3 -Azido-3 -deoxythymidine derivatives

Schwendener RA, et al. New lipophilic acyl/alkyl dinucleoside phosphates as derivatives of 3 -azido-3 -deoxythymidine Inhibition of HIV-1 replication in vitro and antiviral activity against Rauscher leukemia virus infected mice with delayed treatment regimens. Antivir Res 1994 24 79. 

Zidovudine is 3 -azido-3 -deoxythymidine, and is a derivative of deoxythymidine in which an azide group replaces the 3 -hydroxyl. It is better... 

D. Synthesis and anti-HIV activity of some novel phosphorodiamidate derivatives of 3 -azido-3 -deoxythymidine (AZT). Antiviral Chem. Chemother., 1991, 2 35-39. 

Since 3 -azido-3 -deoxythymidine (AZT, Zidovudine, Retrovir) was identified by Mitsuya and co-workers as a potent antiviral agent against immunodeficiency virus type I (HIV-1), a number of other nucleosides have been found to inhibit HIV-I in vitro. The most important representatives are the 2, 3 -didcoxy nucleosides ddl, ddG, and ddA as well as their corresponding 2, 3 -didehydro derivatives. ... 

A chemoenzymatic synthesis of the P-a-methyl 2 -deoxynucleoside triphosphates 122 has been described which involves reaction of the 5 -0-(methylpho-sphonyl)-N-protected nucleosides with pyrophosphate in the presence of CDI. Removal of the base protection by treatment with penicillin amidase gave compounds 122 leaving the labile a-methylphosphonate intact. A number of 2 -deoxythymidine 5 -triphosphate and 3 -azido-2, 3 -dideoxythymidine 5 -tripho-sphate analogues (123) containing a hydrophobic phosphonate group have also been synthesised and evaluated as substrates for several viral and mammalian polymerases. Some y-ester (124) and y-amide (125) derivatives of dTTP and 3 -azido-2, 3 -dideoxythymidine 5 -triphosphate (AZTTP) were also synthesized and studied. The y-phenylphosphonate triphosphate 126 and its conjugation to biotin and fluorescein labels has also been described. 

Chu CK, Bhadti VS, Doshi KJ, et al. Brain targeting of anti-HIV nucleosides—synthesis and in vitro and in vivo studies of dihydropyridine derivatives of 3 -azido-2, 3 -dideoxyuridine and 3 azido-3 -deoxythymidine. J Med Chem 1990 33 2188-2192. 

Wang reported the synthesis of dinucleosides, dinucleotides and oligodeoxynucleotides containing 3 -amino-3 -deoxy-3 -N,5 -(i )-C-ethylenethymidine. The bicyclothymidine was prepared from 3 -azido-3 -deoxythymidine and condensed with 5 -0-(H-phosphonyl)thymidine in the presence of triethylamine and 5 -0-(p-nitrophenoxycarbonyl)thymidine derivatives... 

W. E. G. Muller Application of avarol and avarone derivatives in combination with 3 -azido-3 -deoxythymidine for antiviral therapy, Ger. Offen., DE 3821676 Al, 8th February 1990. 

A nucleoside derivative that has been very much in the news is 3 -azido-3 -deoxythymidine (AZT). This compound has been widely used in the treatment of AIDS (acquired immune deficiency syndrome), as has 2 -3 -dideoxyinosine (DDI). Propose a reason for the effectiveness of these two compounds. Hint How might these two compounds fit into a DNA chain ... 

Since the report in 1986 that 3 -azido-3 -deoxythymidine (AZT, now called zidovudine) (152) was effective against human retroviruses <86GEP(O)3608606>, a plethora of ribonucleoside derivatives have been prepared and their pharmaceutical properties studied and reported. Only a few representative examples (152)-(164) are discussed here space limitations do not allow for a comprehensive overview. 

A variety of derivatives of 3 -azido-2, 3 -dideoxynucleosides have been prepared in order to study the mechanism of action, to improve the transport of the drug or to obtain more selective compounds. These include tritium labelled derivatives of AZT [64, 65], various derivatives of 3 -azido-3 -deoxythymidine triphosphate [66, 67] and quaternary salts and dihydropyridine derivatives of AZT [68]. 

In their initial work, these authors reported a poten-tiometric study on the ability of the Zn " " complex of cyclen (80) to interact with the deoxyribonucleotides 2 -deoxyadenosine (dA), 2 -deoxyguanosine (dG), 2 -deoxy-cytidine (dC), 2 -deoxythymidine (dT), uridine (U), and 3 -azido-3 - deoxythymidine (AZT). [Zn(80)] " had a good selectivity for dT, U, AZT, and the related derivatives Ff (ftorafur, 5-fluoro-l-(tetrahydro-2-furyl)uracil), and... 

Azido-2-deoxy-p-D-arabinofuranosyl)-cytosine (cytarazid) and -thymine have been prepared in an improved way involving Mitsunobu reaction at C-2 of a 3 , 5 -0-TIPDS derivative, and 2 -azido-3 -deoxythymidine has been made from epoxide intermediates. ... 

The 3 -deoxy derivative of 4 -azidothymidine was a prime synthetic target based on the anti-HIV activity present in a great many 3 -deoxynucleosides. However, a simple direct synthesis of 4 -azido-3 -deoxythymidine was not feasible. For instance, commonly used deoxygenation methods which rely on hydrogenation or a radical mechanism are not compatible with an azido group and, therefore, could not be used on 4 -azidothymidine. 

Another contrast with the 2, 3 -dideoxynucleoside family of HIV inhibitors is elucidated by the data in Table 3. Potent activity among the 4 -derivatives is maintained even when a nonpolar substituent (e.g., methyl) is present. While in the case of 2, 3 -dideoxynucleosides, in order to maintain activity, the 3 a position must be hydrogen or certain electronegative groups like azido, fiuoro, or thiol. For example, 3 -deoxy-3 -methylthymidine and 3 -(propyl-2-ene)-2, 3 -dideoxyuridine are known to be inactive against HIV. Furthermore, while 3 -cyano-3 -deoxythymidine is inactive, 4 -cyano-thymidine is among the most potent nucleoside inhibitors known. Thus, the activity elicited by a substituent at the 3 -position of thymidine is not at all predictive of the activity to be expected when the same substituent resides at the 4 -position. 

Several 2,5 -anhydro analogues of 3 -azido-2, 3 -dideoxyuridine (1, AZDU), 3 -azido-3 -deoxythymidine (2, AZT), 3 -azido-5-bromo-2, 3 -dideoxyuridine (5), 3 -azido-2, 3 -dideoxy-5-iodouridine (6), and the 3 -azido derivative of 2 -deoxy-5-methylisocytidine, compounds 38-42, have been synthesized and evaluated against human immunodeficiency virus (HIV-1) and Rauscher-murine leukemia virus (R-MuLV). in general, the parent compounds 1,2,5, and 6 were approximately 1.8 to 6 times more active against HIV-1 than their corresponding 2,5 -anhydro derivatives (compounds 38-41, Table 3). Compounds 38-41 have significant antiviral activity with respective EC50 values of 4.95,0.56, 28, and 27.1 pM. 3 -Azido-2, 3 -dideoxy-5-methylisocytidine (42) also demonstrated anti-HIV-1... 

In order to study the molecular basis of the antiviral activity, as well as the inhibitory activity to mitochondrial DNA synthesis concerning these anhydro nucleoside derivatives, [2-l C]2,5 -anhydro-3 -azido-3 -deoxythymidine ([2-l C]anhydro-AZT) and [2-l C]2,5 -anhydro-3 -azido-2, 3 -dideoxy-5-iodouridine ([2-l C]anhydo-5-I-AZDU) have also been... 

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