Synthesis and biological properties of some 2H-1-benzopyran [7,8-b][1,4]benzodioxin-2-ones.

The synthesis of 2H-benzopyrano[7,8-b][1,4]tetrahydrobenzodioxin-2-ones and 2H-benzopyrano[7,8-b][1,4]benzodioxin-2-ones is reported. This class of compounds, prepared with the aim of obtaining new monofunctional photosensitizing drug, appears to be ineffective upon UVA irradiation but shows a moderate but significant activity in the dark

RNA-protein cross-links induced by sensitization with a pyrroloquinolinone derivative, a furocoumarin analogue.

The capacity of 2,6-dimethyl-9-methoxy-4H-pyrrolo [3,2,1-ij] quinolin-4-one (PQ), a furocoumarin analogue, of inhibiting protein synthesis in Ehrlich cells upon UVA irradiation was investigated. Using 8-methoxypsoralen (8-MOP) as a reference, we observed that in our short-term test the block of RNA synthesis do not affect protein synthesis, which is driven by pre-synthesised molecules of m-RNA; actually 8-MOP, studied at 100 mu M concentration, practically abolished RNA synthesis without affecting significantly protein synthesis. Studying PQ sensitization in HL60 cells by alkaline elution and protein precipitation, the formation of covalent RNA-protein cross-links was observed. 8-MOP, assayed in severe experimental conditions, induced only moderate amounts of such lesion. On the basis of the data obtained in experiments carried out using various scavengers or exposing cells to UVA light in a nitrogen atmosphere, this damage appeared to be due to singlet oxygen formation, which is generated by PQ to a large extent. These results are consistent with the data obtained by H. Singh and J.A. Vadasz (Singlet oxygen: a major reactive species in the furocoumarin photosensitized inactivation of E.coli ribosomes, Photochem. Photobiol., 28 (1978) 539-545) on E.coli ribosomes. The lower activity we observed with 8-MOP might be attributed to a different sensitivity of whole mammalian cells in comparison with isolated ribosomes. (C) 1997 Elsevier Science S.A

ANTIPROLIFERATIVE ACTIVITY OF SOME UNSUBSTITUTED ANGULAR ANALOGOUES OF ELLIPTICINE

With the aim of obtaining further knowledge on the antiproliferative activity of pyrroloquinolines and isoquinolines, we prepared four unsubstituted angular pyridotetrahydrocarbazoles having a fourth non-aromatic ring, via modified Fischer synthesis. These compounds may be considered as simpler analogues of ellipticine. They induced evident antiproliferative effects in Ehrlich ascites and in CHO cells in vitro, but were ineffective on T2 bacteriophage. These compounds formed molecular complexes with DNA in vitro, while in CHO cells in vivo, they induced double-strand breaks in DNA and DNA-protein cross-links. These data suggest that these ellipticine analogoues are capable of inhibiting topoisomerase II, as the parent compound does. The most active derivative was 2N-5H-6,7,8,9-tetrahydropyrido[2,3-a]carbazole, which represents an interesting model for the study of new antitumor drugs

2-Substituted 1H-pyrrolo [3,2-h] quinoline derivatives: Synthesis and aspects of their biological activity

Certain 2-substituted 1H-pyrrolo [3,2-h] quinolines have been prepared and their biological activity in mammalian cells and in some microrganisms have been studied. These compounds represent a simplified ellipticine heterocyclic moiety: in addition they have a different ring condensation, leading to an angular molecular structure instead of a linear one. In mammalian cells all compounds appeared to be able of inducing an antiproliferative effect and an extensive DNA fragmentation, similarly to ellipticine, even if to a reduced extent. The new derivatives behaved in a comparable way also on some microrganisms, such as T2 bacteriophage (which appears to be less sensitive than mammalian cells) and in mutagenesis tests carried out with E. coli WP2 TM9 and S. typhimurium TA 98, which are reverted by base substitution and frame-shift mutagens, respectively. Similarly to the reference compound, all ellipticine analogues appeared to be no mutagenic. The obtained results suggest that they induce the antiproliferative activity in mammalian cells mainly as topoisomerase inhibitors, similarly to ellipticine itself. Therefore, they represent an interesting model to design new potential anticancer drugs