化药合成,抗肿瘤新药(6)

Of all9-substituted b-carboline-3-carboxylate deriva-tives,the compound6d having a benzyl at position-9 displayed strong cytotoxic activities against HepG2, Bel-7402,BGC-823,and Hela with IC50values of38, 45,38,and13l M,respectively.However compounds 5d and7d,having a benzyl at9-position,had little or even no cytotoxic e?ects on the tested cell lines,indicat-

ing that ethoxycarbonyl substituent was preferable for improving cytotoxic activities of this type of com-pounds.The compounds5b,6b,and7b with an ethyl at position-9,respectively,displayed higher cytotoxic activities against human tumor cell lines tested.Mean-while the compound5b showed highly selective cytotox-ic e?ects against PLA-801and Hela with IC50values25 and17l M,respectively.All these results,together with the cytotoxic activity of the compound2b,con?rmed that the ethyl group at position-9might play a crucial role in eliciting distinct cytotoxic activities of these com-pounds.

For the b-carboline-3-carboxylic acid series(8and8a–e),the cytotoxic activities were also enhanced by intro-duction of short alkyl or benzyl substituent into posi-tion-9of the b-carboline ring.The compounds8c and 8e,having an n-butyl and a benzyl at positon-9,respec-tively,showed remarkable cytotoxic activities against Lovo cell lines with IC50values of11and13l M,respec-tively,furthermore the compound8f exhibited the most signi?cant cytotoxic activity against Lovo cell lines with IC50values5l M.

A total analysis of the cytotoxic activities of b-carboline derivatives in vitro clearly suggested that(1)the b-carb-oline nucleus might be an important basis for the design and synthesis of new antitumor drugs;(2)the cytotoxic potencies of b-carboline derivatives depended upon the presence and location and nature of the subtituents, which were introduced into the b-carboline ring.(3) The cytotoxic activities of b-carboline derivatives were enhanced by the introduction of an appropriate substit-uent into position-9of b-carboline ring;(4)the Lovo cell lines were more sensitive to the tested compounds than other tumor cells.

2.3.Assessment of acute toxicity

The LD50values and scores for neurotoxicity of the se-lected b-carboline derivatives in mice after administra-tion were summarized in Table2.Neurotoxicities were the principal acute toxic e?ects observed in mice after receiving the b-carboline derivatives via intraperitoneal (i.p.)route.All the tested compounds resulted in acute toxic manifestation.Of all the compounds investigated, 1,2b,2c,2e,and5a caused remarkable acute toxic e?ects including tremor,twitch,jumping,tetanus,and supination.Death occurred mostly in high dosage group within1min after administration and then reached a peak1h later.For survived animals,the tremor and jumping lasted for about20min and then relieved grad-ually and returned to normal in the next day.Animals were drowsy and exhibited a decrease in locomotor activity after the administration of the compound8, 6d,8d,and8f.Death only occurred in high dosage group10–20min after administration and reached a peak1h later.However,the compounds8c caused no obvious neurotoxic reaction and no death at tested dos-age.Autopsy of the animals that died in the course of experiment and the necropsy?ndings in surviving ani-mals at the end of experimental period(14days)revealed no apparent changes in any organs.The results of toxi-cities suggested that an alkoxycarbonyl or carboxyl sub-stituent at position-3of the b-carboline ring might play a vital role in determining their decreased acute toxici-ties and neurotoxicities,and perhaps the carboxyl sub-stituent is more favorable.

2.4.Evaluation of antitumor activity

The tumor inhibition rates of the selected b-carboline derivatives in mice bearing Lewis lung cancer and Sar-coma180(S180)were summarized in Table3.Harmine (compound1)only showed a moderate antitumor e?ect (34.1%and15.3%against Lewis lung cancer and S180, respectively),however the selected9-substituted b-carb-oline derivatives all exhibited more potent antitumor pounds2c,2d,2e,6d,and8c displayed remarkable antitumor activities with the tumor inhibi-tion rate of more than40%against mice bearing Lewis lung cancer and S180.Moreover the compounds2e and8c demonstrated the highest antitumor e?ect with the tumor inhibition rate of46.9%against mice bearing Lewis lung cancer among all the tested compounds.The results indicated that short alkyl or benzyl substituent at Table2.Acute toxic e?ects of b-carboline derivatives in mice Compound Acute toxicity

LD50(mg/kg,95%CL)Neurotoxic e?ect 159.00(43.50–110.00)++a

2b24.25(22.24–26.44)++

2c26.45(23.91–29.26)++

2e147.82(132.55–164.85)++

5a70.61(64.17–77.70)+

6d240.38(211.38–273.50)À

8135.22(121.62–150.34)À

8c>500À

8d163.48(141.56–188.76)À

8e219.19(193.25–248.61)À

a Acute neurotoxic manifestation were denoted byÔ+ÕandÔÀÕ.AÔ+Õrepresents toxic reactions including tremble,twitch,jumping,teta-nus,and supination,Ô++Õmeans the same reactions with more severity,whileÔÀÕmeans no such reaction.

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