title: Synthesis, G-quadruplex stabilisation, docking studies, and effect on cancer cells of indolo[3,2-b]quinolines with one, two, or three basic side chains.
abstract: 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 (ΔTm values between 17 and 8 °C) with an inter-G4 ΔTm 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.
authors: Medicinal Chemistry Group, Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon (Portugal).
authors: João
authors: J
authors: Lavrado
authors: Pedro M
authors: PM
authors: Borralho
authors: Stephan A
authors: SA
authors: Ohnmacht
authors: Rui E
authors: RE
authors: Castro
authors: Cecília M P
authors: CM
authors: Rodrigues
authors: Rui
authors: R
authors: Moreira
authors: Daniel J V A
authors: DJ
authors: dos Santos
authors: Stephen
authors: S
authors: Neidle
authors: Alexandra
authors: A
authors: Paulo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D054856:G-Quadruplexes / Q000187:drug effects*; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D018631:ras Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: C000602269:2-(diethylamino)ethyl 11-(2-(diethylamino)ethoxy)-10-(2-(diethylamino)ethyl)-10H-indolo(3,2-b)quinoline-7-carboxylate; C000602268:2-(diethylamino)ethyl 5,10-bis(2-(diethylamino)ethyl)-11-oxo-10,11-dihydro-5H-indolo(3,2-b)quinoline-7-carboxylate; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007211:Indoles; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011804:Quinolines; D015363:Quinolones; C030374:indole; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: G‐quadruplexes; alkaloids; cancer; cryptolepine; indoloquinolines