Citotoxic effects against drug-resistant tumor cells of novel 12h-chromeno[2,3-c]isoquinolin-5-amine derivatives targeting g-quadruplex dna and monoamine oxidases

About forty 4H-chromene derivatives fused with imidazo[1,2-a]pyridine and isoquinolin-1-amine, synthesized through sequential three-component domino reactions [1,2], were assayed for the affinity to G-rich oligonucleotides with known tumorigenic properties (c-KIT, c-MYC, HTS), through the thiazole orange (TO) displacement assay. Only the 12H-chromeno[2,3-c]isoquinolin-5-amine scaffold proved to bind G-quadruplex DNA (G4-DNA) sequences, and the derivatives 1 and 2 proved to diplace TO from G4-DNA with a potency similar to berberine (positive control). Recent evidence highlighted the role of monoamine oxidases (MAOs) in sustaining tumor resistance and proliferation [3]. Interestingly, among analogs diversely decorated at C8, C10 and C12, cmpds 1 and 2 achieved MAO A and B inhibition with single digit micromolar IC50s. In addition, they proved to inhibit P-glycoprotein (P-gp), which is associated with multidrug resistance (MDR) in cancer cells The most potent G4-DNA binders and MAO inhibitors, tested in some tumor cell lines, namely MCF-7 (breast carcinoma), HCT116 (colon cancer), SK-OV-3 (ovarian carcinoma with intrinsic resistance to cisplatin), A2780 (ovarian carcinoma cell) and A2780cp8 (ovarian carcinoma with acquired resistance to cisplatin), showed promi promising anticancer activity in the low M range (IC50s < 10 M in most cases). [1] O.A. Storozhenko, A.A. Festa, D.R. Bella Ndoutoume, A.V. Aksenov, A.V. Varlamov, L.G. Voskressensky, Beilstein J. Org. Chem. 2018, 14, 3078-3087. [2] X. Yue, A.A. Festa, O.A. Storozhenko, A.V. Varlamov, K. Subramani, A. Boccarelli, R. Purgatorio, C.D. Altomare, L.G. Voskressensky, Bioorg. Chem. 2020, 104, 169. [3] J.C. Shih, J. Neural Transm. 2018, 125, 1553-1566.