Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of 9-anilinoacridines, based on the anticancer drug amsacrine [4'-(9-acridinylamino)methanesulphon-m-anisidide; m-AMSA], were synthesized and evaluated for their ability to inhibit both the growth of Jurkat leukaemia cells and human DNA topoisomerase II in vitro. Inhibition of topoisomerase II activity occurred via one of two mechanisms of drug action: (i) direct inhibition of the strand-passing activity or (ii) stabilization of cleavable complex formation. Although the majority of compounds evaluated inhibited P4 DNA unknotting activity catalysed by DNA topoisomerase II up to 100 microM, derivatives bearing 1'-substituents containing SO2 moieties (e.g. 1'-NHSO2Me and 1'-SO2NH2 groups) were generally the most potent inhibitors of DNA topoisomerase II-mediated DNA religation, being effective at concentrations of 1-5 microM. No obvious correlation was observed between the cytotoxicity of individual drugs and linear DNA formation in the in vitro topoisomerase II assays, either across the whole drug series or within similar subgroups. However, a selected group of drugs with different cytotoxicities (compounds 5, 12 and 30; Table I) stimulated DNA topoisomerase II-mediated DNA strand breaks in intact Jurkat cells by 3.5-, 11- and 2.2-fold, respectively, at a concentration of 10 microM, while compounds 31 and 32 did not produce protein-associated DNA strand breaks in whole cells. There was a good correlation between the ability of these selected compounds to induce topoisomerase II-mediated DNA strand breaks in vitro or in whole cells, and their cytotoxicity to Jurkat cells.
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PMID:Structure-activity relationships of 9-anilinoacridines as inhibitors of human DNA topoisomerase II. 803 52

A series of 9-anilinoacridines have been prepared and evaluated for their activity against a multidrug-resistant K1 strain of the malaria parasite Plasmodium falciparum in erythrocyte suspensions. 3,6-Diamino substitution on the acridine ring resulted in lower mammalian cell cytotoxicity and higher antiparasitic activity than other substitution patterns, providing compounds with the highest in vitro therapeutic indices. A new synthesis of 3,6-diamino-9-anilinoacridines, via reduction of the corresponding diazides, gives much higher yields than traditional methods. Within the subset of 3,6-diamino-9-anilinoacridines, there was considerable tolerance to substitution at the 1'-anilino position. In a sharp divergence with structure-activity relationships for high mammalian cell toxicity and anticancer effects, derivatives bearing electron-withdrawing 1'-substituents (e.g., SO2-NHR and CONHR) showed the most potent antimalarial activity (IC50 values of 10-20 nM). Representative compounds were shown to be potent inhibitors of the DNA strand-passing activity of human topoisomerase II and of the DNA decatenation activity of the corresponding parasite enzyme. The 1'-SO2NH2derivative 7n completely inhibited strand passage by Jurkat topoisomerase II at 20 microM, and an increase in linear DNA (indicative of inhibition of religation) was seen at or above 1 microM. It also inhibited the decatenating activity of the parasite topoisomerase II at 6 microM and above. In contrast, the analogous compound without the 3,6-diamino substituent was inactive in both assays up to 100 microM. Overall, there was a positive relationship between the ability of the drugs to inhibit parasite growth in culture and their ability to inhibit parasite topoisomerase II activity in an isolated enzyme assay. The 1'-SO2NH2 derivative 7n showed a high IVTI (1000) and was a potent inhibitor of both P. falciparum in vitro (IC50 20 nM) and P. falciparum-derived topoisomerase II. However, the compound was inactive against Plasmodium berghei in mice; reasons may include rapid metabolic inactivation (possibly by N-acetylation) and/or poor distribution.
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PMID:Synthesis and in vitro evaluation of 9-anilino-3,6-diaminoacridines active against a multidrug-resistant strain of the malaria parasite Plasmodium falciparum. 818 7

When a benzenesulfonyl moiety (BS) was bound to the N-piperazinyl ring of antibacterial fluoroquinolones (AMFQs) norfloxacin (NOR) or ciprofloxacin (CIP), the resulting benzenesulfonyl-fluoroquinolone (BSFQs) analogs showed an improved in vitro activity against Gram-positive strains. A bioisosterical replacement of the sulfonyl group for a carbonyl group led to the benzenecarboxamide-fluoroquinolones (BCFQs) that showed a similar trend in the antibacterial activity and spectrum. The BSFQs and BCFQs are considered members of the "dual targeting" fluoroquinolones, targeting both DNA gyrase and topoisomerase IV. To disclose the real contribution of the BS/BC moiety in anti-staphylococcal activity, a 3D-QSAR analysis that included calculation of theoretical molecular descriptors and pharmacophore generation was performed. Previous and present QSAR results have confirmed the positive influence on activity of small electron donating p-substituent on the BS or BC moiety. The generated phamacophore model showed that both phenyl and SO2/CO groups are involved in the interaction with receptor. We postulate that the enhanced potency of BSFQs against Staphylococcus aureus compared to CIP and NOR could be caused by the presence of the BS moiety that resulted in enhanced binding to DNA gyrase of Sa. Additionally, their greater ability to enter bacterial cells by diffusion and a reduced susceptibility to FQ-specific efflux pumps could also make a contribution.
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PMID:SAR analysis of new dual targeting fluoroquinolones. Implications of the benzenesulfonyl group. 2253 Sep 6