Chemical and biological effects of substitution of the 2-position of ring-expanded (‘fat’) nucleosides containing the imidazo[4,5-e][1,3]diazepine-4,8-dione ring system: The role of electronic and steric factors on glycosidic bond stability and anti-HCV activity

Abstract

The attempted removal of the aralkyl group of 2-bromo-1-p-methoxybenzyl-6-octylimidazo [4,5-e] [1,3]diazepine (ZP-33) with trifluoroacetic acid resulted in replacement of the bromo group with a carbonyl at position-2 in addition to the desired deprotection at the 1-position. 2′-Deoxynucleosides of 2-bromo-substituted-imidazole-4,5-diesters (ZP-35 and ZP-103) were synthesized by direct glycosylation of the corresponding heterocycles. The attempted ring-closure of the above nucleosides resulted in deglycosylation to form the starting heterocycles. The 2-phenyl derivatives of the above nucleosides (ZP-45 and ZP-73) were successfully prepared by Suzuki coupling with the appropriate phenylboronic acids, but the attempted ring-closure with guanidines to form the desired 5,7-fused ring-expanded nucleosides (RENs) resulted once again in the formation of the corresponding heterocyclic aglycons (ZP-64 and ZP-75). The first successful 2-substituted REN (ZP-110) was synthesized by replacing the 2-deoxyribose sugar moiety with a ribosyl group and replacing the bromo group with a p-methoxyphenyl substituent at the 2-position. A number of imidazole riboside diester precursors containing a substituted phenyl group at the 2-position were synthesized in order to prepare analogues of ZP-110. The substituents on the phenyl ring included a variety of electrondonating or electron-withdrawing groups operating through inductive and/or resonance effects. However, the final ring-closure of the diesters with guanidines in order to prepare RENs was successful only in a limited number of cases, including the ones containing a p-fluorophenyl (ZP-121), a m-methoxyphenyl (ZP-122), or an unsubstituted phenyl (NZ-53) at the 2-position. Deglycosylation and incomplete ring-closure of the intermediates were the major problems encountered with most other cases. The stability of glycosidic bonds was found to be dependent on several factors including, but not limited to, the electron-donating inductive effect of the 2-phenyl substituents and the temperature of the reaction medium. The three target RENs ZP-110, ZP-121, and ZP-122 were screened for in vitro anti-HCV activity, employing an HCV RNA replicon assay. While ZP-121 was inactive, the other two compounds showed only weak anti-HCV activity.

Ketorolac salt is a newly discovered DDX3 inhibitor to treat oral cancer

“…DEAD box RNA helicases are capable of unwinding duplex RNA and DNA structures by disrupting the hydrogen bonds that maintain the two strands together 25 26 . The enzymatic activity of DDX3 has shown to be involved in replication of HCV, HBV and other family members 27 . Ring expanded nucleoside (REN), analogues have shown to inhibit the viral ATPase/ helicase activity by incorporating into nucleic acids during transcription 28 29 30 31 32 .…”

Synthesis and biological evaluation of unprecedented ring-expanded nucleosides (RENs) containing the imidazo[4,5-d][1,2,6]oxadiazepine ring system

“…1 A number of coformycin analogues have been synthesized, both to investigate the structure-activity relationship and to produce less toxic derivatives. [4][5][6][7][8][9] Furthermore, imidazo [4,5-c]azepine nucleosides, ring-expanded derivatives of xanthosine, guanosine and inosine, have been investigated and their cytotoxic activity has been reported. 10 RENs have shown antiviral properties as well.…”

“…11 From a synthetic point of view, the construction of a nucleoside containing a 5 : 7-fused ring base system can be performed using a sugar unit bearing a functionalized imidazole (or other 5-membered cycles), on which the seven-membered ring closure can be accomplished by inserting an appropriate molecular moiety. 9,10,12 Alternatively, a pre-synthesized 5 : 7-fused heterocyclic system can be joined to a sugar moiety by reaction with an activated glycosyl donor. 7,13,14 The latter approach is longer but it does not suffer from problems due to the weakness of the N-glycosidic bond and it also offers the chance to synthesize both a/b nucleoside isomers.…”

Synthesis of Tetracyclic 2,3-Dihydro-1,3-diazepines from a Dinitrodibenzothiophene Derivative

“…Developing new routes to underexplored heterocyclic motifs is a fundamental driving force in organic chemistry and is essential to identifying new structures of medicinal or technological value. Diazepines are of major pharmaceutical importance. − 1,2-Benzodiazepines and 1,4-benzodiazepines in particular comprise entire classes of drugs, including the antianxiety medications tofisopam (strictly a 2,3-diazepine) and diazepam. − 1,3-Diazepines, and the saturated analogues 1,3-diazepanes, are less prevalent; however they have been studied as HIV protease inhibitors, − as anticancer − and antiviral agents, ,− and also as N -heterocyclic carbene ligands. , In comparison with 1,2- and 1,4-diazepines, routes to 1,3-diazepines are less clearly established. Since the last comprehensive survey of their synthesis only a handful of new synthetic approaches have been reported for monocyclic, − singly − or doubly ring-fused 1,3-diazepines. − …”