Selective delivery of 2-hydroxy APA to Trypanosoma brucei using the melamine motif.
Trypanosoma brucei, the parasite that causes human African trypanosomiasis, is auxotrophic for purines and has specialist nucleoside transporters to import these metabolites. In particular, the P2 aminopurine transporter can also selectively accumulate melamine derivatives. In this Letter, we report the coupling of the melamine moiety to 2-hydroxy APA, a potent ornithine decarboxylase inhibitor, with the aim of selectively delivering this compound to the parasite. The best compound described here shows an increased in vitro trypanocidal activity compared with the parent.
Klee
Nina
N
Division of Biological Chemistry and Drug Discovery, College of Life Science, University of Dundee, Sir James Black Centre, Dundee, UK.
Wong
Pui Ee
PE
Baragaña
Beatriz
B
Mazouni
Farah El
FE
Phillips
Margaret A
MA
Barrett
Michael P
MP
Gilbert
Ian H
IH
D006801:Humans; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011437:Propylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy
C553246:2-hydroxy-(aminooxy)propanamine; D065108:Ornithine Decarboxylase Inhibitors; D011437:Propylamines; D014227:Triazines; D014344:Trypanocidal Agents; D009955:Ornithine Decarboxylase; C011907:melamine