化药合成,抗肿瘤新药(18)

FAB-MS m/e303(M+1);UV k max355,342,267, 239nm;IR(KBr):3457,3409,3250–2250,1683,1624, 1334,1225cmÀ1;1H NMR(500MHz,DMSO-d6)d 12.18(1H,s,COO H),9.15(1H,s,H-4),8.96(1H,s, H-1),8.44–8.45(1H,d,J=8.0Hz,H-8),7.79–7.80(1H, d,J=8.0Hz,H-5),7.63–7.66(1H,m,H-6),7.35–7.38 (1H,m,H-7),7.22–7.31(5H,m,Ar–H),5.85(2H,s, NC H2Ar).Anal.Calcd for C19H14N2O2:C,75.50;H, 4.64;N,9.27.Found:C,75.38;H,4.85;N,9.18.

4.1.31.9-(20,30,40,50,60-Penta?uoro)benzyl-b-carboline-3-carboxylic acid(8e).White solid was obtained(3.84g, 98%).Mp>270°C;FAB-MS m/e393(M+1);UV k max 351,338,261,239,218nm;IR(KBr):3500–2250, 1714,1628,1335cmÀ1;1H NMR(500MHz,DMSO-d6)d12.14(1H,s,COO H),9.10(1H,s,H-4),8.83 (1H,s,H-1),8.45–8.47(1H,d,J=8Hz,H-8),7.65–7.68(1H,m,H-5),7.59–7.61(1H,d,J=8.5Hz,H-6), 7.38–7.41(1H,m,H-7),

5.67(2H,s,C H2Ar).Anal.Cal-cd for C19F5H9N2O2:C,58.16;H,2.30;N,7.14.Found: C,58.03;H,2.39;N,7.18.

4.1.32.9-Phenylpropyl-b-carboline-3-carboxylic acid(8f). Yellow solid was obtained(3.2g,97%).Mp213–215°C; FAB-MS m/e331(M+1);UV k max358,346,268,239, 218nm;IR m max3500–2250,1692,1629,1335, 1215cmÀ1;1H NMR(500MHz,DMSO-d6)d12.09 (1H,s,COO H),9.13(1H,s,H-4),9.00(1H,s,H-1), 8.46–8.48(1H,d,J=7.5Hz,H-8),7.76–7.78(1H,d, J=8.0Hz,H-5),7.69–7.72(1H,m,H-6),7.38–7.41 (1H,m,H-7),7.21–7.26(2H,m,ArH),7.13–7.17(3H, m,Ar–H),4.63–4.66(2H,m,NC H2CH2CH2Ar),2.49–2.51(2H,m,NCH2C H2CH2Ar), 2.14–2.20(2H,m, NCH2CH2C H2Ar).Anal.Calcd for C21H18N2O2:C, 76.36;H,

5.45;N,8.48.Found:C,7

6.22;H,5.69;N, 8.38.

4.2.In vitro cytotoxicity assays

Cytotoxicity assays in vitro were carried out using96 microtiter plate cultures and MTT staining according to the procedures described by Al-Allaf and Rashan26 with a slight modi?cation.Cells were grown in RPMI-1640medium containing10%(v/v)fetal calf serum and100l g/mL penicillin and100l g/mL streptomycin. Cultures were propagated at37°C in a humi?ed atmos-phere containing5%CO2.Cell lines were obtained from Shanghai Cell Institute,Chinese Academy of Science. Drug stock solutions were prepared in DMSO.The?nal concentration of DMSO in the growth medium was2% (v/v)or lower,concentration without e?ects on cell rep-lication.The human tumor cell line panel consisted of nonsmall cell lung carcinoma(PLA-801),liver carci-noma(HepG2and Bel-7402),gastric carcinoma (BGC-823),cervical carcinoma(Hela),colon carcinoma (Lovo).In all of these experiments,three replicate wells were used to determine each point.

4.3.Assay of acute toxicities

Healthy C57BL/6mice(9–12weeks)weighing18–22g were housed in rooms where the temperature was approximately24±2°C,with a relative humidity60–70%,and in12h light-dark cycle.The sterile food and water were provided according to institutional guide-lines.All animals were provided by Shanghai Labora-tory Animal Center of Chinese Academy of Science. All animal procedures were approved by the Animal Ethical Committee of the Sun Yat-sen University.Prior to each experiment,mice were fastened overnight and al-lowed free access to water.Various doses of the b-carb-oline derivatives ranging from10to300mg/kg dissolved in0.5%carboxymethyl cellulose sodium(CMC-Na)salt solution were given via intraperitoneal(i.p.)to di?erent groups of healthy C57BL/6mice,and each group con-tained10mice(?ve males and?ve females).After the administration of the compounds,mice were observed continuously for the?rst2h for any gross behavioral changes and deaths,then intermittently for the next 24h and occasionally thereafter for14days,and for the onset of any delayed e?ects.All animals were sacri-?ced at the14th day after drug administration and checked macroscopically for possible damage to the heart,liver,and kidneys.Mice of immediate death fol-lowing drug administration were also examined for any possible organ damage.LD50values were calculated graphically as described.31

4.4.Assay of antitumor activity

Lewis lung cancer and S180sarcoma cell lines were pro-vided by Shanghai Institute of Pharmaceutical Industry. Tumor cells of Lewis lung cancer and S180sarcoma were inoculated to mice.After7days,tumors were taken out and cells harvested.Viable tumor cells(2·106cells/ mouse)were inoculated to the armpit of mice by subcu-taneous injection.Each compound was injected by intra-peritoneal(i.p.)to di?erent group mice(each group containing10female mice)24h after the inoculation at a dosage of7.5mg/kg once a day for consecutive7days. This dose was the maximum tolerated dose for most compounds based on our preliminary studies.Cyto-phosphane(CTX)at30mg/kg was used as a positive control and vehicle as negative control.The weights of animals were recorded every3days.All animals were sacri?ced at the21st day after tumor inoculation and the tumors were excised and weighed.The inhibition rate was calculated as follows:

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