Poster Presentation 10th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2025

Development of synthetic strategies for peptidomimetics based on haloalkene dipeptide isosteres and their application to cyclic peptides (130606)

Takuya Kobayakawa 1 , Kenichi Yamamoto 1 , Marisa Arioka 1 , Aiichiro Fukutome 1 , Kohei Tsuji 1 , Hirokazu Tamamura 1
  1. Institute of Science Tokyo, Chiyoda-ku, TOKYO, Japan

     Peptidomimetics have emerged as promising alternatives to natural peptides in drug discovery, offering enhanced metabolic stability and improved pharmacological properties.1 We have developed innovative synthetic methodologies for haloalkene dipeptide isosteres, specifically chloroalkene dipeptide isosteres (CADIs) and fluoroalkene dipeptide isosteres (FADIs), as effective amide bond mimetics.2-5

     Our synthetic approach employs a linear synthetic strategy. In this approach, we utilize N-tert-butylsulfonyl (Bus) protected precursors with diastereoselective allylic alkylation using organocopper reagents as the key transformation. This methodology enables stereocontrolled construction of CADIs with excellent Z-selectivity (>20:1) and high diastereoselectivity (>20:1).2-3

     For FADI synthesis, we developed an approach combining chiral tert-butylsulfinamide (Ellman's imine) for N-terminal amino acid construction and camphorsultam (Oppolzer's sultam) for C-terminal residues. This methodology provides stereocontrolled access to both (S,R)- and (S,S)-configured FADIs through reductive defluorination followed by asymmetric alkylation using Gilman cuprates and organozinc reagents.5

     Our methodologies are compatible with Fmoc-based solid-phase peptide synthesis, enabling facile incorporation into complex peptide sequences. Both Fmoc- and Boc-protected haloalkene dipeptide isosteres can be efficiently prepared from common intermediates, making these approaches highly practical for medicinal chemistry applications.

     The synthetic utility of these haloalkene dipeptide isosteres was demonstrated through their successful incorporation into bioactive cyclic peptides. CADIs were applied to cyclic RGD peptides, showing a 20-fold enhancement in inhibitory activity against integrin-mediated cell attachment compared to the parent peptide.3 Additionally, CADI-containing cyclic KLVFF peptidomimetics exhibited superior amyloid-b aggregation inhibition compared to their corresponding parent peptides.4,6

    These developments provide powerful tools for peptide drug discovery, offering new opportunities to enhance the stability and bioactivity of therapeutic peptides through strategic peptidomimetic design.

  1. Tamamura, H.; Kobayakawa, T.; Ohashi, N. “Mid-size Drugs Based on Peptides and Peptidomimetics”, Springer, 2018.
  2. Kobayakawa, T.; Tsuji, K.; Tamamura, H. Bioorg. Med. Chem. 2024, 110, 117811.
  3. Kobayakawa, T.; Matsuzaki, Y.; Hozumi, K.; Nomura, W.; Nomizu, M.; Tamamura, H. ACS Med. Chem. Lett. 2018, 9, 6−10.
  4. Kobayakawa, T. Azuma, C.; Watanabe, Y.; Sawamura, S.; Taniguchi, A.; Hayashi, Y.; Tsuji, K.; Tamamura, H. J. Org. Chem. 2021, 86, 5091−5101.
  5. Kobayakawa, T.; Arioka, M.; Yamamoto, K.; Tsuji K.; Tamamura, H. Org. Biomol. Chem. 2025, 23, 4333-4336.
  6. Kobayakawa, T.; Yamamoto, K.; Fukutome, A.; Arioka, M.; Tsuji, K.; Tamamura, H. Synlett 2025, ASAP.