Reactivity of 5-(3-azidophenyl)-1-(1H-pyrrol-3-yl)pyrroles in TFMSA. A route for new ring systems as DNA-interactive agents.

The applicative synthetic potentiality of arylnitrenium ions, opportunely generated from azidic precursors, leading to polycondensed planar heterocycles structural analogs of noteworthy intercalating DNA agents, were extended. Among them, planar geometry of the molecules represents one of the most important parameter for adequate insertion between the stacked base pairs. These compounds continue to maintain active interest in biological field either for development of new therapeutics and for discovering new DNA targeting agents. To better clarify the mode of interaction with specific sites, a study involving structural modifications through functionalizations on analog substrates molecules of well known mode of action, the need to overcome some unresolved problems such as toxicity, affinity and selectivity are still topical. In this context, we extended the investigations the reactivity of azidic substrates containing the pyrrole moiety in order to undergo biological screening. Previously, experimental reaction conditions were optimized for the isolation of the new dipirrolochinazoline ring system. Applying the same methodology to an isomeric azidic intermediate 1-(pyrrol-3yl)pyrrole an different pathway was observed. The synthetic route involves the use of arylnitrenium ion formed from acid catalyzed decomposition of suitable azidic precursor. Since this type of ions behaves as electrophilic species, they need a sufficient activate moiety to undergo a new carbon-carbon bond. Although the beta position of the 1-(pyrrol-3yl), as reported in literature results enough reactive against poor electrophile so pyrrolcinnoline derivatives were isolated as good yields, in our reaction conditions the alfa position results the more competitive against cyclization. In fact the obtained cyclization products were not the expected planar derivatives dipyrrolo[2,1-a:3,4-c]isoquinoline but the corresponding isomeric non planar derivatives dipyrrolo[2,1-a:3,2-c]isoquinoline. This type of cyclization occurs despite unfavorable thermodinamic (lost of planarity) and steric (bulky substituents) aspects. However a planar derivative was also isolated in the case of the presence of an easily hydrolysable COOEt group as substituent. Anyway, this synthetic pathway showed wide group compatibility and revealed as a valid access to the isolation of new heterocycles in good yields along with the possibility to introduce in the different part of the molecule strategic substituents to make easier structure-activity relationships studies. Therefore, this represents good premises for further development concerning the modulation of the observed activity of previous analogs which displayed anti-HIV and antiproliferative activity.