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.

Design, synthesis, and bio-evaluation of novel triterpenoid derivatives as anti-HIV-1 compounds

Reon Takeuchi, Kasumi Ogihara, Junko Fujimoto, Kohei Sato, Nobuyuki Mase, Kazuhisa Yoshimura, Shigeyoshi Harada, Tetsuo Narumi

Bioorganic & Medicinal Chemistry Letters  2022, 69, 128768.

https://doi.org/10.1016/j.bmcl.2022.128768

Two betulinic acid derivatives, RPR103611 (2) and IC9564 (3) were previously reported to be potent HIV-1 entry inhibitors. In this current study, a SAR study of the triterpenoid moiety of 2 and 3 has been performed and an oleanolic acid derivative (4) was identified as a novel HIV-1 entry inhibitor. In addition, the combination of 4 with several-type of HIV-1 neutralizing antibodies provided significant synergistic effects. The synthetic utility of the C=C double bond in the C-ring of 4 was also demonstrated to develop the 12-keto-type oleanolic acid derivative (5) as a potent anti-HIV compound. This simple transformation led to a significantly increased anti-HIV activity and a reduced cytotoxicity of the compound.

Synthesis and Structural Characterization of β-Turn Mimics Containing (Z)-Chloroalkene Dipeptide Isosteres

Yuki Kodama, Sayuri Takeo, Junko Fujimoto, Kohei Sato, Nobuyuki Mase, Tetsuo Narumi

J. Org. Chem. 2022, 87 (5), 2167–2177.

Described here is the synthetic, spectroscopic, crystallographic, and computational analysis of a series of peptidomimetics containing L-Xaa-D-Yaa-type (Z)-chloroalkene dipeptide isosteres (CADIs) that were measured in an investigation of the β-turn mimicry of this peptide bond surrogate. We found that the 1,3-allylic strain across the chloroalkene moiety engenders the hyperconjugative interactions between the chloroalkene moiety and the C–H bonding or antibonding orbitals of the C–H bonds in allylic positions. These effects contribute significantly to the stabilization of β-turn structures.

Fine-Bubble–Slug-Flow Hydrogenation of Multiple Bonds and Phenols

Takuya Iio, Kohei Nagai, Tomoki Kozuka, Akhtar Mst Sammi, Kohei Sato, Tetsuo Narumi, Nobuyuki Mase∗

Synlett, 2020, 31, 1919-1924

We describe a promising method for the continuous hydrogenation of alkenes or alkynes by using a newly developed fine-bubble generator. The fine-bubble-containing slug-flow system was up to 1.4 times more efficient than a conventional slug-flow method. When applied in the hydrogenation of phenols to the corresponding cyclohexanones, the fine bubble–slug-flow method suppressed over-reduction. As this method does not require the use of excess gas, it is expected to be widely applicable in improving the efficiency of gas-mediated flow reactions.

Late-​stage solubilization of poorly soluble peptides using hydrazide chemistry

Kohei Sato*, Shoko Tanaka, Junzhen Wang, Kenya Ishikawa, Shugo Tsuda, Tetsuo Narumi, Taku YoshiyaTaku Yoshiya

Org. Lett. 2021, 23, 1653–1658. 

A novel late-stage solubilization of peptides using hydrazides is described. A solubilizing tag was attached through a selective N-alkylation at a hydrazide moiety with the aid of a 2-picoline–borane complex in 50% acetic acid–hexafluoro-2-propanol. The tag, which tolerates ligation and desulfurization conditions, can be detached by a Cu-mediated selective oxidative hydrolysis of the N-alkyl hydrazide. This new method was validated through the synthesis of HIV-1 protease.

Stereoselective synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres and their application to 14-mer RGG peptidomimetics

H. Okita, Y. Kato, T. Masuzawa, K. Arai, S. Takeo, K. Sato, N. Mase T. Oyoshi and T. Narumi*

RSC Adv., 2020, 10, 29373-29377.

Stereoselective and efficient synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres is realized by organocuprate-mediated single electron transfer reduction. The synthetic isosteres can be used in Fmoc-based solid phase peptide synthesis, resulting in the preparation of the 14-mer RGG peptidomimetics containing an (E)-methylalkene or a (Z)-chloroalkene unit.