Anti-HIV compounds

To determine if the high in vitro potents of the anti-HIV compound 30 translates into antiviral efficiency in vivo, Datema et al. investigated the inhibition of HIV-1 production and of depletion of human T cells in HIV-1-infected SCID-hu Thy/Liv mice [37]. Steady levels of 100 ng of 30 or higher per mL in plasma resulted in significant inhibition of HIV p24 protein formation. Daily injection of 30 caused a dose-dependent decrease in viral p24 production, and this inhibition could be potentiated by coadministration of AZT (or DDI). This study suggested that 30 alone or in combination with the licensed anti-HIV agents AZT and DDI may decrease the virus load in HIV-infected patients and, by extension, that the infectious cell entry step is a valid target for antiviral chemotherapy of HIV disease. 

So far the most potent anti-HIV compounds in vitro among the macro-cyclic polyamines are dinuclear zinc(II) complex of m-xylyl-biscyclen (23) (by Kimura s group) and p-xylyl-biscyclam (30) (by De Clercq s group). They are active against various strains of HIV-1 and HIV-2, while cytotoxicity towards host MT-4 cells are minimal. Their activity against HIV is selective and they are not active against other viruses tested. Hence, the study of their mode of action is not only useful in developing... 

The rapid identification of anti-HIV compounds in the laboratory following the isolation of the causative virus in 1983 and their subsequent use in treatment was not unexpected. Three decades of previous work has established a scientific basis for the evaluation of antiviral compounds. However, no antiviral yet discovered can cause total blockade of a virus replicating in a cell. The combination of properties of HIV, including latency and antigenic and biochemical variation, is unusual, and the virus represents a daunting challenge for chemotherapy. 

Bourinbaiar AS, Jirathitikal V bow-cost anti-HIV compounds potential apphcation for AIDS therapy in developing countries. Curr Pharm Des 2003 ... 

Brennan TM, Taylor DL, Bridges CG, Leyda JP, Tyms AS. The inhibition of human immunodeficiency virus type 1 in vitro by a non-nucleoside reverse transcriptase inhibitor MKC-442 alone and in combination with other anti-HIV compounds. Antiviral Res 1995 26 173-187. 

Anti-AIDS Agents — Novel Plant Anti-HIV Compounds and Analogs... 

R. W. Jansen, P. Olinga, G. Harms, and D. K. F. Meijer, Pharmacokinetic analysis and cellular distribution of the anti-HIV compound succinylated human serum albumin (Suc-HSA) in vivo and in the isolated perfused rat liver, Pharm. Res. 70 1611-1614 (1993). 

With nearly 20 years of experience on plant-derived natural products, NPRL has identified numerous active anti-HIV compounds including polycyclic diones, saponins, alkaloids, triterpenes, polyphenols, flavonoids and coumarins. Triterpenes have diverse structures and pharmacological activities. 

Example of the bioassay-derived fractionation and isolation of anti-HIV compounds from a typical high priority plant of interest. 

Reports on anti-HIV compounds isolated from marine algae also included proteins. Cyanovirin N, an 11-kDa protein, was identified in the search for antiviral agents [29]. Boyd et al. [30] isolated and sequenced this protein from cultures of the cyanobacterium Nostoc ellipsosporum. Cyanovirin N irreversibly inactivated diverse laboratory strains and... 

Anti-HIV compounds from marine sources also included terpenoids, steroids, peptides and alkaloids. Avarol, Fig. (1) and avarone. Fig. (2), sesquiterpenoid hydroquinones from the marine sponge Dysidea cinerea, are promising anti-HIV compounds [41,42]. Three new... 

Examples of other anti-HIV compounds also included four phlorotannin derivatives, eckol, 8,8 -dieckoI, 8,4 -dieckoI and phlorofucofiiro-eckol A, isolated from the brown alga Ecklonia cava [65]. Among these compounds, 8,8 -dieckol and 8,4 -dieckol exhibited an inhibitory effect on HIV-1 RT and protease. An enzyme kinetic assay... 

Pauwels, R., Balzarini, J., Baba, M., Snoeck, R., Schols, D Herdewijn, P., Desmyter J., and De Clercq, E. (1988) Rapid and automated tetrazolium-basd colorimetric assay for the detection of anti-HIV compounds. J. Virol. Methods 20,309-321. 

Fig. 2. Selective toxicity of EF13 for C8166 cells chronically infected with HIV-1. Uninfected (H9) and chronically HIV-infected (H9RF) cells were cultured for 4 d in the presence of EF13, a potential anti-HIV compound. Cell samples were taken daily and counted in the presence of Trypan blue to determine the proportion of cells that were live and dead. The data points represent the mean of 5 counts plus error bars of one standard deviation.

Ideally it should be possible to add organo-Li and Grignard reagents to prochiral aldehydes and ketones with a chiral catalyst to give alcohols in good enantiomeric excess. This is difficult since the uncatalysed rate of addition is so high. It is possible to add the less reactive lithium acetylides such as 207 to ketones in the presence of stoichiometric lithium derivatives of amino alcohols such as 209, analogues of ephedrine. The product 208 is used in the asymmetric synthesis of the Merck anti-HIV compound Efavirenz.47... 

An alternative diversity-oriented approach for the synthesis of structurally diverse catechins (48), involved the thiourea/AuCl3/AgOTf-catalyzed annulations of aryl epoxides (47) (Scheme 6), with special emphasis on the development of a synthesis protocol to the anti-HIV compound, 8-C-ascorbylepigallocatechin (49). Additionally, Liu etal contains a comprehensive list of references related to the syntheses of various catechins and their analogues. 

Rapid and automated tefrazalium-based calorimetric assay for the detection of anti-HIV compounds, /. Vitrol. Meth., 20 309 (1988). 

Drug resistance mutations are common in patients treated with anti-HIV compounds such as indinavir and nelfinavir. These drugs act by inhibiting HIV protease (HIV PR), one of the essential HIV proteins required for viral growth and infection. These drugs inhibit HIV PR by competing with the peptide substrate to bind in the active site of HIV PR (see Fig. 3.1-1). The rapid emergence of inhibitor resistance is caused, in part, by the low fidelity of... 

An alternative synthesis for the p-xylyl-linked system of type 32, employing a facile de novo procedure has been published (59). Interest in new syntheses for this compound was motivated by the report that this was the compound of choice for further development in the search for new anti-HIV compounds (6). 

Figure 15 The antipolio tetraruthenium cluster [H4Ru4( ) -C6H6)4] + 31 and a vanadocene spermicide/anti-HIV compound 32.

Anti-viral, Anti-cancer and Anti-HIV Compounds... 

---