Zaragozic Acid A
(Synonyms: 萨拉哥酸A,Squalestatin S1) 目录号 : GC12351Zaragozic Acid A是角鲨烯合酶的竞争性抑制剂，Ki值为78pM。
Cas No.:142561-96-4
Sample solution is provided at 25 µL, 10mM.
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Zaragozic Acid A is a competitive inhibitor of squalene synthase, with a Ki value of 78pM [1]. Zaragozic Acid A inhibits hepatic cholesterol synthesis, with an IC50 value of 6μM[2]. Zaragozic Acid A impairs staphyloxanthin formation and is a potent biofilm inhibitor in S. aureus and Bacillus subtilis by targeting CrtM enzyme without causing cell death[3]. Zaragozic Acid A has been widely used to regulate the cholesterol levels within cells and to inhibit the transformation of bronchial fibroblasts into myofibroblasts[4].
In vitro, Zaragozic Acid A treatment (100μM) for 72 hours significantly reduced the cholesterol level and increased the dolichol (Dol)-P-Man levels in human primary skin fibroblasts (HPSFs) with congenital disorders of glycosylation (CDG)[5]. Treatment with 10μg/ml Zaragozic Acid A for 48 hours would impair the maintenance of the Tat2p protein and the absorption of tryptophan in the tryptophan auxotrophic (trp1) yeast cells[6]. Treatment with 10μM Zaragozic Acid A for 48 hours significantly inhibited the replication of live Dengue virus type 2 (DEN-2 NGC) in K562 cells, with an EC50 value of 8.3μM[7].
In vivo, Zaragozic acid A treatment (3mg/kg/day; s.c.) caused massive production of Farnesol-derived dicarboxylic acids in urine of female Swiss Webster mice [8].
References:
[1] Bergstrom J D, Kurtz M M, Rew D J, et al. Zaragozic acids: a family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase[J]. Proceedings of the National Academy of Sciences, 1993, 90(1): 80-84.
[2] Ponpipom M M, Girotra N N, Bugianesi R L, et al. Structure-activity relationships of C1 and C6 side chains of zaragozic acid A derivatives[J]. Journal of medicinal chemistry, 1994, 37(23): 4031-4051.
[3] Liu C I, Jeng W Y, Chang W J, et al. Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase[J]. Journal of Biological Chemistry, 2012, 287(22): 18750-18757.
[4] Michalik M, Soczek E, Kosińska M, et al. Lovastatin-induced decrease of intracellular cholesterol level attenuates fibroblast-to-myofibroblast transition in bronchial fibroblasts derived from asthmatic patients[J]. European Journal of Pharmacology, 2013, 704(1-3): 23-32.
[5] Haeuptle M A, Welti M, Troxler H, et al. Improvement of dolichol-linked oligosaccharide biosynthesis by the squalene synthase inhibitor zaragozic acid[J]. Journal of Biological Chemistry, 2011, 286(8): 6085-6091.
[6] Daicho K, Maruyama H, Suzuki A, et al. The ergosterol biosynthesis inhibitor zaragozic acid promotes vacuolar degradation of the tryptophan permease Tat2p in yeast[J]. Biochimica et Biophysica Acta (BBA)-Biomembranes, 2007, 1768(7): 1681-1690.
[7] Rothwell C, LeBreton A, Ng C Y, et al. Cholesterol biosynthesis modulation regulates dengue viral replication[J]. Virology, 2009, 389(1-2): 8-19.
[8] Vaidya S, Bostedor R, Kurtz M M, et al. Massive production of farnesol-derived dicarboxylic acids in mice treated with the squalene synthase inhibitor zaragozic acid A[J]. Archives of biochemistry and biophysics, 1998, 355(1): 84-92.
Zaragozic Acid A是角鲨烯合酶的竞争性抑制剂，Ki值为78pM[1]。Zaragozic Acid A可抑制肝脏胆固醇合成，IC50值为6μM[2]。Zaragozic Acid A能阻碍葡萄球菌黄素的形成，并通过靶向CrtM酶在不引起细胞死亡的情况下，成为金黄色葡萄球菌和枯草芽孢杆菌的有效生物膜抑制剂[3]。Zaragozic Acid A已广泛用于调节细胞内胆固醇水平，并抑制支气管成纤维细胞向肌成纤维细胞转化[4]。
在体外，Zaragozic Acid A处理（100μM）72小时显著降低了患有先天性糖基化障碍（CDG）的人原代皮肤成纤维细胞（HPSFs）中的胆固醇水平，并增加了dolichol (Dol)-P-Man的水平[5]。用10μg/ml的Zaragozic Acid A处理48小时会损害色氨酸营养缺陷型（trp1）酵母细胞中Tat2p蛋白的维持和色氨酸的吸收[6]。用10μM的Zaragozic Acid A处理48小时显著抑制了登革病毒2型（DEN-2 NGC）在K562细胞中的复制，EC50值为8.3μM [7]。
在体内，Zaragozic Acid A处理（3mg/kg/day；皮下注射）导致雌性Swiss Webster小鼠尿液中大量产生法尼醇衍生的二羧酸[8]。
| Cell experiment [1]: | |
Cell lines | Human primary skin fibroblasts (HPSFs) |
Preparation Method | Approximately 4×107 HPSF cells were cultured in DMEM medium containing low glucose (5mM) for 72 hours, and 2% fetal bovine serum and 100μM Zaragozic Acid A or DMSO were added to the medium as negative controls. The cells were incubated in DMEM medium containing 0.5mM glucose and 125μCi [3H]Man for 30 minutes for labeling. Dol-P-Man and short-chain lipid-linked oligosaccharide (LLO) were extracted once with chloroform/methanol (2:1), and twice with chloroform/methanol (3:2). The organic phases were combined, dried, and washed. The silica gel 60 thin-layer chromatography method was used with chloroform/methanol/water (65:25:4) as the developing agent for separation. After enhancing the signal with spray, the chromatogram plate was analyzed by X-ray photography. The region containing Dol-P-Man was scraped and counted in a liquid scintillation counter. |
Reaction Conditions | 100μM; 72h |
Applications | Zaragozic Acid A treatment notably increased Dol-P-Man levels in HPSFs. |
| Animal experiment [2]: | |
Animal models | Female Swiss Webster mice |
Preparation Method | Female Swiss Webster mice weighing approximately 25g were divided into five groups, three mice per group, and housed in metabolic cages. Groups I and II were treated as controls. Group I was dosed subcutaneously with saline (50μl) and 30min later gavaged with 10μCi of R,S-[5-3H]mevalonolactone. Similar to group I, group II was administered saline subcutaneously and 30min later gavaged with 25μCi of R,S-[5-3H]mevalonolactone containing 375nmol of unlabeled R,S-mevalonolactone. Groups III and IV were dosed with Zaragozic acid A (3mg/kg/day) subcutaneously. Thirty minutes after the Zaragozic acid A treatment, group III was gavaged with 25μCi of R,S-[5-3H]mevalonolactone containing 375nmol of unlabeled R,S-mevalonolactone and group IV was gavaged with 10μCi of R,S-[5-3H]mevalonolactone alone. Group V was gavaged with 5μCi of [1-14C]farnesol containing 45μmol of unlabeled farnesol. Urine from each group was collected for 72h. The dicarboxylic acid fractions were extracted and analyzed by TLC as free acids or converted to methyl esters and characterized by C18 reverse-phase column using HPLC. |
Dosage form | 3mg/kg/day for 3 days; s.c. |
Applications | Zaragozic acid A treatment caused massive production of Farnesol-derived dicarboxylic acids in urine of mice. |
References: | |
| Cas No. | 142561-96-4 | SDF | |
| 别名 | 萨拉哥酸A,Squalestatin S1 | ||
| 化学名 | (1S,3S,4S,5R,6R,7R)-1-((4S,5R)-4-acetoxy-5-methyl-3-methylene-6-phenylhexyl)-6-(((4S,6S,E)-4,6-dimethyloct-2-enoyl)oxy)-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid | ||
| Canonical SMILES | O[C@@H]1[C@H]([C@@]2([C@](C(O)=O)([C@H](O[C@@]1(CCC([C@H]([C@@H](CC3=CC=CC=C3)C)OC(C)=O)=C)O2)C(O)=O)O)C(O)=O)OC(/C=C/[C@H](C[C@H](CC)C)C)=O | ||
| 分子式 | C35H46O14 | 分子量 | 690.73 |
| 溶解度 | H2O : 1 mg/mL (1.45 mM; Need ultrasonic and warming) | 储存条件 | Store at -20°C,protect from light |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.4477 mL | 7.2387 mL | 14.4774 mL |
| 5 mM | 289.5 μL | 1.4477 mL | 2.8955 mL |
| 10 mM | 144.8 μL | 723.9 μL | 1.4477 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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2.
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