Computer Modeling

G-quadruplex (G4) DNA structures in telomeres and oncogenic promoter regions are potential targets for cancer therapy, and G4 ligands have been shown to modulate telomerase activity and oncogene transcription. Herein we report the synthesis and G4 thermal stabilisation effects, determined by FRET melting assays, of 20 indolo[3,2-b]quinolines mono-, di-, and trisubstituted with basic side chains. Molecular modelling studies were also performed in an attempt to rationalise the ligands′ binding poses with G4. Overall, the results suggest that ligand binding and G4 DNA thermal stabilisation increase with an N5-methyl or a 7-carboxylate group and propylamine side chains, whereas selectivity between G4 and duplex DNA appears to be modulated by the number and relative position of basic side chains. From all the indoloquinoline derivatives studied, the novel trisubstituted compounds 3 d and 4 d, bearing a 7-(aminoalkyl)carboxylate side chain, stand out as the most promising compounds; they show high G4 thermal stabilisation (ΔT^m values between 17 and 8 °C) with an inter-G4 ΔT^m trend of Hsp90A>KRas21R≈F21T>c-Kit2, 10-fold selectivity for G4 over duplex DNA, and 100-fold selectivity for the HCT116 cancer cell line (IC⁵⁰ and IC⁹⁰: <10 μM) over primary rat hepatocytes. Compounds 3 d and 4 d also decreased protein expression levels of Hsp90 and KRas in HCT116 cancer cells.

João Lavrado [a], Pedro M. Borralho [b, c], Stephan A. Ohnmacht [d], Rui E. Castro [b, c], Cecília M. P. Rodrigues [b, c], Rui Moreira [a], Daniel J. V. A. dos Santos [a, e], Stephen Neidle [d] and Alexandra Paulo [a]

[a] J. Lavrado, R. Moreira, D. J. V. A. dos Santos, A. Paulo Medicinal Chemistry Group Research Institute for Medicines and Pharmaceutical Sciences Faculty of Pharmacy, University of Lisbon Av. Prof. Gama Pinto, 1649-003 Lisbon (Portugal)

[b] P. M. Borralho, R. E. Castro, C. M. P. Rodrigues Molecular & Cell Biology of Eukaryotic Systems Group Research Institute for Medicines and Pharmaceutical Sciences Faculty of Pharmacy, University of Lisbon Av. Prof. Gama Pinto, 1649-003 Lisbon (Portugal)

[c] P. M. Borralho, R. E. Castro, C. M. P. Rodrigues Department of Biochemistry and Human Biology Faculty of Pharmacy, University of Lisbon Av. Prof. Gama Pinto, 1649-003 Lisbon (Portugal)

[d] S. A. Ohnmacht, S. Neidle The School of Pharmacy, University College London 29/39 Brunswick Square, London WC1N 1AX (UK)

[e] D. J. V. A. dos Santos REQUIMTE, Department of Chemistry & Biochemistry Faculty of Sciences, University of Porto R. do Campo Alegre, 4169-007 Porto (Portugal)

http://dx.doi.org/10.1002/cmdc.201300288