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. 2017 Aug 25;8(9):1856-1862.
doi: 10.1039/c7md00319f. eCollection 2017 Sep 1.

Sugar modified pyrimido[4,5- b]indole nucleosides: synthesis and antiviral activity

Juraj Konč  1 , Michal Tichý  1 , Radek Pohl  1 , Jan Hodek  1 , Petr Džubák  2 , Marián Hajdúch  2 , Michal Hocek  1   3
Affiliations

Sugar modified pyrimido[4,5- b]indole nucleosides: synthesis and antiviral activity

Juraj Konč et al. Medchemcomm. .

Abstract

Three types of sugar modified pyrimido[4,5-b]indole nucleosides (2'-deoxy-2'-fluororibo-, 2'-deoxy-2'-fluoroarabino- and arabinonucleosides) were synthesized by glycosylation of 4,6-dichloropyrimido[4,5-b]indole followed by modification of sugar moiety and introduction of substituents into position 4 by cross-coupling reactions or nucleophilic substitutions. Some 2'-fluororibo- and 2'-fluoroarabinonucleosides displayed interesting anti-HCV activities (IC50 = 1.6-20 μM) and the latter compounds also some anti-dengue activities (IC50 = 10.8-40 μM).

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Figures

Fig. 1
Fig. 1. Previously reported 7-deazapurine nucleosides and fused-7-deazapurine nucleosides with cytostatic and antiviral activities. Custom purine numbering (red) is shown in structure 2, systematic numbering (black) of pyrrolo[2,3-d]pyrimidines and pyrimido[4,5-b]indoles is shown in structures 1 and 3, respectively.
Scheme 1
Scheme 1. Reagents and conditions: a) KOH, TDA-1, MeCN, r.t., 30 min, then Br-arabinose 6 in MeCN, r.t., 20 h; b) aq. NH3, dioxane, 100 °C, 2 days; c) 1 M NaOMe in MeOH, MeOH, r.t., 3 h; d) NaSMe, EtOH, r.t., 4 h; e) (Me)3Al (2 M in toluene), Pd(PPh3)4, THF; 70 °C, 18 h; f) R–B(OH)2, K2CO3, Pd(PPh3)4, toluene, 100 °C, 17–36 h; g) R–SnBu3, PdCl2(PPh3)2, DMF, 100 °C, 17–18 h; h) 1 M NaOMe in MeOH, MeOH, r.t., 2–18 h.
Scheme 2
Scheme 2. Reagents and conditions: a) KOH, TDA-1, toluene, r.t., 30 min, then 10 in toluene, r.t., 24 h; b) 90% aq. TFA, r.t., 30 min.
Scheme 3
Scheme 3. Reagents and conditions: a) TIPDSCl2, py, r.t., 4 h; b) Dess–Martin periodinane, DCM, 0 °C to r.t., 18 h; c) NaBH4, EtOH, 0 °C to r.t., 1.5 h; d) Et3N·3HF, THF, r.t., 18 h; e) aq. NH3, dioxane, 100 °C, 20 h; f) 1 M NaOMe in MeOH, MeOH, r.t., 3 h; g) NaSMe, EtOH, r.t., 3 h; h) (Me)3Al (2 M in toluene), Pd(PPh3)4, THF; 70 °C, 18 h; i) R–B(OH)2, Na2CO3, Pd(OAc)2, TPPTS, H2O/MeCN (2 : 1), 100 °C, 2–4 h.
Scheme 4
Scheme 4. Reagents and conditions: a) Ac2O, Et3N, DMAP, MeCN, r.t., 1 h; b) Et3N·3HF, THF, r.t., 18 h; c) DHP, TsOH, DMF, r.t., 18 h; d) 25–30% NH3 in MeOH, 0 °C, 4 h; e) DAST, py, DCM, 0 °C to r.t., 18 h; f) 90% aq. TFA, r.t., 2 h; g) aq. NH3, dioxane, 100 °C, 20 h; h) 1 M NaOMe in MeOH, MeOH, r.t., 3 h; i) NaSMe, EtOH, r.t., 2 h; j) (Me)3Al (2 M in toluene), Pd(PPh3)4, THF; 70 °C, 24 h; k) R–B(OH)2, Na2CO3, Pd(OAc)2, TPPTS, H2O/MeCN (2 : 1), 100 °C, 2–4 h.
Fig. 2
Fig. 2. Modelled overlay of diphosphates derived from nucleosides 9a, 17a, 23a and ADP in the co-crystal structure of the viral RNA-dependent RNA polymerase HCV NS5B genotype 2A in complex with RNA template, primer, Mn2+, and ADP (PDB code ; 4WTJ, 2.2 Å resolution). a) Detail of the tricyclic base overlayed with ADP; b) detail of ribose binding site, hydrogen bonds of 2′-OH showed as dashed lines and given in Å. Color code: Cenzyme grey, CADP magenta, C9a-DP salmon, C17a-DP yellow, C23a-DP cyan, CRNA green, O red, N blue, F pale cyan.
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