Novel and unusual nucleosides as drugs

Kolb, Vera M.

doi:10.1007/978-3-0348-8861-5_8

Cited by 13 publications

(8 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Examples of the many nucleobases and nucleosides with therapeutic qualities include 6-thioguanine, 5-fluorouracil, and 6-mercaptopurine in leukemia and cancer therapy; AraA, acyclovir, and ganciclovir against DNA viruses; ribavirin and 3-deazaadenosine against RNA viruses; 3Ј-azido-3Ј-deoxythymidine (AZT) and 3Ј-thia-2Ј,3Ј-dideoxycytidine (3TC) against retroviruses; and allopurinol and pyrimethamine against protozoan infections (34). The efficacy and selectivity of these drugs is at least in part dependent on the expression of specific transporters by the target cell (22,35).…”

Section: Discussionmentioning

confidence: 99%

Different Substrate Recognition Motifs of Human and Trypanosome Nucleobase Transporters

Wallace

Candlish

Koning

2002

Journal of Biological Chemistry

142

View full text Add to dashboard Cite

The therapeutic index of antimetabolites such as purine analogues is in large part determined by the extent to which it is selectively accumulated by the target cell. In the current study we have compared the transport of purine nucleobase analogues by the H2 transporter of bloodstream form Trypanosoma brucei brucei and the equilibrative nucleobase transporter of human erythrocytes. The H2 transporter forms hydrogen bonds with hypoxanthine at positions N3, N7, N(1)H, and N(9)H of the purine ring, with apparent ⌬G 0 of 7.7-12.6 kJ/mol. The transporter also appears to H-bond with the amine group of adenine. The human transporter forms hydrogen bonds that form to (6)NH 2 and N1 of adenine. An H-bond is also formed with N3 and the 6-keto and amine groups of guanine but not with the protonated N1, thus explaining the low affinity for hypoxanthine. N7 and N9 do not directly interact with the human transporter in the form of H-bonds, and it is proposed that -stacking interactions contribute significantly to permeant binding. The potential for selective uptake of antimetabolites by the parasite transporter was demonstrated.Purine and pyrimidine antimetabolites are widely used to combat a variety of infectious diseases and other pathologies. However, many therapies suffer from a lack of selectivity, leading to severe side effects. The selectivity and efficacy of purine antimetabolites is achieved at two levels: the cell-surface transporters that mediate access to the cell, and the enzymes of the purine metabolic pathways that convert the prodrug to the cytotoxic metabolite, usually a nucleotide analogue. This report elucidates the mechanisms of selectivity at the transporter level.We have chosen Trypanosoma brucei, the etiological agent of sleeping sickness, as a model organism, because it lives freely in the host bloodstream rather than within a host cell. Therefore, the accumulation of most nucleobase and nucleoside drugs depends exclusively on the transporters expressed by the parasite itself. In addition, African trypanosomes are entirely dependent on purine salvage because they lack the capacity for de novo synthesis (1), and they consequently express several proton symporters that actively accumulate nucleosides (2, 3) and nucleobases (4 -6). For trypanosomes, nucleobases may make more efficient drugs than their corresponding nucleosides, because purine ribonucleosides are rapidly hydrolyzed in bloodstream form T. brucei, limiting their incorporation into the nucleotide pool (7). In contrast, nucleobases are efficiently assimilated by one-step reactions of phosphoribosyltransferases for adenine, hypoxanthineguanine, and xanthine (8). The current study therefore focuses on the main T. brucei brucei and human nucleobase transporters. This approach will allow the identification of groups that determine high affinity uptake by either the trypanosome or the cells of its mammalian host. The escalating epidemic of African trypanosomiasis (9) and the onset of drug resistance (10) necessitate the development of a new genera...

show abstract

Section: Discussionmentioning

confidence: 99%

Different Substrate Recognition Motifs of Human and Trypanosome Nucleobase Transporters

Wallace

Candlish

Koning

2002

Journal of Biological Chemistry

142

View full text Add to dashboard Cite

show abstract

“…Moreover, these transporters mediate the internalization of many purine and pyrimidine antimetabolites used as antibiotics, anticancer or antiviral agents, in chemotherapy against protozoan infections, the treatment of gout or in the prevention of organ rejection (10,36,37).…”

Section: Discussionmentioning

confidence: 99%

Cloning, Heterologous Expression, and in Situ Characterization of the First High Affinity Nucleobase Transporter from a Protozoan

Burchmore

Wallace

Candlish

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

While multiple nucleoside transporters, some of which can also transport nucleobases, have been cloned in recent years from many different organisms, no sequence information is available for the high affinity, nucleobase-selective transporters of metazoa, parazoa, or protozoa. We have identified a gene, TbNBT1, from Trypanosoma brucei brucei that encodes a 435-residue protein of the equilibrative nucleoside transporter superfamily. The gene was expressed in both the procyclic and bloodstream forms of the organism. Expression of TbNBT1 in a Saccharomyces cerevisiae strain lacking an endogenous purine transporter allowed growth on adenine as sole purine source and introduced a high affinity transport activity for adenine and hypoxanthine, with K m values of 2.1 ؎ 0.6 and 0.66 ؎ 0.22 M, respectively, as well as high affinity for xanthine, guanine, guanosine, and allopurinol and moderate affinity for inosine. A transporter with an indistinguishable kinetic profile was identified in T. b. brucei procyclics and designated H4. RNA interference of TbNBT1 in procyclics reduced cognate mRNA levels by ϳ80% and H4 transport activity by ϳ90%. Expression of TbNBT1 in Xenopus oocytes further confirmed that this gene encodes the first high affinity nucleobase transporter from protozoa or animals to be identified at the molecular level.

show abstract

“…[1] Isatin derivatives [2] have been found to possess a wide variety of pharmacological properties as follows-monoamine oxidase inhibitor, [3] antibacterial [4] and antiviral activities. [1] Isatin derivatives [2] have been found to possess a wide variety of pharmacological properties as follows-monoamine oxidase inhibitor, [3] antibacterial [4] and antiviral activities.…”

Section: Synthesis and Antiviral Evaluation Of Isatin Ribonucleosidesmentioning

confidence: 99%

Synthesis and Antiviral Evaluation of Isatin Ribonucleosides

Oliveira¹,

Torres²,

Garden³

et al. 2002

Nucleosides, Nucleotides and Nucleic Acids

View full text Add to dashboard Cite

A series of novel substituted isatin ribonucleosides 3b-3f were synthesized in good yields by a TMSOTf catalysed coupling reaction between the silylated nitrogenated base (1b-1f) and 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose (2). Isatin nucleoside 3a previously reported was also prepared using this method giving high yield. From the compounds tested, ribonucleoside 3f proved to be the most active one when assayed for antiviral activitiy on HSV-1 infected cells, leading to 66% of inhibition of virus yield. All the isatin derivatives tested did not inhibit HIV-1 Reverse Transcriptase (RT) activity.

show abstract

Novel and unusual nucleosides as drugs

Cited by 13 publications

References 68 publications

Different Substrate Recognition Motifs of Human and Trypanosome Nucleobase Transporters

Different Substrate Recognition Motifs of Human and Trypanosome Nucleobase Transporters

Cloning, Heterologous Expression, and in Situ Characterization of the First High Affinity Nucleobase Transporter from a Protozoan

Synthesis and Antiviral Evaluation of Isatin Ribonucleosides

Contact Info

Product

Resources

About