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Antimicrobial Agents and Chemotherapy, January 2008, p. 211-219, Vol. 52, No. 1
0066-4804/08/$08.00+0     doi:10.1128/AAC.00480-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Novel Trypanocidal Analogs of 5'-(Methylthio)-Adenosine{triangledown} ,{dagger}

Janice R. Sufrin,1,2* Arthur J. Spiess,1 Canio J. Marasco Jr.,1,{ddagger} Donna Rattendi,3 and Cyrus J. Bacchi3,4

Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263,1 Program of Molecular Pharmacology and Cancer Therapeutics, Roswell Park Division, State University of New York at Buffalo, Buffalo, New York 14263,2 Haskins Laboratory,3 Department of Biological and Health Sciences, Pace University, New York, New York 10038-15024

Received 6 April 2007/ Returned for modification 26 June 2007/ Accepted 13 October 2007

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.

* Corresponding author. Mailing address: Grace Cancer Drug Center, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: (716) 845-4582. Fax: (716) 845-4445. E-mail: janice.sufrin{at}roswellpark.org

{triangledown} Published ahead of print on 22 October 2007.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

{ddagger} Present address: Department of Mathematics and Natural Sciences, D'Youville College, 320 Porter Avenue, Buffalo, NY 14201.

Antimicrobial Agents and Chemotherapy, January 2008, p. 211-219, Vol. 52, No. 1
0066-4804/08/$08.00+0     doi:10.1128/AAC.00480-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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