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

• Published in: Chemistry : a European journal Vol. 26; no. 57; pp. 13002 - 13015
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 09.10.2020; Wiley Subscription Services, Inc
• Subjects: Antineoplastic Agents - pharmacology; antitumor agents; Antiviral activity; antiviral agents; Antiviral Agents - pharmacology; Apoptosis; Cell activation; Chemical reactions; Chemistry; Chemistry, Multidisciplinary; Coupling (molecular); Cross coupling; Cytotoxicity; Deoxyribonucleic acid; DNA; drug discovery; Glycosylation; Phosphorylation; Physical Sciences; Purines - pharmacology; Pyridines; ribonucleosides; Ribonucleosides - chemical synthesis; Ribonucleosides - pharmacology; Science & Technology; Selectivity; Structure-Activity Relationship; Synthesis; DESIGN; ANALOG; antiviral agents; antitumor agents; ADENOSINE KINASE INHIBITORS; NUCLEOSIDE DERIVATIVES; ribonucleosides; POTENT; HOLE TRANSPORT; drug discovery; DNA; BIOLOGICAL-ACTIVITY; ENZYMATIC INCORPORATION; ANTISEIZURE ACTIVITY; phosphorylation
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202001124

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. Isomers matter: All four isomeric series of novel 4‐substituted pyrido‐fused 7‐deazapurine ribonucleosides possessing pyridine nitrogen at different positions were designed, synthesized, and tested for cytostatic and antiviral activity. The most active showed submicromolar cytotoxic effects and good selectivity for cancer cells. The mechanism of action was also investigated.