Dideoxynucleoside analogs

Kazi S, Cohen PR et al (1996) The diffuse infiltrative lymphocytosis syndrome. Clinical and immunogenetic features in 35 patients. Aids 10(4) 385-391 Keilbaugh SA, Prusoff WH et al (1991) The PC12 cell as a model for studies of the mechanism of induction of peripheral neuropathy by anti-HIV-1 dideoxynucleoside analogs. Biochem Pharmacol 42(1) R5-R8... 

In the past, various serendipitous discoveries have capitalized on the differential expression of enzymes by host and viral infected cells. For example, the prodrug Acyclovir, used widely for the treatment of herpes simplex and herpes zoster infections, is selectively activated through phosphorylation by viral thymidine kinase to acyclovir monophosphate which is then converted to the triphosphate, which inhibits DNA polymerase, by host cellular enzymes. Similarly several 2, 3 -dideoxynucleoside analogs such as Zidovudine (azidothymidine, AZT) and 2, 3 -didehydro-3 -deoxythymidine (D4T) have potent antiviral activity against human immunodeficiency vims (HIV). These compounds are selectively phosphoiylated intracellularly to the 5 -triphosphate derivatives which inhibit the viral reverse transcriptase. 

Zalcitabine toxicides are similar to those of the other dideoxynucleoside analogs didanosine and stavudine. Severe peripheral neuropathy has been reported in up to 15% of patients. Peripheral neuropathy is dose related and more common with preexisting HIV-associated neuropathy and advanced HIV disease. This is a symmetrical dislal sensory neuropathy that begins in the feet but may progress to a stock-ing/glove distribution. Other specific risk factors for neuropathy include alcohol consumption, diabetes, and low vitamin Bi2 concentrations. If the dmg is stopped as soon as symptoms appear, the neuropathy usually stabilizes and should improve or resolve. Pancreatitis occurs rarely with zalcitabine therapy and appears to be less frequent than with didanosine. 

In an earlier study, Balayiannis et al. [ 130] developed a capillary zone electrophoresis method for the analysis of a series of novel synthetic dideoxynucleoside analogs with potential anti-HIV activity. The method was readily applied for purity testing as well as to resolve cis and trans diastereomers. The purity and separation of diastereomers of such analogs are of great importance for further testing of their biological and pharmacological activity. 

M. Nasr, C. Litterest, J. McGowan, Computer-assisted sructure-activity correlations of dideoxynucleoside analogs as potential anti-HIV drugs. Antiviral Res. 14 125 (1990). 

Phosphonoformate is a pyrophosphate analog and inhibits both DNA polymerases and reverse transcriptase. However, toxicity may prevent longterm treatment of AIDS patients. Amantadine has a narrow antiviral specificity. It specifically inhibits initiation of the replication of influenza virus RNA of type A (but not of type B). Active only against retroviruses, 3 -azidothymidine is a reverse transcriptase inhibitor, which acts by a chain termination mechanism. It was synthesized in the early 1960s but only recently has been used in treatment of AIDS victims. More recently a series of 2, 3 -dideoxynucleosides, such as dideoxyinosine, have also been used.d Acyclic phosphonates, such as phosphonylmethoxypropyladenine, avoid the need for metabolic phosphorylation of the drug.6... 

Four incubation mixtures are set up, each containing the DNA template, a specific DNA primer, E. coli DNA polymerase I and all four deoxyribo-nucleoside triphosphates (dNTPs). In addition, each mixture contains a different dideoxynucleoside triphosphate analog, ddATP, ddCTP ddGTP or ddTTP. Incorporation of a dideoxy analog prevents further elongation and so produces a chain termination extension product. The products are electrophoresed on a polyacrylamide gel and the DNA sequence read from the band pattern produced. 

A number of nucleotide analog compounds function by blocking further chain growth at the replication fork. The 2 3 -dideoxynucleosides can be converted to the triphosphates (ddNTPs). In the case of bacteria, these are incorporated onto the 3 -hydroxyl end of a growing DNA chain, and because the new end now lacks a 3 hydroxyl, no further additions can occur. They are used in conjunction with DNA polymerase I in the dideoxy method of Sanger for determining DNA sequences. 

In summary, the nucleoside phosphorylases provide a regio- and stereo-specific route for nucleoside synthesis which is applicable to nucleoside analogs which are modified in either the base or the sugar moiety. These processes provide good yields of products in most cases without the extensive protection and deprotection steps involved in traditional chemical synthesis of nucleosides. Application of this strategy to the synthesis of 2 -deoxy- and 2, 3 -dideoxynucleosides was reported with the use of N-deoxyribosyl transferase from Lactobacillus species1301, 312). 

Several 2, 3 -dideoxynucleosides are given to patients with HIV. These analogs include 3 -azido-2, 3 -dideoxythymidine (zidovudine, AZT), 2, 3 -dideoxycytidine (zalcitabine, ddC), 2, 3 -dideoxyinosine (didanosine, ddl), 2, 3 -didehydro-3 -deoxythymidine (stavudine, d4T), and (-)-2 -deoxy-3 -thiacytidine (lamivudine, 3TC). A related molecule is abacavir (ABC), which contains a cyclopentene-methanol moiety instead of the dideoxyribose moiety of the above-mentioned... 

The 2, 3 -dideoxynucleosides can be used as reagents to inhibit DNA replication. These analogs must be converted to dideoxynucleoside triphosphates in order to have a measurable effect on DNA synthesis. When incorporated into a growing DNA chain, a single dideoxyribonucleoside residue can effectively block subsequent chain extension. 

Although numerous analogs of dideoxynucleosides derived from the natural nucleosides have been synthesized since the discovery of their antiviral activity, the synthesis of structures regioisomeric with the known active "natural" dideoxynucleosides (Scheme 5, Stracture A) have received much less attention. One such class of compounds... 

Dideoxynucleosides and 2, 3 -unsaturated nucleoside analogs are of interest as potential chain terminators of DNA biosynthesis. 2, 3 -Dldeoxycytidlne and the corresponding 2, 3 -unsaturated nucleoside were synthesized via an "epoxy" nucleoside intermediate. The synthesis of 2, 3 -dehydro-5-fluoro-2 -deojqruridine (DHFUDR, XIII) was achieved by... 

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