Azido AIDS treatment

The most potent and selective anti-HIV agents, which seem to act through inhibition of reverse transcriptase, are the 2, 3 -dideoxynucleosides [7, 9, 10]. 3 -Azido-3 -deoxythymidine (Zidovudine, AZT, 7e) has been licensed for AIDS treatment in humans. 2, 3 -Dideoxyadenosine (109a), 2, 3 -dideoxyinosine (109c) and 2, 3 -dideoxycytidine (109d) are undergoing clinical trials in patients with... 

At present there are seven NRTIs, which have been formally approved for the treatment of AIDS 3 -azido-2, 3 -dideoxythymidine (AZT, zidovudine), 2, 3 -dideoxyinosine (ddl, didanosine), 2, 3 -dideoxycytidine (ddC, zalcitabine), 2, 3 -didehydro-2, 3 -dideoxythymidine (d4T, stavudine), (—)-L-3 -thia-2, 3 -dideoxycytidine (3TC, lamivudine), cyclopentenyl V -cyclopropylaminopurine (abacavir, ABC), and (—)-L-5-fluoro-3 -thia-2, 3 -dideoxycytidine ((—)FTC, emtricitabine) (De Clercq 2004a) (Fig. 3). 

AIDS is associated with aberrant lymphocyte production and it has been proposed that Li+ may have a potential role in reversing this. Additionally, 3 -azido-3"deoxythymidine (AZT, zidovudine), an effective inhibitor of viral reverse transcriptase that reduces mortality in AIDS patients, induces hematopoietic suppression in patients resulting in anemia, neutropenia, and overall bone-marrow failure [220]. In murine AIDS, the coadministration of Li+ effectively moderates this toxicity of AZT in vivo [221,222]. There are several case reports where Li+ has been administered to help reduce the hematopoietic suppression in HIV-infected patients taking AZT (for example, see ref. 223). To date, the use of Li+ has been limited to a few weeks of treatment, and varying degrees of success have been achieved nevertheless the outlook in this field is quite hopeful. 

Klecker RW Jr, Collins JM, Yarchoan R, Thomas R, Jenkins JF, Broder S, Myers CE. Plasma and cerebrospinal fluid pharmacokinetics of 3 -azido-3C deoxythymide A novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases. Clin Pharmacol Ther 1987 41 407-12. 

Azathymidine, 3 -azido-3 -deoxythymidine (AZT), after conversion to the corresponding 5 -triphosphate, inhibits viral reverse transcriptase. Hence, AZT is used in the treatment of AIDS (Chapter 25). 

At this time, there is no known cure for AiDS, but progress is being made in delaying the onset of symptoms and prolonging the lives of those infected with HIV. The first advance in treatment came with drugs such as zidovudine, also known as azido-thymine, or AZT. AZT interferes with the ability of HIV to reproduce by blocking the action of reverse transcriptase. As seen by its structure... 

The introduction of an azide functionality with CAN/NaNs as the reagents has been shown to be a useful transformation in organic synthesis. It also offers a convenient protocol for the bis-functionalization of a variety of alkenes. " The treatment of silyl enol ethers with sodium azide and CAN gives the a-azido ketones. The reactions of (substituted)styrenes with sodium azide and CAN in methanol under oxygenated conditions also furnish a-azido ketones (eq 21). With the aid of sodium iodide. 

The addition of hydrazoic acid to a carbodiimide [156] was used by Hiibich in the synthesis of analogues 238 of 3 -azido-3 -deoxythymidine (AZT, 234). AZT (234) is an important drug for the treatment of AIDS that belongs to the class of nucleoside reverse transcriptase inhibitors. AZT (234) was transformed to the carbodiimide 237 through Staudinger reaction with tri-phenylphosphane, followed by reaction of 235 with an alkyl or aryl isocyanate 236. The carbodiimide 237 was then treated with hydrazoic acid in toluene at room temperature for 6 horns to give the desired 5-aminotetrazole 238 in 43-90% yield (Scheme 45) [ 170). 

Nucleoside analogues are widely used as antiviral agents in the treatment in AIDS and AIDS-related complex. The only clinical agent approved in the United States for the treatment of AIDS is 3 -azido-3 -deoxythymidine (AZT) [54,55]. The molecular mechanism of action for this nucleoside includes conversion into its corresponding 5 -monophosphate by the action of cellular nucleoside kinase, followed by stepwise phosphorylation catalyzed by cellular nucleoside kinase to the corresponding 5 -triphosphate. These inhibit proviral DNA synthesis [55-57], catalyzed by HIV reverse transcriptase (RT), and incorporation to the 3 end of the growing DNA chain [55,58]. 

A first application of the new, very efficient asymmetric synthesis of C2-sym-fnetric ketones is described in scheme 7. Since the Center for Disease Control in Atlanta (USA) defined the diagnostic term AIDS (Acquired Immunodeficiency Syndrome) in 1982 [24] only three medications have been authorized for treatment of AIDS 3 -azido-3 -deoxythymidine (AZT, Wellcome, 1987), 2 ,3 -dideoxyinosine (DDI, Bristol Myers Squibb, 1992), and 2 ,3 -dideoxycytosine (DDC, Hoffmann La Roche, 1992), which was recently introduced for limited use. These drugs inhibit the enzyme reverse transcriptase of the human immunodeficiency virus (HIV). Nevertheless, they are only able to prolong somewhat the survival of patients with advanced cases of AIDS. They also lead to considerable side-effects (bone marrow damage, neuropathy) and to the generation of more resistant strains of the virus [25]. 

Replacement of the C-3 hydroxyl group of D-ribonucleosides (or ribonucleotides) with azido or amino groups forms 3 -azidothymidine (AZT) or 3 -amino-3 -deoxythymidine, both of which are used in the treatment of AIDS and cancer. These compounds are synthesized by the mesylation of l-(2 -deoxy-5 -0-trityl-p-D-lyxofuranosyl)-thymidine [100]. The mesyl group is displaced by reaction with lithium azide in DMF at 100°C. The azide can then be catalytically hydrogenated to give the 3 -amino analog (reaction 4.94). 

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