ChemInform Abstract: AMINOLYSIS OF DERIVATIVES OF TRANS‐3‐PHENYLGLYCIDIC ACID, V: DISTINCTION BETWEEN N‐SUBSTITUTED DERIVATIVES OF 3‐PHENYLSERINE AND 3‐PHENYLISOSERINE

Tack, J. W.; Lehmann, Jochen; Zymalkowski, F.

doi:10.1002/chin.197925179

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“…The 8-fold difference in K between leucine (20) and isoleucine (21) reflects the steric restrictions at the S2 subsite of the enzyme. Also aromatic (24,25), polar (26,27), and charged (28, 29) side chains are not well tolerated. Only with ieri-leucine (22) an increase in antiviral activity was achieved, which was observed also for other derivatives (see below).…”

Section: Resultsmentioning

confidence: 99%

Inhibitors of HIV-1 Proteinase Containing 2-Heterosubstituted 4-Amino-3-hydroxy-5-phenylpentanoic Acid: Synthesis, Enzyme Inhibition, and Antiviral Activity

Scholz

Billich²,

Charpiot³

et al. 1994

J. Med. Chem.

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A convenient procedure for the synthesis of 2-heterosubstituted statine derivatives as novel building blocks in HIV-protease inhibitors has been developed. The synthesis starts with protected L-phenylalaninols, which were converted to gamma-amino alpha, beta-unsaturated esters in a one-pot procedure. A highly diastereoselective epoxidation of the N-protected (E)-enoates, followed by regioselective ring opening of the corresponding 2,3-epoxy esters with a variety of heteronucleophiles, resulted in 2-heterosubstituted statine derivatives. The overall stereo-chemical outcome of the transformations meets the required configuration of HIV-protease inhibitors. The short, synthetically flexible, and highly diastereoselective synthesis of 2-heterosubstituted statines has enabled a broad derivation, covering the S3, S2, and S1'-S3' sites of the enzyme. In a series of 46 derivatives, several potent inhibitors were obtained with Ki values as low as 3.4 nM and antiviral activity in the lower nanomolar-range. The structural parameters of the compounds which determine the potency of inhibition and selectivity for the viral enzyme are discussed.

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Section: Resultsmentioning

confidence: 99%

Inhibitors of HIV-1 Proteinase Containing 2-Heterosubstituted 4-Amino-3-hydroxy-5-phenylpentanoic Acid: Synthesis, Enzyme Inhibition, and Antiviral Activity

Scholz

Billich²,

Charpiot³

et al. 1994

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

ChemInform Abstract: AMINOLYSIS OF DERIVATIVES OF TRANS‐3‐PHENYLGLYCIDIC ACID, V: DISTINCTION BETWEEN N‐SUBSTITUTED DERIVATIVES OF 3‐PHENYLSERINE AND 3‐PHENYLISOSERINE

Abstract: Bei der Aminolyse der trans‐Phenylg1ycidsäurederivate (I) mit den Aminen (II) entstehen nicht wie ursprünglich angenommen die Serin‐Derivate (IV), sondern die Isoserin‐"Derivate (III).

Cited by 1 publication

References 1 publication

Inhibitors of HIV-1 Proteinase Containing 2-Heterosubstituted 4-Amino-3-hydroxy-5-phenylpentanoic Acid: Synthesis, Enzyme Inhibition, and Antiviral Activity

Inhibitors of HIV-1 Proteinase Containing 2-Heterosubstituted 4-Amino-3-hydroxy-5-phenylpentanoic Acid: Synthesis, Enzyme Inhibition, and Antiviral Activity

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