Synthesis and structure-activity relationships of a series of penicillin-derived HIV proteinase inhibitors containing a stereochemically unique peptide isostere

Abstract

A series of HIV-1 proteinase inhibitors was synthesized based upon a single penicillin derived thiazolidine moiety. Reaction of the C-4 carboxyl group with (R)-phenylalaninol gave amide 10 which was a moderately potent inhibitor of HIV-1 proteinase (IC50 = 0.15 microM). Further modifications based on molecular modeling studies led to compound 48 which contained a stereochemically unique statine-based isostere. This was a potent competitive inhibitor (Ki = 0.25 nM) with antiviral activity against HIV-1 in vitro (5 microM). Neither modification to the benzyl group in an attempt to improve interaction with the S2' pocket, nor introduction of a hydrogen bond donating group to interact with residue Gly48' resulted in improved inhibitory or antiviral activity.

Issue Information

“…As proof of principle, L ‐alanine (Ala) and L ‐phenylalanine (Phe) were incorporated to demonstrate the preparation of olefin oligomers with a controlled sequence of side chains. Synthesis proceeded by coupling an Fmoc amino acid to N ‐Boc‐ p ‐phenylenediamine ( 1 , 5 ),13 followed by Fmoc deprotection ( 2 , 6 ) 14. The masked aldehyde moiety (Scheme ) was introduced by reacting the amine with diacetyl‐ L ‐tartaric anhydride, followed by basic removal of the acetyl protecting groups ( 3 , 7 ) 15.…”

Synthesis and Structure-Activity Relationships of a Series of Penicillin-Derived HIV Proteinase Inhibitors: Heterocyclic Ring Systems Containing P1' and P2' Substituents

“…The residual dark brown foam was purified by chromatography on silica gel. Elution with a gradient of ethyl acetate/methanol from 9:1 to 4:1 gave the crude intermediate amide as a brown foam: 244 mg (37%); >H NMR (DMSO-d6) 1.27 (s, 9H), 1.42 (s, 3H), 1.61 (s, 3H), 2.25-2.42 (m, 2H), 2.8-3.1 (m, 4H), 3.5 (s, 1H), 3.55 and 3.56 (2s, 1H), 3.65 (m, 1H), 3.9 (m, 2H), 4.20 (m, 1H), 5.4-5.51 (m, 2H), 7.15-7.36 (m, 5H), 7.41 and 7.46 (2s 1H), 8.25 (m, 1H), 8.9 (m, 1H).…”

“…With the aid of computer-assisted molecular modeling we then developed a series of potent inhibitors, e.g, 4 (IC50 = 4.6 nM), having significantly reduced molecular weight and containing a stereochemically unique statine dipeptide isostere. 8 In view of the success of this strategy based upon inhibitors containing a single penicillin-derived thiazolidine unit, we sought alternative means of interacting with the Si' and S2' subsites. The recently published work from Martin and co-workers9 on the biological properties of Ro 31-8959 (5) indicated that the decahydroisoquinoline moiety could fulfill this role and may well significantly affect the antiviral and pharmacokinetic properties of any "hybrid" molecules.…”

Multistep DNA‐Templated Reactions for the Synthesis of Functional Sequence Controlled Oligomers

“…As proof of principle, l-alanine (Ala) and l-phenylalanine (Phe) were incorporated to demonstrate the preparation of olefin oligomers with a controlled sequence of side chains. Synthesis proceeded by coupling an Fmoc amino acid to N-Boc-p-phenylenediamine (1, 5), [13] followed by Fmoc deprotection (2,6). [14] The masked aldehyde moiety (Scheme 2 e) was introduced by reacting the amine with diacetyl-ltartaric anhydride, followed by basic removal of the acetyl protecting groups (3,7).…”