364764-40-9Relevant academic research and scientific papers
Design, synthesis, and biological evaluation of anti-HIV double-drugsconjugates of HIV protease inhibitors with a reverse transcriptase inhibitor through spontaneously cleavable linkers
Matsumoto, Hikaru,Kimura, Tooru,Hamawaki, Tomonori,Kumagai, Akira,Goto, Toshiyuki,Sano, Kouichi,Hayashi, Yoshio,Kiso, Yoshiaki
, p. 1589 - 1600 (2007/10/03)
Based o the prodrug concept as well as the combination of two different classes of anti-HIV agents, we designed and synthesized a series of anti-HIV double-drugs consisitng of HIV protease inhibitors conjugated with a nucleoside reverse transcriptase inhibitor in an effort to enhance the antiviral activity. For the conjugation, a series of linkers that conjoins the two different classes of inhibitors has been investigted. Double-drugs using a succinyl amino acid linker were shown to release the parent drugs via spontaneous imide formation at a faster rate compared ring. Among the double-drugs, KNI-1039 (3B) with a glutaryl-glycine linker exhibited extremely potent anti-HIV activity compared with that of the individual components. Double-drug 3b was relatively stable in culture medium, whereas it regenerated active species in cell homogenate. These results suggested that the synergistic enhancement of anti-HIV activities of 3b may be due to their ability to penetrate into the target cell and subsequent regeneration of two diferent classes of anti-HIV agents in the cytoplasm. Copyright
