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Two novel DNA-direct alkylating agents, consisting of aniline mustard linked to an angular 3H-pyrrolo[3,2-f]quinoline nucleus, were synthetized and assayed for their in vitro antiproliferative activity. Simple convergent synthesis, consisting of separate preparation of 9-chloro-3H-pyrrolo[3,2-f]quinoline and p-amino-aniline derivatives, and following their linkage by substitution reactions 8a, b and 10, yielded the corresponding diol derivatives 7b and 9. Biological properties were evaluated with respect to cell growth inhibition, ability to form cross-links with DNA, and capacity to give rise to a molecular complex with the macromolecule for 7b, 8b, 9 and 10. [Copyright &y& Elsevier]

The newly synthesized 1-[4-(3H-pyrrolo[3,2-f]quinolin-9-ylamino)-phenyl]-ethanone hydrochloride showed high antiproliferative activity by mixed mechanisms of action. The compound acts by forming an intercalative complex with DNA and inhibiting DNA topoisomerase II (topo II) and by blocking the cell cycle in G(2)/M phase. Probable cell death by apoptosis is also suggested by flow cytometry analysis.

Some novel pyrrolo-quinoline derivatives have been synthesized as potential antineoplastic agents. They contain an angular aromatic tricyclic or tetracyclic system, to which the methanesulfon-anisidide side chain typical of amsacrine as such, or lacking the m-methoxy substituent, is connected. A methyl group can be present at position 7 of the pyrrolo-quinoline ring. The novel compounds exhibit interesting cell growth inhibitory properties when tested against the NCI panel of cell lines, in particular those obtained from solid tumors like CNS-, melanoma- and prostate-derived cells. The mechanism of cytotoxic action does not seem to be related to topoisomerase II poisoning ability. Most active proved to be compound 4a, which lacks both methyl and methoxy substituents, followed by 5a, having the methoxy group only. Biological activity is less pronounced in the tetracyclic family of derivatives 6 and 7.

A series of methyl and ethyl quaternary pyridiniumtetrahydrocarbazoles was synthesized and studied in comparison with ellipticine, chosen as a reference. In general, their antiproliferative activity, tested in different biological substrates, appeared to be higher than that of the corresponding non-quaternarized compounds. This fact could be attributed to the introduction of a positive charge in the molecule, which can stabilize the molecular complex they form with DNA. In a prokaryotic system, the T2 bacteriophage, both quaternarized and non-quaternarized compounds inhibited its infectivity moderately, in a similar way to ellipticine. This effect seemed to be connected to a direct activity on the virions rather than on the indicator bacteria. In mammalian cells, the pyridiniumtetrahydrocarbazoles were more effective. In particular, they appeared to be very active in inhibiting DNA synthesis in Ehrlich ascites cells; some of them were as effective as ellipticine. However, pyridiniumtetrahydrocarbazoles were less active in comparison with ellipticine when their capacity for inhibiting the clonal growth in Chinese hamster ovary (CHO) cells was tested. A similar picture was obtained studying the formation of chromosome aberrations and of sister chromatid exchanges in the same cells. These different responses can be explained considering that the data on DNA synthesis reflect effects only on DNA replication within a short time, without considering any later consequences; on the contrary, in the long-term tests, other events, which lead to cell killing or genotoxicity, can take place. Pyridiniumtetrahydrocarbazoles damage DNA, inducing double-strand breaks efficiently. These observations, together with the data already obtained on unsubstituted derivatives, suggest the pyridiniumtetrahydrocarbazoles induce antiproliferative and genotoxic effects, very probably by inhibiting topoisomerase II.

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.

With the aim to obtain new bis-intercalating agents in DNA a series of compounds was prepared linking two identical tricyclic moieties (two 4,5'-8-trimethylpsoralen (TMP)) or different (one TMP and one pyrido[3,2-b]quinoline) through a hydrocarburic aminated flexible chai. Bis-psoralen-amines as well as psoralen-pyrydoquinolin-amines were obtained. For comparison the corresponding mono-psoralen-amines were also prepared condensing a TMP moiety with various hydrocarburic aminated chains. Melting profiles of the complexes between bis-psoralen-amines or psoralen-pyridoquinolin-amines and DNA evidence two different thermal transitions, which can be correlated with bis-intercalation which takes place, at least in part, inside duplex DNA. On the other hand mono-psoralen-amines evidenced only one thermal transition, in line with mono-intercalation. Bis-intercalating agents complexed with DNA, under UVA irradiation photoconjugate covalently to the macromolecule, even if to a lower extent in comparison with mono-intercalating agents. Moreover these bis-intercalating agents in the photoreaction with DNA form inter-strand cross-links; also in this case bis-intercalating agents are less active than mono-intercalating agents.

Certain 2-substituted 1H-pyrrolo [3,2-h] quinolines have been prepared and their biological activity in mammalian cells and in some microorganisms 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 microorganisms, 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.

2-Carbomethoxy-N-methyl-1H-pyrrolo[2,3-f]quinolinium and isoquinolinium iodides were prepared. Their in vitro ability to form complexes with DNA is enhanced in respect to parent compounds. This, however, does not appear to be agreement with their ability to inhibit cellular DNA sunthesis.

Fischer indol synthesis is reported for the preparation of some 2-substituted 1H-pyrrolo[2,3-f]quinoline and isoquinoline derivatives having a structural correlation with naturally occurring compound ellipticine. The prepared compounds proved capable of forming in vitro molecular complexes with native double-stranded DNA by intercalation between two base pairs and showed a relatively good activity in inhibiting the DNA synthesis in Ehrlich ascites tumor cells.

The antimicrobial activity of some 4,7-dihydroxyindole derivatives and indole-4,7-quinones was examined by determining the MIC against selected typical microorganisms (bacteria and fungi). A few of the compounds examined showed only a feeble inhibitory effect against some Gram-positive strains. Activity seems to be correlated with the lipophilic character of the molecules; in fact, all compounds containing a strong hydrophilic group, like a carboxyl, proved completely inactive.

With the aim of obtaining new bifunctional intercalators for DNA, a new series of bis-pyridoquinolines were synthesized by joining two tricyclic planar moieties through a flexible chain. For preparing the corresponding potential monofunctional intercalators also a series of mono-pyridoquinolines were prepared by chemical synthesis by joining the same chromophore with a flexible side-chain. The melting profiles of the complexes between two bis-pyridoquinolines and DNA showed two different thermal transitions supporting the bis-intercalation of the ligand with the macromolecule. On the other hand, two mono-pyridoquinolines showed only one transition in the melting profile indicating a behaviour consistent with a mono-intercalation. The antiproliferative activity was tested in terms of DNA synthesis inhibition in Ehrlich ascite tumor cells; the examined bis-intercalating agent showed to be much more active than the tested mono-intercalating compound.