鬼臼酰肼哌啶腙氮氧自由基和鬼臼乙叉甙对体外培养癌细胞增殖、有丝分裂指数和DNA合成的影响

鬼臼酰肼哌啶腙氮氧自由基(GP_1)和鬼臼乙叉甙(VP_(16))对L_(7712)细胞的增殖有明显的抑制作用,且有时间依赖性。在0.04～20mg/L范围,GP_1增加有丝分裂指数(MI)的作用与VP_(16)降低MI的作用均和剂量相关。5mg/LGP_1处理细胞12h时MI达峰值,为对照的8倍;而VP_(16)组的MI仅为对照的1/3。VP_(16)可对抗GP_1增高MI的作用。用GP_1或VP_(16)24h时细胞死亡、崩解增多。两药对S_(180),AH,L_(1210)和L_(7712)细胞DNA合成均有不同程度的抑制作用。     

4-[4”-(2”,2”,6”,6”-四甲基哌啶氮氧自由基)氨基]-4’-去甲表鬼臼毒抗肿瘤作用

新合成的鬼臼毒素氮氧自由基衍生物4-[4”-(2”,2”,6”,6”-四甲基哌啶氮氧自由基)氨基]-4’-去甲表鬼臼毒(GP-7)显著抑制小鼠移植性肿瘤S180、实体型HePS和Lewis肺癌生长;7.5～20mg/kg,给药10d,抑瘤率分别为36.0％～58.4%、29.6%～60.0%和27.2%～46.5%;抑制作用和鬼臼乙叉甙(VP-16)相似。GP-7小鼠一次ip,LD_(50)为231.2mg/kg,是VP-16的3.3倍;连续给药10d,对小鼠脾和胸腺指数的影响较VP-16小,对小鼠WBC的影响和VP-16相同。GP-7和VP-165mg/L处理L1210细胞24h,抑瘤率分别为75.5%和73.6%;处理SGC-7901细胞72h,抑瘤率分别为81.4%和84.2%。     

4-[4″-(2″,2″,6″,6″-四甲基哌啶氮氧自由基)氨基]-4′-去甲表鬼臼毒对L1210细胞系增殖、克隆形成和DNA合成的影响

新合成的鬼臼毒自旋标记衍生物4-(4″-(2″,2″,6″,6″-四甲基哌啶氮氧自由基)氨基)-4′-去甲表鬼臼毒(GP-7)显著抑制体外培养的L1210细胞生长。抑制作用和浓度及处理时间正相关,作用特点和鬼臼乙叉甙(VP-16)相似,24,48hIC_(50)分别为1.51和0.13μmol/L。GP-7和VP-16对L1210细胞软琼脂克隆形成均有抑制作用,且有浓度依赖性,IC_(50)分别为3.29和2.82μmol/L。GP-70.08～100μmol/L对L1210细胞DNA合成抑制率为18.4～80.7％。本文结果表明GP-7体外抗肿瘤作用与VP-16相似。     

4-磺酸酯-2,2,6,6-四甲基哌啶氮氧自由基对大鼠组织和红细胞的抗脂质过氧化作用

研究了 4 磺酸酯 2 ,2 ,6,6 四甲基哌啶氮氧自由基 (STMP)的抗脂质过氧化作用 .结果表明 ,STMP显著抑制丙二醛 (MDA)的生成 ,其抑制心 ,肝 ,肾MDA生成的IC50 分别为 4 .4 ,3.2及 3.7μmol·L- 1;对抗溶血反应 ,其IC50 为 318.3μmol·L- 1;但不影响O2 ÷ 的生成 .提示STMP通过清除·OH而对抗脂质过氧化     

4-磺酸酯-2，2，6，6-四甲基哌啶氮氧自由基对大鼠组织和红细胞的抗脂质过氧化作用

研究了4-磺酸酯-2,2,6,6-四甲基哌啶氮氧自由基（STMP）的抗脂质过氧化作用. 结果表明,STMP显著抑制丙二醛（MDA）的生成,其抑制心,肝,肾MDA生成的IC₅₀分别为4.4, 3.2及3.7 μmol·L^-1;对抗溶血反应, 其IC₅₀为318.3 μmol·L^-1;但不影响O₂的生成. 提示STMP通过清除·OH而对抗脂质过氧化.     

4-羟基-2,2,6,6-四甲基哌啶对肾性高血压大鼠左室重塑的保护作用及机制探讨

<正>高血压并发的左室重塑主要表现为左心室肥厚和心肌纤维化。在高血压早期是适应性的代偿反应,但长期过量的负荷必然导致失代偿,终至心力衰竭。大量的流行病学资料证明,左室重塑是心血管系统疾病发病率和病死率的独立危     

2-甲基-7-哌啶乙氧基-4′-羟基异黄酮合成工艺的改进

目的对2-甲基-7-羟基-4′-甲氧基异黄酮的合成工艺进行改进。方法以对羟基苯乙酸为原料,经甲基化、F-C酰化、环化、水解得2-甲基-7-羟基-4′-甲氧基异黄酮,再与乙氧基哌啶醚化,最后用氢碘酸在120℃反应3 h,脱去4′-位甲基得目标物。结果与结论改进后的方法与文献方法比较具有反应条件温和,后处理方便,收率高等优点。     

2-氯-4-(哌啶-1-基甲基)吡啶的合成

2-氨基-4-甲基吡啶在过量浓盐酸/亚硝酸钠作用下与氯化亚铜/盐酸反应后,在偶氮二异丁腈(AIBN)作用下与硫酰氯反应制得2-氯-4-(氯甲基)吡啶,再在DMF中与哌啶缩合,得到拉呋替丁的关键中间体2-氯-4-(哌啶-1-基甲基)-吡啶,总收率约62％.     

2-甲基-7-哌啶乙氧基-4'-羟基异黄酮合成工艺的改进

目的对2-甲基-7-羟基-4’-甲氧基异黄酮的合成工艺进行改进。方法以对羟基苯乙酸为原料，经甲基化、F—C酰化、环化、水解得2-甲基-7-羟基-4’-甲氧基异黄酮，再与乙氧基哌啶醚化，最后用氢碘酸在120℃反应3h,脱去4＇-位甲基得目标物。结果与结论改进后的方法与文献方法比较具有反应条件温和，后处理方便，收率高等优点。     

2-苯甲酰肼叉-1,3-二噻茂烷在大鼠原位灌流肝中的代谢动力学

采用反相高压液相色谱的三内标三波长切换技术对不同剂量的农药2-苯甲酰肼叉-1.3二噻茂烷在大鼠原位灌流肝中的代谢动力学进行了研究.结果表明,该农药经门静脉进入大鼠原位灌流肝后,很快分布于肝脏中,而在灌流肝中的消除过程较缓慢。随着给药剂量的增加,大鼠肝灌流液中各种代谢产物的生成量也逐渐增加,尤以肼叉1.3-二噻茂烷和苯甲酸生成量的增加更为显著.可见,该农药在大鼠原位灌流肝中的主要代谢途径为水解作用。     

汉防己甲素的安全性

麻醉家兔急性实验表明,iv 汉防己甲素(Tet)10mg/kg 能显著降低血压并减慢其心率,ECG 有短暂的变化,家兔无中毒死亡,而iv 汉防己甲素15mg/kg 后,血压立即急剧下降,心率明显减慢,ECG 出现异常变化,5—10min 内,家兔出现惊厥,心脏停搏、呼吸停止而死亡(死亡率88.9%)。结果表明一次静脉注射汉防已甲素对麻醉家兔降压的有效量(10mg/kg)与中毒致死量(15mg/kg)之间的范围较窄(有效量约为中毒致死量的66%),提示本品静脉注射给药的安全性值得再评价。小鼠静脉注射汉防已甲素的LD_(50)为37.5±3.6mg/kg。     

丹红注射液的毒理学研究

目的 观察丹红（倍通）注射液的急慢性毒性，对其进行安全性评价。方法 小鼠连续7d静脉给药，测定药物的半数致死量（LD50）。大鼠连续给药90d后，处死大部动物，取血，做血常规、血液生化指标测定，取主要脏器称重进行病理学检查。余下大鼠在停药继续喂养2周后，处死进行病理组织学检查。结果 小鼠LD50为39．5ml／kg。各实验组大鼠在体质量增加、器官系数、血常规、血液生化指标上基本相似，与对照组比较差异无统计学意义（P〉0．05）。主要脏器的病理组织学检查未见明显异常。结论 急慢性毒性实验的结果表明该药安全可靠。     

New compounds, 6-hydroxykarahanaenone and 10-hydroxykarahanaenone,from biotransformation of karahanaenone by CYP2A6

The in vitro biotransformation of karahanaenone was examined in cytochrome P450 (CYP) 2A6. The biotransformation of karahanaenone by CYP2A6 was investigated by gas chromatography (GC) and gas chromatography–mass spectrometry (GC–MS). Karahanaenone was found to be oxidized to two metabolites by CYP2A6. In order to produce large quantity of metabolites by CYP2A6, the biotransformation of karahanaenone by Salmonella typhimurium OY1002/2A6 was investigated. Similarly, two metabolites were confirmed by GC and GC–MS. The structure of metabolites was determined by 1D NMR, 2D NMR, and infrared, as a result there were new compounds, (6R)-hydroxykarahanaenone and 10-hydroxykarahanaenone.     

6-取代苯基-3(2H)哒嗪酮的合成、抗惊活性及其构效关系的研究

本文报道了14个6-取代苯基-4,5-二氢-3(2H)哒嗪酮和15个6-取代苯基-3(2H)哒嚎酮的合成及其抗电惊活性。其ED₅₀值表明,以2′,4′-二氯苯基-3(2H)哒嗪酮的抗惊作用为最强。构效分析表明,苯环上的取代基对化合物的抗惊活性有明显影响,吸电子取代基和疏水性参数值较大的取代基有利于提高化合物的抗惊活性。     

4-叔丁基-5-(12,4,-三唑-1-基)-2-苄亚氨基噻唑的体外抗癌活性研究

目的研究4-叔丁基-5-(1,2,4-三唑-1-基)-2-苄亚氨基噻唑类衍生物对宫颈癌细胞系Hela、肝癌细胞系Bel 7402、鼻咽癌细胞系CNE 2的体外抗癌活性。方法细胞抑制率采用四甲基偶氮唑蓝(MTT)法测定。每种试样设置5个浓度梯度(0.025、0.05、0.10、.25、0.5μmol/ml),每个浓度取4个平行样,并设置无药对照实验,用半数抑制浓度(IC50)评价目标化合物的抗癌活性。结果被测化合物对3种癌细胞均表现出一定的抑制作用,其中化合物5对Hela癌细胞和Bel 7402癌细胞的IC50值分别为0.076 1、0.062 8μmol/ml;化合物6对CNE 2癌细胞的IC50值为0.050 8μmol/ml。结论生物活性测试表明该类型氨基噻唑衍生物具有较好的抗癌活性,值得进一步研究和关注。     

Synthesis and biological activity of 6-substituted-2-oxo-purine nucleosides

We have synthesized various 6-substituted-2-oxo-purine nucleosides from key intermediate, 6-[(4-methylphenylthio)-2-oxo-9-(2,3,5-tri-o-acetyl-β-D-ribofuranosyl)]-2,3-dihydropurine in relatively high yields by one step nucleophilic substitution. Various isoguanosine, xanthosine analogs and other 2-oxo-purine nucleosides containing nitrogen, sulfur and oxygen at C-6 of purine base were easily obtained by this method. The structures of the products were established on the basis of their spectral data studies. And cytotoxicity of resulting synthetic 6-substituted-2-oxo-purine nucleosides against some tumor cell-lines was examined. ED₅₀ values of these synthetic compounds were above 100 μg/ml except isoguanosine, N⁶-methyl isoguanosine and thioxanthosine analogs.     

Inhibitory effects of 6-(3-hydroxyphenyl)-2-naphthol on tyrosinase activity and melanin synthesis

As a part of an ongoing project searching for new skin-lightening agents, the inhibitory property of 6-(3-Hydroxyphenyl)-2-naphthol (HPN) on melanogenesis was investigated. The inhibitory action of HPN (IC₅₀=15.2 μM) on mushroom tyrosinase was revealed. To further explore the action of HPN on melanogenesis, the inhibition of tyrosinase and melanin levels were measured in B16 melanoma cells (B16 cells). Results show that HPN inhibited tyrosinase activity and reduced melanin in B16 cells. Therefore, our data indicate HPN as a new candidate for depigmentation reagents. Contributed equally to this work.     

Antitumour imidazotetrazines--IV. An investigation into the mechanism of antitumour activity of a novel and potent antitumour agent, mitozolomide (CCRG 81010, M & B 39565; NSC 353451)

8-Carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4-(3H )-one- mitozolomide (CCRG 81010, M & B 39565, NSC 353451) is a potent inhibitor of the growth of a number of experimental tumours and can potentially decompose to give either an isocyanate or the monochloroethyltriazene (MCTIC). In vitro CCRG 81010 is not cross-resistant with the bifunctional alkylating agents against the Walker carcinoma. To investigate the mechanism of the antitumour activity of CCRG 81010 a comparison has been made with BCNU and MCTIC on precursor incorporation into macromolecules in TLX5 mouse lymphoma cells. Whereas BCNU produces a rapid and extensive inhibition of both (methyl 3H) thymidine and [5-3H]uridine incorporation into acid-insoluble material, neither CCRG 81010 or MCTIC have an early effect on precursor incorporation. Inhibition of precursor uptake is also not produced by concentrations of 2-chloroethylisocyanate that inhibit intracellular glutathione reductase activity. The potential carbamoylating activity of CCRG 81010 has also been assessed by comparing its effect with that of BCNU and 2-chloroethyl isocyanate on enzymes known to be inhibited by carbamoylation. Such enzymes, glutathione reductase, chymotrypsin and gamma-glutamyltranspepidase are not inhibited by CCRG 81010 under conditions where BCNU and 2-chloroethyl isocyanate show complete inhibition of enzyme activity, suggesting an absence of carbamoylating species. The results suggest that the most likely antitumour metabonate produced from CCRG 81010 is the triazene MCTIC.     

Lipophilicity of analogs of pyridoxal isonicotinoyl hydrazone (PIH) determines the efflux of iron complexes and toxicity in K562 cells

Iron overload secondary to beta-thalassemia and other iron-loading anemias is the most serious obstacle to be overcome in the treatment of these diseases, since there is no physiological mechanism for excretion of the excess iron acquired by chronic blood transfusion. Due to the inconvenience and cost of the current iron chelation therapy, the search for an orally available iron chelator is ongoing. Pyridoxal isonicotinoyl hydrazone (PIH) and many of its analogs are effective at mobilizing iron in vivo and in vitro at doses that are not toxic. PIH analogs were approximately equally effective at binding 59Fe within K562 cells; their efficacy depended upon the kinetics of release of the iron-chelator complex from the cell, which was correlated inversely with the lipophilicity of the chelators. Addition of BSA, which has a well-characterized affinity for lipophilic species, to the extracellular medium enhanced iron-chelator efflux, such that all analogs caused 59Fe release from the cells as quickly as it was chelated; this suggests that BSA acts as an extracellular sink for the iron-chelator complexes, many of which are highly lipophilic. The toxicity of the free chelators varied over two orders of magnitude, and was correlated with the amount of intracellular 59Fe-chelator complexes, implicating the complexes in the mechanism of toxicity of the chelators. Understanding the structural features that determine the efficacy and toxicity of iron chelators in biological systems is of value in the selection of PIH analogs for in vivo examination.