Document Detail

Novel trypanocidal analogs of 5'-(methylthio)-adenosine.
MedLine Citation:
PMID:  17954686     Owner:  NLM     Status:  MEDLINE    
The purine nucleoside 5'-deoxy-5'-(hydroxyethylthio)-adenosine (HETA) is an analog of the polyamine pathway metabolite 5'-deoxy-5'-(methylthio)-adenosine (MTA). HETA is a lead structure for the ongoing development of selectively targeted trypanocidal agents. Thirteen novel HETA analogs were synthesized and examined for their in vitro trypanocidal activities against bloodstream forms of Trypanosoma brucei brucei LAB 110 EATRO and at least one drug-resistant Trypanosoma brucei rhodesiense clinical isolate. New compounds were also assessed in a cell-free assay for their activities as substrates of trypanosome MTA phosphorylase. The most potent analog in this group was 5'-deoxy-5'-(hydroxyethylthio)-tubercidin, whose in vitro cytotoxicity (50% inhibitory concentration [IC50], 10 nM) is 45 times greater than that of HETA (IC50, 450 nM) against pentamidine-resistant clinical isolate KETRI 269. Structure-activity analyses indicate that the enzymatic cleavage of HETA analogs by trypanosome MTA phosphorylase is not an absolute requirement for trypanocidal activity. This suggests that additional biochemical mechanisms are associated with the trypanocidal effects of HETA and its analogs.
Janice R Sufrin; Arthur J Spiess; Canio J Marasco; Donna Rattendi; Cyrus J Bacchi
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-10-22
Journal Detail:
Title:  Antimicrobial agents and chemotherapy     Volume:  52     ISSN:  0066-4804     ISO Abbreviation:  Antimicrob. Agents Chemother.     Publication Date:  2008 Jan 
Date Detail:
Created Date:  2007-12-31     Completed Date:  2008-05-06     Revised Date:  2013-06-06    
Medline Journal Info:
Nlm Unique ID:  0315061     Medline TA:  Antimicrob Agents Chemother     Country:  United States    
Other Details:
Languages:  eng     Pagination:  211-9     Citation Subset:  IM    
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
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MeSH Terms
Deoxyadenosines / chemical synthesis,  chemistry*,  pharmacology
Dose-Response Relationship, Drug
Drug Resistance
Inhibitory Concentration 50
Parasitic Sensitivity Tests
Purine-Nucleoside Phosphorylase / metabolism
Substrate Specificity
Thionucleosides / chemical synthesis,  chemistry*,  pharmacology
Trypanocidal Agents* / chemical synthesis,  chemistry,  pharmacology
Trypanosoma brucei brucei / drug effects*,  enzymology,  growth & development
Trypanosoma brucei rhodesiense / drug effects*,  enzymology,  growth & development
Tubercidin / analogs & derivatives*,  chemical synthesis,  chemistry,  pharmacology*
Grant Support
Reg. No./Substance:
0/Deoxyadenosines; 0/Thionucleosides; 0/Trypanocidal Agents; 634Z2VK3UQ/5'-methylthioadenosine; 69-33-0/Tubercidin; EC Phosphorylase; EC'-methylthioadenosine phosphorylase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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