Thiadiazole-, selenadiazole- and triazole-fused anthraquinones as G-quadruplex targeting anticancer compounds

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.PMID:38387333 | DOI:10.1016/j.ejmech.2024.116222

Source: European Journal of Medicinal Chemistry - February 22, 2024 Category: Chemistry Authors: Daria V Andreeva Tatiana S Vedekhina Alexander S Gostev Lyubov G Dezhenkova Yulia L Volodina Alina A Markova Minh Tuan Nguyen Olga M Ivanova Vladislava А Dolgusheva Anna M Varizhuk Alexander S Tikhomirov Andrey E Shchekotikhin Source Type: research