| Research Abstract |
HIV RNA is reversetranscribed upon infection and subsequently integrated into the genome of the host cell. The provirus thus formed remains latent until certain stimuli activate the transcription of the integrated viral genes. Various viral and host proteins are involved in the transcription of viral genes and are regarded as significant, molecular targets for the treatment of AIDS.
In the present study, we are interested in integrase, HFκB, HIV-EP1, Sp1 and HIV Tat. All of them are zinc proteins or that closely related to zinc.
We have studied on the design and synthesis of zinc-binding artificial molecules containing a pyridine and two chelating side chains, aiming at the inhibition of the function of various zinc proteins. In 2003, we attempted the introduction of aromatic substituents onto the pyridine ring and examined hydroxamic acid in addition to cysteamine as the chelating side chains. We prepared pyridines bearing phenyl 2-tolyl, 3-tolyl, 4-tolyl, 3,5bis(trifluoromethyl)phenyl, 3,4-dimethoxyphenyl, 1-naphthyl,3-chlorophenyl substituents. A zinc chelator having 1-naphthyl group was found to be inhibitory against the farnesyltransferase, an important zinc protein in the signal transduction of Ras protein, with IC_<50> 1.9 μM. This compound induced morphological change in K-ras-NRK cells at.0.5 μg/ml and showed growth inhibition of K-ras-NRK cells with IC_<50> 0.32 μg/ml.
In 2004, the inhibitory effect of polyphenol carboxylic acids, such as aurintricarboxylic acid, gallic acid, and coumarin derivatives on the DNA binding of NFκB were studied. Evans blue was also found to be inhibitory against the DNA binding of NFκB. Molecular modeling studies suggest an explanation for the inhibition.
Thus, we are successful in the synthesis of novel compounds that inhibit function of zinc proteins related to AIDS.
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