临床上明显肝损伤的罕见原因）
In open label trials, serum ALT or AST elevations occurred in 2% to 12% of subjects treated with methoxsalen and UV light. The elevations were usually mild-to-moderate in severity, asymptomatic and self-limited in course. Clinically apparent acute liver injury has also been reported with oral methoxsalen therapy, but only in isolated case reports including one instance attributed to topical methoxsalen therapy. The time to onset has ranged from 1 to 5 months, the typical latency being 6 to 8 weeks. The onset is generally insidious, with appearance of nausea and abdominal pain followed by jaundice. Fever occurs in some cases, but rash and eosinophilia are not common. The typical pattern of injury is hepatocellular. Most published cases of psoralen hepatotoxicity have been mild-to-moderate in severity, but severe jaundice and death from hepatic failure has been described in patients with preexisting cirrhosis who developed further acute liver injury attributed to methoxsalen. Most cases resolve within 6 to 8 weeks.
Psoralen is also present in many herbal products used to treat various conditions including psoriasis and vitiligo. Case reports of acute liver injury have been reported with the use of seeds, powder and teas prepared from Psoralea corylifolia under various Chinese names such as Boh Gol Zhee, Xin Cu Hei Su and Qu Bai Ba Bu Gi Pian. Chemical analyses have shown the presence of psoralen in these products. The clinical features of these cases have resembled those attributed to methoxsalen with a latency of 1 to 2 months, a hepatocellular pattern of injury, absence of immunoallergic or autoimmune features, and self-limited course with recovery within 6 to 8 weeks.
Likelihood score: C (probable rare cause of clinically apparent liver injury)
Not listed by IARC. IARC has assessed other furocoumarins, classifying 8-methoxypsoralen as carcinogenic to humans (Group 1), 5-methoxypsoralen as possibly carcinogenic to humans (Group 2A), and certain other furocoumarins as not being classifiable as to their carcinogenicity to humans (Group 3). (L135)
The furocoumarin 8-methoxypsoralen is carcinogenic to humans, and possibly 5-methoxypsoralen as well (L135). There is some evidence from mouse studies that other furocoumarins are carcinogenic when combined with exposure to UVA radiation (A15105). The SKLM regards the additional risk of skin cancer arising from the consumption of typical quantities of furocoumarin-containing foods, which remain significantly below the range of phototoxic doses, as insignificant. However, the consumption of phototoxic quantities cannot be ruled out for certain foods, particularly celery and parsnips, that may lead to significant increases in furocoumarin concentrations, depending on the storage, processing and production conditions. (L2157) Furocoumarin photochemotherapy is known to induce a number of side-effects including erythema, edema, hyperpigmentation, and premature aging of skin. All photobiological effects of furocoumarins result from their photochemical reactions. Because many dietary or water soluble furocoumarins are strong inhibitors of cytochrome P450s, they will also cause adverse drug reactions when taken with other drugs.
OBJECTIVE: To investigate the nasal absorption regularities of psoralen and isopsoralen of different concentrations. METHOD: Building an experimental model of rat in situ nasal recirculation and determining the contents of psoralen and isopsoralen by HPLC. RESULT: The nasal absorption of psoralen and isopsoralen fitted in with zero order kinetics, getting saturated with the increase of concentration. CONCLUSION: A suitable concentration is necessary for the preparation of nasal remedies psoralen and isopsoralen.
Structural modification of a specific antimicrobial lead against Helicobacter pylori discovered from traditional Chinese medicine and a structure–activity relationship study
摘要：
Psoralen (1a) was found to be a specific and potent antimicrobial lead against Helicobacter pylori (H. pylori) from a traditional Chinese medicine (TCM) in the bioassay directed isolation. A series of structurally diverse analogues of la were thus designed and synthesized to improve the antimicrobial potency, some of which showed more potent activities than the lead compound (1a) against H. pylori. Among them, compound 25a is 16-fold stronger (MIC = 0.39 mu g/mL) than 1a (MIC = 6.25 mu g/mL), and is even potent than the positive control metronidazole (MIC = 0.50 mu g/mL). The in vitro antimicrobial activities against H. pylori of these structurally diverse analogues based on the scaffold of la have also led to an outline of structure-activity relationship. (C) 2010 Elsevier Masson SAS. All rights reserved.
Synthesis of 2,3-Dihydro-3-hydroxy-2-hydroxylalkylbenzofurans from Epoxy Aldehydes. One-Step Syntheses of Brosimacutin G, Vaginidiol, Vaginol, Smyrindiol, Xanthoarnol, and Avicenol A. Biomimetic Syntheses of Angelicin and Psoralen
摘要：
[GRAPHICS]We have developed two practical one-step syntheses of 2,3-dihydro-3-hydroxy-2-hydroxyalkylbenzofurans from readily available optically pure alpha,beta-epoxy aldehydes. Electron-deficient resorcinols react with epoxy aldehydes using either Cs2CO3 in DMF or KOH/CaCl2 in MeOH to give adducts 13, 16, 18, 20, 21, and brosimacutin G (6t). Grignard reagents prepared by low-temperature halogen-metal exchange of acetoxy iodocoumarins 35d and 40 and acetoxy bromonaphthalene 41 add to epoxy aldehyde (S)-26 to complete the first syntheses of vaginidiol (7c), vaginol (7t), smyrindiol (8c), xanthoarnol (8t), and avicenol A (9t). Acid-catalyzed fragmentation of vaginidiol or vaginol provides angelicin, while that of smyrindiol or xanthoarnol affords psoralen. In both cases, the trans isomers fragment only twice as fast as the cis isomers, possibly through the intermediacy of a common benzylic cation. This may have implications for the biosynthesis of angelicin and psoralen.
[EN] NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS<br/>[FR] NOUVEAUX COMPOSÉS ET COMPOSITIONS PHARMACEUTIQUES LES COMPRENANT POUR LE TRAITEMENT DE TROUBLES INFLAMMATOIRES
申请人：GALAPAGOS NV
公开号：WO2017012647A1
公开（公告）日：2017-01-26
The present invention discloses compounds according to Formula (I), wherein R1, R3, R4, R5, L1, and Cy are as defined herein. The present invention also provides compounds, methods for the production of said compounds of the invention, pharmaceutical compositions comprising the same and their use in allergic or inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 and/or interferons. The present invention also methods for the prevention and/or treatment of the aforementioned diseases by administering a compound of the invention.
Leukotriene A4 hydrolase (LTA4H) inhibitors, compositions containing them, and methods of use for the inhibition of LTA4H enzyme activity and the treatment, prevention or inhibition of inflammation and/or conditions associated with inflammation.
Substituted 1-benzoyl-3-cyano-pyrrolo [1,2-a] quinolines and analogs as activators of caspases and inducers of apoptosis
申请人：Cai Xiong Sui
公开号：US20050014759A1
公开（公告）日：2005-01-20
The present invention is directed to substituted 1-benzoyl-3-cyano-pyrrolo[1,2-a]quinolines and analogs thereof, represented by the general Formula I:
wherein R
1
—R
8
, L, Q, dash line and Ar are defined herein. The present invention also relates to the discovery that compounds having Formula I are activators of caspases and inducers of apoptosis. Therefore, the activators of caspases and inducers of apoptosis of this invention can be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.
Substituted 4-aryl-4h-pyrrolo[2,3-h]chromenes and analogs as activators of caspases and inducers of apoptosis and the use thereof
申请人：Cai Xiong Sui
公开号：US20060104998A1
公开（公告）日：2006-05-18
The present invention is directed to substituted 4H-chromenes and analogs thereof, represented by the Formula (I): wherein R
1
, R
3
-R
5
, A, D, Y and Z are defined herein. The present invention also relates to the discovery that compounds having Formula (I) are activators of caspases and inducers of apoptosis. Therefore, the activators of caspases and inducers of apoptosis of this invention can be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.
Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of store-operated calcium (SOC) channels. Also described herein are methods of using such SOC channel modulators, alone and in combination with other compounds, for treating diseases or conditions that would benefit from inhibition of SOC channel activity.
