Novel nitrated derivatives of 5,8-diazabenzo[c]phenanthrene and 9,14-diazadibenz[a,e]acephenanthrylene: new classes of potent mutagenic compounds.
We report the synthesis of 4-nitro-5,8-diazabenzo[c]phenanthrene (4-NDBP) and 11-nitro-9,14-diazadibenz[a,e]acephenanthrylene (11-NDDA) and the remarkable mutagenic activity of the latter. These two compounds and their non-nitrated parents, 5, 8-diazabenzo[c]phenanthrene (DBP) and 9,14-diazadibenz[a, e]acephenanthrylene (DDA), were screened in Ames plate incorporation assays against Escherichia coli WP2uvrA and Salmonella typhimurium TA98 both in the presence and absence of S9 liver fraction from Aroclor 1254-induced rats. None of the four compounds were cytotoxic up to the limits of their solubility and none showed mutagenic activity in E.coli WP2uvrA, which suggested that any such activity they may have had was not mediated via a base substitution mechanism. DBP and DDA also displayed a lack of activity in TA98 up to their precipitating doses (560 and 33.5 microg/plate, respectively). The two nitrated compounds, however, were genotoxic. 4-NDBP was active at a dose of 500 ng/plate, in the absence of S9, producing 80.0 +/- 28.0 prototrophic organisms (equivalent to 44 revertants/nmol) and at 0.5 ng/plate, in the presence of S9, giving 147 +/- 6.6 revertants (equivalent to 81 000/nmol) and allowed the description of this tetracycle as a potent mutagen. Much more striking was the activity of 11-NDDA: in the absence of S9 a dose of 8.0 ng produced 2000 revertants/nmol and, remarkably, in the presence of S9 80 pg produced the equivalent of 643 000 revertants/nmol. This makes the hexacyclic 11-NDDA the most potent mutagen to date, in the Ames procedures described here.
Upton
M
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Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
Upton
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D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D004926:Escherichia coli / Q000187:drug effects; D009152:Mutagenicity Tests; D009153:Mutagens / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D010616:Phenanthrenes / Q000737:chemistry / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects
C404782:11-nitro-9,14-diazadibenz(a,e)acephenanthrylene; D003374:Coumarins; D009153:Mutagens; D010616:Phenanthrenes; C097144:4-nitro-6H-dibenzo(b,d)pyran-6-one