lovastatin acid

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羟基酸及其衍生物
• 英文名称: lovastatin acid
• 英文别名: lovastatin β-hydroxy acid；(3R)-7-[(1S,2S,6R,8S,8aR)-2,6-dimethyl-8-[(2S)-2-methylbutanoyl]oxy-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]-3,5-dihydroxyheptanoic acid
• 化学式: C₂₄H₃₈O₆
• 分子量: 422.562
• InChiKey: QLJODMDSTUBWDW-FBGYVUILSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  30
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  104
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  lovastatin acid 在 三氟乙酸 作用下， 以 乙酸乙酯 为溶剂， 反应 0.17h， 生成 洛伐他汀
  参考文献：
  名称：

  Bioprospecting lovastatin production from a novel producer Cunninghamella blakesleeana

  摘要：

  除了具有抗胆固醇的活性外，洛伐他汀在治疗各种疾病（尤其是癌症）方面的应用也受到全世界的关注。研究人员从土壤样本中分离出 36 种丝状真菌，并通过酵母生长生物测定法对其生产的洛伐他汀进行了筛选。C9 菌株（后被鉴定为 Cunninghamella blakesleeana）被筛选为生产洛伐他汀的潜在菌株。使用 TLC、HPTLC 和 HPLC 对化合物进行了进一步确认，分别观察到与标准洛伐他汀相似的 Rf 值、密度图峰和色谱峰。纯化后的洛伐他汀在红外分析中显示出与标准洛伐他汀相似的内酯环峰，位于 1763.63 cm-1 处。对纯化的洛伐他汀进行进一步的结构分析，包括核磁共振和液相色谱-质谱分析，证实其分子式和分子量与标准品相似。在定量方面，C.blakesleeana、赤曲霉和黄曲霉在未进行任何优化的情况下分别产生了1.4 mg g-1 DWS、0.83 mg g-1 DWS和0.3 mg g-1 DWS的洛伐他汀（p <0.0001）。洛伐他汀具有明显的抗氧化性，IC50：145.9 µg mL-1（140 µL），在199.5 µg/mL时抑制率最大，具有统计学意义（p <0.0001）。

  DOI：

  10.1007/s13205-018-1384-y
• 作为产物：
  描述：

  洛伐他汀 在 sodium hydroxide 作用下， 以 水 为溶剂， 反应 0.5h， 生成 lovastatin acid
  参考文献：
  名称：

  单羧酸盐转运蛋白在大鼠培养的系膜细胞中介导洛伐他汀酸的摄取。

  摘要：

  为了阐明他汀类药物的摄取机制，我们检查了单羧酸盐转运蛋白（MCT）是否有助于大鼠培养的肾小球系膜细胞对洛伐他汀酸的摄取。在肾小球系膜细胞中证实了MCT1、2和4的mRNA表达。肾小球膜细胞对洛伐他汀的摄取随细胞外pH的降低而增加。在存在但不存在向内定向的H（+）梯度的情况下，ATP耗竭的细胞对洛伐他汀酸的摄取存在明显的过调。代表性的MCT底物/抑制剂可抑制洛伐他汀酸的摄取。特别地，在80mM的浓度下L-乳酸对洛伐他汀酸摄取的抑制达到70％，并且L-乳酸和丙戊酸竞争性地抑制摄取。在用L-乳酸或丙戊酸预加载肾小球系膜细胞后，洛伐他汀酸的摄取被显着刺激。L-乳酸对洛伐他汀酸摄取的抑制常数为32 mM，该值可与其他地方描述的MCT4的L-乳酸的米氏常数（> 20 mM）相媲美。这些结果表明，洛伐他汀酸主要通过MCT被系膜细胞吸收，并表明MCT4可能有助于洛伐他汀酸在细胞中的摄取。

  DOI：

  10.1002/jps.10246

文献信息

• Lipophilic statins inhibit growth and reduce invasiveness of human endometrial stromal cells
  作者：Anna Sokalska、Amanda B. Hawkins、Toshia Yamaguchi、Antoni J. Duleba

  DOI：10.1007/s10815-018-1352-9

  日期：2019.3

  To compare effects of lipid-soluble statins (simvastatin, lovastatin, atorvastatin) and water-soluble statin (pravastatin) on growth and invasiveness of human endometrial stromal (HES) cells. Endometrial biopsies were collected during the proliferative phase from five volunteers. HES cells were isolated and cultured in the absence or in the presence of simvastatin, lovastatin, atorvastatin, and pravastatin. Effects of statins on DNA synthesis, cell viability, activity of caspases 3/7 and invasiveness were evaluated. The proliferation of HES cells was significantly decreased by simvastatin (by 47–89%), lovastatin (by 46–78%), and atorvastatin (by 21–48%) in a concentration-dependent manner. Activity of executioner caspases 3/7 was significantly increased by simvastatin (by 10–25%), lovastatin (by 19%) and atorvastatin (by 7–10%) in a concentration-dependent manner. The greatest effects were observed in response to simvastatin. Accounting for the effects of statins on cell number, the invasiveness of HES cells was significantly decreased in cells treated with simvastatin (by 49%), lovastatin (by 54%), and atorvastatin (by 53%). Pravastatin had little or no effects on any of the tested endpoints. Present findings demonstrate that only lipid-soluble among tested statins were effective in inhibition of growth and invasiveness of HES cells. These findings may have clinical relevance in treatment of endometriosis.

  比较脂溶性他汀类药物（辛伐他汀、洛伐他汀、阿托伐他汀）和水溶性他汀类药物（普伐他汀）对人子宫内膜基质（HES）细胞生长和侵袭性的影响。在增殖期采集了五名志愿者的子宫内膜活检组织。在辛伐他汀、洛伐他汀、阿托伐他汀和普伐他汀不存在或存在的情况下，分离并培养 HES 细胞。评估了他汀类药物对 DNA 合成、细胞活力、Caspases 3/7 活性和侵袭性的影响。辛伐他汀（47%-89%）、洛伐他汀（46%-78%）和阿托伐他汀（21%-48%）以浓度依赖的方式显著降低了 HES 细胞的增殖。辛伐他汀（增加 10%-25%）、洛伐他汀（增加 19%）和阿托伐他汀（增加 7%-10%）以浓度依赖的方式显著增加了执行者 Caspases 3/7 的活性。辛伐他汀的作用最大。考虑到他汀类药物对细胞数量的影响，辛伐他汀（49%）、洛伐他汀（54%）和阿托伐他汀（53%）处理的 HES 细胞侵袭性显著降低。普伐他汀对所有测试终点几乎没有影响。目前的研究结果表明，在测试的他汀类药物中，只有脂溶性他汀类药物能有效抑制 HES 细胞的生长和侵袭性。这些发现可能对治疗子宫内膜异位症有临床意义。
• DUAL ACTION INHIBITORS AGAINST HISTONE DEACETYLASES AND 3-HYDROXY-3-METHYLGLUTARYL COENZYME A REDUCTASE
  申请人：National Taiwan University

  公开号：US20140206645A1

  公开（公告）日：2014-07-24

  Disclosed herein are novel compounds of formula (I), and uses thereof. The compounds of Formula (I) are inhibitors of histone deacetylases (HDACs) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR). Also provided are methods of using the compounds of Formula (I) for inhibiting the activity of HDACs and HMGR, treating diseases associated with HDACs or HMGR (e.g., cancer, hypercholesterolemia, an acute or chronic inflammatory disease, autoimmune disease, allergic disease, pathogen infection, neurodegenerative disease, or a disease associated with oxidative stress,

  本文披露了式（I）的新化合物及其用途。式（I）的化合物是组蛋白去乙酰化酶（HDACs）和3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶（HMGR）的抑制剂。还提供了使用式（I）的化合物抑制HDACs和HMGR活性、治疗与HDACs或HMGR相关的疾病（如癌症、高胆固醇血症、急性或慢性炎症性疾病、自身免疫疾病、过敏性疾病、病原体感染、神经退行性疾病或与氧化应激相关的疾病）的方法。
• [EN] METHOD OF PREPARING STATINS INTERMEDIATES<br/>[FR] PROCEDE POUR PREPARER DES INTERMEDIAIRES DE STATINES
  申请人：CJ CORP

  公开号：WO2004096789A1

  公开（公告）日：2004-11-11

  Provided is a method for preparing a simvastatin intermediate. The method includes hydrolysis of mevinolinic acid as a starting material, lactonization, and protection of a hydroxy group of a lactone ring. Therefore, process steps are reduced and the simvastatin intermediate is produced in high yield.

  提供了一种制备辛伐他汀中间体的方法。该方法包括以麦维诺林酸为起始物质的水解，内酯化和保护内酯环的羟基。因此，减少了工艺步骤并且高产率地生产出辛伐他汀中间体。
• [EN] A METHOD FOR THE MANUFACTURE OF LOVASTATIN<br/>[FR] PROCEDE DE FABRICATION DE LA LOVASTATINE
  申请人：LUPIN LTD

  公开号：WO2005035515A1

  公开（公告）日：2005-04-21

  A method for the manufacture of Lovastatin of formula (I) is disclosed. The method comprises of: A. lactonisation of Mevinolinic acid (II) and isolation of impure Lovastatin (I), B. purification of impure Lovastatin (I), C. optionally, repurification of pure Lovastatin (I) from a mixture of alumina and a water miscible solvent.

  公开了一种制备化学式（I）的洛伐他汀的方法。该方法包括：A.内酯化甲维诺酸（II）并分离出不纯的洛伐他汀（I），B.纯化不纯的洛伐他汀（I），C.可选地，从氧化铝和水亲和溶剂的混合物中重新纯化纯洛伐他汀（I）。
• Association between risk of myopathy and cholesterol-lowering effect: A comparison of all statins
  作者：Masaki Kobayashi、Ikumi Chisaki、Katsuya Narumi、Kazuhiro Hidaka、Toshiki Kagawa、Shirou Itagaki、Takeshi Hirano、Ken Iseki

  DOI：10.1016/j.lfs.2008.02.019

  日期：2008.4

  In the present study, we examined the mechanisms underlying the cytotoxicity of pitavastatin, a new statin, and we compared the in vitro potencies of muscle cytotoxicity using a prototypic embryonal rhabdomyosarcoma cell line (RD cells), a typical side effect of statins and compared the cholesterol-lowering effects of statins using Hep G2 hepatoma cells. Pitavastatin reduced the number of viable cells and caused caspase-9 and -3/7 activation in a time- and concentration-dependent manner. The comparison of cytotoxities of statins showed that statins significantly reduced cell viability and markedly enhanced activity of caspase-3/7 in concentration-dependent manner. On the other hand, the effects of hydrophilic statins, pravastatin, rosuvastatin were very weak. The rank order of cytotoxicity was cerivastatin > sinavastatin acid> fluvastatin > atorvastatin > lovastatin acid > pitavastatin >> rosuvastatin, pravastatin. Statin-induced cytotoxicity is associated with these partition coefficients. On the other hand, the cholesterol-lowering effect of statins did not correlate with these partition coefficients and cytotoxicity. Thus, it is necessary to consider the association between risk of myopathy and cholesterol-lowering effect of a statin for precise use of statins. (c) 2008 Elsevier Inc. All rights reserved.