CN-121987787-A - Application of cembrane diterpenoid compounds in preparation of medicines for preventing or treating inflammatory diseases mediated by inflammatory corpuscles

Abstract

The invention relates to an application of a cembrane diterpenoid compound in preparing a medicine for preventing or treating inflammatory diseases mediated by inflammatory corpuscles, wherein the cembrane diterpenoid compound is isolated from Sinularia flexibilis soft corals or Sinularia manaarensis soft corals, and the cembrane diterpenoid compound is cembrane diterpenoid lactone (cembranolide).

Inventors

• HUANG CONGLONG
• XU ZHIHONG
• ZHANG DAIJIA
• LIU YIYING
• CHEN YULI

Assignees

• 长庚学校财团法人长庚科技大学

Dates

Publication Date

20260508

Application Date

20251031

Priority Date

20241101

Claims (10)

1. 1. Use of a composition in the manufacture of a medicament for preventing or treating an inflammatory disease mediated by an inflammatory body in a subject, wherein the composition comprises a cembrane diterpenoid.
2. 2. The use of claim 1, wherein the cembrane diterpenoid compound is a cembrane diterpenoid lactone.
3. 3. The use of claim 2, wherein the cembrane diterpene lactone comprises dehydro-softening corallolactone (dehydrosinulariolide), dihydro-australian-butanone alcohol (dihydroaustrasulfone alcohol), dihydro-softening corallolide (dihydrosinularin), 5-epi-softening corallolide (5-epi-sinuleptolide), 11-epi-softening corallolide acetate (11-epi-sinulariolide acetate), softening corallolide (sinularin), gorgonian lactone (sinulariolide) or softening corallolide (sinuleptolide).
4. 4. The use of claim 3, wherein the cembrane diterpene lactone is sarcodictyins (sinularin).
5. 5. The use of claim 1, wherein the effective dose of the cembrane diterpenoid compound is from 0.4 mg/kg body weight to 6.1 mg/kg body weight of a 60 kg human.
6. 6. The use of claim 1, wherein the effective dose of the cembrane diterpenoid compound is from 0.4 mg/kg body weight to 0.8 mg/kg body weight of a 60 kg human injected dose.
7. 7. The use of claim 1, wherein the effective dose of the cembrane diterpenoid compound is from 2 mg/kg body weight to 4.1 mg/kg body weight of a 60 kg human topical application dose.
8. 8. The use of claim 1, wherein the inflammatory body-mediated inflammatory disease comprises stroke, type 2 diabetes, atherosclerosis, severe acute respiratory syndrome coronavirus type 2, acute respiratory distress syndrome, acute lung injury, inflammatory bowel disease, atopic dermatitis, psoriasis, alopecia areata, systemic lupus erythematosus, lupus nephritis caused by systemic lupus erythematosus, gouty arthritis, rheumatic diseases, human autoimmune skin diseases, alzheimer's disease, parkinson's disease, huntington's disease, or cold-imidacloprid-related periodic syndrome.
9. 9. The use of claim 8, wherein the cold-imidazoline-related periodic syndrome comprises familial cold autoinflammatory syndrome, muckle-Wells syndrome, or chronic infant neurocutaneous joint syndrome.
10. 10. The use of claim 1, wherein the individual is a human or non-human mammal.

Description

Application of cembrane diterpenoid compounds in preparation of medicines for preventing or treating inflammatory diseases mediated by inflammatory corpuscles Technical Field The invention relates to application of a cembrane diterpenoid compound in preparing a medicine for preventing or treating inflammatory diseases mediated by inflammatory corpuscles, in particular to application of a cembrane diterpenoid lactone compound comprising dehydro-soft coralline (dehydrosinulariolide), dihydro-australian-butanone alcohol (dihydroaustrasulfone alcohol), dihydro-soft coralline (dihydrosinularin), 5-epi-sinuleptolide), 11-epi-soft coralline acetate (11-epi-sinulariolide acetate), soft coralline (sinularin), willow coralline (sinulariolide) or soft coralline (sinuleptolide) in preparing a medicine for preventing or treating inflammatory diseases mediated by inflammatory corpuscles. Background Nucleotide binding oligomerization domain-like receptor protein 3 (nucleic acid-binding oligomerization domain-like receptor FAMILY PYRIN domain containing; NLRP 3) inflammation partner (inflammasome) is a multiprotein complex formed by the combination of NLRP3 protein and apoptosis-related speckle-like protein (apoptosis-associated speck-like protein containing a CARD; ASC) and procaspase-1 (pro-caspase-1), and when cells are stimulated to initiate NLRP3 inflammation partner activation, NLRP3, ASC and pro-caspase-1 undergo oligomerization, ASC aggregates to form ASC spots (ASC speck), which initiate pro-caspase-1 self-cleavage to form activated caspase-1, thereby promoting maturation of inflammatory factors and triggering a specific lytic programmed cell death (lytic programmed CELL DEATH), called apoptosis (pyroptosis). The manifestation and action of NLRP3 inflammatory corpuscles are regulated by two steps, a pretreatment step (PRIMING STEP; later signal I) and an activation step (later signal II). Signal I can provide substances required for NLRP3 inflammatory corpuscles. In signal I, macrophage membrane surface receptor recognizes pathogen-associated molecular patterns pathogen-associated molecular patterns (PAMPs) released from infected or injured cells, initiates the nuclear factor-activated B cell kappa light chain enhancer (NF-. Kappa.B), and promotes transcription and translation of NLRP3 inflammatory minibody-associated proteins. Lipopolysaccharide (lipopolysaccharides, LPS) on bacterial surface is common PAMPs, and can activate NF- κB through Toll-like receptor-4 (Toll like receptor-4, TLR 4), and promote expression of NLRP3, interleukin-1 beta precursor (proIL-1 beta) and interleukin-18 precursor (proIL-18) proteins in cells. In the step of activating NLRP3 inflammasome, a number of substances are known to act as activators of NLRP3 inflammasome, which produce activated NLRP3 inflammasome through different action pathways in cells. Adenosine triphosphate (adenosine triphosphate; ATP), monosodium urate (monosodium urate crystals; MSU), imiquimod (IMQ) and nigericin (nigericin) are common NLRP3 inflammatory body activators, which can cause the phenomena of intracellular potassium ion outflow, reactive oxygen species (reactive oxygen species; ROS) generation, lysosome rupture and the like, activate NLRP3 inflammatory bodies, and cause procaspase-1 (pro-caspase-1) to self-lyse and release caspase-1 (caspase-1). Caspase-1 not only matures interleukin-1 beta (interleukin beta; IL-1 beta) and interleukin-18 (interleukin; IL-18) inflammatory factors, but also activates GASDERMIN D (GSDMD), causing holes to form on the cell membrane, inducing apoptosis and aggravating inflammatory response of surrounding tissues. The natural compound has the advantages of rich sources and diversified skeletons, and is an important basis for drug development. From 1981 to 2019, nearly half of the drugs newly approved by the U.S. food and drug administration come from natural substances or derivatives thereof, such as cocaine (cocaine) -derived narcotics, morphine (morphine) -derived analgesics, vincristine (vincristine), doxorubicin (doxorubicin) and paclitaxel (paclitaxel) for treating cancers, fungus-derived penicillin (penicillin) was used as an antibiotic, etc., and therefore, the present invention actively studied which natural compounds have the effect of inhibiting NLRP3 inflammatory bodies and further developed the potential of novel drugs for treating or preventing inflammatory body-mediated inflammatory diseases. Disclosure of Invention The invention separates the cilostane diterpenoid (cembrane-TYPE DITERPENE) compound from the soft coral and tests the inhibition effect of the compound on nucleotide binding oligomerization domain-like receptor protein 3 (nucleotide-binding oligomerization domain-like receptor FAMILY PYRIN domain containing; NLRP 3) inflammation corpuscles. In some embodiments, the cembrane diterpenoid compounds of the present invention are isolated from Sinularia flexibilis soft corals or Sinularia manaarensis so