CN117138054A - Polypeptide conjugate of triptolide and application thereof - Google Patents

Polypeptide conjugate of triptolide and application thereof Download PDF

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Publication number
CN117138054A
CN117138054A CN202210570748.XA CN202210570748A CN117138054A CN 117138054 A CN117138054 A CN 117138054A CN 202210570748 A CN202210570748 A CN 202210570748A CN 117138054 A CN117138054 A CN 117138054A
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substituted
cancer
syndrome
unsubstituted
disease
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贺庆利
仝露
赵群飞
林国强
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Shanghai University of Traditional Chinese Medicine
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Shanghai University of Traditional Chinese Medicine
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic

Abstract

The invention relates to a polypeptide conjugate of triptolide and application thereof. Specifically, the invention discloses a polypeptide-triptolide conjugate formed by coupling triptolide shown in a formula I and analogues thereof with polypeptide molecules through different connecting arms. The polypeptide conjugates have targeted delivery capability, higher antiproliferative activity and improved tolerability compared to triptolide compounds.

Description

Polypeptide conjugate of triptolide and application thereof
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a polypeptide conjugate of triptolide and application thereof in the aspect of treating cancers.
Background
Triptolide is one of the active ingredients of the vine Chinese medicine tripterygium wilfordii. It has been conventionally demonstrated to have anti-inflammatory, immunosuppressive and anticancer activities, etc. Its molecular target has been identified as the XPB (ERCC 3) subunit of the universal transcription factor TFIIH. Its principle of operation is to inhibit RNApol II transcription initiation and nucleoside excision repair. Triptolide and its analogues have been developed as new anticancer and immunosuppressive drugs. However, dose-limiting toxicity and poor water solubility have become major obstacles in their development as new drugs.
In view of this, there is a need in the art to develop a new triptolide drug with targeted delivery capability, higher antiproliferative activity and improved tolerability.
Disclosure of Invention
It is an object of the present invention to provide a triptolide polypeptide conjugate that has a higher anti-tumor proliferation activity and improved tolerance and can target the delivery of Fibroblast Activation Protein (FAP) and its use in the treatment of cancer, immune-related diseases and organ transplant immune rejection.
In a first aspect, the present invention provides the use of a polypeptide conjugate of triptolide of formula I, or a racemate, cis-trans isomer, enantiomer, diastereomer, pharmaceutically acceptable salt, solvate or combination thereof, for the preparation of a pharmaceutical composition for the treatment of cancer and immune related diseases,
Z-L-P-T(I)
wherein,
z has the following structure:
wherein,
r1 is a substituted or unsubstituted C1-C4 alkyl group, said substitution being such that one or more H are substituted with a group selected from the group consisting of: hydroxy, methyl, hydroxymethyl;
r2 is hydroxy; r3 is halogen; or R2 and R3 share the same oxygen (constituting-O-);
R4 is hydroxy; r5 is hydrogen, or R4 and R5 share the same oxygen;
r6 is C1-C3 ketocarbonyl, substituted or unsubstituted C1-C4 alkyl, said substitution being one or more H substituted with a group selected from the group consisting of: hydroxy, methyl, hydroxymethyl;
r'6 is-O- (C1-C4) alkylene-;
ring A is
R7 is absent; r8 is H, in which case,represents a double bond; or R7 and R8 share the same oxygen, in which case->Is a single bond;
r11 and R12 are each independently hydroxyl or hydrogen;
l is represented by-E-W-G-, wherein E and G are each independently absent, -CH 2 -、-CO-、-SO、-SO 2 -、 -OPO-、-OPO 2 -, -NH-; w is an unsubstituted, substituted or unsubstituted group selected from the group consisting of: - (C1-C6) alkylene-, - (CH) 2 ) n O (C1-C6) alkylene-, - (CH) 2 ) n C (O) (C1-C6) alkylene-, - (CH) 2 ) n C (O) O (C1-C6) alkylene-, - (CH) 2 ) n NH (C1-C6) alkylene-, - (CH) 2 ) n C (O) NH (C1-C6) alkylene-, - (CH) 2 ) n S (C1-C6) alkylene-, - (CH) 2 ) n C(O)(CH 2 ) n S (C1-C6) alkylene-, - (C2-C6) alkenylene-, - (CH) 2 ) n (C2-C6) alkenylene-, - (CH) 2 ) n C (O) (C2-C6) alkenylene-, - (CH) 2 ) n C (O) O (C2-C6) alkenylene-, - (CH) 2 ) NH (C2-C6) alkenylene-, - (CH) 2 ) n C (O) NH (C2-C6) alkenylene-, - (CH) 2 ) n S (C2-C6) alkenylene-, - (CH) 2 ) n C(O)(CH 2 ) n S (C2-C6) alkenylene-, - (C2-C6) alkynylene-, - (CH) 2 ) n O (C2-C6) alkynylene-, - (CH) 2 ) n C (O) (C2-C6) alkynylene- (CH) 2 ) n C (O) O (C2-C6) alkynylene- (CH) 2 ) NH (C2-C6) alkynylene- (CH) 2 ) n C (O) NH (C2-C6) alkynylene- (CH) 2 ) n S (C2-C6) alkynylene- (CH) 2 ) n C(O)(CH 2 ) n S (C2-C6) alkynylene-; by substituted is meant that one or more H in the alkylene, alkenylene, alkynylene moiety is substituted with a substituent selected from the group consisting of: C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, amino, hydroxy, oxo, C6-C10 aryl, 5-to 10-membered heteroaryl, carboxy, cyano, nitro, trifluoromethyl;
with the proviso that E, W and G are not both absent;
wherein n is each independently 0, 1, 2, 3, 4, 5, 6;
p is formed by dehydration condensation of two conjugated amino acid molecules P1 and P2, wherein P is connected with L through a carbon atom end of a main chain and is connected with T through an N atom end of the main chain;
wherein P1 has the following structure:
p2 has the following structure:
* Each independently represents a stereochemical isomerism of a carbon atom as R and/or S;
wherein R9 is each independently H, substituted or unsubstituted C1-C6 alkyl; r10 is each independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; or R9 and R10 together with the N and C atoms to which they are attached form a groupA substituted or unsubstituted 5-6 membered heterocyclic ring, said heterocyclic ring containing 1N heteroatom; said substitution means that one or more H is substituted with halogen, C1-C3 alkyl, hydroxy, mercapto, phenyl, hydroxyphenyl, carboxy, -CONH 2 、-NH 3 + Substitution;
each m is independently 1, 2, 3 or 4;
t has the following structure:
wherein B is a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted 5-10 membered heteroaryl, a substituted or unsubstituted C6-C10 cycloalkyl, a substituted or unsubstituted 6-10 membered heterocyclyl, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted C1-C6 alkoxy, said substitution being by 1, 2 or 3 groups selected from the group consisting of: hydroxy, oxo, alkoxy,
In another preferred embodiment, Z has the following structure:
wherein,
r1 is a substituted or unsubstituted isopropyl group, said substitution being that one or more H are substituted with a group selected from the group consisting of: hydroxy, methyl, hydroxymethyl;
r2 and R3 share the same oxygen;
r4 and R5 share the same oxygen;
r6 is C1-C3 ketocarbonyl or hydroxy-substituted C1-C4 alkyl;
ring A is
R7 and R8 share the same oxygen, and in this case,is a single bond;
r11 and R12 are hydrogen;
l is-E-W-G-, wherein E and G are each independently absent, -CO-, -NH-; w is an unsubstituted, substituted or unsubstituted group selected from the group consisting of: - (C1-C6) alkylene-, - (CH) 2 ) n O (C1-C6) alkylene-, - (CH) 2 ) n C (O) (C1-C6) alkylene-, - (CH) 2 ) n NH (C1-C6) alkylene-, said substitution being wherein one or more H's in the alkylene moiety are substituted with a substituent selected from the group consisting of: C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, amino, hydroxy, oxo, carboxy, cyano, nitro, trifluoromethyl;
with the proviso that E, W, G is not absent at the same time;
wherein n is each independently 0, 1, 2 or 3;
p is formed by dehydration condensation of two conjugated amino acid molecules P1 and P2, wherein P is connected with L through a carbon atom end of a main chain and is connected with T through an N atom end of the main chain;
wherein P1 has the following structure:
p2 has the following structure:
* Represents a stereochemical isomerism of a carbon atom, each independently R and/or S;
wherein R9 is each independently H, substituted or unsubstituted C1-C6 alkyl; r10 is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; or R9 and R10 together with the N and C atoms to which they are attached form a 5-6 membered heterocyclic ring; the heterocycle contains 1N atom; the substitution means one or moreH is halogen, C1-C3 alkyl, hydroxy, mercapto, phenyl, hydroxyphenyl, carboxyl, -CONH 2 、-NH 3 + Substitution;
each m is independently 1, 2, 3, 4;
T has the following structure:
wherein B is a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted 5-10 membered heteroaryl, a substituted or unsubstituted 6-10 membered heterocyclyl, a substituted or unsubstituted C1-C6 alkyl, said substitution being by 1, 2 or 3 groups selected from the group consisting of: hydroxy, oxo, alkoxy,
In another preferred embodiment, L is selected from the group consisting of:
in another preferred embodiment, R6 is ketocarbonyl, hydroxymethyl.
In another preferred embodiment, R1 is hydroxy-substituted isopropyl.
In another preferred embodiment, R'6 is-O-CH 2 -。
In another preferred embodiment, the halogen is chlorine.
In another preferred embodiment, B is selected from the group consisting of: a benzene ring,
In another preferred embodiment, L is selected from the group consisting of:
in another preferred embodiment, Z is selected from the group consisting of:
in another preferred embodiment, each of P1 or P2 is independently selected from the group consisting of:
in another preferred embodiment, P1 or P2 are each independently selected from the group consisting of:
in another preferred embodiment, T has a structure selected from the group consisting of:
in another preferred embodiment, the polypeptide conjugate of triptolide is selected from the group consisting of:
in another preferred embodiment, the cancer is selected from the group consisting of: bladder cancer, breast cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, colon cancer, endometrial cancer, head and neck cancer, lung cancer, melanoma, multiple myeloma, non-hodgkin's leukemia, lymphoma, prostate cancer, rectal cancer, malignant melanoma, digestive tract/gastrointestinal cancer, liver cancer, skin cancer, renal cancer, muscle cancer, bone cancer, brain cancer, eye cancer, rectal cancer, colon cancer, oral cancer, benign malignancy, uterine cancer, testicular cancer, renal cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myelogenous leukemia, ewing's sarcoma, kaposi's sarcoma, basal cell carcinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, vascular endothelial tumor, wilms' tumor, neuroblastoma, esophageal cancer, laryngeal carcinoma, neurofibromatosis, tuberous sclerosis, hemangioma and lymphangiogenesis, or a combination thereof.
In another preferred embodiment, the cancer is prostate cancer.
In another preferred embodiment, the cancer is a metastatic cancer.
In another preferred embodiment, the immune-related disorder comprises: organ transplant immune rejection and bone marrow transplant immune rejection.
In another preferred embodiment, the immune-related disorder is selected from the group consisting of: acute Disseminated Encephalomyelitis (ADEM), addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome (ALPS), autoimmune multiple endocrine/multiple glandular syndrome, autoimmune thrombocytopenic purpura, purpura cardiomyopathy, celiac disease-dermatitis herpetiformis, chronic Fatigue Immune Dysfunction Syndrome (CFIDS), chronic inflammatory demyelinating neuropathy, cicatricial pemphigoid, celiac disease, condensation collectin disease, CREST syndrome, crohn's disease, cystic fibrosis, degos ' disease, diabetic dermatitis), early dementia, eczema, endotoxin shock, primary mixed cryoglobulinemia, familial mediterranean fever, fibromyalgia, fibrositis, chronic Fatigue Immune Dysfunction Syndrome (CFIDS) Goldpaster syndrome, graves ' disease, graves-Barlich syndrome (GBS), hashimoto's thyroiditis, suppurative sweat gland, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, igA nephropathy, lanbert-Earthwork weakness syndrome, leukemia, lichen planus, meniere's disease, mixed connective tissue disease, multiple sclerosis, multiple phase disseminated encephalomyelitis, myasthenia gravis, neuromyelitis optica, paraneoplastic syndrome, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, multiple chondritis, polymyositis rheumatica, polymyositis, idiopathic anpropyl globinemia, idiopathic biliary cirrhosis, plaque psoriasis, psoriatic arthritis, raynaud's phenomenon, reiter syndrome, restenosis after angioplasty, rheumatic fever, paraneoplastic disease, rheumatoid arthritis, rheumatoid psoriasis, sarcoidosis, scleroderma, sepsis, sezary's disease, sjogren's syndrome, stiff person syndrome, lupus including Systemic Lupus Erythematosus (SLE), takayasu's arteritis, temporal arteritis (also known as "giant cell arteritis"), transplant or allograft rejection, ulcerative colitis, uveitis, vasculitis, vitiligo, graft-and-host disease, pustular psoriasis, and wegener's granulomatosis (now known as granulomatosis with polyangiitis (GPA), inflammatory bowel disease, acute necrotizing hemorrhagic leukoencephalitis, agaropectinemia, alopecia areata, amyloidosis, anti-GBM/anti-TBM nephritis, anti-phospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia autoimmune autonomic dysfunction, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune Inner Ear Disease (AIED), autoimmune myocarditis, autoimmune thyroid disease, autoimmune urticaria, axonal and neuronal neuropathy, celiac disease, chagas's disease, chronic fatigue syndrome, chronic Inflammatory Demyelinating Polyneuropathy (CIDP), chronic Recurrent Multifocal Ostomy (CRMO), churg-Strauss syndrome, cicatricial pemphigoid/benign mucosal pemphigoid, cogans syndrome, congenital heart block, coxsackie myocarditis, CREST disease, demyelinating neuropathy, dermatitis herpetiformis, devic disease (neuromyelitis optica), discoid lupus, chronic demyelinating polyneuropathy (CIDP), derwiler syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, ewens syndrome, fibroalveolar inflammation, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, granulomatous Polyangiitis (GPA) (formerly known as Wegener's granulomatosis), hashimoto's encephalitis, hashimoto's thyroiditis, hemolytic anemia allergic purpura, herpes gestation, hypogammaglobulinemia, idiopathic Thrombocytopenic Purpura (ITP), igG 4-related sclerosis, immunoregulatory lipoproteins, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes (type 1 diabetes), juvenile myositis, kawasaki syndrome lambert-eaton syndrome, leukocyte-fragmenting vasculitis, lichen sclerosis, ligneous conjunctivitis, linear IgA disease (LAD), lupus (SLE), lyme disease, chronic, microscopic polyangiitis, mor's ulcers, mu Xia-haberman disease, myositis, narcolepsy, neutropenia, ocular cicatricial pemphigus, optic nerve palindromic rheumatism, PANDAS (pediatric autoimmune neuropsychiatric disease associated with streptococci), paraneoplastic cerebellar degeneration, paroxysmal Nocturnal Hemoglobinuria (PNH), parry romig syndrome, parsonnagage-Turner syndrome, pars planitis (exo Zhou Putao membrane inflammation), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, poe ms syndrome, I, II and type III autoimmune polyadendric syndrome, post myocardial infarction syndrome, post-pericarotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure red cell dysregeneration, reactive arthritis, reflex sympathetic dystrophy, recurrent polychondritis, restless leg syndrome, retroperitoneal fibrosis, rheumatic fever, schmitt syndrome, scleritis, sperm and testis autoimmunity, subacute Bacterial Endocarditis (SBE), sulsaxae syndrome, sympathogenic ophthalmitis, thrombocytopenic purpura (TTP), tolassa-hunter syndrome, transverse myelitis, type 1 diabetes mellitus, undifferentiated Connective Tissue Disease (UCTD), and bullous skin disease, or combinations thereof.
In another preferred embodiment, the pharmaceutical composition comprises (a) a therapeutically effective amount of a polypeptide conjugate of triptolide of formula I, or a racemate, cis-trans isomer, enantiomer, diastereomer, pharmaceutically acceptable salt, solvate, or combination thereof, as an active ingredient, and (b) a pharmaceutically acceptable carrier or excipient.
In a second aspect, the present invention provides a polypeptide conjugate of triptolide having a structure of formula I, or a racemate, cis-trans isomer, enantiomer, diastereomer, pharmaceutically acceptable salt, solvate, or combination thereof, according to the first aspect of the present invention,
Z-L-P-T(I)
wherein Z has the following structure:
wherein,
r1 is a substituted or unsubstituted C1-C4 alkyl group, said substitution being such that one or more H are substituted with a group selected from the group consisting of: hydroxy, methyl, hydroxymethyl;
r2 is hydroxy; r3 is halogen; or R2 and R3 share an oxygen (constituting-O-);
r4 is hydroxy; r5 is hydrogen, or R4 and R5 share one oxygen;
r6 is C1-C3 ketocarbonyl, substituted or unsubstituted C1-C4 alkyl, said substitution being one or more H substituted with a group selected from the group consisting of: hydroxy, methyl, hydroxymethyl;
R'6 is-O- (C1-C4) alkylene-;
ring A is
R7 is absent; r8 is H, in which case,represents a double bond;or R7 and R8 share the same oxygen, in which case->Is a single bond;
r11 and R12 are each independently hydroxyl or hydrogen;
l is represented by-E-W-G-, wherein E and G are each independently absent, -CH 2 -、-CO-、-SO、-SO 2 -、 -OPO-、-OPO 2 -, -NH-; w is an unsubstituted, substituted or unsubstituted group selected from the group consisting of: - (C1-C6) alkylene-, - (CH) 2 ) n O (C1-C6) alkylene-, - (CH) 2 ) n C (O) (C1-C6) alkylene-, - (CH) 2 ) n C (O) O (C1-C6) alkylene-, - (CH) 2 ) n NH (C1-C6) alkylene-, - (CH) 2 ) n C (O) NH (C1-C6) alkylene-, - (CH) 2 ) n S (C1-C6) alkylene-, - (CH) 2 ) n C(O)(CH 2 ) n S (C1-C6) alkylene-, - (C2-C6) alkenylene-, - (CH) 2 ) n (C2-C6) alkenylene-, - (CH) 2 ) n C (O) (C2-C6) alkenylene-, - (CH) 2 ) n C (O) O (C2-C6) alkenylene-, - (CH) 2 ) NH (C2-C6) alkenylene-, - (CH) 2 ) n C (O) NH (C2-C6) alkenylene-, - (CH) 2 ) n S (C2-C6) alkenylene-, - (CH) 2 ) n C(O)(CH 2 ) n S (C2-C6) alkenylene-, - (C2-C6) alkynylene-, - (CH) 2 ) n O (C2-C6) alkynylene-, - (CH) 2 ) n C (O) (C2-C6) alkynylene- (CH) 2 ) n C (O) O (C2-C6) alkynylene- (CH) 2 ) NH (C2-C6) alkynylene- (CH) 2 ) n C (O) NH (C2-C6) alkynylene- (CH) 2 ) n S (C2-C6) alkynylene- (CH) 2 ) n C(O)(CH 2 ) n S (C2-C6) alkynylene-; by substituted is meant that one or more H in the alkylene, alkenylene, alkynylene moiety is substituted with a substituent selected from the group consisting of: C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, amino, hydroxy, oxo, C6-C10 aryl, 5-to 10-membered heteroaryl, carboxy, cyano, nitro, trifluoromethyl;
With the proviso that E, W and G are not both absent;
wherein n is each independently 0, 1, 2, 3, 4, 5, 6;
p is formed by dehydration condensation of two conjugated amino acid molecules P1 and P2, wherein P is connected with L through a carbon atom end of a main chain and is connected with T through an N atom end of the main chain;
wherein P1 has the following structure:
p2 has the following structure:
* Each independently represents a stereochemical isomerism of a carbon atom as R and/or S;
wherein R9 is each independently H, substituted or unsubstituted C1-C6 alkyl; r10 is each independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; or R9 and R10 together with the N and C atoms to which they are attached form a substituted or unsubstituted 5-6 membered heterocyclic ring containing 1N heteroatom; said substitution means that one or more H is substituted with halogen, C1-C3 alkyl, hydroxy, mercapto, phenyl, hydroxyphenyl, carboxy, -CONH 2 、-NH 3 + Substitution;
each m is independently 1, 2, 3 or 4;
t has the following structure:
wherein B is a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted 5-10 membered heteroaryl, a substituted or unsubstituted C6-C10 cycloalkyl, a substituted or unsubstituted 6-10 membered heterocyclyl, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted C1-C6 alkoxy, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof By substitution is meant substitution with 1, 2 or 3 groups selected from the group consisting of: hydroxy, oxo, alkoxy,
In a third aspect of the invention, there is provided a method of treating cancer comprising the steps of: administering to a subject in need thereof a safe and effective amount of a polypeptide conjugate of triptolide of formula I, or a racemate, cis-trans isomer, enantiomer, diastereomer, a pharmaceutically acceptable salt, solvate, or combination thereof, wherein the polypeptide conjugate of triptolide of formula I is as described in the first aspect of the invention.
In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the group consisting of: a solid formulation, a liquid formulation, or a combination thereof.
In another preferred embodiment, the dosage form is selected from the group consisting of: injection (such as injection or lyophilized powder for injection), oral preparation (such as capsule, tablet, pill, powder, granule, syrup, oral liquid or tincture), and more preferably, the dosage form is oral preparation.
In another preferred embodiment, the pharmaceutical composition is administered in a manner selected from the group consisting of: oral, subcutaneous, intradermal, intraperitoneal, intravenous, or combinations thereof.
In a fourth aspect of the invention, there is provided a method of immune related disease comprising the steps of: administering to a subject in need thereof a safe and effective amount of a polypeptide conjugate of triptolide of formula I, or a racemate, cis-trans isomer, enantiomer, diastereomer, a pharmaceutically acceptable salt, solvate, or combination thereof, wherein the polypeptide conjugate of triptolide of formula I is as described in the first aspect of the invention.
In a fifth aspect of the present invention, there is provided a method of treating organ transplant immune rejection comprising the steps of: administering to a subject in need thereof a safe and effective amount of a polypeptide conjugate of triptolide of formula I, or a racemate, cis-trans isomer, enantiomer, diastereomer, a pharmaceutically acceptable salt, solvate, or combination thereof, wherein the polypeptide conjugate of triptolide of formula I is as described in the first aspect of the invention.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
FIG. 1 shows the effect of TPL, triptolide polypeptide conjugates A1, A2 and A4 on MIA PaCa-2 cell proliferation.
FIG. 2 shows the effect of TPL, triptolide polypeptide conjugates A1, A3 on HEK293T cell proliferation.
FIG. 3 shows the effect of TPL, triptolide polypeptide conjugates A1, A3 on HUVEC cell proliferation.
FIG. 4 shows the effect of polypeptide conjugate A1 of TPL and triptolide on RNApol II catalytic subunit stability.
FIG. 5 shows the inhibition of RNApol II activity by polypeptide conjugates A2-A4 of TPL and triptolide.
Detailed Description
The present inventors have studied intensively for a long time, and have unexpectedly found and synthesized a polypeptide conjugate of triptolide, or its racemate, cis-trans isomer, enantiomer, diastereomer, pharmaceutically acceptable salt, solvate, or a combination thereof, which is less toxic and better in water solubility, by mass screening. The triptolide polypeptide conjugate has targeting delivery capability, higher antiproliferative activity and improved tolerance, and can be used for inhibiting cell proliferation. On this basis, the present invention has been completed.
Terminology
As used herein, the terms "triptolide polypeptide conjugate" and "triptolide polypeptide conjugate" are used interchangeably.
As used herein, unless otherwise specified, the term "substituted" refers to the substitution of one or more hydrogen atoms on a group with a substituent selected from the group consisting of: C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxy, halogen, hydroxy, carboxyl (-COOH), C1-C10 aldehyde, C2-C10 acyl, C2-C10 ester, amino, phenyl; the phenyl group comprises unsubstituted phenyl or substituted phenyl with 1-3 substituents selected from the group consisting of: halogen, C1-C10 alkyl, cyano, hydroxy, nitro, C3-C10 cycloalkyl, C1-C10 alkoxy and amino.
Unless otherwise specified, each chiral carbon atom in all compounds of the invention may optionally be in the R configuration or S configuration, or a mixture of R and S configurations.
The term "C1-C4 alkyl" refers to a straight or branched alkyl group having 1 to 4 carbon atoms, preferably a straight or branched alkyl group having 1 to 4 carbon atoms; such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
The term "heterocyclyl" refers to a saturated or partially saturated cyclic group having heteroatoms selected from N, S and O, which may be monocyclic or bicyclic, e.g., fused, bridged or spiro. The heterocyclic group is preferably a 4-to 10-membered heterocyclic group, more preferably a 5-to 7-membered heterocyclic group, and still more preferably a 5-to 6-membered heterocyclic group. Examples of heterocyclyl groups include, but are not limited to: azetidine, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, and the like. The heterocyclic group may be fused to an aryl, heteroaryl, heterocyclic or cycloalkyl ring (e.g., to form a [5+3], [5+5], [5+6], [6+5] or [6+6] fused ring system, etc.), wherein the ring attached to the parent structure is a heterocyclic group. Five-membered heterocyclic ring is meant to include five-membered heterocyclic rings and 3-7 membered rings, spiro rings formed by five-membered heterocyclic rings and 3-7 membered rings, bridged rings formed by five-membered heterocyclic rings and 4-7 membered rings. The six-membered heterocyclic ring is intended to include a spiro ring formed by a six-membered and 3-7-membered ring, a spiro ring formed by a six-membered heterocyclic ring and a 3-7-membered ring, and a bridged ring formed by a six-membered heterocyclic ring and a 4-7-membered ring.
In the present invention, the term "aryl" refers to an aromatic ring group containing no heteroatoms in the ring, which may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. Such as phenyl (i.e., C6 aryl or six-membered aryl), naphthyl (i.e., C10 aryl or [6+6] aryl), and the like, wherein six-membered aryl is also intended to include six-membered aryl and 5-6 membered cycloalkyl and six-membered aryl and 5-6 membered heterocyclyl. The term "[5+6] aryl" refers to a fused 6, 5 bicyclic ring system. Aryl is preferably C6-C14 aryl, more preferably C6-C10 aryl. Examples of aryl groups include phenyl, naphthyl. Aryl groups may be optionally substituted or unsubstituted.
The term "heteroaryl" refers to a cyclic aromatic group having 1 to 3 atoms which are heteroatoms selected from the group N, S and O, which may be monocyclic or in the form of condensed rings. In the present invention, the heteroaryl group is preferably a 5-6 membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1, 2, 3) -triazolyl, (1, 2, 4) -triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. The term "[5+6] heteroaryl" refers to fused 6, 5 bicyclic ring systems such as benzothienyl, benzofuranyl, benzimidazolyl, benzotriazole, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, and the like.
The term "halogen" refers to F, cl, br and I.
Unless otherwise indicated, the formulae described herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers), such as R, S configuration containing an asymmetric center, the (Z), (E) isomers of double bonds and the conformational isomers of (Z), (E).
The term "tautomer" means that structural isomers having different energies can exceed the low energy barrier and thus interconvert. For example, proton tautomers (i.e., proton transfer) include interconversions by proton transfer, such as 1H-indazole with 2H-indazole, 1H-benzo [ d ] imidazole with 3H-benzo [ d ] imidazole, valence tautomers include interconversions by recombination of some bonding electrons.
Herein, "C1-C4" is formed, meaning that the group may have 1 to 4 carbon atoms, for example 1, 2, 3, or 4.
In addition to the compounds of the present invention, those skilled in the art will appreciate that chemotherapeutic agents may be used either prior to, concurrently with, or after treatment with the compounds of the present invention. Exemplary agents include, but are not limited to, paclitaxel, cytochalasin B, gramicidin D, ethidium bromide, eta Mi Ting, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracenedione, mitoxantrone, actinomycin D-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin, and analogs or homologs thereof. Therapeutic antibodies or other proteins are also included in the combination therapies of the invention.
As used herein, the term "cancer" or "cancerous growth" refers to uncontrolled abnormal growth of cells and includes within its scope all well known diseases caused by uncontrolled and abnormal growth of cells. Common cancers include bladder cancer, breast cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, colon cancer, endometrial cancer, head and neck cancer, lung cancer, melanoma, multiple myeloma, leukemia (e.g., myeloid, lymphoid, myeloid and lymphocytic leukemia), non-hodgkin's lymphoma, prostate cancer, rectal cancer, and malignant melanoma.
As used herein, the term "share the same oxygen" means that the-O-structure is formed; at this time, the configuration of the "common oxygen" moiety is as follows:
active ingredient
In the present invention, an active ingredient effective in anti-tumor proliferation activity is provided. The active ingredient is a compound shown in a general formula I, and has targeting delivery capability, higher anti-tumor proliferation activity and improved tolerance.
It is to be understood that the active ingredient of the present invention includes a compound of formula (I) as described in the second aspect of the present invention, or a racemate, cis-trans isomer, enantiomer, diastereomer, pharmaceutically acceptable salt, solvate, or combination thereof. It is to be understood that the active ingredients of the present invention also include crystalline, amorphous, and deuterated forms of the compounds of formula (I).
The "pharmaceutically acceptable salts" are conventional non-toxic salts of compounds of formula (I) formed by reaction with inorganic or organic acids. For example, conventional non-toxic salts can be prepared by reacting a compound of formula (I) with inorganic acids including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid, phosphoric acid, and the like, or with organic acids including citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, sulfanilic acid, 2-acetoxybenzoic acid, isethionic acid, and the like; or the compound of the general formula (I) forms sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt with inorganic base after forming ester with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid or glutamic acid; or a methylamine salt, ethylamine salt or ethanolamine salt of a compound of the general formula (I) with an organic base; or the compound of the general formula (I) forms ester with lysine, arginine and ornithine and then forms corresponding inorganic acid salt with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid or corresponding organic acid salt with formic acid, acetic acid, picric acid, methanesulfonic acid or ethanesulfonic acid.
Pharmaceutical composition and application
The invention also provides the application of the mixture of one or more of racemates, cis-trans isomers, enantiomers, diastereoisomers, pharmaceutically acceptable salts and solvates as the active ingredients in preparing the medicaments for treating cancers and immune related diseases, wherein the mixture has targeting delivery capability, higher anti-tumor proliferation activity and improved tolerance.
The pharmaceutical composition provided by the invention preferably contains 0.001-99wt% of active ingredient, the preferable proportion is that the compound of the general formula (I) is used as the active ingredient to account for 0.1wt% -90wt% of the total weight, and the rest is pharmaceutically acceptable carrier, diluent or solution or salt solution.
If necessary, one or more pharmaceutically acceptable carriers can be added into the medicine. The carrier comprises diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants and the like which are conventional in the pharmaceutical field.
The compounds and pharmaceutical compositions provided herein may be in a variety of forms, such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols and the like, and may be presented in a suitable solid or liquid carrier or diluent and in a suitable sterilization apparatus for injection or infusion.
The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The dosage form formulations generally contain from 0.05 to 400mg of the compound of formula (I) per unit dose, preferably from 1 to 500mg of the compound of formula (I) per unit dose.
The compounds and pharmaceutical compositions of the present invention may be used clinically in mammals, including humans and animals, by oral, nasal, dermal, pulmonary or gastrointestinal routes of administration. Most preferably orally. Most preferably, the daily dosage is 0.01-400 mg/kg body weight, and the medicine is taken at one time or is taken in divided parts of 0.01-200 mg/kg body weight. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment. Usually starting from a small dose, gradually increasing the dose always finds the most appropriate dose.
The agents or inhibitors of the invention may be administered by a variety of different means, for example, by injection, spraying, nasal drops, eye drops, permeation, absorption, physical or chemical mediated methods, into the body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue; or mixed or wrapped by other materials and introduced into the body.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; sixth, adsorbing agents such as kaolin; (i) Lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like. In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like. Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof. Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., other antiviral agents).
The methods of treatment of the present invention may be administered alone or in combination with other therapeutic means or agents.
Compared with the prior art, the invention has the main advantages that:
(a) The polypeptide conjugate of triptolide has higher anti-tumor proliferation activity and improved tolerance.
(b) The polypeptide conjugate of triptolide provided by the invention has better water solubility and lower toxicity.
(c) The triptolide polypeptide conjugate has a targeted delivery effect.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
EXAMPLE 1 Synthesis of polypeptide-triptolide conjugate A1
(a) Synthesis of intermediate X
2-chlorotrityl resin (0.5 g,0.7 mmol) was accurately weighed, swollen for half an hour in 5mL DCM, DCM was removed and washed 2 times with 5mL DMF; fmoc-L-Pro-OH (2 eq), DIEA (12 eq) was added and after 4h reaction on a horizontal shaker the solvent was removed; in 5mL DCM: meOH: DIEA (16:3:1) mixture was washed 2 times for 10min each with MeOH 3 times; finally, the mixture was washed with 5mL of DMF 2 times. Fmoc was removed with 20% pyridine solution and reacted on a horizontal shaker for half an hour, washed 1 time with 5mL DMF, 5 times with 5mL DCM, and 1 time with 5mL DMF. Fmoc-Gly-OH (2 eq) was added and HBTU/HOBt/DIEA (1:1:2) as condensing agent, 2eq, 4eq were added separately and reacted on a horizontal shaker for 3-4 hours, washed three times with DCM and finally once with DMF. Fmoc was removed with 20% pyridine solution and reacted on a horizontal shaker for half an hour, washed 1 time with 5mL DMF, 5 times with 5mL DCM, and 1 time with 5mL DMF. Isonicotinic acid (2 eq) was added, HBTU/HOBt/DIEA (1:1:2) as condensing agent, 2eq, 4eq were added respectively, reacted on a horizontal shaker for 3-4 hours, washed three times with DCM and finally once with DMF. Washing with DCM three times, reacting with 1% TFA in the resin on a horizontal shaker for 30min, washing with DCM three times, washing with MeOH 3 times, taking the washing solution, removing the solvent, and precipitating with cold diethyl ether to obtain the tripeptide crude product. Purification by C18 packed column chromatography, meOH in ammonium acetate gradient. And removing the solvent in vacuum to obtain an intermediate X tripeptide product.
(b) Synthesis of polypeptide-triptolide conjugate A1
TPL (50 mg), N-Boc-GABA-OH (8 eq), DCC (8 eq), DMAP (1 eq), 25g anhydrous Na 2 SO 4 20mL of DCM was added to a 50mL reaction flask and reacted at room temperature for 6h, TLC monitored the reaction, EA: PE (1:1, v/v) developing agent, hani's western style coloring agent as a color developing agent, filtering after the raw material point disappears, taking filtrate, removing solvent, dissolving with a small amount of DCM, filtering, taking filtrate, and obtaining a crude product. Purification of the product by silica gel column chromatography, EA: PE system 10% -40% gradient elution, vacuum removing solvent. 16mg of the reaction product of the previous step was taken as a starting material and 25% TFA (3 mL) was added, stirred for 15min under ice bath conditions, saturated NaHCO was added 3 The solution was quenched, extracted 3 times with DCM, the organic phase was taken and the solvent was removed for the next reaction. Tripeptide (2 eq,15.36 mg), HBTU (2 eq,21.01 mg), HOBt (2 eq, 7.49 mg), DIEA (4 eq,18.3 μl) and 0.5mL DMSO were added to the product of the previous step, anhydrous and anaerobic operation, and stirred overnight at room temperature. Freeze-drying the reaction system, separating the product on a semi-preparation liquid phase instrument, wherein the detection wavelength is 235nm, and the separation condition is 30% ACN: h 2 And (3) isocratic elution of the O-formic acid system.
1H NMR (600 MHz, methanol-d 4): delta 8.89 (d, J=5.5 Hz, 2H), 8.22-8.17 (m, 2H), 5.07 (s, 1H), 4.85-4.74 (m, 2H), 4.45-4.41 (m, 1H), 4.34-4.23 (m, 2H), 3.96 (s, 1H), 3.77-3.71 (m, 1H), 3.70-3.64 (m, 1H), 3.62 (s, 1H), 3.46 (dd, J=5.7, 1.9Hz, 1H), 2.80-2.73 (m, 1H), 2.65 (d, J=2.0 Hz, 1H), 2.54-2.35 (m, 2H), 2.29-2.18 (m, 3H), 2.11-1.97 (m, 4H), 1.95 (s, 1H), 3.7-3.64 (m, 1H), 3.62 (dd, 1H), 3.46 (dd, J=5.7, 1.9Hz, 1H), 2.80-2.73 (m, 1H), 2.65 (d, J=2.0 Hz, 1H), 2.54-2.35 (m, 2H), 2.29-2.18 (m, 3H), 2.11-1.97 (m, 4H), 1.95 (3H), 3.7 Hz, 3.7 (3H) 37 H 44 N 4 O 10 required[M+1]+m/z 705.3130, found m/z 705.3292.13C NMR (600 MHz, methanol-d 4): delta 174.65, 173.12,172.65,167.89,164.74,162.44,145.46,124.11,123.86,71.39,70.57, 63.56,62.79,61.39,60.71,59.72,55.43,54.76,46.51,42.05,40.02,38.20,35.41, 31.00,29.51,29.40,28.07,24.37 (d, J=3.6 Hz), 22.75.
EXAMPLE 2 Synthesis of polypeptide-triptolide conjugate A2
Experimental protocol the experimental procedure was the same as in scheme i except that the starting materials for intermediates X and L were different from scheme i. The product was A2. The synthetic raw materials of the intermediate X are Fmoc-L-Gly-OH, fmoc-L-Pro-OH and isonicotinic acid, and the raw materials of the intermediate X are N-Boc-beta-Ala-OH.
1H NMR(600MHz,Methanol-d4)δ8.70(d,J＝6.2Hz,2H),7.83(d,J＝6.3 Hz,2H),5.09(s,1H),4.46–4.41(m,1H),4.31–4.18(m,2H),3.97(d,J＝3.2Hz, 1H),3.68–3.61(m,2H),3.55–3.45(m,3H),2.81–2.72(m,1H),2.70–2.57(m, 2H),2.30–2.15(m,3H),2.15–1.98(m,4H),1.96–1.83(m,3H),1.51–1.44(m, 1H),1.38–1.26(m,3H),1.00(s,3H),0.94(d,J＝6.9Hz,3H),0.82(d,J＝7.0Hz, 3H).13C NMR(600MHz,Methanol-d4)δ174.64,173.08,171.03,168.11,166.50, 162.39,149.65,149.62,141.89,124.13,121.62,71.60,70.57,63.56,62.77,61.58, 60.67,59.82,55.55,54.77,41.93,40.01,35.39,34.94,33.46,29.43,29.41,28.10, 24.27,22.75,16.52,16.49,15.72,12.84.
EXAMPLE 3 Synthesis of polypeptide-triptolide conjugate A3
Experimental protocol the experimental procedure was the same as in scheme i except that the starting materials for intermediates X and L were different from scheme i. The product was A3.
The synthetic raw materials of the intermediate X are Fmoc-L-Gly-OH, fmoc-L-Pro-OH and isonicotinic acid, and the L raw material is N-Boc-Gly-OH.
1H NMR (600 MHz, methanol-d 4): delta 8.72-8.68 (m, 2H), 7.86-7.80 (m, 2H), 5.10 (s, 1H), 4.83-4.74 (m, 2H), 4.52 (dd, J=8.5, 3.3Hz, 1H), 4.27 (d, J=9.1 Hz, 1H), 4.07 (d, J=7.2 Hz, 1H), 3.95 (dd, J=9.7, 3.2Hz, 1H), 3.80-3.74 (m, 1H), 3.69-3.62 (m, 2H), 3.47 (d, J=5.6 Hz, 1H), 2.79-2.75 (m, 1H), 2.32-2.10 (m, 5H), 2.10-2.00 (m, 2H), 1.99-1.85 (m, 3H), 1.50-1 Hz, 1.9 Hz, 1H), 3.80-3.74 (m, 1H), 3.69-3.62 (m, 2H), 3.47 (d, J=5.6 Hz, 1H), 2.79-2.75 (m, 1H), 2.32-2.10 (m, 3Hz, 1H), 1.10-2.9 (3H), 3.9 (3H, 3H) 39 H 48 N 4 O 10 required[M+1]+m/z 677.2817, found m/z 677.2851.13C NMR (600 MHz, methanol-d 4): delta 174.63,173.51,169.14,168.22, 166.58,162.37,149.60,141.93,124.13,121.61,72.16,70.56,63.43,62.78,61.41, 60.44,59.46,55.39,54.74,46.44,41.89,40.67,40.03,35.39,29.44,29.29,27.46, 24.23,22.74,16.49,16.41,15.64,12.80.
EXAMPLE 4 Synthesis of polypeptide-triptolide conjugate A4
Experimental protocol the experimental procedure was the same as in scheme i except that the starting materials for intermediates X and L were different from scheme i. The product was A4.
The synthetic raw materials of the intermediate X are Fmoc-L-Gly-OH, fmoc-L-Pro-OH and m-hydroxybenzoic acid, and the L raw material is N-Boc-Gly-OH.
1H NMR(600MHz,Methanol-d4)δ7.33–7.25(m,3H),6.98–6.93(m,1H), 5.10(s,1H),4.55–4.47(m,1H),4.23(s,1H),4.01(s,1H),3.93(d,J＝3.2Hz,1H), 3.80–3.73(m,1H),3.69–3.59(m,2H),3.47(d,J＝5.7Hz,1H),2.79–2.74(m, 1H),2.29–1.85(m,11H),1.47–1.41(m,1H),1.35–1.26(m,3H),1.01(s,3H), 0.93(d,J＝7.0Hz,3H),0.82(d,J＝6.9Hz,3H).13C NMR(600MHz, Methanol-d4))δ174.67,169.15,162.40,157.55,129.29,124.14,118.45,117.82, 113.90,72.13,70.57,62.80,61.42,60.44,59.44,55.42,54.74,41.91,40.72,40.03, 35.38,29.44,29.28,27.38,24.19,22.73,16.49,16.38,15.61,12.78.
Example 5
Experimental protocol the experimental procedure was the same as in scheme i except that the starting materials for intermediates X and L were different from scheme i. The product was A5.
The synthetic raw materials of the intermediate X are Fmoc-L-Gly-OH and isonicotinic acid, and the L raw material is N-Boc-Gamma-ABU-OH.
1H NMR(600MHz,Methanol-d4):δ8.89-8.78 (m, 2H), 8.11-8.03 (m, 2H), 5.08 (s, 1H), 4.85-4.73 (m, 2H), 4.11 (d, j=1.8 hz, 2H), 3.96 (d, j=3.1 hz, 1H), 3.89 (s, 2H), 3.62 (d, j=3.1 hz, 1H), 3.47 (d, j=5.7 hz, 1H), 2.81-2.72 (m, 1H), 2.55-2.39 (m, 2H), 2.31-2.17 (m, 2H), 2.06 (s, 1H), 1.95-1.79 (m, 4H), 1.52-1.43 (m, 1H), 1.38-1.29 (m, 1H), 1.01 (s, 3H), 0.93 (dd, j=7.0, 1.7hz, 1H), 2.55-2.39 (m, 2H), 2.31-2.17 (m, 2H), 1.95-1.79 (m, 4H), 3.52-1.43 (m, 3H) 34 H 40 N 4 O 10 required[M+1]+m/z 665.2817, found m/z 665.2849.13C NMR (600 MHz, methanol-d 4) delta 174.69,172.68, 170.35,170.17,165.80,162.48,147.27,144.47,124.12,122.95,71.37,70.59, 63.53,62.80,61.41,59.72,55.41,54.78,43.06,42.12,40.03,38.29,35.41,31.06, 29.41,28.05,24.35,22.75,16.51,15.70,12.78.
Example 6
Experimental protocol the experimental procedure was the same as in scheme i except that the starting materials for intermediates X and L were different from scheme i. The product was A6.
The synthetic raw materials of the intermediate X are Fmoc-beta-Ala-OH, fmoc-L-Pro-OH and isonicotinic acid, and the L raw material is N-Boc-Gamma-ABU-OH.
1 H NMR(600MHz,Methanol-d 4 ) Delta 8.90 (s, 2H), 8.21 (d, J=6.3 Hz, 2H), 5.08 (s, 1H), 4.37 (dd, J=8.6, 4.1Hz, 1H), 3.97 (d, J=3.3 Hz, 1H), 3.76-3.56 (m, 5H), 3.46 (d, J=5.6 Hz, 1H), 2.83-2.68 (m, 3H), 2.52-2.38 (m, 2H), 2.30-2.17 (m, 3H), 2.11-1.81 (m, 9H), 1.47 (dd, J=12.6, 5.4Hz, 1H), 1.34 (dt, J=12.1, 6.1 Hz, 2H), 1.01 (d, J=4.5 Hz, 2H), 0.96-0.90 (m, 3H), 0.83 (dd, 6.17 (m, 3H), 2.11-1.81 (m, 5Hz, 1H), 1.34 (j=12.1, 1Hz, 1H), 1.34 (d, 3.9) 38 H 46 N 4 O 10 required[M+1] + m/z 719.3287, found m/z 719.3301. 13 C NMR(600MHz,Methanol-d 4 ):δ174.67,173.49,172.73,171.04, 164.16,162.45,147.91,144.91,124.07(d,J＝11.7Hz),71.39,70.58,63.58,62.80, 61.42,60.36,59.75,55.47,54.74,40.01,38.14,35.91,35.41,33.23,30.98,29.75, 29.42,28.07,24.42,24.33,22.74,16.52(d,J＝5.3Hz),15.72,12.81.
Example 7
Cytotoxicity test
Cytotoxicity experiments were performed on human pancreatic cancer cell MIA-PaCa-2 cell lines, and each drug (triptolide, polypeptide conjugates A1, A2 and A4 of triptolide, respectively) was administered in parallel 3 times. After the end of the administration, incubation was carried out for 72 hours, cell viability was measured using Alamar Blue, fluorescence intensity was measured after 6 hours of addition of Alamar Blue solution, and cytotoxicity curves were plotted. Cell culture conditions were 5% CO 2 、37℃。
As shown in FIG. 1, the results demonstrate that the compounds of the present invention exhibit toxicity to cancer cell MIA-PaCa-2 cell lines comparable to Triptolide (TPL).
Cytotoxicity experiments were performed in human embryonic kidney cell HEK293T cell line and HUVEC cells, respectively, in 3 replicates for each drug (triptolide, polypeptide conjugates A1 and A3 of triptolide, respectively). After the end of the administration, incubation was carried out for 72 hours, cell viability was measured using Alamar Blue, fluorescence intensity was measured after 6 hours of addition of Alamar Blue solution, and cytotoxicity curves were plotted. Cell culture conditions were 5% CO 2 The results are shown in FIGS. 2 and 3 at 37 ℃.
The IC50 and DC50 values of TPL, triptolide polypeptide conjugates A1, A3 on human embryonic kidney cells HEK293T and HUVEC are shown in Table 1.
Table 1 IC 50 Value and normalized IC 50 Value (100% TPL)
TPL A1 A3
HUVEC cell IC 50 (nM) 13.72 202.90 15.44
HUVEC cell DC 50 Value of (100％) (1479％) (113％)
HEK293T cell IC 50 (nM) 2.29 14.65 3.98
HEK293T cell DC 50 Value of (100％) (640％) (174％)
As can be seen from table 1, the toxicity of the compound A1 and the compound A3 to normal cells is significantly reduced compared with that of triptolide, which proves that the structural modification of Triptolide (TPL) of the present invention effectively improves the safety thereof. In particular, compound A1 was about 14-fold and 6-fold safer for HUVEC cells and HEK293T cells than TPL. Compound A3 also showed higher safety against human embryonic kidney cells HEK 293T.
Example 8 RNAPol II degradation experiment
In this example, the activity of different triptolide polypeptide conjugates was evaluated in vitro, and their inhibition of the activity of the transcriptional proteins was evaluated.
The more the triptolide polypeptide conjugate or the positive control compound (triptolide) is tested to induce and catalyze RNAPol II to degrade, the stronger the inhibition capability of the compound on the activity of the transcription protein is shown.
RNAPol II degradation experiments were detected using western blotting. TPL and triptolide polypeptide conjugates with different concentrations are given to cells, and degradation conditions of RNApol II in the cells are detected after 6 hours, and beta-actin is used as an internal reference.
The results are shown in FIGS. 4 and 5.
The lower the RNApol II transcriptional protein content, the stronger the inhibition of RNA Pol II activity by the triptolide polypeptide conjugate, thus indicating that the cytotoxic potential mechanism of the triptolide polypeptide conjugate is to inhibit protein transcription. According to the experimental results, A4 has stronger inhibition capability on RNAPol II catalytic subunit, and A1 and A2 show weaker activity. All triptolide polypeptide conjugates showed similar transcriptional protein inhibition by triptolide.
Example 9
FAP enzymolysis experiment
After first incubating 100. Mu. Mol/L of the triptolide polypeptide conjugate with 0.5. Mu.g/mL of rhFAP in PBS buffer (pH 7.4) at 37 ℃, the hydrolysis efficiency of the rhFAP protein on the triptolide polypeptide conjugate was evaluated. The enzymatic hydrolysis of triptolide polypeptide conjugates was monitored by adding acetonitrile inactivating protein at each time point, collecting samples, and analyzing the samples using LR LC-MS. Detection conditions: UV detection at 230 nm; chromatographic column: COSMOSIL pi NAP naphthalene primary spectrum column, 4.61ID x 250mm; flow rate: 1.0mL/min; eluent: acetonitrile/0.1% (v/v) aqueous formic acid; the procedure is as follows: 5% -100% acetonitrile in 20 min (gradient elution); sample injection amount: 20. Mu.L. And (3) detecting hydrolysis conditions according to the total ion flow extraction target peak, integrating and quantifying on ultraviolet chromatography, and analyzing the enzymolysis efficiency of the triptolide polypeptide conjugate on FAP.
The results are shown in Table 2.
TABLE 2
Compounds of formula (I) A1 A2 A3 A4
FAP enzymolysis efficiency 33.65％ 83.82％ 99.02％ 92.18％
According to Table 2, it can be seen that polypeptide modified triptolide can be digested by FAP, and is a prodrug capable of targeted delivery. The compounds A3 and A4 have higher enzymolysis efficiency and lower enzymolysis efficiency of A1. The higher enzymolysis efficiency shows that the targeting delivery effect is better, and A3 and A4 have better targeting delivery effects.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (10)

1. The use of a polypeptide conjugate of triptolide of formula I, or a racemate, cis-trans isomer, enantiomer, diastereomer, pharmaceutically acceptable salt, solvate or combination thereof, for the preparation of a pharmaceutical composition for the treatment of cancer and immune related diseases,
Z-L-P-T (I)
wherein,
z has the following structure:
wherein,
r1 is a substituted or unsubstituted C1-C4 alkyl group, said substitution being such that one or more H are substituted with a group selected from the group consisting of: hydroxy, methyl, hydroxymethyl;
r2 is hydroxy; r3 is halogen; or R2 and R3 share the same oxygen;
r4 is hydroxy; r5 is hydrogen, or R4 and R5 share the same oxygen;
r6 is C1-C3 ketocarbonyl, substituted or unsubstituted C1-C4 alkyl, said substitution being one or more H substituted with a group selected from the group consisting of: hydroxy, methyl, hydroxymethyl;
R'6 is-O- (C1-C4) alkylene-;
ring A is
R7 is absent; r8 is H, in which case,represents a double bond; or R7 and R8 share the same oxygen, in which case->Is a single bond;
r11 and R12 are each independently hydroxyl or hydrogen;
l is represented by-E-W-G-, wherein E and G are each independently absent, -CH 2 -、-CO-、-SO、-SO 2 -、-OPO-、-OPO 2 -, -NH-; w is an unsubstituted, substituted or unsubstituted group selected from the group consisting of: - (C1-C6) alkylene-, - (CH) 2 ) n O (C1-C6) alkylene-),-(CH 2 ) n C (O) (C1-C6) alkylene-, - (CH) 2 ) n C (O) O (C1-C6) alkylene-, - (CH) 2 ) n NH (C1-C6) alkylene-, - (CH) 2 ) n C (O) NH (C1-C6) alkylene-, - (CH) 2 ) n S (C1-C6) alkylene-, - (CH) 2 ) n C(O)(CH 2 ) n S (C1-C6) alkylene-, - (C2-C6) alkenylene-, - (CH) 2 ) n (C2-C6) alkenylene-, - (CH) 2 ) n C (O) (C2-C6) alkenylene-, - (CH) 2 ) n C (O) O (C2-C6) alkenylene-, - (CH) 2 ) NH (C2-C6) alkenylene-, - (CH) 2 ) n C (O) NH (C2-C6) alkenylene-, - (CH) 2 ) n S (C2-C6) alkenylene-, - (CH) 2 ) n C(O)(CH 2 ) n S (C2-C6) alkenylene-, - (C2-C6) alkynylene-, - (CH) 2 ) n O (C2-C6) alkynylene-, - (CH) 2 ) n C (O) (C2-C6) alkynylene- (CH) 2 ) n C (O) O (C2-C6) alkynylene- (CH) 2 ) NH (C2-C6) alkynylene- (CH) 2 ) n C (O) NH (C2-C6) alkynylene- (CH) 2 ) n S (C2-C6) alkynylene- (CH) 2 ) n C(O)(CH 2 ) n S (C2-C6) alkynylene-; by substituted is meant that one or more H in the alkylene, alkenylene, alkynylene moiety is substituted with a substituent selected from the group consisting of: C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, amino, hydroxy, oxo, C6-C10 aryl, 5-to 10-membered heteroaryl, carboxy, cyano, nitro, trifluoromethyl;
With the proviso that E, W and G are not both absent;
wherein n is each independently 0, 1, 2, 3, 4, 5, 6;
p is formed by dehydration condensation of two conjugated amino acid molecules P1 and P2, wherein P is connected with L through a carbon atom end of a main chain and is connected with T through an N atom end of the main chain;
wherein P1 has the following structure:
p2 has the following structure:
* Each independently represents a stereochemical isomerism of a carbon atom as R and/or S;
wherein R9 is each independently H, substituted or unsubstituted C1-C6 alkyl; r10 is each independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; or R9 and R10 together with the N and C atoms to which they are attached form a substituted or unsubstituted 5-6 membered heterocyclic ring containing 1N heteroatom; said substitution means that one or more H is substituted with halogen, C1-C3 alkyl, hydroxy, mercapto, phenyl, hydroxyphenyl, carboxy, -CONH 2 、-NH 3 + Substitution;
each m is independently 1, 2, 3 or 4;
t has the following structure:
wherein B is a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted 5-10 membered heteroaryl, a substituted or unsubstituted C6-C10 cycloalkyl, a substituted or unsubstituted 6-10 membered heterocyclyl, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted C1-C6 alkoxy, said substitution being by 1, 2 or 3 groups selected from the group consisting of: hydroxy, oxo, alkoxy,
2. The use according to claim 1, wherein,
z has the following structure:
wherein,
r1 is a substituted or unsubstituted isopropyl group, said substitution being that one or more H are substituted with a group selected from the group consisting of: hydroxy, methyl, hydroxymethyl;
r2 and R3 share an oxygen;
r4 and R5 share an oxygen;
r6 is C1-C3 ketocarbonyl or hydroxy-substituted C1-C4 alkyl;
ring A is
R7 and R8 share the same oxygen, and in this case,is a single bond;
r11 and R12 are hydrogen;
l is-E-W-G-, wherein E and G are each independently absent, -CO-, -NH-; w is an unsubstituted, substituted or unsubstituted group selected from the group consisting of: - (C1-C6) alkylene-, - (CH) 2 ) n O (C1-C6) alkylene-, - (CH) 2 ) n C (O) (C1-C6) alkylene-, - (CH) 2 ) n NH (C1-C6) alkylene-, said substitution being wherein one or more H's in the alkylene moiety are substituted with a substituent selected from the group consisting of: C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, amino, hydroxy, oxo, carboxy, cyano, nitro, trifluoromethyl;
with the proviso that E, W, G is not absent at the same time;
wherein n is each independently 0, 1, 2 or 3;
p is formed by dehydration condensation of two conjugated amino acid molecules P1 and P2, wherein P is connected with L through a carbon atom end of a main chain and is connected with T through an N atom end of the main chain;
Wherein P1 has the following structure:
p2 has the following structure:
* Represents a stereochemical isomerism of a carbon atom, each independently R and/or S;
wherein R9 is each independently H, substituted or unsubstituted C1-C6 alkyl; r10 is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; or R9 and R10 together with the N and C atoms to which they are attached form a 5-6 membered heterocyclic ring; the heterocycle contains 1N atom; said substitution means that one or more H is substituted with halogen, C1-C3 alkyl, hydroxy, mercapto, phenyl, hydroxyphenyl, carboxy, -CONH 2 、-NH 3 + Substitution;
each m is independently 1, 2, 3, 4;
t has the following structure:
wherein B is a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted 5-10 membered heteroaryl, a substituted or unsubstituted 6-10 membered heterocyclyl, a substituted or unsubstituted C1-C6 alkyl, said substitution being by 1, 2 or 3 groups selected from the group consisting of: hydroxy, oxo, alkoxy,
3. Use according to claim 1, wherein L is selected from the group consisting of:
4. use according to claim 1, wherein Z is selected from the group consisting of:
5. the use according to claim 1, wherein P1 or P2 are each independently selected from the group consisting of:
6. The use according to claim 1, wherein T has a structure selected from the group consisting of:
7. the use according to claim 1, wherein the polypeptide conjugate of triptolide is selected from the group consisting of:
8. the use of claim 1, wherein the cancer is selected from the group consisting of: bladder cancer, breast cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, colon cancer, endometrial cancer, head and neck cancer, lung cancer, melanoma, multiple myeloma, non-hodgkin's leukemia, lymphoma, prostate cancer, rectal cancer, malignant melanoma, digestive tract/gastrointestinal cancer, liver cancer, skin cancer, renal cancer, muscle cancer, bone cancer, brain cancer, eye cancer, rectal cancer, colon cancer, oral cancer, benign malignancy, uterine cancer, testicular cancer, renal cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myelogenous leukemia, ewing's sarcoma, kaposi's sarcoma, basal cell carcinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, vascular endothelial tumor, wilms' tumor, neuroblastoma, esophageal cancer, laryngeal carcinoma, neurofibromatosis, tuberous sclerosis, hemangioma and lymphangiogenesis, or a combination thereof.
9. The use according to claim 1, wherein the immune-related disorder is selected from the group consisting of: acute Disseminated Encephalomyelitis (ADEM), addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome (ALPS), autoimmune multiple endocrine/multiple glandular syndrome, autoimmune thrombocytopenic purpura, purpura cardiomyopathy, celiac disease-dermatitis herpetiformis, chronic Fatigue Immune Dysfunction Syndrome (CFIDS), chronic inflammatory demyelinating neuropathy, cicatricial pemphigoid, celiac disease, condensation collectin disease, CREST syndrome, crohn's disease, cystic fibrosis, degos ' disease, diabetic dermatitis), early dementia, eczema, endotoxin shock, primary mixed cryoglobulinemia, familial mediterranean fever, fibromyalgia, fibrositis, chronic Fatigue Immune Dysfunction Syndrome (CFIDS) Goldpaster syndrome, graves ' disease, graves-Barlich syndrome (GBS), hashimoto's thyroiditis, suppurative sweat gland, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, igA nephropathy, lanbert-Earthwork weakness syndrome, leukemia, lichen planus, meniere's disease, mixed connective tissue disease, multiple sclerosis, multiple phase disseminated encephalomyelitis, myasthenia gravis, neuromyelitis optica, paraneoplastic syndrome, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, multiple chondritis, polymyositis rheumatica, polymyositis, idiopathic anpropyl globinemia, idiopathic biliary cirrhosis, plaque psoriasis, psoriatic arthritis, raynaud's phenomenon, reiter syndrome, restenosis after angioplasty, rheumatic fever, paraneoplastic disease, rheumatoid arthritis, rheumatoid psoriasis, sarcoidosis, scleroderma, sepsis, sezary's disease, sjogren's syndrome, stiff person syndrome, lupus including Systemic Lupus Erythematosus (SLE), takayasu's arteritis, temporal arteritis (also known as "giant cell arteritis"), transplant or allograft rejection, ulcerative colitis, uveitis, vasculitis, vitiligo, graft-and-host disease, pustular psoriasis, and wegener's granulomatosis (now known as granulomatosis with polyangiitis (GPA), inflammatory bowel disease, acute necrotizing hemorrhagic leukoencephalitis, agaropectinemia, alopecia areata, amyloidosis, anti-GBM/anti-TBM nephritis, anti-phospholipid syndrome (APS), autoimmune angioedema, autoimmune regenerative anemia, autoimmune autonomic nerve dysfunction autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune Inner Ear Disease (AIED), autoimmune myocarditis, autoimmune thyroid disease, autoimmune urticaria, axonal and neuronal neuropathy, celiac's celiac disease, chagas's disease, chronic fatigue syndrome, chronic Inflammatory Demyelinating Polyneuropathy (CIDP), chronic recurrent multifocal stomatitis (CRMO), churg-Strauss syndrome, cicatricial pemphigoid/benign pemphigoid, cogans syndrome, congenital heart block, coxsackie myocarditis, CREST disease, demyelinating neuropathy, dermatitis herpetiformis, devic disease (neuromyelitis optica), discoid lupus, texler syndrome, chronic recurrent multifocal stomatitis (CRMO), endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, EWens ' syndrome, fibroalveolar inflammation, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, granulomatous Polyangiitis (GPA) (formerly known as Wegener granulomatous), hashimoto's encephalitis, hashimoto's thyroiditis, hemolytic anemia allergic purpura, herpes gestation, hypoproteinemia, idiopathic Thrombocytopenic Purpura (ITP), igG 4-related sclerosis, immunomodulatory lipoproteins, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes (type 1 diabetes), juvenile myositis, kawasaki syndrome, lanbert-Eton syndrome leucocyte-disintegrating vasculitis, lichen sclerosus, lignan conjunctivitis, linear IgA disease (LAD), lupus (SLE), lyme disease, chronic, microscopic polyangiitis, moren's ulcer, mu Xia-Haeman's disease, myositis, narcolepsy, neutropenia, ocular cicatricial pemphigoid, optic palindromic rheumatism, PANDAS (Streptococcus-associated pediatric autoimmune neuropsychiatric disease), paraneoplastic cerebellar degeneration, paroxysmal Nocturnal Hemoglobinuria (PNH), parry Romberg syndrome, parsonnag-Turner syndrome, pars planitis (exo Zhou Putao membranitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, POEMS syndrome, I, II and type III autoimmune polyadenopathy syndrome, post myocardial infarction syndrome, post-pericardial syndrome, post-operative syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure erythrocyte dysregeneration, reactive arthritis, reflex sympathetic dystrophy, recurrent polychondritis, restless leg syndrome, retroperitoneal fibrosis, rheumatic fever, schmitt syndrome, scleritis, sperm and testis autoimmunity, subacute Bacterial Endocarditis (SBE), soxak syndrome, sympathogenic ophthalmitis, thrombocytopenic purpura (TTP), toloxa-hunter syndrome, transverse myelitis, type 1 diabetes, undifferentiated Connective Tissue Disease (UCTD) and bullous dermatoses, or combinations thereof.
10. The use according to claim 1, wherein the pharmaceutical composition comprises (a) a therapeutically effective amount of a polypeptide conjugate of triptolide of formula I, or a racemate, cis-trans isomer, enantiomer, diastereomer, pharmaceutically acceptable salt, solvate, or combination thereof, as an active ingredient, and (b) a pharmaceutically acceptable carrier or excipient.
CN202210570748.XA 2022-05-24 2022-05-24 Polypeptide conjugate of triptolide and application thereof Pending CN117138054A (en)

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