The antineoplastic quinobenoxazines A-62176 and A-74932 were shown to be potent inhibitors of mammalian DNA topoisomerase II in vivo. This was demonstrated by their selective inhibition of the SV40 DNA replication stages that require topoisomerase II. Neither drug stabilized a covalent complex of the enzyme with SV40 DNA, which suggests that they are not poisons of DNA topoisomerase II. A-77601, an analog having little antitumor activity, barely inhibited DNA topoisomerase II in vivo, even at high concentrations. These findings were supported by in vitro studies which showed that A-62176 and A-74932, but not A-77601, strongly inhibited the catalytic activity of mammalian DNA topoisomerase II. A-62176 did not cause topoisomerase II-mediated DNA strand breaks in vitro under conditions in which adriamycin produced extensive DNA breakage. The antineoplastic and topoisomerase inhibitory activities of the quinobenoxazines correlate with their ability to unwind DNA. A-62176 antagonized the poisoning of topoisomerase II by VM-26 in vivo and in vitro, but had no effect on DNA breakage induced by camptothecin, a DNA topoisomerase I poison. A-62176 and A-74932 thus inhibit DNA topoisomerase II reactions at a step prior to the formation of the "cleavable complex" intermediate. These findings indicate that stabilization of the DNA topoisomerase II-DNA cleavable complex is not necessary for the antitumor activity of this class of quinolones and that the catalytic inhibition of DNA topoisomerase II may contribute significantly to the anticancer activity of other DNA topoisomerase II inhibitors.
The preparation of 1,3,2-benzodithiazole S-oxide analogs exhibiting in vitro antifungal activity against several strains of Candida is described. For the preparation of derivatives bearing aromatic substituents, a novel electrophilic aromatic thiolation reaction was utilized which produced substituted aromatic 1,2-dithiol intermediates. The reactions of nucleophiles with the parent heterocyclic system have led to an efficient transamidation process which allows for the direct production of these analogs. The S-oxide bond exhibits poor stereochemical stability and has been found to epimerize under ambient conditions. The structure-activity data report that a side chain of greater than 10 carbons effects a loss in activity as does the placement of polar groups in this chain.
The antibacterial activities of the series of novel N'-(alpha-aminoacyl)- and N'-alpha-(N-akylamino)acyl derivatives of eremomycin and vancomycin containing hydrophobic moieties have been investigated. The N'-(N-alkylglycyl) derivatives of vancomycin are more active against vancomycin-susceptible staphylococci and enterococci and glycopeptide intermediate-resistant Staphylococcus aureus (GISA) than the corresponding eremomycin derivatives, but except for N'-[N-(p-octyloxybenzyl)glycyl-vancomycin] (28) and N'-[N-(p-octyloxybenzyl)-L-alanyl-vancomycin (33)--they are less active against glycopeptide-resistant enterococci (GRE). Derivatives 28 and 33 are the most active compounds (MIC's for glycopeptide-sensitive staphylococci and enterococci are 0.25 approximately 1 microg/ml, for GISA 1 approximately 2 microg/ml, for GRE 2 approximately 6 microg/ml). In in vivo studies, derivative 28 was active against S. aureus infections in mice with ED(50) 1 mg/kg versus 2 mg/kg for vancomycin (iv). In general N'-(N-alkylglycyl)-derivatives of vancomycin and eremomycin were more active than the corresponding N'-aminoacylated derivatives of these antibiotics containing other than glycin amino acids (L-Lys, L-Met, L-Orn, L- and D-Ala) and also L- and D-Phe or benzyl-O-L-Tyr.
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