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CN-122010974-A - Bird nest alkane diterpenoid compound and application thereof in preparation of medicine for treating Alzheimer disease

CN122010974ACN 122010974 ACN122010974 ACN 122010974ACN-122010974-A

Abstract

The invention belongs to the technical field of medical microbiological chemistry. The invention discloses a bird nest alkane diterpenoid compound with obvious anti-neuroinflammation activity, neurotrophic protection effect, AD (AD) activity and anti-aging activity, which has the following structural formula; Wherein R 1 is COOH, COOCH 3 、CH 2 OH or CH 3 ;R 2 is CH 2 OH or COOH, R 3 is OH or H, R 4 is H or=O, and a single bond or a double bond is between C12 and C13.

Inventors

  • LIU HONGWEI
  • DAI HUANQIN
  • WANG ZIXIAO
  • CHEN BAOSONG
  • MA DENGXING
  • HAN JUNJIE
  • SUN JINGZU

Assignees

  • 中国科学院微生物研究所

Dates

Publication Date
20260512
Application Date
20241112

Claims (9)

  1. 1. A bird nest alkane diterpenoid compound which has the following structural formula; Wherein: R 1 is COOH, COOCH 3 、CH 2 OH or CH 3 ; r 2 is CH 2 OH or COOH; r 3 is OH or H; R 4 is H or = O; between C12 and C13 is a single bond or a double bond.
  2. 2. The bird's nest alkane diterpenoid according to claim 1, wherein R 1 is COOH, R 2 is CH 2 OH, R 3 is OH, R 4 is H, and a single bond is between C12 and C13.
  3. 3. The bird's nest alkane diterpenoid according to claim 1, wherein R 1 is COO CH 3 , R 2 is CH 2 OH, R 3 is OH, R 4 is H, and a single bond is between C12 and C13.
  4. 4. The bird's nest alkane diterpenoid compound according to claim 1, wherein R 1 is CH 2 OH, R 2 is CH 2 OH, R 3 is OH, R 4 is H, and a single bond is formed between C12 and C13.
  5. 5. The bird's nest alkane diterpenoid according to claim 1, wherein R 1 is COOH, R 2 is COOH, R 3 is H, R 4 is H, and a double bond is between C12 and C13.
  6. 6. The bird's nest alkane diterpenoid according to claim 1, wherein R 1 is CH 2 OH, R 2 is COOH, R 3 is H, R 4 is H, and a double bond is between C12 and C13.
  7. 7. The bird's nest alkane diterpenoid according to claim 1, wherein R 1 is CH 3 , R 2 is COOH, R 3 is H, R 4 is =o, and a double bond is between C12 and C13.
  8. 8. The use of a nest alkane diterpenoid compound according to claim 1 for anti-inflammatory activity, promoting nerve cell synaptic growth activity, promoting neurotrophic activity, anti-AD activity or anti-neuritis.
  9. 9. The use of a guanane diterpenoid compound according to claim 2 in the preparation of anti-aging drugs and drugs for treating alzheimer's disease.

Description

Bird nest alkane diterpenoid compound and application thereof in preparation of medicine for treating Alzheimer disease Technical Field The invention belongs to the technical field of medical microbiological chemistry. Background Alzheimer's Disease (AD) is also known as Alzheimer's Disease and senile dementia, and is a common brain neurodegenerative Disease for the elderly. The brain function of the patient gradually declines, and the cognitive function is reduced, emotion and character change are caused, and finally daily life is seriously influenced. AD is often accompanied by aging, and the risk of developing disease increases significantly with age. However, there is very limited awareness of the pathogenesis of AD, which is known to include cholinergic dysfunction, aβ (amyloid beta) plaques, tau aggregation, inflammation, DNA damage and mitochondrial dysfunction. The current treatment strategies mainly restore neurotransmitter levels in the brain, and clinically used AD therapeutic drugs such as acetylcholinesterase inhibitors (donepezil, galantamine and rivastigmine) have limited ability to improve disease progression, and the current pathogenesis of AD is not clear, the pathogenesis is complex, the course of the disease is long and continuously progressed, and the development of anti-AD drugs is severely restricted. Disclosure of Invention In view of the above, it is an object of the present invention to provide a nest alkane diterpenoid compound having excellent anti-AD activity. The nest alkane diterpenoid compound has a typical nest alkane diterpenoid skeleton structure, and the general structural formula of the nest alkane diterpenoid compound is consistent with the following structure; Wherein: R 1 is COOH, COOCH 3、CH2 OH or CH 3; r 2 is CH 2 OH or COOH; r 3 is OH or H; R 4 is H or = O; between C12 and C13 is a single bond or a double bond. The invention also provides a preparation method of the compound, which comprises the following steps: 1) Culturing strain Brevibacterium longum (Cyathus striatus) CGMCC NO 5.1147 in rice culture medium to obtain culture. The culture of the nidulans carinii is subjected to ultrasonic extraction for three times after being soaked by ethyl acetate, ultrasonic extraction is performed once after being soaked by ethanol, the ultrasonic time length of each time is 1h, and organic phases are combined. Concentrating the organic phase by vacuum rotary evaporator to obtain total extract, adding ethyl acetate for dissolving, filtering, and concentrating the filtrate to obtain extract. 2) The extract (CS) is separated by a forward silica gel chromatographic column, 21 sub-fractions are obtained by dichloromethane-methanol gradient elution (v/v 50:1, 25:1, 10:1, 5:1, 0:100), 3 column volumes are eluted by each gradient, the fractions with similar analysis results are combined into four fractions (CS-1-CS-4) by TLC and HPLC analysis, and bird nest diterpenoid compounds exist in the fractions CS-2 and CS-3. 3) CS-2 obtained by dichloromethane-methanol gradient elution (v/v 25:1) is subjected to gradient elution by adopting an ODS reversed phase column and 10% -100% methanol/acid water (0.1%trifluoroacetic acid is added into water, and the same applies below), wherein the volume of each elution column is 3, and 4 sub-fractions CS-2-A-D are obtained. CS-2-A was separated by HPLC on a C8 semi-preparative column under conditions of 35% acetonitrile and aqueous acid to give compound 10 (12.2 mg, t R =22.9 min) by isocratic elution. CS5-2-B was isolated by C8 semi-preparative HPLC under conditions of 33% acetonitrile and aqueous acid and isocratic elution to give compound 9 (8.1 mg, t R =23.9 min), compound 4 (14.1 mg, t R =25.3 min), and compound 7 (5.1 mg, t R =26.0 min). 4) CS-3 obtained by dichloromethane-methanol gradient elution (v/v 10:1) is subjected to ODS reversed phase column, and 10% -100% methanol/acid water is subjected to gradient elution, so that 6 sub-fractions CS-3-A-F are obtained CS-3-B was isolated by C18 semi-preparative HPLC under conditions of 61% methanol and aqueous acid and isocratic elution to give Compound 11 (1.5 mg, t R =20.5 min), compound 1 (4878 mg, t R =27.5 min), compound 2 (6957 mg, t R =30.0 min). CS-3-C was isolated by C8 semi-preparative HPLC using 28% acetonitrile and aqueous acid and isocratic eluting to give compound 5 (3 mg, t R =24.5 min) and compound 3 (2.5 mg, t R =25.5 min). CS-3-E was isolated by C8 semi-preparative HPLC under conditions of 32% acetonitrile and aqueous acid and isocratic elution to give compound 6 (7mg, t R =21.6 min), compound 8 (16 mg, t R =24.5 min). Preferably, in the step 1), the fermentation condition is that the fermentation is performed for 4 weeks under 28 ℃; The culture medium adopted by the fermentation is prepared by 80g of rice and 120mL of distilled water at 115 ℃ and sterilized for 30min. Preferably, in the step 2), the specification of the packing in the normal phase silica gel column is 200-300 me