Synthesis and antitumour activity of trimethylsilylpropyl substituted benzimidazoles

被引:82
作者
Lukevics, E [1 ]
Arsenyan, P [1 ]
Shestakova, I [1 ]
Domracheva, I [1 ]
Nesterova, A [1 ]
Pudova, O [1 ]
机构
[1] Latvian Inst Organ Synth, LV-1006 Riga, Latvia
关键词
benzimidazoles; benzimidazolinium salts; benzimidazole complexes; cytotoxic activity; antitumour activity;
D O I
10.1016/S0223-5234(01)01241-7
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The quaternisation of N-substituted benzimidazoles by heating with various alkyl, allyl, propargyl and benzyl chlorides and bromides leads to the formation of benzimidazolinium salts. The interaction of N-monosubstituted benzimidazoles with various salts (CuCl2, ZnCl2, CoCl2, PdCl2, and AgNO3) Yielded stable sol-id complexes. Potential cytotoxic activity of synthesised benzimidazolinium salts and benzimidazole metal complexes was tested in vitro on four monolayer tumour cell Hues: MG-22A (mouse hepatoma), HT-1080 (human fibrosarcoma), B16 (mouse melanoma), Neuro 2A (mouse neuroblastoma) and normal mouse fibroblast cells. A preliminary analysis of the structure-activity relationship for the benzimidazole derivatives clearly indicates that the character of substituents in the benzimidazole ring has strong influence on the cytotoxic activity. The insertion of the silicon atom into the N-alkyl chain increases the cytotoxic activity of benzimidazolinium salts significantly, which show a very significant potency in vitro against all studied tumour cell lines, being particularly active in experiments with B16 (mouse melanoma). TD, for the most active compounds are in the range 0.001-0.008 mug ml(-1). Cytotoxicity of benzimidazole metal complexes (L2MX2) strongly depends on the metal nature. 1-(3-Trimethylsilylpropyl)benzimidazole in dose 1 mg kg(-1) inhibits carcinoma S-180 tumour growth by 62% (on ICR mice). (C) 2001 Editions scientifiques et medicales Elsevier SAS.
引用
收藏
页码:507 / 515
页数:9
相关论文
共 18 条
[1]   Synthesis of 6-aziridinylbenzimidazole derivatives and their in vitro antitumor activities [J].
Ahn, CM ;
Kim, SK ;
Han, JL .
ARCHIVES OF PHARMACAL RESEARCH, 1998, 21 (05) :599-609
[2]   Synthesis and in vitro antitumor activity of 2-alkyl, 2-aryl, and 2-piperazinyl benzimidazole-4,7-dione derivatives [J].
Ahn, CM ;
Tak, JA ;
Choi, SJ .
ARCHIVES OF PHARMACAL RESEARCH, 2000, 23 (04) :288-301
[3]   Design of highly active analogues of the pyrrolo[1,2-a]benzimidazole antitumor agents [J].
Craigo, WA ;
LeSueur, BW ;
Skibo, EB .
JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (17) :3324-3333
[4]   Synthesis of a heterocyclic aza-enediyne and its DNA-cleavage properties [J].
David, WM ;
Kumar, D ;
Kerwin, SM .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (22) :2509-2512
[5]  
El-Hawash SAM, 1999, PHARMAZIE, V54, P341
[6]   NITRIC-OXIDE PRODUCTION BY TUMOR TARGETS IN RESPONSE TO TNF - PARADOXICAL CORRELATION WITH SUSCEPTIBILITY TO TNF-MEDIATED CYTOTOXICITY WITHOUT DIRECT INVOLVEMENT IN THE CYTOTOXIC MECHANISM [J].
FAST, DJ ;
LYNCH, RC ;
LEU, RW .
JOURNAL OF LEUKOCYTE BIOLOGY, 1992, 52 (03) :255-261
[7]  
Freshney P. J., 1994, CULTURE ANIMAL CELLS, P296
[8]   Synthesis and antiviral activity of some N-benzenesulphonylbenzimidazoles. [J].
Garuti, L ;
Roberti, M ;
Cermelli, C .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1999, 9 (17) :2525-2530
[9]   Selective induction of apoptosis in multidrug resistant HL60R cells by the thiazolobenzoimidazole derivative 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole (TBZ) [J].
Grimaudo, S ;
Tolomeo, M ;
Chimirri, A ;
Zappala, M ;
Gancitano, RA ;
D'Alessandro, N .
EUROPEAN JOURNAL OF CANCER, 1998, 34 (11) :1756-1763
[10]   Synthesis and characterization of a potent and selective protein tyrosine phosphatase inhibitor, 2-[(4-methylthiopyridin-2-yl)methylsufinyl]benzimidazole [J].
Hamaguchi, T ;
Takahashi, A ;
Kagamizono, T ;
Manaka, A ;
Sato, M ;
Osada, H .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (23) :2657-2660