6-Benzylthioinosine analogues: Promising anti-toxoplasmic agents as inhibitors of the mammalian nucleoside transporter ENT1 ( es)

• Published in: Biochemical pharmacology Vol. 71; no. 1; pp. 69 - 73
• Main Authors: Gupte, Amol, Buolamwini, John K., Yadav, Vikas, Chu, Chung K., Naguib, Fardos N.M., el Kouni, Mahmoud H.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 19-12-2005; Elsevier Science
• Subjects: 6-Benzylthioinosine analogues; Animals; Antiprotozoal Agents - pharmacology; Biological and medical sciences; Chemotherapy; Equilibrative Nucleoside Transporter 1 - antagonists & inhibitors; Human protozoal diseases; Humans; Infectious diseases; K562 Cells; Medical sciences; Nucleoside transport inhibitors; Parasitic diseases; Pharmacology. Drug treatments; Protozoal diseases; Toxoplasma; Toxoplasma - drug effects; Toxoplasmosis; Toxoplasma; 6-Benzylthioinosine analogues; 5-(SAENTA); Chemotherapy; Nucleoside transport inhibitors; Protozoa; Apicomplexa; Protozoal disease; ENT1 nucleoside transporter; Biological transport; Parasitosis; Infection; Vertebrata; Toxoplasma 6-Benzylthioinosine analogues Nucleoside transport inhibitors Chemotherapy; Mammalia; Treatment; Toxoplasmosis; Analog; Nucleoside; Inhibitor
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2005.10.031

Certain 6-benzylthioinosine analogues have been identified as potential chemotherapeutic agents against
Toxoplasma gondii in cell culture and animal models. These compounds are selectively transported and metabolized by toxoplasma infected, but not uninfected, cells. In sharp contrast to mammalian nucleoside transporters, the toxoplasma adenosine/purine transporter (TgAT) allows the transport of these 6-benzylthioinosine analogues into infected cells. After entering the infected cell, these compounds act as subversive substrates for toxoplasma, but not the host, adenosine kinase (EC.2.7.1.20). Hence, 6-benzylthioinosine analogues become toxic to toxoplasma infected cells, but not uninfected host cells or animals. The basis for the lack of uptake of the anti-toxoplasmic 6-benzylthioinosines by uninfected host cells is currently unknown. These anti-toxoplasmic 6-benzylthioinosines may not be substrates for the mammalian nucleoside transporters or they may act as inhibitors of these transporters. Previous studies have shown that some 6-benzylthioinosines are inhibitors of the mammalian nucleoside transporter ENT1 (
es). Therefore, we examined the efficacy of promising anti-toxoplasmic 6-benzylthioinosines as inhibitors of ENT1 (
es) in an effort to elucidate the basis for the lack of uptake of anti-toxoplasmic 6-benzylthioinosines by uninfected host cells. The results showed that these compounds are inhibitors of ENT1 (
es). In general, electron-withdrawing substituents at the
ortho,
meta or
para positions of the benzyl ring improved binding. The most potent inhibitors identified were
m- and
p-nitro-6-benzylthioinosine, which had
K
i
values in the subnanomolar range. Therefore, anti-toxoplasmic 6-benzylthioinosines are not only selectively toxic to parasites and parasite infected cells, they are also inhibitors of nucleoside transport in host cells. This inhibition of the host nucleoside transport is an added advantage for these 6-benzylthioinosine analogues as anti-toxoplasmic agents. Inhibitors of nucleoside transport in mammalian cells can selectively protect the host from the toxicity of toxic purine nucleosides that may be used in future combination therapy against toxoplasmosis or from metabolites of the 6-benzylthioinosine analogues that may be released by the destruction of infected cells. These findings further advance the rationale for developing 6-benzylthioinosine analogues as selective therapeutic agents for the treatment of toxoplasmosis.