Ring substituent effects on biological activity of vinyl sulfones as inhibitors of HIV-1.
In a previous study, we prepared a small library of chicoric acid analogs that possessed both potent anti-integrase and antiviral activity. It was also shown that active compounds fell into one of two groups: those that inhibited an early stage in viral replication and those that inhibited at a later stage. In this study, a series of vinyl geminal disulfone-containing compounds possessing a range of ring substituents has been synthesized to probe the impact of structure on inhibitory mechanisms. Four active compounds were identified using HIV drug susceptibility assays. Three of the inhibitors possessing either no substituents or electron-withdrawing substituents on the aromatic rings led to high levels of cytotoxicity and antiviral activity. Intrigued by the potential implications of electronic effects on activity, we probed whether the active compounds could be nonspecifically reacting via 1,4-addition. To investigate this hypothesis, the compounds were incubated with glutathione and upon LC/MS analysis, molecular ion peaks corresponding to both mono and double addition adducts were identified. Second, we synthesized analogs lacking the ability to participate in 1,4-addition and tested them for antiviral activity and cytotoxicity, and found the compounds inactive for both activities. Taken together, the studies reported herein suggest that compounds lacking electron-donating substituents on the aromatic ring are promiscuous acceptors of biological nucleophiles, whereas compounds possessing electron-donating substituents seem to resist addition or at least be more selective and significantly less toxic.
Meadows
D Christopher
DC
Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.
Sanchez
Tino
T
Neamati
Nouri
N
North
Thomas W
TW
Gervay-Hague
Jacquelyn
J
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007118:Immunoassay; D007202:Indicators and Reagents; D013058:Mass Spectrometry; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000378:metabolism; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology*; D014753:Vinyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*
D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D019428:HIV Integrase Inhibitors; D007202:Indicators and Reagents; D009841:Oligonucleotides; D013450:Sulfones; D014753:Vinyl Compounds