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Synthesis and Cytotoxic and Antiviral Activity Profiling of All‐Four Isomeric Series of Pyrido‐Fused 7‐Deazapurine Ribonucleosides
Author(s) -
Veselovská Lucia,
Kudlová Natálie,
Gurská Soňa,
Lišková Barbora,
Medvedíková Martina,
Hodek Ondřej,
Tloušťová Eva,
Milisavljevic Nemanja,
Tichý Michal,
Perlíková Pavla,
MertlíkováKaiserová Helena,
Trylčová Jana,
Pohl Radek,
Klepetářová Blanka,
Džubák Petr,
Hajdúch Marián,
Hocek Michal
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202001124
Subject(s) - chemistry , pyrimidine , stereochemistry , nucleophile , selectivity , pyridine , glycosylation , dna , coupling reaction , derivatization , combinatorial chemistry , medicinal chemistry , biochemistry , high performance liquid chromatography , organic chemistry , catalysis
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, NH 2 , MeS, or CH 3 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.