Nitrogen-Functionalized Amphilectane-Type Diterpenoids with Anti-HBV Activity from the Okinawan Marine Sponge Stylissa sp.

Journal of Natural Products, vol. 89, pp. 2718–2725

Abstract

Abstract Current treatments for hepatitis B virus (HBV) infection are constrained by adverse effects, drug resistance, and the need for long-term administration. Therefore, the development of safer and more effective therapeutic agents remains an important priority. In this study, two new amphilectane-type diterpenoids, 7-isocyanatoneoamphilecta-11,15-diene (1) and 7-isothiocyanatoneoamphilecta-11,15-diene (2), together with three known analogues (3−5), were isolated as anti-HBV agents from the Okinawan marine sponge Stylissa sp. The structures of 1 and 2 were elucidated by spectroscopic analysis, single-crystal X-ray diffraction, microcrystal electron diffraction (microED), and chemical derivatization. The previously reported amphilectanes 6 and 7 from an Adociidae sponge were also evaluated to examine structure−activity relationships. Compounds 3 and 6 showed the most potent anti-HBV activity and significantly suppressed the formation of HBV covalently closed circular DNA (cccDNA) without affecting HBV binding, entry, or RNA transcription. These results suggest that the combination of an isocyanide group and an exomethylene moiety is critical for activity. This study expands the chemical diversity of amphilectane diterpenoids and highlights their potential as promising scaffolds for the development of anti-HBV therapeutics.

Authors 10

1. Trianda A. Tyas

   University of the Ryukyus

   Affiliation as printed

   University of the Ryukyus , , 1 Senbaru , , ,

2. Yasuhiro Hayashi

   University of Miyazaki

   Affiliation as printed

   University of Miyazaki , , 101 Gakuen-kibanadai-nishi , ,

3. Keiyo Nakai
   Affiliation as printed

   SPERA PHARMA, Inc. , , 17-85, Jusohonmachi 2-Chome, Yodogawa-ku , ,

4. Kuniyoshi Miki
   Affiliation as printed

   SPERA PHARMA, Inc. , , 17-85, Jusohonmachi 2-Chome, Yodogawa-ku , ,

5. Kanami Mori‐Yasumoto

   Tokyo University of Science

   Affiliation as printed

   Tokyo University of Science , , 6-3-1 Niijuku, Katsushika , ,

6. Mina Yasumoto-Hirose

   University of the Ryukyus

   Affiliation as printed

   Tropical Technology Plus , , ,

   University of the Ryukyus , , 1-Senbaru , , ,

7. Nicole J. de Voogd Aachen Naturalis Biodiversity Center

   Leiden University · Naturalis Biodiversity Center

   Affiliation as printed

   Leiden University , , ,

   Naturalis Biodiversity Center , ,

8. Toshiaki Teruya

   University of the Ryukyus

   Affiliation as printed

   University of the Ryukyus , , 1 Senbaru , , ,

9. Junichi Tanaka

   University of the Ryukyus

   Affiliation as printed

   University of the Ryukyus , , 1 Senbaru , , ,

10. Takahiro Jomori

    University of the Ryukyus

    Affiliation as printed

    University of the Ryukyus , , 1 Senbaru , , ,