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The coumarins 5-methoxy-6,7-methylenedioxycoumarin 1 5-(3-methyl-2-butenyloxy)-6,7-methylenedioxycoumarin 2 and 5-(2,3-dihydroxy-3-methylbutyloxy)-6,7-methylenedioxycoumarin 3 isolated from Pterocaulon species showed significant cytotoxicity against two glioma cells lines. Compound 1 presented IC(50) values of 34.6 μM and 31.6 μM against human (U138-MG) and rat (C6) glioma cells, respectively, and this compound was at least two times more potent than compounds 2 and 3. This result could be explained by the planar conformation adopted by 1 through a non-classical hydrogen bond between a hydrogen of the methoxy and the oxygen of the methylenedioxy groups. Another important finding was that the cytotoxic effect induced by 1 in glioma cells was not observed in organotypic cultures, indicating a selective cytotoxicity for tumor cells., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Tetracyclic amidines (tetrahydroquino[4.3-b][l]benzazepine: compound 11 and tetrahydrobenzo[k]naphthyridine: compound 12) bearing a putrescine moiety possess significant DNA-binding affinity. We report here that these compounds and their a and b isomers inhibit tumor cell growth and putrescine uptake in 3LL carcinoma cells in vitro. Moreover, compound 11 reduced by 50% the accumulation of putrescine in intestinal brush border membrane vesicles. In CHO-MG, a cell line deficient for the specific polyamine uptake system, the cytotoxicity of these compounds was significantly reduced compared to the CHO wild cell line. The IC50 for CHO-MG was significantly higher than for CHO, demonstrating that the polyamine transport system increased the efficacy of these compounds. The efficacy of compounds 11 and 12 might therefore be related to their ability to interact with DNA as well as their structural analogy with polyamines. Moreover, we clearly show that DFMO enhances the efficacy of these tetracyclic amidines in vivo. Potential mechanisms include: a) lower intracellular polyamine levels reduces polyamine DNA-stabilizing functions, increasing accessibility for DNA-binding drugs; b) DFMO enhances the polyamine uptake system in tumor cells, increasing the entry of tetracyclic amidines bearing a putrescine moiety as well as their accessibility to final DNA-binding sites. The fact that natural polyamine uptake is reduced by the same compounds constitutes an additive mechanism for antitumoral efficiency.