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Synthetic aporphine alkaloids are potential therapeutics for Leigh syndrome.
Kobayashi, Mizuki; Miyauchi, Akihiko; Jimbo, Eriko F; Oishi, Natsumi; Aoki, Shiho; Watanabe, Miyuki; Yoshikawa, Yasushi; Akiyama, Yutaka; Yamagata, Takanori; Osaka, Hitoshi.
Afiliación
  • Kobayashi M; Department of Pediatrics, Division of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
  • Miyauchi A; Department of Pediatrics, Division of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
  • Jimbo EF; Department of Pediatrics, Division of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
  • Oishi N; Department of Pediatrics, Division of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
  • Aoki S; Department of Pediatrics, Division of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
  • Watanabe M; Department of Pediatrics, Division of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
  • Yoshikawa Y; School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, 226-8501, Japan.
  • Akiyama Y; Department of Computer Science, School of Computing, Tokyo Institute of Technology, Meguro-ku, Tokyo, 152-8550, Japan.
  • Yamagata T; Middle-Molecule IT-Based Drug Discovery Laboratory (MIDL), Tokyo Institute of Technology, Kawasaki, Kanagawa, 210-0821, Japan.
  • Osaka H; School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, 226-8501, Japan.
Sci Rep ; 14(1): 11561, 2024 05 21.
Article en En | MEDLINE | ID: mdl-38773300
ABSTRACT
Mitochondrial diseases are mainly caused by dysfunction of mitochondrial respiratory chain complexes and have a variety of genetic variants or phenotypes. There are only a few approved treatments, and fundamental therapies are yet to be developed. Leigh syndrome (LS) is the most severe type of progressive encephalopathy. We previously reported that apomorphine, an anti- "off" agent for Parkinson's disease, has cell-protective activity in patient-derived skin fibroblasts in addition to strong dopamine agonist effect. We obtained 26 apomorphine analogs, synthesized 20 apomorphine derivatives, and determined their anti-cell death effect, dopamine agonist activity, and effects on the mitochondrial function. We found three novel apomorphine derivatives with an active hydroxy group at position 11 of the aporphine framework, with a high anti-cell death effect without emetic dopamine agonist activity. These synthetic aporphine alkaloids are potent therapeutics for mitochondrial diseases without emetic side effects and have the potential to overcome the low bioavailability of apomorphine. Moreover, they have high anti-ferroptotic activity and therefore have potential as a therapeutic agent for diseases related to ferroptosis.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Aporfinas / Enfermedad de Leigh / Mitocondrias Límite: Humans Idioma: En Año: 2024 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Aporfinas / Enfermedad de Leigh / Mitocondrias Límite: Humans Idioma: En Año: 2024 Tipo del documento: Article