title: Synthesis and significant cytostatic activity of 7-hetaryl-7-deazaadenosines.
abstract: A series of 7-aryl- and 7-hetaryl-7-deazaadenosines was prepared by the cross-coupling reactions of unprotected or protected 7-iodo-7-deazaadenosines with (het)arylboronic acids, stannanes, or zinc halides. Nucleosides bearing 5-membered heterocycles at the position 7 exerted potent in vitro antiproliferative effects against a broad panel of hematological and solid tumor cell lines. Cell cycle analysis indicated profound inhibition of RNA synthesis and induction of apoptosis in treated cells. Intracellular conversion to triphosphates has been detected with active compounds. The triphosphate metabolites showed only a weak inhibitory effect on human RNA polymerase II, suggesting potentially other mechanisms for the inhibition of RNA synthesis and quick onset of apoptosis. Initial in vivo evaluation demonstrated an effect of 7-(2-thienyl)-7-deazaadenine ribonucleoside on the survival rate in syngeneic P388D1 mouse leukemia model.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Bourderioux
authors.forename: Petr
authors.initials: P
authors.lastname: Naus
authors.forename: Pavla
authors.initials: P
authors.lastname: Perlíková
authors.forename: Radek
authors.initials: R
authors.lastname: Pohl
authors.forename: Iva
authors.initials: I
authors.lastname: Pichová
authors.forename: Ivan
authors.initials: I
authors.lastname: Votruba
authors.forename: Petr
authors.initials: P
authors.lastname: Dzubák
authors.forename: Petr
authors.initials: P
authors.lastname: Konecný
authors.forename: Marián
authors.initials: M
authors.lastname: Hajdúch
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Stray
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
authors.forename: Joy Y
authors.initials: JY
authors.lastname: Feng
authors.forename: Gabriel
authors.initials: G
authors.lastname: Birkus
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
authors.forename: Michal
authors.initials: M
authors.lastname: Hocek
mesh_terms: D000248:Adenosine Kinase / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D054697:Cytostatic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D054697:Cytostatic Agents; D000248:Adenosine Kinase; D012319:RNA Polymerase II; D014372:Tubercidin