原黄素 | 92-62-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 中文名称: 原黄素
• 中文别名: 普鲁黄素；二氨基丫啶；双氯丫啶；吡啶-3,6-二胺
• 英文名称: proflavine
• 英文别名: 3,6-acridinediamine；acridine-3,6-diamine
• CAS: 92-62-6
• 化学式: C₁₃H₁₁N₃
• mdl: MFCD00005030
• 分子量: 209.25
• InChiKey: WDVSHHCDHLJJJR-UHFFFAOYSA-N

物化性质

• 熔点：
  281° (Schpff); mp 288° (Albert)
• 沸点：
  338.61°C (rough estimate)
• 密度：
  1.1847 (rough estimate)
• 溶解度：
  DMSO：23 mg/mL (109.92 mM)；乙醇：2 mg/mL (9.56 mM)
• 物理描述：
  Yellow solid; [Merck Index]
• 颜色/状态：
  Yellow needles from alcohol. Solutions are brownish and when diluted are fluorescent.
• 蒸汽压力：
  0.00000009 [mmHg]
• 分解：
  When heated to decomposition it emits toxic fumes of /nitric oxides/
• 解离常数：
  8.06 (at 20 °C)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  16
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  64.9
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

普罗法维尔（3,6-二氨基吖啶）具有作为鱼类抗感染剂的潜力，因此研究了其在虹鳟鱼中的代谢。在通过动脉内弹丸式注射10毫克/公斤普罗法维尔14小时后，使用反相高效液相色谱（HPLC）和262纳米的紫外检测，在肝脏和胆汁中发现了三种代谢物，在血浆中发现了一种代谢物。用盐酸处理后，三种代谢物转化为普罗法维尔，这表明代谢物是普罗法维尔的结合物。使用β-葡萄糖醛酸酶和己糖酸1,4-内酯（一种特定的β-葡萄糖醛酸酶抑制剂）的处理表明，两种代谢物是普罗法维尔的葡萄糖苷酸。为了确定紫外-可见吸收光谱和质谱，从肝脏中分离出HPLC纯化的代谢物。这些实验的数据表明，普罗法维尔的代谢物是3-N-葡萄糖苷酸普罗法维尔（PG）、3-N-葡萄糖苷酸,6-N-乙酰普罗法维尔（APG）和3-N-乙酰普罗法维尔（AP）。通过化学合成验证了代谢物的身份。当合成的PG和AP与从鳟鱼中分离出的两种代谢物进行比较时，它们通过基质辅助激光解吸离子化飞行时间质谱测定的分子量相同。此外，它们在不同的流动相条件下在HPLC中共洗脱。最后，使用肝脏亚细胞制剂的体外培养证实了这种特征，并提供了证据表明APG可以通过AP的葡萄糖苷酸化或PG的乙酰化形成。

Proflavine (3,6-diaminoacridine) has potential for use as an antiinfective in fish, and its metabolism by rainbow trout was therefore studied. Fourteen hours after intraarterial bolus administration of 10 mg/kg of proflavine, three metabolites were found in liver and bile, and one metabolite was found in plasma using reversed-phase HPLC with UV detection at 262 nm. Treatment with hydrochloric acid converted the three metabolites to proflavine, which suggested that the metabolites were proflavine conjugates. Treatment with beta-glucuronidase and saccharic acid 1,4-lactone, a specific beta-glucuronidase inhibitor, revealed that two metabolites were proflavine glucuronides. For determination of UV-VIS absorption and mass spectra, HPLC-purified metabolites were isolated from liver. Data from these experiments suggested that the proflavine metabolites were 3-N-glucuronosyl proflavine (PG), 3-N-glucuronosyl,6-N-acetyl proflavine (APG), and 3-N-acetylproflavine (AP). The identities of the metabolites were verified by chemical synthesis. When synthetic PG and AP were compared with the two metabolites isolated from trout, they had the same molecular weight as determined by matrix-assisted, laser desorption ionization, time-of-flight MS. In addition, they coeluted on HPLC under different mobile phase conditions. Finally, the in vitro incubation with liver subcellular preparations confirmed this characterization and provided the evidence that APG can be formed by glucuronidation of AP or acetylation of PG.

来源:Hazardous Substances Data Bank (HSDB)

代谢

一种液相色谱（LC）方法被开发用于测定鲶鱼肌肉中acriflavine（ACR）和proflavine（PRO）的残留物。残留物用酸性甲醇溶液提取，提取液通过C18固相萃取柱进行净化。在LC氰基柱上，使用454nm的光谱光度法检测残留物浓度。鲶鱼肌肉分别用纯化的ACR（来自商业产品）和PRO以5、10、20、40和80 ppb的浓度进行加标（每个水平5个重复）。从加标肌肉中每个水平的平均回收率在86%到95%之间，相对标准偏差（RSDs）为2.5%到5.7%。该方法应用于鲶鱼经水暴露商业acriflavine（10 ppm总染料，4小时）后肌肉中产生的ACR和PRO残留物。产生的ACR和PRO残留物的RSDs与加标肌肉的RSDs在同一范围内。低残留浓度（小于暴露水浓度的1%）表明鲶鱼对ACR和PRO的吸收较差。

A liquid chromatographic (LC) method was developed for determination of acriflavine (ACR) and proflavine (PRO) residues in channel catfish muscle. Residues were extracted with acidified methanol solution, and extracts were cleaned up with C18 solid-phase extraction columns. Residue concentrations were determined on an LC cyano column, with spectrophotometric detection at 454 nm. Catfish muscle was individually fortified with ACR (purified from commercial product) and PRO at concentrations of 5, 10, 20, 40, and 80 ppb (5 replicates per level). Mean recoveries from fortified muscle at each level ranged from 86 to 95%, with relative standard deviations (RSDs) of 2.5 to 5.7%. The method was applied to incurred residues of ACR and PRO in muscle after waterborne exposure of channel catfish to commercial acriflavine (10 ppm total dye for 4 h). RSDs for incurred residues of ACR and PRO were in the same range as those for fortified muscle. Low residue concentrations (< 1% of exposure water concentration) suggested poor absorption of ACR and PRO in catfish.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

致癌性分类：1）人类证据：无数据；2）动物证据：有限。对人类致癌风险的总体评估为第3组：该物质对人类致癌性不可分类。/普罗氟瓦因盐类；来自表格/

Classification of carcinogenicity: 1) evidence in humans: no data; 2) evidence in animals: limited. Overall summary evaluation of carcinogenic risk to humans is Group 3: The agent is not classifiable as to its carcinogenicity to humans. /Proflavine salts; From table/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，协助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……监测休克，如有必要，进行治疗……预计可能出现癫痫，如有必要，进行治疗……对于眼睛污染，立即用水冲洗眼睛。在转运过程中，用生理盐水连续冲洗每只眼睛……不要使用催吐剂。对于摄入，如果患者能够吞咽，有强烈的干呕反射，并且不流口水，用水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……在去污后，用干无菌敷料覆盖皮肤烧伤……/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于无意识、严重肺水肿或呼吸停止的患者，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。监测心率和必要时治疗心律失常。开始静脉输液，使用D5W /SRP: "保持开放"，最低流速。如果出现低血容量的迹象，使用乳酸钠林格氏液。注意液体过载的迹象。考虑使用药物治疗肺水肿。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象。使用地西泮（安定）治疗癫痫。使用丙美卡因氢氯化物协助眼部冲洗。/毒药A和B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/SPECIAL STUDIES/ 通过在培养的MRC-5人成纤维细胞中研究结构相关的嵌入剂普罗发白和9-氨基吖啶对非计划性DNA合成（UDS）的诱导以及半保留DNA复制的改变...普罗发白影响了DNA合成，但并未引起任何UDS。

/SPECIAL STUDIES/ The induction of unscheduled DNA synthesis (UDS) and the alteration of semiconservative DNA replication by the structurally related intercalating agents proflavine and 9-aminoacridine were studied in MRC-5 human fibroblasts in culture ... Proflavine affected DNA synthesis, but did not elicit any UDS.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验动物：急性暴露/研究了8-甲氧基补骨脂素（MOP）、中性红（NR）和普罗发白（PF）对雌性瑞士白化小鼠（品系955）皮肤的光敏化效应，使用分批暴露于长波紫外线（300-400纳米）和可见光（钨丝发光）。结果显示（1）确认了MOP的光致癌性，（2）证明了NR和PF都是光致癌物，并且进一步（3）显示出上述紫外线，即使313纳米的总剂量比小鼠最小紫外肿瘤剂量低100倍，其2.6%的fluence at 313 nm 也是一个长期致癌因素。肿瘤包括乳腺腺癌、皮肤附件癌、肉瘤、淋巴瘤和一例甲状腺腺癌。讨论了上述数据关于光化学治疗中致癌风险争议的含义。

/LABORATORY ANIMALS: Acute Exposure/ A study of the photosensitizing effects of 8-methoxypsoralen (MOP), neutral red (NR), and proflavine (PF) on the skin of female Swiss albino mice, strain 955, was carried out using fractionated exposure to long ultraviolet light (300-400 nm) and visible light (tungsten emission). The results (1) confirmed MOP photocarcinogenicity, (2) demonstrated that both NR and PF are photocarcinogens, and, further, (3) showed that the above UV light with 2.6% of fluence at 313 nm is a long-term carcinogenic agent even though the total dose of 313 nm was 100 times less than the minimal UV tumorigenic dose in mice. The tumors were mammary adenocarcinomas, carcinomas of skin appendages, carcino-mixo-sarcomas, lymphomas, and one case of thyroid adenocarcinoma. The implications of the above data regarding the controversy about oncogenic risks in photochemotherapy are discussed.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

荧光药物普罗发白的摄取量通过流式细胞术在正常和暴露于致癌物（2-乙酰氨基芴，AAF）的大鼠肝细胞悬浮液中进行了测量。来自暴露于致癌物的大鼠的肝细胞对药物的摄取量通常低于来自正常大鼠的肝细胞。从正常和AAF喂养的大鼠肝脏中制备的孤立细胞核显示出类似的普罗发白摄取。然而，来自AAF喂养的大鼠的肝细胞对药物的摄取可以通过预先暴露于代谢抑制剂而增加。因此，药物摄取的差异可能反映了细胞膜的变化，以及细胞代谢完整性的改变。来自AAF喂养大鼠的肝细胞对药物的摄取在每个细胞制剂中都是均匀的低。然而，药物摄取不仅在AAF喂养大鼠肝脏中出现的肿瘤之间有所不同，而且在每个肿瘤细胞制剂内也有所变化。这项研究表明，流式细胞术可以提供一种有效的方法来分析在肝致癌过程中出现的细胞群体对药物的摄取。

The uptake of the fluorescent drug proflavine was measured in suspensions of hepatocytes from normal and carcinogen (2-acetylaminofluorine, AAF)-fed rats by flow cytometry. Drug uptake into hepatocytes from carcinogen-fed animals was consistently lower than that into hepatocytes from normal animals. Isolated nuclei, prepared from the livers of normal and AAF-fed rats showed similar proflavine uptake. Drug uptake into hepatocytes from AAF-fed animals, however, was increased by prior exposure to a metabolic inhibitor. Thus, differences in drug uptake may reflect changes in the cell membrane, together with an alteration in the metabolic integrity of the cells. The uptake of drug in hepatocytes from AAF-fed rats was uniformly low within each cell preparation. However, drug uptake varied not only between tumours arising in the livers of these animals but also within each tumour cell preparation. This study indicates that flow cytometry can provide an effective means for analysing drug uptake into cell populations arising during hepatocarcinogenesis.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

1. 对黄色素（PRO）和荧光素（ACR）在鲶鱼体内的分布进行了研究，包括静脉注射（i.v.）（1毫克/千克）和水暴露（10毫克/升，持续4小时）。 2. 静脉注射后，母体PRO和ACR的血浆浓度-时间曲线分别最好用两室和三室药代动力学模型来描述。PRO和ACR在血浆中的末端消除半衰期分别为8.7和11.4小时。 3. 在用14C-PRO或14C-ACR处理的动物中，总药物等效浓度在排泄器官中最高，在肌肉、脂肪和血浆中最低。在PRO处理的动物中，肝脏和躯干肾脏中的残留物主要由PRO的葡萄糖醛酸和乙酰结合物组成；肌肉中的残留物主要由母体药物组成（超过95%）。在ACR处理的动物中，母体化合物构成了所检查组织中总残留物的90%以上。 4. PRO和ACR在水暴露过程中在鲶鱼体内的吸收很差。在4小时暴露结束时，肌肉中母体PRO和ACR的浓度分别为0.064和0.020微克/克。肌肉中的水平在1-2周内降至检测限（0.005微克/克）以下。

1. The disposition of proflavine (PRO) and acriflavine (ACR) were examined in channel catfish after intravascular (i.v.) dosing (1 mg/kg) or waterborne exposure (10 mg/l for 4 h). 2. After i.v. dosing, plasma concentration-time profiles of parent PRO and ACR were best described by two- and three-compartment pharmacokinetic models respectively. Terminal elimination half-lives of PRO and ACR in plasma were 8.7 and 11.4 h respectively. 3. In animals dosed with 14C-PRO or 14C-ACR, total drug equivalent concentrations were highest in the excretory organs and lowest in muscle, fat and plasma. In PRO-dosed animals, residues in the liver and trunk kidney were composed primarily of glucuronosyl and acetyl conjugates of PRO; residues in muscle were composed mostly (> 95%) of the parent drug. In ACR-dosed animals, the parent compound comprised > 90% of the total residues in all tissues examined. 4. PRO and ACR were poorly absorbed in catfish during waterborne exposure. At the end of a 4-h exposure, parent PRO and ACR concentrations in muscle were 0.064 and 0.020 microgram/g respectively. Levels in muscle declined below the limit of determination (0.005 microgram/g) within 1-2 weeks.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2933990090
• 储存条件：
  存放于惰性气体中，避免与空气接触。

制备方法与用途

生物活性

Proflavine（3,6-二氨基吖啶）是一种消毒抑菌剂，能够有效抑制多种革兰氏阳性菌。它通常作为局部杀菌剂应用于伤口敷料中。