AZT

Basically, AZT is anabohcaHy phosphorylated to AZT mono-, di-, and tri-phosphates by various enzymes (kinases) of a target ceU (159). AZT-triphosphate competes with other phosphorylated pyrimidine nucleosides for incorporation into HIV DNA by the viral reverse transcriptase. Incorporation of the AZT-triphosphate into reverse transcriptase results in viral DNA chain termination. Reverse transcriptase is essential in the repHcative cycle of HIV. 

Another dideoxypyrimidine nucleoside active against human immunodeficiency vims is 3 -azido-2/3 -dideoxyuridine [84472-85-5] (AZDU or CS-87, 64) C H N O. Since its synthesis, (167) CS-87 has been identified as a promising antiHIV agent (168) and is currentiy undergoing phase I clinical trials in patients with AIDS and AIDS-related complex. It appears to be less potent than AZT against HIV in a peripheral blood mononuclear (PBM) cell screening system and in MT-4 cell lines. This lower activity in PBM cells appears to be related to a lower affinity of CS-87 for the enzyme responsible for its initial phosphorylation (169). However, CS-87 has significantly lower toxicity on bone marrow cells than AZT (170) and penetration of the CNS as a 5 -dihydropyridine derivative. 

AH 2/3 -dideoxynucleoside analogues are assumed to be intraceUularly phosphorylated to thek active form (5 -triphosphate), and then targeted at the vims-associated reverse transcriptase. The rate and extent of the 2 /3 -dideoxynucleosides phosphorylate to the 5 -triphosphates may be of equal or greater importance than the differences in the relative abiUties of these 5 -triphosphates to inhibit the vkal reverse transcriptase (171). At the level of vkal reverse transcriptase, the 5 -triphosphate of AZT and other dideoxynucleosides may either serve as a competitive inhibitor with respect to the natural substrates or may act as an alternate substrate, thus leading to chain termination (172). 

Phosphonylmethoxyethyl)adenine [106941-25-7] (PMEA, 65) (173), synthesized in 1987 (174), is foremost among the acycHc nucleoside analogues proven to be effective inhibitors of HIV-1 repHcation. The in vitro potency and selectivity of PMEA is comparable to the antiHIV-1 potency and selectivity of 2, 3 -dideoxy-adenosine (175). Although less potent than AZT in vitro PMEA, CgH22N 04P, is markedly more potent than AZT as an in vivo inhibitor of retrovims repHcation (176). In fact, PMEA has proven efficacious in the treatment of murine, feline, and simian retrovims infections in mice, cats, and monkeys, respectively. 

CarbocycHc 2/3 -didehydro-2/3 -dideoxyguanosine [118353-05-2] (carbovk, CBV, 66), C H 2N502, synthesized in 1988 (177), is a promising candidate for the chemotherapy of AIDS. CBV inhibits HIV repHcation and HIV-induced cytopathic effects in a variety of human T-lymphoblastoid ceU lines at concentrations approximately two hundred- to four hundredfold below its cytotoxic concentrations (177). CBV is as effective as AZT and DDC in reducing the expression of vkal antigen in HIV-infected CEM ceUs (177). The antivkal potency and selectivity of carbovk is comparable to the anti-HIV-1 potency and selectivity of 2/3 -dideoxyadenosine (178). The exact mode of antivkal action of carbovk has not yet been elucidated, but may be the modulating effect of intraceUular nucleotides on 5 -nucleotidase activity (179). 

P-(P -D-aiabinofuianosyl)-9ff-puiin-6-amine] [5536-17 ], an antineoplastic and antiviral compound known by a number of trade names, and AZT (3 -azido-3 -deoxythymidine [30516-87-1]) an antiviral compound also known by a variety of trade names (see Antiviral agents). 

Neopentanoyl chloride has been used in the preparation of AZT (56), which is used in the treatment of acquired immune deficiency syndrome (AIDS) (see Antiviral agents). 

Other nucleosides such as 2, 3 -dideoxyinosine (ddl) also block the action of reverse transcriptase and are often combined with AZT in drug cocktails. Using a mixture of drugs makes it more difficult for a virus to develop resistance than using a single drug. 

WirkungS Azt, /. kind of action mode of acting mode of operation, -bereich, m. range of action or effect, effective range, -bombe, /. demolition bomb, high-capacity bomb, -dauer, /. period (or duration) of action or effect. 

Molecular similarity searching provides the possibility of finding unrelated but functionally analogous molecules. This is a very nice feature because many distinct structures in contact with a CSP often share the same active sites. The compounds which have a structure similar to the structure of the sample query can be displayed automatically in order of their similarity. The degree of similarity is measured by a numerical value on a scale of 0 to 100 that may be included in the output form. An example of a similarity search is shown in Fig. 4-3. In this example, a search is being performed for the AZT with a similarity value >65 %. 

Fig. 4-3. Molecular similarity searching of AZT in CHIRBASE. (Compounds reported in Refs. [7-12].)...

Meyer PR, Matsuura SE, Mian AM, So AG, Scott WA (1999) A mechanism of AZT resistance an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase. Mol Cell 4 35 3... 

Patel BA, Boudinot FD, Schinazi RF, Gallo JM, Chu CK (1990) Comparative pharmacokinetics and interspecies scaling of 3 -azido-3 -deoxythymidine (AZT) in several mammalian species. J Pharmacobiodyn 13 206-211... 

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