Novel trypanocidal analogs of 5'-(methylthio)-adenosine.
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.
Sufrin
Janice R
JR
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. janice.sufrin@roswellpark.org
Spiess
Arthur J
AJ
Marasco
Canio J
CJ
Rattendi
Donna
D
Bacchi
Cyrus J
CJ
D000818:Animals; D003839:Deoxyadenosines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D020128:Inhibitory Concentration 50; D021261:Parasitic Sensitivity Tests; D011683:Purine-Nucleoside Phosphorylase / Q000378:metabolism; D013379:Substrate Specificity; D013872:Thionucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D003839:Deoxyadenosines; D013872:Thionucleosides; D014344:Trypanocidal Agents; C008500:5'-methylthioadenosine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D014372:Tubercidin