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Thiadiazole-, selenadiazole- and triazole-fused anthraquinones as G-quadruplex targeting anticancer compounds
Ist Teil von
European journal of medicinal chemistry, 2024-03, Vol.268, p.116222-116222, Article 116222
Ort / Verlag
France: Elsevier Masson SAS
Erscheinungsjahr
2024
Quelle
MEDLINE
Beschreibungen/Notizen
G-quadruplex (G4) ligands attract considerable attention as potential anticancer therapeutics. In this study we proposed an original scheme for synthesis of azole-fused anthraquinones and prepared a series of G4 ligands carrying amino- or guanidinoalkylamino side chains. The heterocyclic core and structure of the terminal groups strongly affect on binding to G4-forming oligonucleotides, cellular accumulation and antitumor potency of compounds. In particular, thiadiazole- and selenadiazole- but not triazole-based ligands inhibit the proliferation of tumor cells (e.g. K562 leukemia) and stabilize primarily telomeric and c-MYC G4s. Anthraselenadiazole derivative 11a showed a good affinity to c-MYC G4 in vitro and down-regulated expression of c-MYC oncogene in cellular conditions. Further studies revealed that anthraselenadiazole 11a provoked cell cycle arrest and apoptosis in a dose- and time-dependent manner inhibiting K562 cells growth. Taken together, this work gives a valuable example that the closely related heterocycles may cause a significant difference in biological properties of G4 ligands.
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•A method for synthesis of azole-fused anthraquinone derivatives has been developed.•Selenadiazole- and thiadiazole-based ligands effectively stabilize G4s.•Guanidination of the aminoalkyl side chains increases the thermal shifts of G4s melting.•In vitro anticancer activity of the ligands correlates to G4s binding and intracellular uptake.