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New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.

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Antitumor Polycyclic Acridines. Part 3. A Two-Step Conversion of 9-Azidoacridine to 3,acridines by Graebe-Ullmann Thermolysis of Substituted 9-(1,2,3-Triazol-1-yl)acridines. -1,3-Dipolar cycloaddition of 9-azidoacridines (I) with substituted alkynes (II) provides regioisomeric 9-triazolylacridines (III) and (IV), in general, which undergo Graebe-Ullmann fragmentation furnishing pyridoacridines [cf. (V), (VI)]. The pentacyclic acridinium salt (VII) derived from the thermolysis of the triazole derivative (IVe) shows a broad spectrum of inhibitory effects against human tumor cells in vitro. -(HAGAN, D. J.; CHAN, D.; SCHWALBE, C. H.; STEVENS, M. F. G.; J. Chem. Soc., Perkin Trans. 1 [old] (1998) 5, 915-923; Dep. Pharm. Sci., Univ. Nottingham, Nottingham NG7 2RD, UK; EN)

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.