Publications

A series of new polyanions was synthesized via gamma-polymerization, in aqueous micellar solution, of omega-unsaturated anionic surfactants whose polar head was derived from amino acids or dipeptides. The obtained polyanions were evaluated for their activity against human immunodeficiency virus (HIV-1, HIV-2) and various other RNA and DNA viruses. All the test compounds proved active against HIV-1 and HIV-2, their 50% inhibitory concentration (IC50) being in the range of 0.04-7.5 micrograms/mL, while they were not toxic to the host cells (CEM-4 or MT-4) at concentrations up to 100 micrograms/mL or higher. The HIV-inhibitory effect increased with the hydrophilic character of the amino acid moiety. The compounds were found to interact with both the viral envelope glycoprotein gp120 and the cellular CD4 receptor, thus blocking virus-cell binding and virus-induced syncytium formation. These polyanions also proved active against human cytomegalovirus at about the same IC50 as for HIV. In addition, they were also active, albeit at somewhat higher IC50 values (0.8-20 micrograms/mL), against other enveloped viruses such as respiratory syncytial virus and arenaviruses (Junin and Tacaribe). At yet higher IC50 values ( > or = 20 micrograms/mL), some of the compounds showed activity against influenza A virus. No activity was observed with any of the compounds against vesicular stomatitis virus, Sindbis virus, Semliki forest virus, influenza B, parainfluenza type 3, and the nonenveloped viruses Coxsackie type B4, polio type 1, and reovirus type 1.

A series of structurally related 2,5-disubstituted 6-(1-naphthylmethyl)-pyrimidin-4(3H)-ones, compounds 6a-6r, were synthesized and evaluated for their in vitro anti-HIV activities in MT-4 cells. Most of the new compounds investigated showed moderate-to-good activities against wild-type HIV-1, with IC(50) values in the range 5.64-0.21 microM. Compound 6d was the most potent congener (IC(50)=0.21 microM, SI=724) in inhibiting HIV-1 replication, which is ca. 25 times more effective than the reference compound 2',3'-dideoxyinosine (DDI). Preliminary structure-activity relationship (SAR) studies revealed that both modulation of the amino function at C(2) and of the alkyl group at C(5) of the pyrimidine ring are crucial for high anti-HIV-1 activity.

Polyhydroxycarboxylates (MW: 3,800-14,000) derived from phenolic (PDP) compounds have been found to inhibit the cytopathicity of HIV-1 and HIV-2 in MT-4 cells at concentrations that are not toxic to the host cells. The PDP compounds also inhibited syncytium formation in cocultures of MOLT-4 cells with HIV-1- or HIV-2-infected HUT-78 cells. They also interfered with the binding of OKT4A/leu3a monoclonal antibody (mAb) to the CD4 receptor, the binding of anti-gp120 mAb to HIV-1 gp120, and attachment of HIV-1 virions to MT-4 cells. The anti-HIV activity in this series of compounds can be ascribed to inhibition of the gp120-CD4 interaction and seems to depend on the presence of the anionic carboxylate groups. Their mechanism of action is similar to that of the heterogeneous polymer aurintricarboxylic acid (ATA).

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.