Deacylketoconazole   中文名称: 酮康唑杂质D 标准品

CYP3A4; CYP24A1; ergosterol synthesis; active metabolite of Ketoconazole

脱酰基酮康唑(R-39519)也能影响金黄色葡萄球菌的生长，咪康唑的活性分别是R-39519和酮康唑的12.5倍和14倍。[2]

根据[(3)H]次黄嘌呤摄取和寄生虫数量统计，脱酰酮康唑对恶性疟原虫的活性是酮康唑的15- 50倍。相比之下，这些药物对念珠菌临床分离株的活性没有显著差异。[1]

酮康唑(KC)是一种抗真菌药物，口服时很少引起严重的肝损伤。据报道，KC主要水解为n-去乙酰酮康唑(N-deacetyl酮康唑，DAK)，然后由含黄素单加氧酶(FMO)将DAK进行n-羟基化。虽然KC的代谢被认为与肝毒性有关，但负责的酶仍不清楚。本研究的目的是确定人类KC水解的负责酶，并阐明它们与KC诱导的毒性的相关性。利用人肝微粒体(HLM)和重组酶的动力学分析和抑制研究表明，人芳基乙酰胺脱乙酰酶(AADAC)负责KC水解形成DAK，并证实FMO3是负责DAK n -羟基化的酶。在HLM中，KC水解的清除程度与DAK n -羟基化的清除程度相同，这表明这两个过程都不是限速途径。用HepaRG细胞和人原代肝细胞评价KC和DAK的细胞毒性。用DAK处理HepaRG细胞24小时，显示出剂量依赖性的细胞毒性，而用KC处理由于AADAC的低表达而没有显示出细胞毒性。在腺病毒表达系统的HepaRG细胞中过表达AADAC可引起KC的细胞毒性，AADAC抑制剂氟磷酸二异丙基可减弱KC在人原代肝细胞中的细胞毒性。总之，本研究表明，人AADAC水解KC引发肝细胞毒性。[3]

[1]. Pfaller MA, et al., Activity of ketoconazole and its deacyl derivative against Plasmodium falciparum and Candida isolates. Antimicrob Agents Chemother. 1982 Nov;22(5):917-9.
[2]. Bossche H V, et al., Molecular basis for the antimycotic and antibacterial activity of N‐substituted imidazoles and triazoles: The inhibition of isoprenoid biosynthesis. Pesticide science, 1984, 15(2): 188-198.
[3]. Fukami T, et al., Human arylacetamide deacetylase hydrolyzes ketoconazole to trigger hepatocellular toxicity. Biochem Pharmacol. 2016 Sep 15;116:153-61.

The antimycotic N-substituted imidazoles and triazoles, such as imazalil, ketoconazole and itraconazole, interfere selectively at low concentrations (≥0.01nm) with the 14α-demethylase system (which is dependent on cytochrome P-450) of fungal cells, for example, Candida albicans and Penicillium italicum. This results in a decreased availability of ergosterol and the accumulation of 14α-methyl-sterols such as lanosterol. Cholesterol synthesis in a subcellular fraction of rat liver, in intact fibroblasts, and in vivo in rat liver, was much less sensitive, for example, to ketoconazole. The imidazole derivatives imazalil, miconazole, ketoconazole and parconazole, and the triazole derivatives propiconazole, terconazole and itraconazole affect the cytochrome P-450 species of microsomal fractions from Saccharomyces cerevisiae and rat liver. Cytochrome P-450 of rat-liver microsomes was much less sensitive to these azole derivatives, in parallel with the lower sensitivity of cholesterol synthesis. Using unilamellar vesicles composed of phosphatidylcholine, phosphatidyl-ethanolamine and diphosphatidylcholine, multilamellar vesicles of dipalmitoylphos-phatidylcholine, and intact S. cerevisiae, it was shown that the substitution of ergosterol by lanosterol leads to functional changes in the membranes. It is speculated that the selective interaction of the azole derivatives with the yeast microsomal cytochrome P-450 leads to the accumulation of 14a-methyl-sterols and results in changes in the permeability of the membranes and leakages. The observed inhibition of growth may have its origin in these changes. Miconazole, ketoconazole and deacylated ketoconazole (R-39519) also affect the growth of Staphylococcus aureus, miconazole being 12.5 and 14 times, respectively, more active than R-39519 and ketoconazole. The greater antibacterial activity of miconazole coincides with its greater inhibition of the biosynthesis of C-55 isoprenoid alcohol and vitamin K. The phosphorylated derivative of C-55 isoprenoid alcohol has functional importance in the biosynthesis of bacterial cell wall and membrane polymers, and the menaquinone vitamin K plays a role in the electron transport of Gram-positive bacteria. The reduced synthesis of these vital compounds may contribute to the antibacterial activity of miconazole.[2]

C24H26CL2N4O3

489.397

488.138

C, 58.90; H, 5.36; Cl, 14.49; N, 11.45; O, 9.81

67914-61-8

12854716

White to off-white solid powder

4.34

60.78

1

6

7

33

621

2

c1cc(ccc1N2CCNCC2)OC[C@H]3CO[C@](O3)(Cn4ccnc4)c5ccc(cc5Cl)Cl

LOUXSEJZCPKWAX-URXFXBBRSA-N

InChI=1S/C24H26Cl2N4O3/c25-18-1-6-22(23(26)13-18)24(16-29-10-7-28-17-29)32-15-21(33-24)14-31-20-4-2-19(3-5-20)30-11-8-27-9-12-30/h1-7,10,13,17,21,27H,8-9,11-12,14-16H2/t21-,24-/m0/s1

1-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine

Deacyl ketoconazole; 67914-61-8; Deacetyl Ketoconazole; Deacylketoconazole; N-Deacetylketoconazole; P7P4A1FD7Z; CIS-1-[4-[[2-(2,4-DICHLOROPHENYL)-2-(1H-IMIDAZOL-1-YLMETHYL)-1,3-DIOXOLAN-4-YL]METHOXY]PHENYL]PIPERAZINE; rel-1-(4-(((2R,4S)-2-((1H-Imidazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazine; Piperazine, 1-(4-((2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)-, cis-; Deacylketoconazole

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。