Original articleSynthesis of a new class of pyrrolo[3,4-h]quinazolines with antimitotic activity
Graphical abstract
Introduction
Quinazolines are considered an attractive target for medicinal chemists, because they are the scaffold of several potent antitumor drugs. Leading examples are the well known Erlotinib (trade name Tarceva) [1] and Gefitinib (trade name Iressa) [2], but many other examples are currently under clinical investigation. Among these, the quinazoline derivative LZ-11 (1) has recently emerged as effective and selective telomeric G-quadruplex ligand [3]. Moreover, tricyclic compounds incorporating the quinazoline moiety, such as the pyrazolo[4,3-h]quinazoline-3-carboxamides of type 2, have been largely investigated as kinases inhibitors [4]. Considering our interest in pyrrole and indole systems with antitumor properties [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], we have recently reported the synthesis of pyrrolo[3,2-h]quinazolines 3 with the aim of developing a new series of quinazolines containing the pyrrole moiety. These compounds expressed their activity upon light activation of a proper wavelength, showing potent growth inhibitory effects in cell proliferation in several human tumor cell lines reaching submicromolar level (GI50 0.2–15.2 μM) [15]. Herein, we report the synthesis of a new series of pyrrolo[3,4-h]quinazolines of type 4 and the evaluation of their antitumor properties (Chart 1).
At first, considering our previous results on the pyrroloquinazolines of type 3, the new derivatives of the title ring system were screened to evaluate the growth inhibitory effect in cell proliferation upon light irradiation. However, pyrrolo[3,4-h]quinazolines 4 did not undergo photoactivation, and the antitumor effect was very poor. In contrast, they gave interesting results “in the dark” showing antimitotic activity.
Section snippets
Chemistry
Tetrahydroindol-7-ones 5a–s, suitable substrates for our purpose, were prepared by different synthetic routes with a good substitution pattern on the pyrrole moiety by methods previously reported by us (Scheme 1) [16], [17], [18]. Functionalization in α position to the carbonyl group, transformated ketones 5a–s either into the corresponding hydroxymethylketones or into enaminoketones which have demonstrated versatile key intermediates for further annelation upon reaction with several
Antiproliferative assays
Cellular cytotoxicity was carried out in vitro in 5 different human tumor cell lines: K562, Jurkat, LoVo, MCF-7 and A-431. Cytotoxicity was evaluated by the MTT test after 72 h of cellular incubation in the presence of different concentrations of compounds as described in experimental section (5.2). For each compound, GI50 value was calculated and is shown in Table 1. The compounds whose GI50 was higher than 20 μM in all cell lines were not included in Table 1.
Most compounds reduced cell
Conclusion
In conclusion, a new series of pyrrolo[3,4-h]quinazolines has been successfully prepared by annelation of the pyrimidine ring on the isoindole moiety. The synthetic pathway presented herein was never described before in the isoindole series and proved to be versatile allowing the preparation of a large number of derivatives. Some of them showed an interesting cytotoxicity in many tumor cell lines and were active even in a multi-drug resistant cell line.
The most cytotoxic derivatives 8l, 8m, 8r,
Synthesis and characterization
All melting points were taken on a Buchi-Tottoli capillary apparatus and were uncorrected; IR spectra were determined, in CHBr3, with a Jasco FT/IR 5300 spectrophotometer; 1H and 13C NMR spectra were measured in DMSO-d6 or CDCl3 solutions, at 200 and 50.3 MHz respectively, using a Bruker Avance II series 200 MHz spectrometer. Column chromatography was performed with Merck silica gel 230–400 mesh ASTM or with a SEPACORE chromatography apparatus BÜCHI. Elemental analyses (C, H, N) were within
Acknowledgments
This work was financially supported by Ministero dell'Istruzione dell'Università e della Ricerca. We would like to thank Tine D. Rasmussen for excellent technical assistance.
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