Synthesis and anti-HIV activities of low molecular weight aurintricarboxylic acid fragments and related compounds.
Several compounds corresponding to fragments of the schematic representation of the polymeric structure of aurintricarboxylic acid (ATA) have been prepared and tested for prevention of the cytopathic effect of HIV-1 and HIV-2 in MT-4 cell culture and HIV-1 in CEM cell culture. Both the triphenylcarbinol 3 as well as the triphenylmethane 5 were found to afford protection against the cytopathogenicity of HIV-2 in MT-4 cells and HIV-1 in CEM cells, but they were inactive against HIV-1 in MT-4 cells. Both substances were also found to inhibit syncytium formation when MOLT-4 cells were cocultured with HIV-2-infected HUT-78 cells, but were inactive in this assay against HIV-1-infected cells. When observed, the activity is generally moderate in degree of protection and requires concentrations in the 10(-4) molar range. In contrast to ATA, both of these substances were inactive when tested for prevention of the binding of the OKT4A monoclonal antibody to the CD4 receptor and also for inhibition of HIV-1 reverse transcriptase. These substances therefore appear act by a mechanism that is distinct from that of polymeric ATA. Several active and inactive structural analogues of 3 and 5 were also synthesized. The anti-HIV activity in this series seems to depend on the presence of anionic carboxylate groups, since the methyl esters 4, 6, and 12 were uniformly inactive. The diphenylmethanes 8, 14, 18, and 19 also reproducibly inhibited the cytopathic effect of HIV-1 in CEM cell culture.
Cushman
M
M
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47097.
Kanamathareddy
S
S
De Clercq
E
E
Schols
D
D
Goldman
M E
ME
Bowen
J A
JA
D000998:Antiviral Agents / Q000138:chemical synthesis*; D001312:Aurintricarboxylic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015704:CD4 Antigens / Q000378:metabolism; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D015498:HIV-2 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007202:Indicators and Reagents; D015394:Molecular Structure; D008970:Molecular Weight; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D015704:CD4 Antigens; D007202:Indicators and Reagents; D018894:Reverse Transcriptase Inhibitors; D001312:Aurintricarboxylic Acid