AZT-resistant strain

Hydroarylation of alkynoates with phenols is applied to the synthesis of calanolides A 17 and B 18, which are active against AZT-resistant strains of HIV-1.163 The key step is the palladium-catalyzed coumarin formation reaction, as shown in Scheme 18. 

Flavin et al. reported on the anti-HTV-1 activity of synthetic ( )-calanolide A and resolved (-l-)-calanolide A (1) and ( )-calanolide A [( )- ] against both strains and clinical isolates of HTV-l shown in Table 8-1. The cytotoxicity in the different ceU lines examined of the ( )-l, (+)-l, and ( )-calanolide A was approximately the same levels. However, only (+)-l exhibited HTV-l activity, which was similar to the data reported for the namral product [(+)-calanolide A, (1)], and ( )-l was inactive. Both the AZT-resistant strain G910-6 and the pyridinone-resistant strain A17 were inhibited by ( )-l and (-T)-l. The (-T)-l was more active than ( )-I against the AZT-resistant strain G910-6 with an EC50 value of 0.027 and 0.108 pM, respectively. It was interesting that the activity of ( )-l... 

Interestingly, AZT-resistant strains were found to be cross-resistant to related S -azido-substituted dideoxynucleosides including AzddU (92) and AzddG (102) but, in general, retained their sensitivity to those dideoxynucleosides without an azido group, most notably 2, 3 -dideoxycytidine (96) and 2, 3 -dideoxyinosine (101) [238-240]. This observation suggests that the 3 -unsubstituted nucleosides should be effective in the treatment of infection due to AZT-resistant strains, although the clinical implications of resistance to AZT are as yet unknown, and strains resistant to 2, 3 -dideoxycytidine... 

Efavirenz (DMP 266) (1) is an effective non-nucleoside inhibitor of reverse transcriptase of the human immunodeficiency virus (HIV) recently registered by the US Food Drug Administration (FDA) for treatment of the acquired immunodeficiency syndrome (AIDS).1 2 3 Inhibition of HIV reverse transcriptase by nucleosides like azidothymidine (AZT) (2) is a proven therapy for delaying the progression to AIDS. However, the rapid viral mutation to resistant strains requires the development of new therapeutic agents. The recent development of both protease inhibitors and non-nucleoside reverse transcriptase inhibitors offers hope of effective treatment especially when coadministered. 

Rosowsky, A., Eu, H., Pai, N., Mellors, J., Richman, D.D.. and Hostetler, K.Y., Synthesis and in vitro activity of long-chain 5 -0-[(alkoxycarbonyl)phosphinyl]-3 -azido-3 -deoxythymidines against wild-type and AZT- and foscamet-resistant strains of IIIV-I. J. Med. Chem., 40, 2482, 1997. 

Several reviews have been published dealing with natural products-derived antiviral compounds [11,12,16-23]. Presently, there are only two plant-derived compounds under clinical development [2]. (+)-Calanolide A (12) is a C22 coumarin isolated from the Malaysian rainforest tree, Calophyllum langigerum by the U.S. National Cancer Institute [2]. It shows a potent HIV-RT inhibitory activity [2]. In vitro studies of 12 demonstrated activity against HIV-1 including AZT and other nonnucleoside RT inhibitors-resistant strains. It also shows synergistic anti-HIV activity in combination with nucleoside RT inhibitors 7, 8 and 9 [2]. To overcome the difficulty of supply of 12, its total chemical synthesis was accomplished [2]. In June 1997, clinical development of 12 was started as a potential drug for treatment of AIDS. A single -center 7-month U.S. phase la clinical trial of 12 was started to assess its safety and... 

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]. 

The p-triphosphate derivatives of ATP and AZT were synthesised and shown to inhibit DNA polymerase activity even using NRTI and NRTII resistant strains. dNTPs have been labelled at the y-phosphate by fluorophores for use in real-time PCR ° and as a method for the labelling of microtubules.Using a method known as compartmentalised selfreplication (CSR), the DNA polymerase from Pyrococcus furiosus has been evolved such that dNTPs bearing a fluorophore attached at the y-phosphate are better substrates.Ferrocene, attached via a linker as a y-phosphor-amidate has been used in an electrochemical assay to study kinase-catalysed phosphorylation reactions.The photoactivatable diazirine derivative (37) also attached to the y-phosphate was shown to be a specific label for tropomysin even in the presence of other actinomysin components. 

The potent activity of D-DOT against AZT- and 3TC-resistant HIV-1 strains together with its excellent pharmacokinetic profile in rhesus monkeys suggest that further development of D-DOT towards HIV-1 chemotherapy is warranted (Asif et al. 2007). 

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