A photolabile backbone amide linker for the solid-phase synthesis of cyclic peptides. Cysteine-free native chemical ligation. Synthesis and biological evaluation of a library of resveratrol analogues

Soo Sung Kang, Purdue University

Abstract

A new backbone amide linker has been developed for the synthesis of cyclic and C-terminally modified peptides that permits photochemical detachment of the synthesized peptide from the solid support, thus avoiding the problems associated with acid deprotection conditions. An initial survey of known photolabile motifs for their ability to produce a linker-bound model dipeptide in high yield and their ability to undergo efficient photochemical detachment of the model dipeptide found that the 6-nitroveratryl (Nve) motif afforded the most efficient release of dipeptide. The problematic acylation of Nve-bound amino esters was solved through the development of the 2-hydroxy-4-carboxy-6-nitrobenzyl (Hcnb) linker, which utilizes an O to N transacylation to afford efficient acylation of even sterically hindered linker-bound amino esters. The Hcnb linker was found to afford high yields of amino acid loading, acylation and photolytic cleavage of model dipeptides. Attachment of the Hcnb linker to the aminoethyl TG resin permitted the solid phase synthesis of several representative cyclic peptides in high overall yield and purity. Cysteine-free Native Chemical Ligation (NCL) was studied using the photolabile Hcnb linker. Transacylation of peptide C-terminal thioesters to the Hcnb auxiliary and intramolecular O to N acyltransfer were promoted well by the electron deficient character of Hcnb in a pH 7.5 phosphate buffer. However, it needed sterically less-hindered C-terminal thioesters, and a general solution is under investigation. Resveratrol is a naturally occurring antioxidant that inhibits cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), transcription factor NF-κB, and quinine reductase-2 (QR-2). A 78-membered library of resveratrol analogues in which the substituents on the two aryl rings and the alkene were varied was synthesized using a solid-phase Wittig olefination reaction. The library contains inhibitors against all four proteins that were more potent than resveratrol itself. Preliminary structure–activity relationships were also obtained from these data that permitted the derivation of crude pharmacophore models for each of the three targets. A 27-membered library of benzanilides in which the two aromatic rings mimic the structure of bioactive resveratrols was synthesized by amide bond formation. The synthetic efforts were for the increasing molecular diversity and the observation of the aromatic rings, rotational conformation.

Degree

Ph.D.

Advisors

Lipton, Purdue University.

Subject Area

Organic chemistry

COinS