| Abstract: |
DNA minor groove binder hybrid molecules, netropsin derivatives such as N-[2-(dimethylamino)-ethyl]-1-methyl-4-aminopyrrolo-2-carboxamide (MePy) or its derivatives containing two units of N-methylpyrrolecarboxamide (diMePy) and bisbenzimidazole (Ho33258), were linked to the NH2 function of AHMA or to the CH2OH group of AHMA-ethylcarbamate to form AHMA-N-netropsins (13-16) and AHMA-ethylcarbamate-O-netropsins (19-22), and AHMA-bisbenzimidazole (AHMA-Ho33258, 25), respectively. These conjugates' in vitro antitumor activity, inhibition of a variety of human tumor cell growth, revealed that AHMA-ethylcarbamate-O-netropsin derivatives were more cytotoxic than AHMA-N-netropsin compounds. In the same studies, all compounds bearing MePy were more potent than those compounds linked with diMePy. Moreover, AHMA-netropsin derivatives bearing a succinyl chain as the linking spacer were more potent than those compounds having a glutaryl bridge. Among these hybrid molecules, AHMA-ethylcarbamate-O-succinyl-MePy (19) was 2- to 6-fold more cytotoxic than the parent compound AHMA (5) in various cell lines, whereas compound 25 had very poor solubility and was inactive. Studies on the inhibitory effect against topoisomerase II (Topo II) and DNA interaction of these conjugates showed no correlation between the potency of DNA binding and inhibitory activity against Topo II. |
| Keywords: |
controlled study; unclassified drug; human cell; antineoplastic agents; cell division; antineoplastic activity; drug potency; drug screening assays, antitumor; tumor cells, cultured; drug synthesis; structure-activity relationship; dna; amino terminal sequence; enzyme inhibitors; molecular interaction; aniline compounds; dna binding; antineoplastic antibiotic; acridines; carbamates; dna topoisomerases, type ii; amide; drug solubility; dna, superhelical; aniline derivative; humans; human; article; 2' [4 [3 (9 acridinylamino) 5 hydroxymethylanilino]carbonylpropoxyphenyl] 5 (4 methyl 1 piperazinyl) 2,5' bi 1h benzimidazole; 3 (9 acridinylamino) 5 hydroxymethylaniline derivative; benzimidazole; congocidine derivative; ho 33258; n [2 (dimethylamino)ethyl] 1 methyl 4 [1 methyl 4 [1 methyl 4 [[[3 (9 acridinylamino) 5 hydroxymethylanilino]carbonylpropanoyl]amino]pyrrole 2 carboxamido]pyrrole 2 carboxamide; n [2 (dimethylamino)ethyl] 1 methyl 4 [1 methyl 4 [[[3 (9 acridinylamino) 5 (ethoxycarbonylamino)benzyloxy]carbonylbutanoyl]amino]pyrrole 2 carboxamido]pyrrole 2 carboxamide; n [2 (dimethylamino)ethyl] 1 methyl 4 [1 methyl 4 [[[3 (9 acridinylamino)benzyloxy]carbonylpropanoyl]amino]pyrrole 2 carboxamido]pyrrole 2 carboxamide; n [2 (dimethylamino)ethyl] 1 methyl 4 [1 methyl [[[3 (9 acridinylamino) 5 hydroxymethylanilino]carbonylbutanoyl]amino]pyrrole 2 carboxamido]pyrrole 2 carboxamide; n [2 (dimethylamino)ethyl] 1 methyl 4 [[[3 (9 acridinylamino) 5 (ethoxycarbonylamino)benzyloxy]carbonylbutanoyl]aminopyrrole 2 carboxamide; n [2 (dimethylamino)ethyl] 1 methyl 4 [[[3 (9 acridinylamino) 5 (ethoxycarbonylamino)benzyloxy]carbonylpropanoyl]amino]pyrrole 2 carboxamide; n [2 (dimethylamino)ethyl] 1 methyl 4 [[[3 (9 acridinylamino) 5 hydroxymethylanilino]carbonylbutanoyl]amino]pyrrole 2 carboxamide; n [2 (dimethylamino)ethyl] 1 methyl 4 [[[3 (9 acridinylamino) 5 hydroxymethylanilino]carbonylpropanoyl]amino]pyrrole 2 carboxamide; n methylpyrrolecarboxamide; netropsin
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