The glycosilic analogues of 6-aza-cytidine: synthesis and antiviral activity

Abstract

Інститут мікробіології і вірусології ім. Д. К. Заболотного НАН України Вул. Академіка Заболотного, 154, Київ, 03143, Україна За спрощеним варіантом «силільної конденсації» синтезовано низку N 1-глікопіранозидних і N1-глікофуранозидних аналогів 6-азацитидину (6-АС) та досліджено їхню протиаденовірусну активність у порівнянні з базовою молекулою 6-АС. Показано, що до антиаденовірусної дії 6-АС причетне збереження D-рибофуранозного фрагмента. Заміна рибофуранози на рибопіранозу або на інший цукор (D-ксилозу, D-глюкозу, L-арабінозу) призводить до втрати аналогом біологічної активності, характерної для базової сполуки

Synthesis and Comparative Study of Anti-Adenoviral Activity of 6-Azacytidine and Its Analogues

“…The glycosidic bond of N2-triazinyl nucleosides (in contrast to that in N4-derivatives) is known to be stable to alkaline hydrolysis. [11] Deblocking of protecting groups in triacetyl glycosides 1, 10, 13 by treatment with aqueous ammonia/ethanol (4:1, v/v, RT) resulted in simultaneous substitution of 5-methylmercapto group for amino group and formation of corresponding N-glycosides of 6-azacytosine (Scheme 1). This general procedure previously reported by our laboratory was easily applied for 6-azaCyd analogues.…”

“…This general procedure previously reported by our laboratory was easily applied for 6-azaCyd analogues. [11] Also, the selective amination of triazinebase and ammonolyzis acetoxy-groups ribofuranoside (16) into the target 6-azaCyd thio-analogue (17) was achieved in fairly good yield by action of methanolic ammonia in a sealed vessel at room temperature (Scheme 2). The treatment of acetylated nucleosides 1, 10, 13 with an excess (1.5-2.0 eq.)…”

“…Glycosylation position was confirmed by a bathochromic shift of UV absorbance maxima of nucleosides in acidic medium (0.1 M HCl), which is a characteristic for N2-glycosides of 5-amino-1,2,4-triazune. [15] The Anti-Adenoviral Activity of 6-Azacytidine and Analogues 567 resulting acylated N2-glycosides of 5-metylmercapto-1,2,4-triazin-3(2Н)-one (MMT) (compounds 1, 10, 13) and 3,5-dithio-(2,3,4,5)-tetrahydro-1,2,4-triazine (DTT) N2-riboside (16) then underwent amination and/or ammonolyzis for obtaining the corresponding N -glycosides of 1,2,4-triazine base (2-7, 12, 15, 17) and compounds with modifications at both nucleoside fragments (11,14). The glycosidic bond of N2-triazinyl nucleosides (in contrast to that in N4-derivatives) is known to be stable to alkaline hydrolysis.…”

“…[12,14] The application of 6-azaСyd on a model of disseminated AdV infection in newborn Syrian hamsters led to significant decrease of virus titer and shortening of the time of virus clearance in organs. [11,12] This work describes the synthesis and comparative results of the studies of anti-adenoviral activity of novel and already known 6-azaСyd structural analogues (N -α-L-glycosides 6-azacytosine, its N 4 -derivatives, and seco-6-azanucleosides). The goal of the present study was to find the most effective inhibitor against AdV in its parental nucleoside form and to determine separate molecular fragment that enhances the anti-AdV activity.…”

“…[6,7] More recent research on antiviral properties of 6-azaСyd has demonstrated its high activity relative to human AdV in vitro and in vivo systems. [8][9][10][11][12][13] In cell cultures, the anti-adenoviral effect of 6-azaСyd was expressed by inhibiting the formation of virus-specific intranuclear DNA-containing inclusion bodies, the synthesis of viral proteins and infectious virus. [12,14] The application of 6-azaСyd on a model of disseminated AdV infection in newborn Syrian hamsters led to significant decrease of virus titer and shortening of the time of virus clearance in organs.…”