Constrained bisantrene derivatives as G-quadruplex binders

Abstract

We here report the synthesis and evaluation of constrained derivatives of a bisantrene isomer known to bind DNA when structured in G-quadruplex. Enhanced high-resolution mass spectrometry was used to evaluate the binding efficiency and stoichiometry of the compounds towards G-quadruplex DNA using a duplex sequence for comparison. Fluorimetric DNA binding studies supported and confirmed these preliminary observations. One of the newly synthesized compounds showed a high tendency and specificity to bind the structured G-quadruplex DNA.

Combining Electrospray Mass Spectrometry (ESI-MS) and Computational Techniques in the Assessment of G-Quadruplex Ligands: A Hybrid Approach to Optimize Hit Discovery

“…This mechanism justifies the generally observed charge states for oligomers (from −4 to −7 for a 23-mer GQ). 85 , 88 , 89 Recent improvements of the experimental conditions allow the study of GQs in a condition that is both closer to the physiological environment and more significant from a biological point of view using potassium as the cation for sequence stabilization. 90 The former approach consisted of folding the GQ in physiological potassium concentrations and the subsequent removal of the noncoordinated ions by filtration or ethanol precipitation.…”

“… 95 , 96 The number of cation adducts is indeed indicative of the number of tetrads involved in GQ formation. 89 , 97 …”

“…In previous studies from our group, the ligand–GQ interaction was studied using several ESI instruments based on different setups: a LCQ fleet ion trap (Thermo Fisher Scientific, Waltham, MA) instrument, 42 , 44 a Xevo G2-XS QTof (Waters Corporation, Milford, MA) instrument, 98 , 99 and a LTQ Orbitrap Velos (Thermo Fisher Scientific, Waltham, MA) instrument. 89 A higher resolution allows the resolution of a more complex mixture of species. This is desirable, particularly when carrying out a competition assay between compounds generating ligand–GQ complexes with similar molecular weights.…”

“…Concerning the flow rate, when measurements are carried out with a conventional ESI source, a 0.1–5 μL/min rate can be used. 42 , 89 …”

2-(3,4-Dihydroxyphenyl)-4-(2-(4-nitrophenyl)hydrazono)-4H-chromene-3,5,7-triol

“…Hydrazones are generally prepared from carbonyl compounds by reaction with an opportune hydrazine in acidic conditions [28,29]. Hydrochloric, acetic or 3-chloroperbenzoic acid are usually adopted for the synthesis of hydrazones, and the use of catalysts has been reported [30,31]. Compound 1 was synthesized by reacting quercetin with an excess of 4-nitrophenylhydrazine in a 1:1 mixture of acetic acid and ethanol.…”