John K. Buolamwini* Pages 35 - 66 ( 32 )
A survey of structure-activity relationships and potential therapeutic applications of nucleoside transport inhibitors is presented. Among the two equilibrative (facilitated diffusion), and five concentrative (sodium-dependent) nucleoside transporters identified in mammalian cells, only the equilibrative transporters (es and e1) and one concentrative transporter (cs) can be effectively blocked by one or more of the nucleoside transport inhibitors discovered to date. A structurally diverse array of compounds have been shown to exert nucleoside transport inhibitory activity to varying degrees. The most important of these are i) nucleoside analogs of which s6-(4-nitrobenzyl)mercaptopurine riboside (NBMPR, nitrobenzylthioinosine) is the prototype, ii) pyrimidopyrimidine and pteridine derivatives of which dipyridamole (Persantine) is the prototype, and iii) alkyl- and cycloalkyldiamine and piperazine calcium channel antagonists of which dilazep and lidoflazine are the representatives, respectively. All of these are effective inhibitors of the es transporter, but dipyridamole is also a potent inhibitor of the ei transporter with variable activity depending on the cell type. Surprisingly, NBMPR and dipyridamole are also potent inhibitors of the newly identified cs concentrative transporter in fresh leukemia cells from patients. Not only does the es inhibitory potency of these compounds depend on tissue type, but it also varies widely among different mammalian species.
Nucleoside transport inhibitors have potential for therapeutic uses in 1) adenosine potentiation in cardioprotection and cerebroprotection in ischemic heart disease and stroke, respectively, 2) the modulation of the effects of antimetabolite anticancer and antiviral agents, and 3) host tissue protection in chemotherapy with cytotoxic nucleosides. Additional areas of potential therapeutic application of NT inhibitors include kidney transplantation, analgesia and hypertension. Most of the compounds in the present repertoire of potent NT inhibitors do not meet the requisite pharmacological profiles for successful clinical application, which calls for the discovery of better inhibitors. Advances are being made in the molecular cloning and functional expression of nucleoside transporters that augur well for future drug design efforts.