canavanine | 13269-28-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: canavanine
• 英文别名: O-[(aminoiminomethyl)amino]-L-homoserine；2-amino-4-guanidooxybutanoic acid；O-guanidino-DL-homoserine；DL-Canavanin；2-Amino-4-(diaminomethylideneazaniumyloxy)butanoate；2-amino-4-(diaminomethylideneazaniumyloxy)butanoate
• CAS: 13269-28-8
• 化学式: C₅H₁₂N₄O₃
• mdl: MFCD20542787
• 分子量: 176.175
• InChiKey: FSBIGDSBMBYOPN-UHFFFAOYSA-N

物化性质

• 熔点：
  180-184 °C
• 沸点：
  365.8±52.0 °C(Predicted)
• 密度：
  1.61±0.1 g/cm3(Predicted)
• 颜色/状态：
  Crystals from absolute alcohol
• 溶解度：
  In water, 1.0X10+6 mg/L at 25 °C (est)
• 蒸汽压力：
  3.18X10-8 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions.
• 旋光度：
  Specific optical rotation: +7.9 deg at 20 °C/D (c = 3.2)
• 解离常数：
  pKa1 = 2.10 (carboxylic); pKa2 = 9.31 (amine) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  -4.8
• 重原子数：
  12
• 可旋转键数：
  5
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  137
• 氢给体数：
  4
• 氢受体数：
  5

ADMET

代谢

L-刀豆素（CAV）是从杰克豆（Canavalia ensiformis）中分离出的精氨酸（ARG）类似物。CAV被整合进MIA PaCa-2人类胰腺癌细胞中的细胞蛋白，并且异常的刀豆素蛋白并没有被优先降解。通过精氨酸酶介导，CAV水解切割成刀豆醇（CAN）和尿素。CAN是一种强效代谢物，能够使含有维生素B6的酶失活，并可能抑制细胞生长。为了确定MIA PaCa-2细胞中精氨酸酶的存在及其对ARG和CAV的特异性，使用了一种放射性测定法，该方法通过量化由精氨酸酶介导的L-[脒基-(14)C]ARG或L-[脒基羟-(14)C]CAV水解切割释放的(14)C来进行测定。当细胞暴露于[(14)C]CAV或[(14)C]ARG时，释放的(14)CO2量微不足道。胰腺癌细胞分泌的精氨酸酶量极少。比较了CAN和CAV在不同浓度的ARG暴露下的细胞毒性效应。这些研究表明，CAV对MIA PaCa-2细胞的细胞毒性效应不能归因于转化为活性代谢物CAN。精氨酸酶对CAV的水解较慢且减少，使得CAV能够持续存在，并增加其整合进这些细胞蛋白中的机会。胰腺中缺乏大量的精氨酸酶使得CAV成为胰腺癌进一步研究的值得候选物。

L-Canavanine (CAV) is an arginine (ARG) analog isolated from the jack bean, Canavalia ensiformis. CAV becomes incorporated into cellular proteins of MIA PaCa-2 human pancreatic cancer cells and the aberrant, canavanyl proteins are not preferentially degraded. Hydrolytic cleavage of CAV to canaline (CAN) and urea is mediated by arginase. CAN is a potent metabolite that inactivates vitamin B6-containing enzymes and may inhibit cell growth. To determine the presence of arginase and its specificity for ARG and CAV in MIA PaCa-2 cells, a radiometric assay, which quantifies the (14)C released from the hydrolytic cleavage of L-[guanidino-(14)C]ARG or L-[guanidinooxy-(14)C]CAV mediated by arginase, was employed. Insignificant amounts of (14)CO2 were released when cells were exposed to [(14)C]CAV or to [(14)C]ARG. Pancreatic cancer cells secrete a negligible amount of arginase. Cytotoxic effects of CAN and CAV were compared on cells exposed to varying concentrations of ARG. These studies provide evidence that CAV's cytotoxic effects on MIA PaCa-2 cells cannot be attributed to conversion to the active metabolite CAN. A slower and decreased hydrolysis of CAV by arginase allows CAV to persist and increases its chances of incorporating into proteins in these cells. Lack of considerable amounts of arginase in the pancreas makes CAV a worthy candidate for further studies in pancreatic cancer.

来源:Hazardous Substances Data Bank (HSDB)

代谢

L-刀豆氨酸及其通过精氨酸酶催化的代谢物L-刀豆胺是正在开发中的两种新型抗癌药物。由于在药物开发过程中对开发中的药物进行免疫毒性评估是一个关键组成部分，因此评估了L-刀豆氨酸和L-刀豆胺在体外的抗增殖效果。L-刀豆氨酸和L-刀豆胺都对培养中的外周血单核细胞（PBMCs）具有细胞毒性。此外，单核细胞同时暴露于L-刀豆氨酸或L-刀豆胺以及可能作为L-刀豆氨酸和L-刀豆胺作用代谢抑制剂的化合物系列之一（L-精氨酸、L-鸟氨酸、D-精氨酸、L-赖氨酸、L-同型精氨酸、腐胺、L-ω-硝基精氨酸甲酯和L-瓜氨酸）。评估这些化合物克服L-刀豆氨酸或L-刀豆胺的细胞毒性的能力，以为了解可能介导这两种新型抗癌药物毒性的生化机制提供洞察。这些研究的结果表明，L-刀豆氨酸的毒性机制是通过L-精氨酸利用机制介导的，而L-刀豆胺作为L-刀豆氨酸的代谢物，通过破坏多胺生物合成对人类PBMCs产生毒性。阐明与L-刀豆氨酸和L-刀豆胺对淋巴细胞增殖影响相关的生化机制可能有助于最大化这些新型抗癌药物的治疗效果并最小化其毒性。

L-Canavanine and its arginase-catalyzed metabolite, L-canaline, are two novel anticancer agents in development. Since the immunotoxic evaluation of agents in development is a critical component of the drug development process, the antiproliferative effects of L-canavanine and L-canaline were evaluated in vitro. Both L-canavanine and L-canaline were cytotoxic to peripheral blood mononucleocytes (PBMCs) in culture. Additionally, the mononucleocytes were concurrently exposed to either L-canavanine or L-canaline and each one of a series of compounds that may act as metabolic inhibitors of the action of L-canavanine and L-canaline (L-arginine, L-ornithine, D-arginine, L-lysine, L-homoarginine, putrescine, L-omega-nitro arginine methyl ester, and L-citrulline). The capacity of these compounds to overcome the cytotoxic effects of L-canavanine or L-canaline was assessed in order to provide insight into the biochemical mechanisms that may underlie the toxicity of these two novel anticancer agents. The results of these studies suggest that the mechanism of L-canavanine toxicity is mediated through L-arginine-utilizing mechanisms and that the L-canavanine metabolite, L-canaline, is toxic to human PBMCs by disrupting polyamine biosynthesis. The elucidation of the biochemical mechanisms associated with the effects of L-canavanine and L-canaline on lymphoproliferation may be useful for maximizing the therapeutic effectiveness and minimizing the toxicity of these novel anticancer agents.

来源:Hazardous Substances Data Bank (HSDB)

代谢

L-刀豆氨酸是一种具有显著抗肿瘤效果的非常规氨基酸，对其代谢进行了研究。以2.0克/千克的剂量给予L-刀豆氨酸，并补充了5微居里的L-[脒基氧-(14)C]刀豆氨酸（58微居里/微摩尔），通过静脉注射、皮下注射或口服给体重约200克的大鼠。24小时内尿液中14C的回收率分别为给药剂量的83%、68%或61%。另外5-8%的(14)C以(14)CO2的形式呼出。口服给药的(14)C有21%存在于胃肠道中。血清、粪便、组织和新生成的蛋白质只占原始剂量的几个百分点。分析含有14C的尿液代谢物发现，静脉注射后[(14)C]尿素占尿液放射活性的88%，皮下给药后占75%，口服给药后占50%。无论哪种给药途径，[(14)C]脒基代表尿液中5%的放射性，[(14)C]脒基乙酸占2%。血清和尿液氨基酸分析显示鸟氨酸水平显著升高。尿液中的碱性氨基酸，如组氨酸、赖氨酸和精氨酸也有所升高。在口服刀豆氨酸剂量为1.0、2.0和4.0克/千克后，测定了血浆氨水平。只有在4.0克/千克的剂量下观察到血浆氨的快速但短暂的升高。这表明，在本研究中使用的药物浓度下，血浆氨升高不是刀豆氨酸毒性的可能原因。

The metabolism of L-canavanine, a nonprotein amino acid with significant antitumor effects, was investigated. L-Canavanine, provided at 2.0 g/kg, was supplemented with 5 uCi of L-[guanidinooxy-(14)C]canavanine (58 uCi/mumol) and administered iv, sc, or orally to female Sprague-Dawley rats weighing approximately 200 g. 14C recovery in the urine at 24 hr was 83, 68, or 61%, respectively, of the administered dose. Another 5-8% of the (14)C was expired as (14)CO2. The gastrointestinal tract contained 21% of orally administered (14)C. Serum, feces, tissues, and de novo synthesized proteins only accounted for a few percent of the original dose by any administrative route. Analysis of the (14)C-containing urinary metabolites revealed that [(14)C] urea accounted for 88% of the urinary radioactivity for an iv injection, 75% for sc administration, and 50% following an oral dose. By all routes of administration, [(14)C]guanidine represented 5% of the radioactivity in the urine and [(14)C]guanidinoacetic acid accounted for 2%. Serum and urine amino acid analysis showed a markedly elevated ornithine level. Basic amino acids such as histidine, lysine, and arginine were also higher in the urine. Plasma ammonia levels were determined following oral canavanine doses of 1.0, 2.0, and 4.0 g/kg. A rapid but transient elevation in plasma ammonia was observed only at the 4.0 g/kg dose. This indicates that elevated plasma ammonia is not a likely cause of canavanine toxicity at the drug concentrations used in this study.

来源:Hazardous Substances Data Bank (HSDB)

代谢

之前观察到，在氨基酸氧化酶与刀豆氨酸（2-氨基-4-胍氧基丁酸）反应中会形成羟基胍。目前的工作表明，羟基胍是通过非酶促的beta,gamma-消除反应形成的，该反应在alpha-C位置经过酶促氧化，并且beta-H的抽象是由一般碱催化的。消除反应需要在alpha位置有一个能稳定负离子的基团——质子化的亚胺基（亚胺离子基团）或羰基。亚胺离子基团比羰基更具激活作用。消除反应还通过胍氧基团的质子化得到进一步促进。消除反应形成的另一种产物被确认为乙烯醛（2-氧代-3-丁烯酸），这是一种非常强的亲电子物质。经氧化后水解的产物被确认为alpha-酮基-gamma-胍氧基丁酸（酮刀豆氨酸）。羟基胍与酮刀豆氨酸的比例取决于碱催化剂的浓度和碱度，以及pH值。在脒肼存在的情况下，消除反应被阻止，因为酮刀豆氨酸的脒肼衍生物中的亚胺基团没有显著质子化。将刀豆氨酸与5'-脱氧吡哆醛一起培养也产生了羟基胍。由于消除反应在温和条件下进行，它们可能在活体内发生，在L-刀豆氨酸（摄入或内源形成）或其他在gamma位置有良好离去基团的氨基酸（例如，S-腺苷甲硫氨酸、甲硫氨酸亚砜、同型半胱氨酸或半胱氨酸-同型半胱氨酸混合二硫化物）的alpha-C位置经过L-氨基酸氧化酶、转氨酶或脱氢酶氧化后。因此，乙烯醛可能是哺乳动物的正常代谢物，在浓度升高时，可能会对刀豆氨酸和上述一些其他氨基酸的体内毒性产生影响。

It was observed previously that hydroxyguanidine is formed in the reaction of canavanine(2-amino-4-guanidinooxybutanoate) with amino acid oxidases. The present work shows that hydroxyguanidine is formed by a nonenzymatic beta,gamma-elimination reaction following enzymatic oxidation at the alpha-C and that the abstraction of the beta-H is general-base catalyzed. The elimination reaction requires the presence in the alpha-position of an anion-stabilizing group--the protonated imino group (iminium ion group) or the carbonyl group. The iminium ion group is more activating than the carbonyl group. Elimination is further facilitated by protonation of the guanidinooxy group. The other product formed in the elimination reaction was identified as vinylglyoxylate (2-oxo-3-butenoate), a very highly electrophilic substance. The product resulting from hydrolysis following oxidation was identified as alpha-keto-gamma-guanidinooxybutyrate (ketocanavanine). The ratio of hydroxyguanidine to ketocanavanine depended upon the concentration and degree of basicity of the basic catalyst and on pH. In the presence of semicarbazide, the elimination reaction was prevented because the imino group in the semicarbazone derivative of ketocanavanine is not significantly protonated. Incubation of canavanine with 5'-deoxypyridoxal also yielded hydroxyguanidine. Since the elimination reactions take place under mild conditions, they may occur in vivo following oxidation at the alpha-C of L-canavanine (ingested or formed endogenously) or of other amino acids with a good leaving group in the gamma-position (e.g., S-adenosylmethionine, methionine sulfoximine, homocyst(e)ine, or cysteine-homocysteine mixed disulfide) by an L-amino acid oxidase, a transaminase, or a dehydrogenase. Therefore, vinylglyoxylate may be a normal metabolite in mammals which at elevated concentrations may contribute to the in vivo toxicity of canavanine and of some of the other above-mentioned amino acids.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：L-刀豆氨酸是一种固体。它是L-精氨酸的一种潜在有毒的 antimetabolite，被许多豆科植物储存。它对多种动物携带的癌症和癌细胞系具有明显的抗肿瘤活性。L-刀豆氨酸曾被用作一种实验性药物。人类暴露和毒性：L-刀豆氨酸是一种天然存在的L-氨基酸，由于它与这种L-氨基酸的结构类似，它干扰了使用L-精氨酸的酶。在表达诱导型一氧化氮合酶（iNOS）的巨噬细胞和多形核白细胞中，L-刀豆氨酸能够阻止由L-精氨酸衍生的 nitric oxide（NO）的合成。L-刀豆氨酸对人类血小板的相对浓度产生不同的影响：在低水平下，它通过独立于NOS抑制的作用产生抗聚集效果，而在高水平下，它抑制NO的合成并且不产生抗聚集效果。L-刀豆氨酸对培养中的人外周血单核白细胞（PBMCs）具有细胞毒性。这些研究的结果表明，L-刀豆氨酸毒性的机制是通过L-精氨酸利用机制介导的，L-刀豆氨酸的代谢物，L-刀豆醇，通过破坏聚胺生物合成对人类PBMCs具有毒性。动物研究：在成年大鼠和10天大的大鼠中，L-刀豆氨酸对大鼠的毒性很小：成年大鼠的LD50为5.9 +/- 1 8 g/kg，10天大的大鼠为5.0 +/- 1.0 g/kg。重复sc给药导致更严重的毒性。在大鼠连续7天每天sc注射L-刀豆氨酸后观察到体重减轻和脱发。在这种给药方案下，成年大鼠的摄食量减少了80%，但在L-刀豆氨酸注射停止后恢复正常。对每天用3.0 g/kg L-刀豆氨酸处理6天的成年大鼠的组织进行组织学研究发现胰腺腺泡细胞萎缩和纤维化。在单次sc注射2.0 g/kg L-刀豆氨酸后，血清淀粉酶和脂肪酶水平升高；三次每日注射后，两种血清酶都被耗尽。观察到血清葡萄糖和尿素氮升高以及胆固醇降低。最显著的变化是血清天冬氨酸转氨酶、丙氨酸转氨酶和碱性磷酸酶活性的严重降低。十八只雌性小鼠被喂食含有1.56% L-刀豆氨酸硫酸盐（1%基）的饮食，另外十八只被喂食对照饮食，从第84天到第477天。从第84天到第164天，每只小鼠每天喂食4 g，之后每天喂食5 g。只有6只喂食L-刀豆氨酸的带有交配栓的小鼠（对照组为5只中的5只）在17天妊娠期内携带任何幼崽。黄体、胚胎和再吸收部位的计数表明，这些对妊娠的显著影响可能是由于着床失败。只有50%的对照组小鼠和89%的喂食L-刀豆氨酸的小鼠存活到477天。这些结果表明，L-刀豆氨酸可能延长小鼠的寿命，但干扰它们的繁殖。为了阐明每种化合物的细胞毒性的机制，研究了L-刀豆氨酸及其代谢物L-刀豆醇对Salmonella typhimurium TA100和Bacillus subtilis h 17 rec+ & M 45 rec-的诱变活性。这两种化合物及其从大鼠肝匀浆中获得的代谢物没有引起DNA结构上的碱基对替换和移码活性。显然，这些化合物不是直接作用于DNA，而是其他机制，例如形成含有L-刀豆氨酸的蛋白质，似乎影响DNA代谢。L-刀豆氨酸显著抑制了大鼠结肠癌的生长。

IDENTIFICATION AND USE: L-canavanine is a solid. It is a potentially toxic antimetabolite of L-arginine that is stored by many leguminous plants. It has demonstrative antineoplastic activity against a number of animal-bearing carcinomas and cancer cell lines. L-canavanine has been used as an experimental medication. HUMAN EXPOSURE AND TOXICITY: L-Canavanine is a naturally occurring L-amino acid that interferes with L-arginine-utilizing enzymes owing to its structural analogy with this L-amino acid. In macrophages and polymorphonuclear leukocytes, which express inducible nitric oxide synthase (iNOS), L-canavanine is able to prevent the L-arginine-derived synthesis of nitric oxide (NO). L-canavanine exerts differential effects on human platelets in relation to the concentrations: at low levels, it exerts antiaggregating effects by actions independent of NOS inhibition, whereas, at high levels, it inhibits NO synthesis and does not exert antiaggregating effects. L-canavanine was cytotoxic to human peripheral blood mononuclear leucocytes (PBMCs) in culture. The results of these studies suggest that the mechanism of L-canavanine toxicity is mediated through L-arginine-utilizing mechanisms and that the L-canavanine metabolite, L-canaline, is toxic to human PBMCs by disrupting polyamine biosynthesis. ANIMAL STUDIES: It was only slightly toxic to rats following a single sc injection: the LD50 was 5.9 +/- 1 8 g/kg in adult rats and 5.0 +/- 1.0 g/kg in 10-day-old rats. Repeated sc administration of canavanine resulted in more severe toxicity. Weight loss and alopecia were observed in rats given daily sc canavanine injections for 7 days. Food intake was decreased by 80% in adult rats subjected to this dosing regimen, but returned to normal after canavanine injections were terminated. Histological studies of tissues from adult rats treated with 3.0 g/kg canavanine daily for 6 days revealed pancreatic acinar cell atrophy and fibrosis. Serum amylase and lipase levels were elevated following one sc injection of 2.0 g/kg canavanine; after three daily injections both serum enzymes were depleted. Elevations in serum glucose and urea nitrogen, and depletion of cholesterol, were observed. The most significant changes were severe attenuations of serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activity. Eighteen female mice were fed a diet containing 1.56% canavanine sulphate (1% base) and eighteen others were fed a control diet from day 84 to day 477 of age. Four g/d/mouse diet were fed from day 84 to day 164 of age and 5 g/d/mouse were fed thereafter. Only 6 of 10 canavanine-fed mice with copulatory plugs (vs 5 of 5 controls) carried any pups to 17d of gestation. Counts of corpora lutea, embryos and resorption sites indicate that these significant effects on pregnancy may have been due to failure of implantation. Only 50% of control mice and a full 89% of canavanine-fed mice survived to 477 days of age. These results indicate that canavanine may extend the life of mice, but interferes with their reproduction. Mutagenic activities of l-canavanine and metabolite l-canaline on Salmonella typhimurium TA100 and Bacillus subtilis h 17 rec+ & M 45 rec- were investigated in order to elucidate the mechanism of cytotoxicity of each compound. Both compounds and their metabolites obtained from rat liver homogenate did not cause base-pair substitutions and frameshift activities on DNA structure. Apparently, the compounds do not act on DNA directly, but other mechanisms, such as formation of l-canavanine-containing proteins, appear to influence DNA metabolism. Canavanine induced marked growth inhibition of the rat colon carcinoma.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

烟草天蛾（Manduca sexta，天蛾科）幼虫在终期阶段，如果喂食含有2.5毫摩尔/升刀豆素的饮食，其生长和发展会受到明显干扰。当这些生物被喂食添加了1:10摩尔比例的L-精氨酸、L-瓜氨酸、L-鸟氨酸或L-2,4-二氨基丁酸的刀豆素饮食时，由刀豆素介导的幼虫生长干扰会大大增强；幼虫会出现增强的血淋巴体积（水肿）和不完全的幼虫到蛹蜕皮导致的显著死亡率。

The growth and development of final-stadium tobacco hornworm, manduca sexta (sphingidae) larvae fed a 2.5 mmole l-canavanine containing diet was markedly disrupted. Such canavanine-mediated disruption of larval growth was intensified greatly when these organisms were fed a canavanine-containing diet supplemented with a 1:10 molar ratio of l-arginine, l-citrulline, l-ornithine, or l-2,4-diaminobutyric acid; the larvae possess enhanced hemolymph volume (edema) and a significant mortality results from incomplete larval-pupal ecdysis.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

这项研究调查了非选择性内皮素受体拮抗剂波森坦（bosentan）与相对选择性的诱导型一氧化氮合酶抑制剂氨胍（aminoguanidine）和L-刀豆素（L-canavanine）对内毒素血症引起的肠系膜血流减少、肝脏和脾脏损伤的调节作用。瑞士白化小鼠（20-40克）在腹腔注射盐水或大肠杆菌内毒素（10 mg/kg）前十分钟，分别给予了波森坦（3、10或30 mg/kg）、氨胍（15 mg/kg）或L-刀豆素（20或100 mg/kg）。四小时后，对小鼠进行麻醉，测量肠系膜血流量，确定脾脏和肝脏的重量与体重比，并对器官进行组织病理学检查。内毒素减少了肠系膜血流量（毫升/分钟），盐水：3.0 ± 0.2；内毒素：2.2 ± 0.2；n=10，p<0.05），增加了肝脏（每千克体重的克数，盐水：47.5 ± 2.0；内毒素：60.8 ± 1.9；n=10，p<0.05）和脾脏（每千克体重的克数，盐水：3.9 ± 0.5；内毒素：8.6 ± 0.9；n=10，p<0.01）的重量，并对两个器官造成了显著的病理学损伤。波森坦在3 mg/kg剂量下无效，但在10和30 mg/kg剂量下，它完全消除了内毒素的所有有害影响。氨胍阻断了内毒素的大部分影响，除了对脾脏的影响。相比之下，L-刀豆素仅阻断了内毒素引起的肝脏重量增加，但它本身增加了脾脏重量，并未阻断内毒素的任何其他影响。因此，可以推测氨胍的有益效果主要是通过选择性诱导型一氧化氮合酶抑制以外的机制产生的，因为L-刀豆素并不完全有效。使用波森坦抑制内皮素的有益效果可以进一步用于理解和治疗与败血症相关的综合征。

The modulatory effects of a non-selective endothelin receptor antagonist, bosentan, were investigated together with those of relatively selective inducible nitric oxide synthase inhibitors, aminoguanidine and L-canavanine, on mesenteric blood flow decrease, liver and spleen injury elicited by endotoxemia. Swiss albino mice (20-40 g) were administered intraperitoneally bosentan (3, 10 or 30 mg/kg), aminoguanidine (15 mg/kg) or L-canavanine (20 or 100 mg/kg) 10 min before they received saline or Escherichia coli endotoxin (10 mg/kg). After 4 hr, the mice were anesthetized, mesenteric blood flow values were measured, spleen and liver weight/body weight ratios were determined and the organs were examined histopathologically. Endotoxin decreased mesenteric blood flow (mL/min), saline: 3.0 +/- 0.2; endotoxin: 2.2 +/- 0.2: n=10, p<0.05), increased the weight of liver (g per kg body weight, saline: 47.5 +/- 2.0; endotoxin: 60.8 +/- 1.9: n=10, p<0.05) and spleen (g per kg body weight, saline: 3.9 +/- 0.5; endotoxin: 8.6 +/- 0.9; n=10, p<0.01) while it inflicted significant histopathological injury to both organs. Bosentan was ineffective at 3 mg/kg but at 10 and 30 mg/kg doses, it abolished all the deleterious effects of endotoxin without exception. Aminoguanidine blocked most of the effects of endotoxin except those on spleen. In contrast, L-canavanine blocked only the endotoxin-induced increase in liver weight but itself increased spleen weight and failed to block any other effects of endotoxin. Thus, it can be speculated that the beneficial effects of aminoguanidine are produced largely by mechanisms other than selective inducible nitric oxide synthase inhibition since L-canavanine was not fully effective. The beneficial effects of endothelin inhibition by using bosentan in endotoxemia can be further exploited for the understanding and the therapy of sepsis-related syndromes.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

研究了L-刀豆氨酸（一氧化氮合酶的抑制剂）对戊巴比妥麻醉大鼠内毒素诱导休克的影响。内毒素输注（2.5 mg kg-1 hr-1，持续6小时）导致血压和血糖进行性显著下降。电子显微镜检查显示肾脏发生了明显变化，包括严重的内皮细胞破坏和血管内血小板的积聚。在肺部，小血管内出现了明显的多形核白细胞积聚和内皮细胞破坏。用L-刀豆氨酸治疗（每次10 mg kg-1，于内毒素或生理盐水输注后70分钟开始，每小时静脉注射一次）显著减少了内毒素诱导的血压下降，而对低血糖无影响。这种治疗显著减少了内毒素诱导的肾脏和肺部的电子显微镜下变化。尽管L-刀豆氨酸和L-硝基精氨酸甲酯（L-NAME）一样，在体外抑制了小脑组成型和脾脏诱导型一氧化氮合酶，但与L-NAME不同的是，它没有改变对照组大鼠的动脉血压或颈动脉血流量。数据表明L-刀豆氨酸至少在体内是一种选择性的诱导型一氧化氮合酶抑制剂，并且提示这种酶的抑制剂可能对内毒素诱导的休克有益。

The effects of L-canavanine, an inhibitor of nitric oxide synthase, on endotoxin-induced shock was investigated in the pentobarbitone anesthetized rat. Endotoxin infusion (2.5 mg kg-1 hr-1 over 6 hr) produced progressive and marked hypotension and hypoglycemia. Electron microscopy showed marked changes in the kidney, comprising severe endothelial cell disruption and the accumulation of platelets in the blood vessels. In the lung, there was marked accumulation of polymorphonuclear leukocytes in small blood vessels and endothelial disruption. Treatment with L-canavanine (10 mg kg-1 by bolus injection each hour starting 70 min after endotoxin or saline infusion) significantly reduced endotoxin-induced hypotension, without any effect on the hypoglycemia. This treatment markedly reduced the endotoxin-induced electron microscopical changes in the kidneys and lungs. Although L-canavanine, like L-NAME, inhibited both cerebellar constitute and splenic inducible nitric oxide synthase in vitro, in contrast to L-NAME it did not modify either arterial blood pressure or carotid artery blood flow in control rats. The data are consistent with L-canavanine being a selective inhibitor of inducible nitric oxide synthase, at least in vivo, and suggest that inhibitors of this enzyme may be beneficial in endotoxin-induced shock.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

L-刀豆素和镉对HeLa S3细胞的核糖核蛋白组成的影响已经进行了分析。这两种化学物质都会在不同RNP结构以及RNA和蛋白质合成中诱导出相似的变化模式。脉冲和追踪放射性自显影实验揭示，刀豆素和镉都会优先抑制核仁RNA的合成，并减缓核仁和核外RNA的运输或加工。核仁变得圆润且紧密。周围出现染色质颗粒和纤维的积累，染色质间纤维减少，并且出现了似乎参与在处理过程中积累的周围染色质颗粒形态发生的核结构。29到35纳米颗粒簇的出现可能与周围染色质颗粒组成成分的组装不足有关。不同转录过程抑制剂对周围染色质颗粒积累的影响表明，这些颗粒代表了一种特殊的hnRNP亚群。

The effects of L-canavanine and cadmium on the ribonucleoprotein constituents of HeLa S3 cells have been analyzed. Both chemicals induce a similar pattern of alterations in different RNP structures as well as in both RNA and protein synthesis. Pulse and chase autoradiographic experiments reveal that both canavanine and cadmium induce a preferential inhibition of nucleolar RNA synthesis and a slowdown in the transport or processing of nucleolar and extranucleolar RNA. Nucleoli become round and compact. Accumulation of perichromatin granules and fibrils occurs, there is a depletion of interchromatin fibrils, and nuclear formations appear which seem to be involved in the morphogenesis of perichromatin granules accumulated during the treatments. The appearance of clusters of 29- to 35-nm granules might be related with a deficient assembling of constituents of perichromatin granules. The effects of different inhibitors of the transcriptional processes on the accumulation of perichromatin granules suggest that these granules represent a particular subpopulation of hnRNP.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

L-刀豆碱的毒性进行了研究，因为它被证明具有作为抗癌药物的潜力。这种天然产物在大鼠中通过单次皮下注射的毒性很小：成年大鼠的LD50为5.9 ± 1.8 g/kg，10天大的大鼠为5.0 ± 1.0 g/kg。在成年大鼠中，单次剂量为2.0 g/kg时，刀豆碱的系统清除值为0.114升/小时，稳态分布体积为0.154升，半衰期为1.56小时。在静脉注射后，48%的剂量未改变地通过尿液排出，16%的皮下剂量通过尿液回收。2.0 g/kg皮下剂量的生物利用度为72%。与皮下注射相比，单次口服刀豆碱对成年大鼠的毒性较小。2.0 g/kg口服剂量的生物利用度为43%，只有1%的给药刀豆碱通过尿液回收。口服剂量后24小时，21%的给药刀豆碱残留在胃肠道中。在给予2.0 g/kg剂量的L-[脒基氧-(14)C]刀豆碱后4或24小时，成年和新生大鼠蛋白质中结合的刀豆碱不到1%。重复皮下给药刀豆碱导致更严重的毒性。在接受每日皮下刀豆碱注射7天的老鼠中观察到体重减轻和脱发。在接受这种给药方案的成年大鼠中，食物摄入量减少了80%，但在停止刀豆碱注射后恢复正常。对接受每日3.0 g/kg刀豆碱治疗6天的成年大鼠的组织进行组织学研究发现胰腺腺泡细胞萎缩和纤维化。在单次皮下注射2.0 g/kg刀豆碱后，血清淀粉酶和脂肪酶水平升高；在三次每日注射后，两种血清酶均耗尽。观察到血清葡萄糖和尿素氮升高，以及胆固醇降低。最显著的变化是血清天冬氨酸转氨酶、丙氨酸转氨酶和碱性磷酸酶活性严重降低。

The toxicity of L-canavanine was investigated because of its demonstrated potential as an antitumor drug. This natural product was only slightly toxic to Sprague-Dawley rats following a single sc injection: the LD50 was 5.9 +/- 1 8 g/kg in adult rats and 5.0 +/- 1.0 g/kg in 10-day-old rats. Following a single dose of 2.0 g/kg, the systemic clearance value for canavanine in adult rats was 0.114 liter/hr, the volume of distribution at steady state was 0.154 liter, and the half-life was 1.56 hr. Forty-eight percent of the dose was excreted unaltered in the urine following an iv injection, and 16% of a sc dose was recovered in the urine. Bioavailability of a 2.0 g/kg sc dose was 72%. Single oral doses of canavanine were less toxic to adult rats than sc injections. Bioavailability of a 2.0 g/kg po dose was 43%, and only 1% of the administered canavanine was recovered in the urine. Twenty-one percent of the administered canavanine remained in the gastrointestinal tract 24 hr after an oral dose. Less than 1% of a 2.0 g/kg dose of L-[guanidinooxy-(14)C]canavanine was incorporated into the proteins of adult and neonatal rats 4 or 24 hr following administration. Repeated sc administration of canavanine resulted in more severe toxicity. Weight loss and alopecia were observed in rats given daily sc canavanine injections for 7 days. Food intake was decreased by 80% in adult rats subjected to this dosing regimen, but returned to normal after canavanine injections were terminated. Histological studies of tissues from adult rats treated with 3.0 g/kg canavanine daily for 6 days revealed pancreatic acinar cell atrophy and fibrosis. Serum amylase and lipase levels were elevated following one sc injection of 2.0 g/kg canavanine; after three daily injections both serum enzymes were depleted. Elevations in serum glucose and urea nitrogen, and depletion of cholesterol, were observed. The most significant changes were severe attenuations of serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activity.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  canavanine 以 乙醇 、 水 为溶剂， 生成 D-2-amino-3-(guanidinooxy) propionic acid
  参考文献：
  名称：

  Canavanine analogs and their use as chemotherapeutic agents

  摘要：

  这项发明涉及到卡瓦宁类似物、它们的药物组合物以及治疗癌症的方法，特别是胰腺癌。

  公开号：

  US05859295A1
• 作为产物：
  描述：

  L-刀豆氨酸 在 乙酸酐 作用下， 生成 canavanine
  参考文献：
  名称：

  Nakatsu, Journal of Biochemistry, 1959, vol. 46, p. 1343,1344

  摘要：

  DOI：

文献信息

• The Synthesis of DL-Canaline, DL-Canavanine and Related Compounds¹
  作者：David D. Nyberg、Bert E. Christensen

  DOI：10.1021/ja01562a050

  日期：1957.3
• YAMADZI, TEHJDZO;ADZUMA, SIDZUO;XIRAMATSU, TOSIYUKI;ITIKAVA, YATARO
  作者：YAMADZI, TEHJDZO、ADZUMA, SIDZUO、XIRAMATSU, TOSIYUKI、ITIKAVA, YATARO

  DOI：——

  日期：——
• Nakatsu, Journal of Biochemistry, 1959, vol. 46, p. 1343,1344
  作者：Nakatsu

  DOI：——

  日期：——
• Canavanine analogs and their use as chemotherapeutic agents
  申请人：University of Kentucky Research Foundation

  公开号：US05859295A1

  公开（公告）日：1999-01-12

  This invention relates to canvanine analogs, their pharmaceutical compositions, and a method for treatment of cancer, particularly pancreatic cancer.

  这项发明涉及到卡瓦宁类似物、它们的药物组合物以及治疗癌症的方法，特别是胰腺癌。