Several non-natural D-amino acid derivatives were introduced as P2/P3 residues in allophenylnorstatine-containing (Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) HIV protease inhibitors. The synthetic analogues exhibited potent inhibitory activity against HIV-1 protease enzyme and HIV-1 replication in MT-4 cells. Structure-activity relationships revealed that D-cysteine or serine derivatives contributed to highly potent anti-HIV activities. Interestingly, anti-HIV activity of all the D-amino acid-introduced inhibitors was remarkably enhanced in their anti-HIV activities against a Nelfinavir-resistant clone, which has a D30N mutation in the protease, over that of the wild-type strain. HIV inhibitory activity of several analogues was moderately affected by an inclusion of alpha1-acid glycoprotein in the test medium.
L-Vinylglycine (I) is subjected to a cycloaddition reaction with a non-stabilized carbonyl ylide, generated from bis(chloromethyl) ether (II) yielding the THF-glycine (III) as a mixture of Diastereomers. Subsequently, the nitrogen protecting group of (III) is substituted to give the Fmoc-protected form of THF-glycine, (V), in three straightforward steps. THF-glycine (V) is used in the synthesis of modified substrates for HIV-1 protease. The strong HIV protease inhibitory activity of the modified S9 substrate indicates the function reversal from a substrate to an inhibitor by the incorporation of THF-glycine. -(RAJESH, S.; AMI, E.; KOTAKE, T.; KIMURA, T.; HAYASHI, Y.; KISO*, Y.; Bioorg. Med.
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