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Substitution Effects of Alkene Dipeptide Isosteres on Adjacent Peptide Bond Rotation

Chihiro Iio, Kohei Sato, Nobuyuki Mase, Tetsuo Narumi

Chem. Pharm. Bull. 2024, 72, 596-599.

Alkene dipeptide isosteres (ADIs) are promising surrogates of peptide bonds that enhance the bioactive peptide resistance to enzymatic hydrolysis in medicinal chemistry. In this study, we investigated the substitution effects of an ADI on the energy barrier of cis–trans isomerization in the acetyl proline methyl ester (Ac-Pro-OMe) model. The (E)-alkene-type proline analog, which favors a cis-amide conformation, exhibits a lower rotational barrier than native Ac-Pro-OMe. A van’t Hoff analysis suggests that the energy barrier is primarily reduced by enthalpic repulsion. It was concluded that although carbon–carbon double bonds and pyrrolidine rings individually increase the rigidity of the incorporation site, their combination can provide structural flexibility and disrupt bioactive conformations. This work provides new insights into ADI-based drug design.

Amide-to-chloroalkene substitution for overcoming intramolecular acyl transfer challenges in hexapeptidic neuromedin U receptor 2 agonists

Tetsuo Narumi, Daichi Toyama, Junko Fujimoto, Ryuji Kyan, Kohei Sato, Kenji Mori, James T. Pearson, Nobuyuki Mase, Kentaro Takayama

Chem. Commun. 2024, 60, 3563-3566.

CPN-116 is a peptidic agonist that activates human neuromedin U receptor type 2 (NMUR2) but suffers from chemical instability due to inherent backbone isomerization on the Dap residue. To address this, a Leu-Dap-type (Z)-chloroalkene dipeptide isostere was synthesized diastereoselectively as a surrogate of the Leu-Dap peptide bond to develop a (Z)-chloroalkene analogue of CPN-116. The synthesized CPN-116 analogue is stable in 1.0 M phosphate buffer (pH 7.4) without backbone isomerization and can activate NMUR2 with similar potency to CPN-116 at nM concentrations (EC₅₀ = 1.0 nM).

Late-Stage Derivatization of Oleanolic Acid-Based Anti-HIV-1 Compounds

Reon Takeuchi, Junko Fujimoto, Yoshinori Taguchi, Ryuji Ide, Ryuji Kyan, Kohei Sato, Nobuyuki Mase, Masaru Yokoyama, Shigeyoshi Harada, Tetsuo Narumi

Chem. Pharm. Bull. 2024, 72, 330-335.

A 12-keto-type oleanolic acid derivative (4) has been identified as a potent anti-human immunodeficiency virus type-1 (HIV-1) compound that demonstrates synergistic effects with several types of HIV-1 neutralizing antibodies. In the present study, we used a common key synthetic intermediate to carry out the late-stage derivatization of an anti-HIV compound based on the chemical structure of a 12-keto-type oleanolic acid derivative. To execute this strategy, we designed a diketo-type oleanolic acid derivative (5) for chemoselective transformation, targeting the carboxy group and the hydroxyl group on the statine unit, as well as the 3-carbonyl group on the oleanolic acid unit, as orthogonal synthetic handles. We carried out four types of chemoselective transformations, leading to identification of the indole-type derivative (16) as a novel potent anti-HIV compound. In addition, further optimization of the β-hydroxyl group on the statine unit provided the R-4-isobutyl γ-amino acid-type derivative (6), which exhibited potent anti-HIV activity comparable to that of 4 but with reduced cytotoxicity.

Peptidomimetic Catalysts as Chemical Probes of Weak Intermolecular Forces: An Insight into The N-H…Cl-C H-Bonding Interaction

Chihiro Iio, Takuma Nishizawa, Takuya Chiba, Junko Fujimoto, Yuki Kodama, Kohei Sato, Nobuyuki Mase, Tetsuo Narumi

ChemRxiv, 2023. DOI: 10.26434/chmrxiv-2023-zp00r

Despite the widespread use of amide bond isosteres, there is only a limited understanding of their H-bonding mimicry of amides. With experimental and computational approaches, we have explored the hydrogen bonding acceptor potential of the chlorine substituent in chloroalkene dipeptide isosteres (CADIs). The (Z)-chloroalkene and (E)-methylalkene analogues of peptide catalysts were synthesized and employed as probe molecules to assess the H-bonding acceptor capabilities of CADIs. These peptidomimetic studies provide experimental evidence supporting the existence of an intermolecular H-bonding interaction between the chlorine substituent in CADIs and the amide proton of the carbamate substrate. These findings show the capability of peptide catalysts to experimentally evaluate weak intermolecular forces. DFT calculations elucidated that the chlorine substituent in CADIs prefers to form p-type hydrogen bonding interactions on the lateral portions of the chlorine atom, which is different from the carbonyl oxygen of amides which predominantly forms s-type H-bonds in peptide secondary structures.