title: Design and synthesis of a series of truncated neplanocin fleximers.
abstract: In an effort to study the effects of flexibility on enzyme recognition and activity, we have developed several different series of flexible nucleoside analogues in which the purine base is split into its respective imidazole and pyrimidine components. The focus of this particular study was to synthesize the truncated neplanocin A fleximers to investigate their potential anti-protozoan activities by inhibition of S-adenosylhomocysteine hydrolase (SAHase). The three fleximers tested displayed poor anti-trypanocidal activities, with EC50 values around 200 μM. Further studies of the corresponding ribose fleximers, most closely related to the natural nucleoside substrates, revealed low affinity for the known T. brucei nucleoside transporters P1 and P2, which may be the reason for the lack of trypanocidal activity observed.
authors.affiliation: Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Zimmermann
authors.affiliation: Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
authors.forename: Elizaveta
authors.initials: E
authors.lastname: O'Neill
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK.
authors.forename: Godwin U
authors.initials: GU
authors.lastname: Ebiloma
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK.
authors.forename: Lynsey J M
authors.initials: LJ
authors.lastname: Wallace
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK.
authors.forename: Harry P
authors.initials: HP
authors.lastname: De Koning
authors.affiliation: Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA. kseley@umbc.edu.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Seley-Radtke
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D001692:Biological Transport; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D020128:Inhibitory Concentration 50; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology
chemical_list: D015800:Protozoan Proteins; D014344:Trypanocidal Agents; C031096:neplanocin A; D043383:Adenosylhomocysteinase; D000241:Adenosine