Indenocinnoline derivatives as G-quadruplex binders, topoisomerase IIα inhibitors and antiproliferative agents.
DNA intercalating agents are a consolidated therapeutic option in the treatment of tumor diseases. Starting from previous findings in the antiproliferative efficacy of a series of indeno[1,2-c]cinnoline-11-one derivatives, we performed a suitable decoration of this scaffold by means of a simple and straightforward chemistry, aiming to a) enlarge the planar core to a pentacyclic benzo[h]indeno[1,2-c]cinnoline-13-one and b) introduce a basic head tethered through a simple polymethylene chain. In fluorescence melting and fluorescence intercalator displacement assays, these new compounds displayed fair to very good intercalating properties on different nucleic acid strands, with preference for G-quadruplex sequences. Inhibition of human topoisomerase IIα and antiproliferative assays on HeLa and MCF7 tumor cell lines outlined a multitarget antiproliferative profile for tetracyclic 6 and pentacyclic derivative 20, both bearing a N,N-dimethylamine as the protonatable moiety. Particularly, compound 6 displayed a very potent inhibition of tumor cell proliferation, while 20 returned the highest thermal stabilization in melting experiments. In summary, these results outlined a potential of such highly planar scaffolds for nucleic acid binding and antiproliferative effects.
School of Health Sciences, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, GR-15771 Athens, Greece.
Grigoris
G
Zoidis
Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Via F. Marzolo 5, 35131 Padova, Italy.
Alice
A
Sosic
Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Via F. Marzolo 5, 35131 Padova, Italy.
Silvia
S
Da Ros
Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Via F. Marzolo 5, 35131 Padova, Italy.
Barbara
B
Gatto
Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Via F. Marzolo 5, 35131 Padova, Italy.
Claudia
C
Sissi
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
Fausta
F
Palluotto
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
Angelo
A
Carotti
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy. Electronic address: marco.catto@uniba.it.
Marco
M
Catto
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D052160:Benzothiazoles / Q000737:chemistry; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D054856:G-Quadruplexes; D006367:HeLa Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D008024:Ligands; D061986:MCF-7 Cells; D011804:Quinolines / Q000737:chemistry; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*
D000970:Antineoplastic Agents; D052160:Benzothiazoles; D006576:Heterocyclic Compounds, 4 or More Rings; D007364:Intercalating Agents; D008024:Ligands; D011804:Quinolines; D059005:Topoisomerase II Inhibitors; C051000:thiazole orange; D027101:DNA Topoisomerase IV; D004250:DNA Topoisomerases, Type II
Antitumor agents; G-quadruplex binders; Indenocinnoline derivatives; Intercalating agents; Topoisomerase inhibitors