Indenocinnoline derivatives as G-quadruplex binders, topoisomerase IIα inhibitors and antiproliferative agents. Issue 9 (1st May 2017)

• Record Type: Journal Article
• Authors: Zoidis, Grigoris; Sosic, Alice; Da Ros, Silvia; Gatto, Barbara; Sissi, Claudia; Palluotto, Fausta; Carotti, Angelo; Catto, Marco
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 9(2017)
• Page Start: 2625
• Page End: 2634
• Publication Date: 2017-05-01
• Subjects: DDQ 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone -- FID fluorescence intercalator displacement -- G4 G-quadruplex -- TO thiazole orange -- Topo topoisomerase; Indenocinnoline derivatives -- Intercalating agents -- Topoisomerase inhibitors -- Antitumor agents -- G-quadruplex binders; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.03.019
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Tetra- and pentacyclic indenocinnoline derivatives had good DNA binding properties. Several tetra- and pentacyclic indenocinnoline derivatives were good inhibitors of human topoisomerase IIα. The presence of a basic residue as the substituent is required for topoisomerase inhibition. Tetracyclic indenocinnolines displayed the best antiproliferative activities. The length of linker of basic head influenced the thermal stabilization of DNA. Abstract: 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.