化药合成,抗肿瘤新药(8)

position-9of the b-carboline ring facilitated the increase of their antitumor activities.

3.Conclusions

The present investigation reported for the?rst time that b-carboline derivatives had signi?cant antitumor activi-ties in mice bearing Lewis lung cancer and Sarcoma180 but also exhibited remarkable acute neurotoxicity in experimental mice models.Alkyl or benzyl substituent at position-9of b-carboline ring might facilitate their antitumor activities and minimize their acute toxicities but not neurotoxicities.However alkoxycarbonyl or carboxyl substituent at position-3played a crucial role in determining their decreased acute toxicities and neu-rotoxicities.Furthermore,the compounds with appro-priate substituents both at positon-3and9displayed enhanced antitumor activities and decreased neurotoxi-cities simultaneously.The compound8c,having an n-butyl and a carboxyl at position-9and3,respectively, exhibited the highest antitumor e?ect and the lowest acute neurotoxicity and was found to be the most prom-ising leading compound for further investigation.These data suggested that(1)appropriate substituents at both position-9and3of b-carboline derivatives might play a crucial role in determining their enhanced antitumor activities and decreased acute toxicities and neurotoxic e?ects;(2)the b-carboline derivatives have the potential to be used as antitumor drug leads.

Although the antitumor e?ects of the studied b-carbo-line derivatives presented here remained relatively mod-est,it should be noted that the acute neurotoxicities of some compounds decreased dramatically by introduc-tion of an alkoxycarbonyl or carboxyl substituent into position-3of the b-carboline ring.This investigation and?nding would be helpful to further design and de-velop more potent antitumor agents together with low neurotoxicities.Further investigations are in progress in our laboratory to elucidate the molecular mechanisms involved in antitumor activities and neurotoxicities of b-carboline derivatives.To acquire more information about the structural requirements for enhancing antitu-mor activities and minimizing neurotoxicities,the syn-thesis of more new b-carboline derivatives with di?erent substituents at other positions is needed.

4.Experimental

4.1.Materials

All reagents were purchased from commercial suppliers and were dried and puri?ed when pound 1(Harmine)was extracted from Peganum multisectum Maxim,a plant indigenous to western China,according to the method by Duan et al.2Compounds3and5–8 were synthesized from the starting material L-trypto-phan according to the procedures described by Hagen et al.19and Lippke et al.18with a slight modi?cation, respectively.

Melting points were determined in capillary tubes on an electrothermal PIF YRT-3apparatus and without cor-rection.UV spectra were measured on Shimadzu UV 2501PC Spectrometer.FAB-MS spectra were obtained from VG ZAB-HS spectrometer.FTIR were run on a Bruker Equinox55Fourier Transformation Infarred Spectrometer.1H NMR spectra were recorded on a Var-ian INOVA500NB spectrometer.Elemental analyses were carried out on an Elementar Vario EL CHNS Ele-mental Analyzer.Silica gel F254were used in analytical thin-layer chromatography(TLC)and silica gel were used in column chromatography,respectively.

4.1.1.7-Methoxy-1,9-dimethyl-b-carboline(2a).A mix-ture of Harmine1(2.12g,10mmol),anhydrous DMF (50mL),and anhydrous THF(50mL)was stirred at rt until clear,and then60%NaH(0.6g,15mmol)and iodomethane(2mL,30mmol)were added and stirred at rt ter the mixture was evaporated in re-duced pressure.The resulting solution was poured into H2O(100mL),and extracted with ethyl acetate (3·150mL).The organic phase was washed with water and brine,then dried over anhydrous sodium sulfate,?l-tered,and evaporated.The oil obtained was puri?ed by silica column chromatography with ethyl acetate as the eluent.Upon recrystallization,white crystals of2a were obtained(1.8g,80%),mp121–123°C(from ether); FAB-MS m/e227(M+1);UV k max345,332,302,264, 244,214nm;IR(KBr):3380,2744,1628,1570,1469, 1348,1249,1152,1045,810cmÀ1;1H NMR(500MHz, CDCl3):8.24–8.25(1H,m,H-5),7.93–7.96(1H,m,H-3),7.69–7.71(1H,m,H-4), 6.86–6.89(1H,m,H-8), 6.81–6.83(1H,m,H-6), 4.04–4.07(3H,m,NC H3), 3.94–3.95(3H,m,OC H3), 3.04–3.05(3H,m,C H3). Anal.Calcd for C14H14N2O:C,74.33;H, 6.19;N, 12.39.Found:C,74.21;H,6.37;N,12.31.

4.1.2.7-Methoxy-9-ethyl-1-methyl-b-carboline(2b).A mixture of Harmine1(2.12g,10mmol),anhydrous DMF(50mL),and anhydrous THF(50mL)was stirred at rt until clear,and then60%NaH(0.6g,15mmol)and iodoethane(2.5mL,30mmol)were ter the mixture was treated in a manner similar to that de-scribed for2a to a?ord2b(2.0,83%),mp99–101°C (from ether);FAB-MS m/e241(M+1);UV k max345,

Table 3.Antitumor e?ects of b-carboline derivatives against mice

bearing Sarcoma180and Lewis lung carcinoma

Compound Tumor inhibition rate(%)

Lewis lung carcinoma Sarcoma180

134.115.3

2b42.037.6

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