KR-20260068076-A - Berberubin-related compounds

Abstract

A berberubin-related compound having useful physiological activity and a composition containing the same are provided. A composition containing quinoid-type berberubin is provided. Additionally, a berberubin acetic acid adduct and an aqueous solution thereof are provided. Additionally, a composition containing a berberubin acetic acid adduct or an aqueous solution thereof is provided. Additionally, a method for preparing a berberubin acetic acid adduct or an aqueous solution thereof is provided. Additionally, a composition containing quinoid-type berberubin and a composition containing a berberubin acetic acid adduct or an aqueous solution thereof are provided, which are used as pharmaceutical compositions, food compositions, cosmetic compositions, or agricultural compositions.

Inventors

• 야나기 시게루
• 이노우에 사토시
• 오카자키 야스시
• 스기우라 아유무
• 오카다 후토시
• 아베 히데키
• 다니와카 게이토
• 시이바 잇신
• 다나부 다이시
• 오이케 유이치
• 다카시마 아키히코
• 소에다 요시유키
• 하라다 히로노리

Assignees

• 가부시키가이샤 마이토제닉

Dates

Publication Date

20260513

Application Date

20240909

Priority Date

20230907

Claims (20)

1. The following equation (I): A composition comprising quinoid-type berberubin represented by
2. In Article 1, A composition in which the compound represented by formula (I) is an isolated quinoid-type berberubin.
3. In Article 1, A composition that is a pharmaceutical composition.
4. In Article 1, A composition that is a food composition.
5. In Article 1, A composition that is a cosmetic composition.
6. In Article 1, A composition that is an agricultural composition.
7. In Article 1, A composition for activating mitochondria.
8. In Article 1, A composition for the treatment or prevention of mitochondrial disease.
9. In Article 1, A composition for the treatment or prevention of Parkinson's disease.
10. In Article 1, A composition for the treatment or prevention of mitochondrial encephalomyopathy, lactic acid acidosis, and stroke-like seizure syndrome (MELAS).
11. In Article 1, A composition for the treatment or prevention of cancer.
12. In Article 11, A composition in which the cancer is epithelial carcinoma, carcinoma, cervical cancer, sarcoma, or myelodysplastic syndrome (MDS).
13. In Article 1, A composition for the treatment or prevention of muscle disease.
14. In Article 13, Muscle disease, flail, locomotive syndrome, or sarcopenia, composition.
15. In Article 1, A composition for the treatment or prevention of neurological diseases.
16. In Article 15, A neurological disease, dementia, composition.
17. In Article 1, A composition for the treatment or prevention of heart disease.
18. In Article 17, Composition of heart disease, heart failure.
19. In Article 17, Composition of heart disease, cardiomyopathy.
20. In Article 1, A composition for improving or preventing cardiac hypertrophy.

Description

Berberubin-related compounds The present disclosure relates to berberubin-related compounds, and in particular, to a composition comprising quinoid-type berberubin, a berberubin acetic acid adduct and a method for producing the same, and a composition comprising a berberubin acetic acid adduct. Berberubin is a derivative of berberine, an alkaloid found in plants such as Coptis japonica and Phellodendron amurense. Berberine is a component of herbal medicines that possesses stomachic, anti-inflammatory, and sedative effects, and berberubin is believed to be a metabolite of berberine. Non-patent document 1 describes that berberubin can take the form of (i) a quinoid form, (ii) an enol form, or (iii) a paired form. Figure 1a is the solid 13C NMR spectrum of quinoid-type berberubin by the CPMAS method. Figure 1b is the solid 13C NMR spectrum of quinoid-type berberubin by the DDMAS method. Figure 2a is the solid 13C NMR spectrum of a berberubin acetic acid adduct by the CPMAS method. Figure 2b is the solid 13C NMR spectrum of a berberubin acetic acid adduct by the DDMAS method. Figure 3a is the solid 13C NMR spectrum of berberubin acetate by the CPMAS method. Figure 3b is the solid 13C NMR spectrum of berberubin acetate by the DDMAS method. Figure 4a shows the change in oxygen consumption (OCR) over time in C2C12 cells supplemented with quinoid-type berberubin. The time point 24 hours after supplementation was set as 0 hours (min). At the time points of 20 min, 40 min, and 70 min (black arrows), an ATP synthase inhibitor (oligomycin), a deconjugation agent (carbonylcyanide-m-chlorophenylhydrazone (CCCP)), and a mitochondrial complex inhibitor (rotenone and antimycin) were added, respectively. Figure 4b shows the change in oxygen consumption (OCR) over time in C2C12 cells supplemented with berberubin acetate adduct. The time point 24 hours after addition was set as 0 hours (min). At the time points of 20 min, 40 min, and 70 min (black arrows), an ATP synthase inhibitor (oligomycin), a deconjugation agent (carbonylcyanide-m-chlorophenylhydrazone (CCCP)), and a mitochondrial complex inhibitor (rotenone and antimycin) were added, respectively. Figure 4c shows the OCR (corresponding to the amounts of basal respiration, ATP production, and maximum respiration in mitochondria, respectively) at the time points of 30, 60, and 90 minutes (white arrows) in Figure 4a. Figure 4d shows the OCR (corresponding to the amounts of basal respiration, ATP production, and maximum respiration in mitochondria, respectively) at the time points (white arrows) of 30, 60, and 90 minutes in Figure 4b. Figure 5 shows the results of detecting the formation of a mitochondrial respiratory chain supercomplex in C2C12 cells to which quinoid-type berberubin or berberubin acetate adduct was added. Figure 6a shows a comparison of the expression levels of mitochondrial proteins OPA1, HSP60, and Mfn2 and the expression levels of cellular proteins Tub (α-tubulin) or Actin (actin) in mouse fetal pituitary primary culture cells administered with berberubin acetate adduct. Figure 6b shows the results of observing mouse fetal pituitary primary culture cells administered with berberubin acetate, nuclei stained with Hoechst and mitochondria stained with Tom20, respectively, under a fluorescence microscope (magnification: 60x). Figure 7 shows the results of observing Pink1 KO MEF cells and MEF cells administered quinoid-type berberubin or berberubin acetate adducts, respectively, by staining the nuclei with Hoechst and the mitochondria with Tom20, and observing them under a fluorescence microscope (magnification: 60x). A is a wild-type MEF cell (control, administered DMSO only), B is a wild-type MEF cell administered quinoid-type berberubin, and C is a wild-type MEF cell administered berberubin acetate adduct. Also, D is an MEF_pink1 KO cell (control, administered DMSO only), E is an MEF_pink1 KO cell administered quinoid-type berberubin, and F is an MEF_pink1 KO cell administered berberubin acetate adduct. Figure 8a shows the ratio of the number of HeLa cells after administration of quinoid-type berberubin (quinoid-type berberubin) to the number of HeLa cells in the control (administration of DMSO only) (control). Figure 8b shows the ratio of the number of HeLa cells after administration of berberubin acetate adduct (berberubin acetate adduct) to the number of HeLa cells in the control (water only administered) (control). Figure 9 shows the ratio of the number of MDS clones to the number of blood cells in bone marrow transplant (BMT) mice administered a berberubin acetate adduct. Figure 10a shows the results of Western blotting on Neuro2A cells in which tau protein was aggregated within the cell, after adding quinoid-type berberubin, and detecting the tau protein using antibodies against S396 position phosphorylated Tau (pS396), S422 position phosphorylated Tau (pS422), and Tau full length (JM). Figure 10b shows the results of Western blotting on Neuro2A cell