Synthesis and Evaluation of Quinazolone Derivatives as a New Class of c-KIT G-Quadruplex Binding Ligands

Abstract

The c-KIT G-quadruplex structures are a novel class of attractive targets for the treatment of gastrointestinal stromal tumor (GIST). Herein, a series of new quinazolone derivatives with the expansion of unfused aromatic ring system were designed and synthesized. Subsequent biophysical studies demonstrated that the derivatives with adaptive scaffold could effectively bind to and stabilize c-KIT G-quadruplexes with good selectivity against duplex DNA. More importantly, these ligands further inhibited the transcription and expression of c-KIT gene and exhibited significant cytotoxicity on the GIST cell line HGC-27. Overall, these quinazolone derivatives represent a new class of promising c-KIT Gquadruplex ligands. The experimental results have also reinforced the idea of inhibition of c-KIT expression through targeting c-KIT G-quadruplex DNA.

Design of Modular G‐quadruplex Ligands

“…Quinazolone derivatives 76 – 83 have also been synthesized as G4 ligands (Figure ) . The FRET melting data demonstrate that all of the derivatives effectively stabilize the telomeric G4, exhibiting preference over dsDNA, as confirmed by competitive experiments.…”

“…Quinazolone derivatives 82 and 83 containing an expanded aromatic system by the introduction of a benzene ring and a vinylphenyl group in the quinazolone moiety and two ionizable amino side chains have also been designed and studied . The FRET results show that compounds 82 a – c with shorter side chains have relatively modest G4 stabilizing ability, whereas compounds 82 d – f with longer chains induce increased T m values of the G4.…”

“…primary amine (46, 48, 51, 52) ! pyrrolidine (47,53). Modifications in the length of the side chain linked to the quinoline moiety also have as mall effect, but generally,t he efficiency is higher for ligandsw ith chain lengths of three carbon atoms over two carbon atoms.…”

Targeting G-quadruplex nucleic acids with heterocyclic alkaloids and their derivatives

“…Incorporating thiazole orange (29) [99] or a coumarinehemicyanine fluorophore (30) [100] to the isaindigotone framework lead to a big leap from colorimetric probe to colorimetric and fluorescent dual probe for detecting Gquadruplexes. In another series of quinazolinone derivatives (31) recently reported to stabilize c-KIT G-quadruplex, the best compound 31e reduced the transcription of c-KIT by 52.5% and exhibited significant cytotoxicity in a gastrointestinal stromal tumor cell line [101]. SAR analysis showed that the expanded aromatic system, via the introduction of a benzene ring, a benzylidene group and two cationic amino side chains into the quinazolone moiety, not only maximizes the stacking interaction of the derivatives with G-quartet but also incorporates features of flexibility that prevent it from intercalating into the duplex DNA.…”

Distinct novel quinazolinone exhibits selective inhibition in MGC-803 cancer cells by dictating mutant p53 function

“…As a result of their diverse pharmacological activities such as anticancer [12,13], antimicrobial [14e16], antimalarial [17,18], anti-inflammatory [19e22], antihypertensive [23,24], anticonvulsant [25,26] and cholinesterase inhibition activities [27], these derivatives have received considerable attention. However, a lack of studies is clearly noticed that are to utilize the property that quinazolinone derivatives could arrest mutant p53 while maintaining steady-state protein levels.…”