Twelve N2'-branched acyclic nucleoside phosphonates and bisphosphonates were synthesized as potential inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPRT), the key enzyme in the purine salvage pathway for production of purine nucleotides. The chemical structures were designed with the aim to study selectivity of the inhibitors for PfHGXPRT over human HGPRT. The newly prepared compounds contain 9-deazahypoxanthine connected to a phosphonate group via a five-atom-linker bearing a nitrogen atom (N2') as a branching point. All compounds, with the additional phosphonate group(s) in the second aliphatic linker attached to N2' atom, were low micromolar inhibitors of PfHGXPRT with low to modest selectivity for the parasite enzyme over human HGPRT. The effect of the addition of different chemical groups/linkers to N2' atom on the inhibition constants and selectivity is discussed.

• Klíčová slova
• Acyclic nucleoside phosphonates, Plasmodium falciparum, hypoxanthine-guanine-(xanthine) phosphoribosyltransferase, inhibitors, malaria,
• MeSH
• antimalarika * farmakologie   chemie   MeSH
• hypoxanthinfosforibosyltransferasa metabolismus   farmakologie   MeSH
• hypoxanthiny farmakologie   MeSH
• inhibitory enzymů farmakologie   chemie   MeSH
• lidé MeSH
• nukleosidy farmakologie   chemie   MeSH
• organofosfonáty * farmakologie   chemie   MeSH
• pentosyltransferasy MeSH
• Plasmodium falciparum MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 9-deazahypoxanthine MeSH Prohlížeč
• antimalarika * MeSH
• hypoxanthinfosforibosyltransferasa MeSH
• hypoxanthiny MeSH
• inhibitory enzymů MeSH
• nukleosidy MeSH
• organofosfonáty * MeSH
• pentosyltransferasy MeSH

A series of novel 7-aryl-7-deazaadenine-based N-branched acyclic nucleoside phosphonates (aza-ANPs) has been prepared using the optimized Suzuki cross-coupling reaction as the key synthetic step. The final free phosphonates 15a-h were inactive, due to their inefficient transport across cell membranes, but they inhibited Trypanosoma brucei adenine phosphoribosyltransferase (TbrAPRT1) with Ki values of 1.7-14.1 μM. The corresponding phosphonodiamidate prodrugs 14a-h exhibited anti-trypanosomal activity in the Trypanosoma brucei brucei cell-based assay with EC50 values in the range of 0.58-6.8 μM. 7-(4-Methoxy)phenyl-7-deazapurine derivative 14h, containing two phosphonate moieties, was the most potent anti-trypanosomal agent from the series, with EC50 = 0.58 μM and SI = 16. Finally, phosphonodiamidate prodrugs 14a-h exerted low micromolar cytotoxicity against leukemia and/or cancer cell lines tested.

• Klíčová slova
• Acyclic nucleoside phosphonates, Nucleotides, Suzuki reaction, Trypanosoma, Tubercidin,
• MeSH
• nukleosidy farmakologie   MeSH
• organofosfonáty * farmakologie   MeSH
• prekurzory léčiv * farmakologie   MeSH
• puriny MeSH
• Trypanosoma brucei brucei * MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 7-deazapurine MeSH Prohlížeč
• nukleosidy MeSH
• organofosfonáty * MeSH
• prekurzory léčiv * MeSH
• puriny MeSH

Invited for the cover of this issue is Kamil Parkan and co-workers at University of Chemistry and Technology and Institute of Organic Chemistry and Biochemistry, Prague. The cover graphic depicts a schematic representation of the assembly of aryl-C-glycosides based on a protecting-group-free Hiyama reaction. Read the full text of the article at 10.1002/chem.202101052.

• MeSH
• benzhydrylové sloučeniny * MeSH
• glukosidy * MeSH
• glykosidy MeSH
• lidé MeSH
• organická chemie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzhydrylové sloučeniny * MeSH
• dapagliflozin MeSH Prohlížeč
• glukosidy * MeSH
• glykosidy MeSH

Access to unprotected (hetero)aryl pseudo-C-glucosides via a mild Pd-catalysed Hiyama cross-coupling reaction of protecting-group-free 1-diisopropylsilyl-d-glucal with various (hetero)aryl halides has been developed. In addition, selected unprotected pseudo-C-glucosides were stereoselectively converted into the corresponding α- and β-C-glucosides, as well as 2-deoxy-β-C-glucosides. This methodology was applied to the efficient and high-yielding synthesis of dapagliflozin, a medicament used to treat type 2 diabetes mellitus. Finally, the versatility of our methodology was proved by the synthesis of other analogues of dapagliflozin.

• Klíčová slova
• Hiyama reaction, aryl C-glycosides, cross-coupling, dapagliflozin, protecting-group-free,
• MeSH
• benzhydrylové sloučeniny MeSH
• diabetes mellitus 2. typu * farmakoterapie   MeSH
• glukosidy MeSH
• katalýza MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzhydrylové sloučeniny MeSH
• dapagliflozin MeSH Prohlížeč
• glukosidy MeSH