Synthesis and Cytotoxic and Antiviral Activity Profiling of All‐Four Isomeric Series of Pyrido‐Fused 7‐Deazapurine Ribonucleosides.

Veselovská, Lucia; Kudlová, Natálie; Gurská, Soňa; Lišková, Barbora; Medvedíková, Martina; Hodek, Ondřej; Tloušťová, Eva; Milisavljevic, Nemanja; Tichý, Michal; Perlíková, Pavla; Mertlíková‐Kaiserová, Helena; Trylčová, Jana; Pohl, Radek; Klepetářová, Blanka; Džubák, Petr; Hajdúch, Marián; Hocek, Michal

All four isomeric series of novel 4‐substituted pyrido‐fused 7‐deazapurine ribonucleosides possessing the pyridine nitrogen atom at different positions were designed and synthesized. The total synthesis of each isomeric fused heterocycle through multistep heterocyclization was followed by glycosylation and derivatization at position 4 by cross‐coupling reactions or nucleophilic substitutions. All compounds were tested for cytostatic and antiviral activity. The most active were pyrido[4′,3′:4,5]pyrimidine nucleosides bearing MeO, NH2, MeS, or CH3 groups at position 4, which showed submicromolar cytotoxic effects and good selectivity for cancer cells. The mechanism involved activation by phosphorylation and incorporation to DNA where the presence of the modified ribonucleosides causes double‐strand breaks and apoptosis.

RIBONUCLEOSIDES; PYRIMIDINE nucleosides; ANTINEOPLASTIC antibiotics; NUCLEOPHILIC substitution reactions

Chemistry - A European Journal, 2020, Vol 26, Issue 57, p13002

0947-6539

Academic Journal

10.1002/chem.202001124