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

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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

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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.

児玉有輝 (D3) が第58回ペプチド討論会にてExcellent Poster Presentation Awardを受賞しました！

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D3の児玉有輝くんが2021年10月20日〜22日にオンラインで開催された第58回ペプチド討論会  にてExcellent Poster Presentation Awardを受賞しました。

受賞コメントがペプチドニュースレターNo.123に掲載されておりますので、ぜひご覧ください。

Stereoselective synthesis of highly functionalized (Z)-chloroalkene dipeptide isosteres containing an α,α-disubstituted amino acid

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Stereoselective synthesis of highly functionalized (Z)-chloroalkene dipeptide isosteres containing an α,α-disubstituted amino acid

Yuki Kodama, Saki Imai, Junko Fujimoto, Kohei Sato, Nobuyuki Mase and Tetsuo NARUMI

Chem. Commun., 2021, 57, 6915-6918.

Described here is the first stereoselective synthesis of highly functionalized chloroalkene dipeptide isosteres containing an α,α-disubstituted amino acid (ααAA). This synthesis requires the construction of a quaternary carbon center, and this challenge was achieved by the Aza-Darzens condensation of ketimine with α,α-dichloroenolate, producing 2-chloroaziridines with quaternary carbon centers including spirocyclic motifs, which are valuable for the previously elusive synthesis of various ααAA-containing chloroalkene isosteres.

β,γ-trans-selective γ-butyrolactone formation via homoenolate cross-annulation of enals and aldehydes catalyzed by sterically hindered N-heterocyclic carbene

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β,γ-trans-selective γ-butyrolactone formation via homoenolate cross-annulation of enals and aldehydes catalyzed by sterically hindered N-heterocyclic carbene

Ryuji Kyan, Yuya Kitagawa, Ryuji Ide, Kohei Sato, Nobuyuki Mase, Tetsuo Narumi

Tetrahedron, 2021, 91, 1321

Highly sterically hindered N-heterocyclic carbenes (NHCs), can be readily prepared from the corresponding anilines, and serve as organocatalysts in NHC-catalyzed homoenolate cross-annulation of α,β-enals and aryl aldehydes. This catalysis enables the convergent construction of β,γ-trans-disubstituted γ-butyrolactones that are an important class of molecules in synthetic and medicinal chemistry. The steric features of N-aryl substituents contribute to the selectivity and electronic ones affected the efficiency of this reaction, which proceeds with high diastereoselectivity and affords a variety of β,γ-diaryl-γ-butyrolactones in up to 91% yield with up to 1:99 dr.

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

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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

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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.