抗肿瘤药物研究Ⅱ:去甲斑蝥素去氧脱氢类似物的合成与抗癌活性

In order to search for new compounds with higher anti-cancer activities and lower toxicities, 18 dehydrogenated carboncyclic analogs of norcantharidin, of which 17 are unknown compounds, were designed and synthesized. Preliminary screening results revealed that compound Ⅴ₆, Ⅵ₆ and Ⅵ₄ exhibited fairly apparent inhibitory activity against the growth of human-hepatoma cells, Bei-7402, in vitro. The inhibitory rate of Ⅵ₄ is 52%, almost the same as that of norcantharidin, in the concentration of 0.05 μmol/ml.     

硝基(芳亚胺基)二乙基硫代硫酸钠和硝基苯丙氮酸衍生物的合成和放射增敏作用

A series of compounds was synthesized, these compounds were tested for Hela-S₃cells in vitro for radiosensitizing activity. Five of them are 2,2′- (arylimino)-diethyl-sodium thio-sulfate and two of them are phenylalanine derivatives. Most of them showed various degrees of ra-diosensitizing activity. Among them, SER of L07 was 1.89 at 3 mmol, and had low cytotoxicity toHela-S₃ cells;ID₅₀ was 18.8 mmol. The relationship between radiosensitizing effects and chemicalstructure was discussed. It offers a base for further exploration of selectively hypoxic cell radiosens-itizers.     

6-取代二氢哒嗪酮类化合物的合成及血小板聚集抑制作用

In order to develop more potent and less toxic, antithrombotic agents, ten 6-(4-substituted piperazinyl acetyl aminophenyi)-4, 5-dihydro-3(2H)-pyridazinones were synthesized. The title compounds were tested in vitro for platelet aggregation inhibitory activity with ADP-induced rat platelets and PAF-induced rabbit platelets. Preliminary tests showed that all of the pyridazinones could inhibit ADP-induced rat platelet aggregation. Ⅰ₇, Ⅰ₈, Ⅰ₉ were more potent than the control compound CI 930. Ⅰ₉ was the most potent compound with IC₅₀ of 0.99 μmol/L. Pertaining to PAF-induced rabbit platelet aggregation. Ⅰ₉ was the most potent inhibitor with IC₅₀ of 3.7 μmol/L.     

二氢叶酸还原酶抑制剂:5-取代苯硫基(硒基)-2,4-二氨基嘧啶类化合物的合成和抑酶活性

According to the principle of isosterism the-CH₂-group of 5-(substituted benzyl)-2, 4-diaminopyrimidine was modified by—S—and—Se—and some 5-(substituted phenyl)thio-2, 4-diaminopyrimidines and 5-(substituted phenyl)seleno-2,4-diaminopyrimidines were synthesized. Their inhibitory activities on L. casei and chicken liver dihydrofolate reductase were determined. Preliminary data showed that the inhibitory activities of these compounds were less than those of the corresponding 5-(substituted benzyl)-2, 4-diaminopyrimidines. Their selectivities are also decreased.     

抗肿瘤药物研究Ⅰ:去甲斑蝥素氨基酸衍生物的合成与抗癌活性

In order to search for new compounds with higher anti-cancer activities and lower toxicities, 19 amino acid derivatives of norcantharidin, of which 16 are unknown compounds, were designed and synthesized. Preliminary screening results revealed that 2-(syn-exo-7-oxabicyclo [2. 2. 1] heptane-2, 3-dicarboxylic imido)-N-phenyl glutaramic acid exhibited a fairly apparent inhibitory activity against human-hepatoma cells in vitro (inhibitory rate 39.4% at 0.025 μtmol/ml).     

上海地区人群甲型H1N1流感抗体水平监测分析

Objective To understand levels of antibody to swine-origin influenza A(H1 N1) virus (A/ H1N1) among different age groups in Shanghai, and to compare the levels between antibodies to A/H1N1 and to 2008-2009 seasonal influenza vaccine virus A/Brisbane/59/2007(H1N1). Methods The anti-A/HlN1 antibody levels were determined among 5 age groups (0-5 months, 6 months-4 years, 5-24 years, 25-59 years, and ≥60 years) with routine micro-hemagglutination inhibition test. The positive rates of the antibodies among different age groups were compared by Pearson's X2 test and Fisher' s exact probability test. Results The positive rate of antibody to A/H1N1 in the whole population in Shanghai was 9.2% (37/404). The highest rate was 25.0% (21/84) in the age group of ≥60 years, the next was 10. 0% (8/80) in the age group of 25-59 years, the positive rates in other groups were lower. The result of Pearson's X2 test showed that there were statistically significant differences in the positive rates of the antibodies among different age groups. Of 329 sera positive for antibody to 2008 -2009 seasonal influenza vaccine virus A/Brisbane/59/ 2007 (H1N1), 31 had anti-A/HlNl antibodies, and of 75 sera negative for antibody to A/Brisbane/59/ 2007(H1N1), 6 had anti-A/HlNl antibodies. The result of Pearson's X2 test showed that there were no significant differences in positive rates of antibody to A/H1N1 between the two types of population. Conclusions The anti-A/HlNl levels in Shanghai population are low, and people are generally susceptible to A/H1N1. The sera positive for antibody to A/Brisbane/59/2007(H1N1) can not provide cross-protection against A/H1N1.     

上海地区人群甲型H1N1流感抗体水平监测分析

Objective To understand levels of antibody to swine-origin influenza A(H1 N1) virus (A/ H1N1) among different age groups in Shanghai, and to compare the levels between antibodies to A/H1N1 and to 2008-2009 seasonal influenza vaccine virus A/Brisbane/59/2007(H1N1). Methods The anti-A/HlN1 antibody levels were determined among 5 age groups (0-5 months, 6 months-4 years, 5-24 years, 25-59 years, and ≥60 years) with routine micro-hemagglutination inhibition test. The positive rates of the antibodies among different age groups were compared by Pearson's X2 test and Fisher' s exact probability test. Results The positive rate of antibody to A/H1N1 in the whole population in Shanghai was 9.2% (37/404). The highest rate was 25.0% (21/84) in the age group of ≥60 years, the next was 10. 0% (8/80) in the age group of 25-59 years, the positive rates in other groups were lower. The result of Pearson's X2 test showed that there were statistically significant differences in the positive rates of the antibodies among different age groups. Of 329 sera positive for antibody to 2008 -2009 seasonal influenza vaccine virus A/Brisbane/59/ 2007 (H1N1), 31 had anti-A/HlNl antibodies, and of 75 sera negative for antibody to A/Brisbane/59/ 2007(H1N1), 6 had anti-A/HlNl antibodies. The result of Pearson's X2 test showed that there were no significant differences in positive rates of antibody to A/H1N1 between the two types of population. Conclusions The anti-A/HlNl levels in Shanghai population are low, and people are generally susceptible to A/H1N1. The sera positive for antibody to A/Brisbane/59/2007(H1N1) can not provide cross-protection against A/H1N1.     

对-氯苯丙炔酰胺类化合物的合成及其与肼反应产物的研究

Synthesis of p-chlorophenylpropiolylamides and itsreaction produets with hydrazine hydrate were studied. It was found that the reaction products varied with the different Substituent groups in the amidel When the substituent group was isopropyl or sec-butyl group, p-chloro-β-hydrazino-cinnamamides (Ⅱ) were obtained. Under similar reaction conditions, when the substituent, group was n-propyl, n-butyl or diethyl group, cyclization reaction occurred and the reaction product was 3-(p-chlorophenyl)-pyrazol-5-one (Ⅲ). All the compounds were tested in mice for anticonvulsant activity. Prelimary data showed that p-chlorophenyl-propiolyl-sec-butylamide (I₄) and p-chlorophenyl-propiolyl-n-propylamide (I₁) exhibited moderate anticonvulsant activity. The ED₅₀ was 54.5(34.4～86.4), and 56.1(31.6～99.6) mg/kg respectively. The compounds of p-chloro-β-hydrazino-cinnamamide (Ⅱ)and 3-(p-chlorophenyl)-pyrazol-5-one (Ⅲ) showed no significant effect on antieonvulsant activity. p-Chloro-cinnamoyl-hydrazide (Ⅳ) provided good anticonvulsant activity.     

N-取代多亚甲基二甲酰胺类癌细胞分化诱导剂的合成

N-Alkyl polymethylene dicarboxamides are known potent inducers of erythroid differentiation in murine erythroleukemia cells. The most active inducer N, N, N', N'-tetramethyl-1, 6-hexane-dicarboxamide has the same effectiveness as HMBA which has entered clinical trials as a differentiating agent. These compounds also have inducing activity in HL-60 human promyelocytic leukemia cells. In this paper, the synthesis of a series of N,N'-bis[2-(2-thiazolinyl)], N,N'-bis [5-(1-methyl-2-pyridonyl)], N, N'-bis [3-(1- phenyl- 5- pyrazolonyl )] polymethylene dicarboxamides and 3,3'-(polymethylene dicarbonyl)bis(1-methyl-2-imidazolidine-thiones) is reported. The inducing activities of the compounds were evaluated in vitro with HL-60 human promyelocytic leukemia cell line. Among them, N, N'-bis[-2- (2-thiazolinyl)]-1,8-octamethylene-dicarboxamide (Ⅰ₄) and N, N'-bis[5- (1-methyl- 2-pyridonyl)]-1,6-hexamethylenedicarboxamide (Ⅱ₃) were shown to be relatively effective inducers of differentiation.     

疟疾防治药物的研究——ⅩⅤ.双-(2,4-二氨基喹唑啉-6-取代氨甲基)芳香类化合物的合成及其抗疟作用

A series of bis(2,4-diamino-quinazol-6-yl-substituted aminomethyl) aromatic derivatives were synthesized. Compounds Ⅱ_1～5 were synthesized by two ways. In the first, 2,4,6-triaminoquinazoline was condensed with the corresponding aryl dialdehydes to form Schiff bases which were reduced with sodium borohydride; the second used a new method in which 2,4,6-triaminoquinazoline was directly condensed with the corresponding aralkyl dihalides to afford the same products. The derivatives Ⅱ_6～16 were prepared by formylation, nitrosation or methylation respectively.The inhibition activities of the title compounds on dihydrofolate reductase in rat liver were assayed. The activities of formylated or nitrosated products were 6-9 times, and of methylated products were twofold as active as that of the parent compounds. Ⅱ₆, Ⅱ₉, Ⅱ₁₀ and Ⅱ₁₄ were nearly as potent as pyrimethamine. Primary antimalarial screening in mice showed that no one possessed significant activity.     

In the search for new anticancer drugs. 17. Linear and cyclic polyether analogues of N,N:N',N':N',N'-tri-1,2-ethanediylphosphoric triamide and N,N:N',N':N',N'-tri-1,2-ethanediylphosphorothioic triamide

Linear and cyclic polyether derivatives of N,N:N',N':N',N'-tri-1, 2-ethanediylphosphoric triamide (TEPA) and N,N:N',N':N',N'-tri-1,2-ethanediylphosphorothioic triamide (thio-TEPA) are synthesized and evaluated for their antineoplastic activity against the murine lymphocytic leukemia P388. All compounds, except for 7d, were active ranging from 42% to 287% increase in life span (% ILS). All CD2F1 male mice treated with the most active compound (7a) at 90 mg/kg per day for 9 days were alive after 30 days, whereas all mice treated with the clinical drug thio-TEPA were dead. The % ILS for compound 7a on day 60 was 525. A correlation is presented between the structural features of compounds and their lipophilicities and antineoplastic activities.     

In the search for new anticancer drugs. 19. A predictive design of N,N:N',N':N',N'-tri-1,2-ethanediylphosphorothioic triamide (TEPA) analogues

The nitroxyl-labeled analogues of N,N:N',N':N",N"-tri-1,2-ethanediylphosphoric triamide (TEPA), N,N:N',N'-bis(1,2-ethanediyl)-N"-[[(2,2,6,6-tetramethyl-1-oxypiperidi n-4- yl)amino]carbonyl]phosphoric triamide (5a) and N,N:N',N'-bis(1,2-ethanediyl)-N"-[[(2,2,5,5-tetramethyl-1-oxypyrrolid in-3- yl)amino]carbonyl]phosphoric triamide (11a), possess therapeutic indexes that are 8-12 times higher than those of thio-TEPA (1) and TEPA (2). The introduction of methyl groups into the aziridine ring, or the replacement of the nitroxyl moiety with hydroxylamine or amine derivatives, or with an adamantane moiety, results in compounds of lesser activity. An attempt is made to rationalize these results using a lipophilicity scale. A predictive design pattern is established.     

Urinary excretion of thioTEPA and its metabolites in patients treated with high-dose cyclophosphamide, thioTEPA and carboplatin.

The urinary excretion of N,N',N"-triethylenethiophosphoramide (thioTEPA), and its metabolites N,N',N"-triethylenephosphoramide (TEPA), N,N'-diethylene,N"-2-chloroethylphosphoramide (monochloroTEPA) and thioTEPA--mercapturate was determined in patients receiving thioTEPA as part of a high-dose combination chemotherapy regimen with cyclophosphamide and carboplatin. The thioTEPA dose was 40 or 60 mg/m(2) in short infusions, twice daily, during 4 days. Urine samples were collected after each voiding on each day of drug administration until 24--48 h after the last thioTEPA infusion. ThioTEPA, TEPA and monochloroTEPA concentrations were determined with gas chromatography and thioTEPA--mercapturate with liquid chromatography--mass spectrometry with direct sample injection. ThioTEPA was present in urine 30 min after infusion and was still excreted 18 h after the last infusion. All metabolites were detected in urine 1 h after infusion. Patients with a creatinine clearance above 140 ml/minl showed higher excretion of TEPA than patients with a creatinine clearance below 140 ml/min (12.8 versus 4.9%, p=0.01). The excretion of monochloroTEPA relative to the excreted amount of TEPA increased at lower pH values of the urine. The excretion of thioTEPA--mercapturate relative to the dose was higher in patients treated with 60 mg/m(2). Excretion of thioTEPA and monochloroTEPA both accounted for only 0.5% of the dose, while TEPA and thioTEPA--mercapturate both accounted for 11.1%.     

Synthesis of hydrophobic N'-mono and N',N"-double alkylated eremomycins inhibiting the transglycosylation stage of bacterial cell wall biosynthesis

A series of hydrophobic N'-mono and N',N"-double alkylated derivatives of the glycopeptide antibiotic eremomycin were synthesized by reductive alkylation after preliminary protection of the N-terminal amino group of the peptide backbone. The investigation of the antibacterial activity in vitro showed that N'-C10H21- and N'-p-(p-chlorophenyl)benzyl derivatives of eremomycin are the most active against vancomycin-resistant enterococci among the compounds obtained though they are less effective than the corresponding lipophilic derivatives of vancomycin. The introduction of two hydrophobic substituents led to a decrease in activity against both susceptible and resistant bacteria. The biochemical evaluation of the mode of action revealed that in addition to binding to D-Ala-D-Ala these compounds also have an alternative mechanism of action that does not require substrate binding.     

3-Dialkylamino-substituted 2H-1,4-benzoxazines

N,N,N',N'-Tetrasubstituted 2-(2-aminophenoxy)malonamides (IX) in the presence of phosphorus oxychloride led to the formation of N,N-dialkyl-3-(dialkylamino)-2H-1,4-benzoxazine-2-carboxamides (XII). In the same way 2-(2-amino-3-pyridyloxy)-N,N,N',N'-tetraethylmalonamide (X) yielded 3-(diethylamino)-N,N-diethyl-2H-pyrido[3,2-b] [1,4]oxazine-2-carboxamide (XIII). Also N,N-dialkyl-2-(2-aminophenoxy)acetamides (XIV) by the action of phosphorus oxychloride afforded 3-(dialkylamino)-2H-1,4-benzoxazines (XV). Some compounds when submitted to pharmacological screening showed a weak depressant activity in the Irwin test.     

Discovery of cis-preference of aromatic N-methylamides and its application to molecular constructions

Aromatic secondary amides such as benzanilide (1) exist in a trans-amide form both in the crystal and in the solution, whereas N-methylbenzanilide (2) exists in cis form in the crystal, and predominantly in a cis form in the solution. Similar cis conformational preferences were observed in aromatic N,N'-dimethylated ureas and guanidines, in which two aromatic rings are located face to face. The cis preferences of N-methylated amides, ureas and guanidines could be utilized to construct interesting aromatic architecture. N,N',N"-Trimethyl-N,N',N"-triphenyl-1,3,5-benzenetricarboxamide (20) and a cyclic triamide (24) have crystal structures in which three N-phenyl groups direct to the same orientation (syn conformation). 1,2-Bis(N-benzoyl-N-methylamino)benzene (22), which have no fixed asymmetric center, afforded chiral crystals by simple recrystallization. Furthermore, aromatic multi-layered structures could be built and applied to obtain aromatic molecules which have potent DNA-binding ability.     

4-甲氧基-N,N′-二(2-取代苯基)-1,3-苯二磺酰胺类化合物的合成及体外抗血小板聚集活性研究

目的 寻找新的抗血小板聚集药物并研究4-甲氧基-N,N′-二(2-取代苯基)- 1,3-苯二磺酰胺类化合物的不同2-位取代苯基对抗血小板聚集活性的影响。方法 以吡考他胺为先导化合物,用取代苯磺酰氨基代替3-吡啶甲氨基对先导化合物进行结构改造：以苯甲醚为原料,采用文献方法与氯磺酸反应直接制得重要中间体4-甲氧基-1,3-苯二磺酰氯;该中间体与2-取代苯胺类化合物经胺解反应制得目标化合物。以吡考他胺和阿司匹林为阳性对照药物,采用Born比浊法对目标化合物进行体外抗血小板聚集活性初筛。结果与结论 共制得12个化合物(4a~4l),其化学结构由IR、1H-NMR和MS光谱确证,其中9个化合物(4a~4c, 4e~4i和4l)未见文献报道。药理试验结果表明,5个化合物表现出较好的体外抗血小板聚集活性：化合物4g、4f和4b的活性优于吡考他胺和阿司匹林;化合物4i的活性略低于阿司匹林;化合物4h的活性与吡考他胺相当。     

The degradation of N,N',N"-triethylenephosphoramide in aqueous solutions: a qualitative and kinetic study

The degradation of N,N',N"-triethylenephosphoramide (TEPA) in aqueous solutions has been investigated over a pH range of 3-14. Samples were analyzed using a gas chromatographic system with nitrogen/phosphorus selective detection. The degradation kinetics were studied as function of pH, sodium chloride concentration and temperature. The degradation of TEPA in buffers follows pseudo first order kinetics. The logk(obs)8 the methoxy derivative of TEPA was formed, as a consequence of the applied procedure.     

Design, synthesis, and biological activity of certain quinazolinedione derivatives as potent phosphodiestrase4 inhibitors

In this study, a series of 3-butylquinazolinedione linked with different substituent to N1 of quinazoline nucleus have been synthesized. Some of the new final compounds tested in vitro for their inhibitory activity against phosphodiestrase 4B which is the enzyme responsible for the hydrolysis of cyclic adenosine mono phosphate, the second messenger involved in the regulation of important cell functions. Compound 7f (100%) showed inhibition better than rolipram (90%), while the other tested compounds showed moderate activity. Docking study has been done to rationalize the obtained biological results.