61 results about "Podophyllotoxin derivatives" patented technology

[PROBLEMS] A novel podophyllotoxin derivative, which is capable of releasing a drug without depending on biological enzymes and can be expected to have an effective therapeutic effect and is soluble in water has been demanded.[MEANS FOR SOLVING PROBLEMS] A polymer having a polyethyleneglycol structural unit and two or more succinic monoamide structural units, particularly a polymer conjugate of a podophyllotoxin in which a carboxylic acid group of polyethyleneglycol / polyaspartic acid copolymer and a hydroxyl group of podophyllotoxin and linked via an ester bond is provided.

The invention refers to new compounds, e.g. podophyllotoxin derivatives, as well as to the use thereof and of known compounds as specific inhibitors of the insulin-like growth factor-1 receptor (IGF-1R). Said compounds can be used for treatment of IGF-1 / IGF-1R dependent diseases, such as cancer, psoriasis, arteriosclerosis, certain endocrine and metabolic disorders etc.

The invention discloses a sulfur-substituted podophyllotoxin derivative as well as a synthetic method and application thereof. The podophyllotoxin derivative, shown by a formula (V), with significantly improved anti-tumor activity and reduced toxic or side effect is obtained by introducing an aromatic heterocyclic compound with rigidity and a further sulfonamide product of 3-amino-5-mercapto-1,2,4-triazole, 2-amino-5-mercapto-1,3,4-thiadiazole, and 4-methyl benzenesulfonyl chloride or 4-methoxy benzenesulfonyl chloride, serving as substituent groups, into the fourth position of a C ring of podophyllotoxin or 4'-demethylepipodophyllotoxin respectively. An activity inhibition experiment of tumor cells in vitro shows that the anti-tumor activity of the compound shown by the formula (V) is significantly improved as compared with that of podophyllotoxin or 4'-demethylepipodophyllotoxin.

Disclosed in the present invention is a podophyllotoxin derivative, and a preparation method, pharmaceutical composition and use thereof. The preparation method disclosed in the present invention comprises the following step: in an organic solvent, in the presence of a base, carrying out a condensation reaction between the compound as shown in formula II and the compound as shown in formula III under the action of a condensating agent. The pharmaceutical composition disclosed in the present invention comprises the podophyllotoxin derivative as shown in formula I and a pharmaceutically acceptable excipient. Also disclosed in the present invention is the use of the podophyllotoxin derivative as shown in formula I in the preparation of a drug for treating a cancer. The podophyllotoxin derivative of the present invention has a good tumour cell inhibitory activity, and the preparation method and post-treatment thereof are simple, with good prospects for market development.

The invention discloses a 4-amino oxadiazole epipodophyllotoxin derivative and a preparation method and application thereof. The 4-amino oxadiazole epipodophyllotoxin derivative has a structure shown as a Formula (1), wherein R1 represents hydrogen or methyl, and R2 represents hydrogen, alkyl, aryl, heteroaryl or heteroaryl alkyl. The derivative is prepared according to the following steps of: firstly, subjecting podophyllotoxin serving as a raw material to azido reaction, reduction, addition and elimination to obtain isothiocyanate epipodophyllotoxin; secondly, reacting an isothiocyanate epipodophyllotoxin intermediate with a hydrazide compound to obtain a thiosemicarbazide derivative; and finally, subjecting to cyclization, and thus obtaining a corresponding 4-amino oxadiazole derivative. The preparation method is simple and is easy to operate. Initial in-vitro screening tests show that the toxicity of the derivative on normal cells is obviously reduced, meanwhile, certain compounds have better anti-tumor activity, and high-efficiency and low-toxicity anti-tumor drugs can be expected to be prepared.

The invention relates to improvements in the field of drug delivery. More particularly, the invention relates to polypeptides having a hydrolyzable covalent bond to a therapeutic agent that includes, etoposide, etoposide 4′-dimethylglycine or doxorubicin. These polypeptide conjugates can be used as vectors to transport the podophyllotoxin derivative across the blood brain barrier (BBB) or into particular cell types such as ovary, liver, lung, or kidney. The invention also relates to pharmaceutical compositions that include the compounds of the invention and to uses thereof in methods of treatment.

The invention discloses a nitrogen-substituted podophyllotoxin derivative with anti-tumor activity and a preparation method and use thereof. According to the method, 2-aminopyrimidine, 2-aminopyridine, 2-amino-3-methylpyridine, 2-amino-4-methylpyridine, 2-amino-5-methylpyridine, 2-amino-4,6-dimethyl pyridine, 3-aminopyridine, 3-amino-4-methylpyridine, 5-amino-2-methylpyridine, 3-amino-2-chloropyridine or 4-amino-2-chloropyridine is respectively introduced to an activated C-ring fourth position of a podophyllotoxin compound through nitrogen substitution reaction, so as to obtain the nitrogen-substituted podophyllotoxin derivative, represented by a formula (V) shown in the specification, with excellent anti-tumor activity. The nitrogen-substituted podophyllotoxin derivative disclosed by the invention acts on tumor cells through multiple ways and multiple target points, and the anti-tumor activity of the nitrogen-substituted podophyllotoxin derivative is remarkably improved compared with that of the podophyllotoxin compound. The compound disclosed by the invention can be used for preparing anti-tumor drugs and is clinically applied to anti-tumor treatment.

The invention relates to improvements in the field of drug delivery. More particularly, the invention relates to polypeptides having a hydrolyzable covalent bond to a therapeutic agent that includes, etoposide, etoposide 4′-dimethylglycine or doxorubicin. These polypeptide conjugates can be used as vectors to transport the podophyllotoxin derivative across the blood brain barrier (BBB) or into particular cell types such as ovary, liver, lung, or kidney. The invention also relates to pharmaceutical compositions that include the compounds of the invention and to uses thereof in methods of treatment.

The invention belongs to the technical field of chemical pharmacy, and particularly relates to podophyllotoxin derivatives and application of the podophyllotoxin derivatives in aspect of tumor suppression. Corresponding compound is obtained through a synthesis technology, and activity studies on antitumor in vitro show that the podophyllotoxin derivatives have strong inhibitory activity to tumor cell strains.

The invention discloses an aromatic heterocyclic ester podophyllotoxin derivative represented by formula (I), its preparation method and its use in the preparation of antitumor drugs. The present invention combines podophyllotoxin with 4-thiazole formic acid, 1-methylpyrazole-4-formic acid, 1-methylimidazole-4-formic acid, isoquinoline-1-formic acid, 2-quinoxaline formic acid, 1- Esterification with cyclopropyl-1,4-dihydro-4-oxo-6-fluoro-7-chloroquinoline-3-carboxylic acid, 1-methylindazole-3-carboxylic acid or thioindene-2-carboxylic acid , to obtain the aromatic heterocyclic ester podophyllotoxin derivatives represented by the formula (I) with antitumor activity. In vitro cell activity experiments prove that the aromatic heterocyclic ester podophyllotoxin derivatives of the present invention can inhibit the proliferation of tumor cells, have significant antitumor activity, and are expected to be prepared as podophyllotoxin antitumor drugs.

The invention relates to 4-deoxidized-iso-podophyllotoxin derivatives displayed by formula (1) and the intermediate series of compounds of 4-deoxidized-iso-podophyllotoxin derivatives or the pharmaceutical salt or solvates of the 4-deoxidized-iso-podophyllotoxin derivatives. The invention also relates to the preparation method, the drug combinations, and the pharmaceutical applications of compounds in the formula (1). The compounds possess strong activity in inhibiting tumor cell growth, some of which having stronger cytotoxic activity to human body tumor cell lines in vitro than etoposide, the prior first class anti-tumor drug, thereby the compounds are expected to serve the purpose of such cancer drugs as anti-lung cancer drugs, anti-hepatoma drugs, and anti-cerbical cancer drugs; since the cytotoxicity of the related compounds to KB cells and PC-3 cells is approximate to or equivalent to etoposide, and meanwhile the compounds have strong etoposide to CNE cells, the compounds are expected to used in anti-tumor drugs, such as, anti-oral epithelial carcinoma drugs, nasopharyngeal carcinoma drugs, and prostate cancer drugs.

The invention discloses a podophyllotoxin derivative with a structure as shown in a formula I or a pharmaceutically acceptable salt or solvate. The invention further discloses application of the podophyllotoxin derivative or the pharmaceutically acceptable salt or solvate in preparation of a tubulin inhibitor, proliferation of tumor cells can be inhibited on the cellular level, growth of transplanted tumors in nude mice can be inhibited on the animal level, and the podophyllotoxin derivative or the pharmaceutically acceptable salt or solvate can be used for treating various cancers. And the podophyllotoxin derivative has low toxic and side effects, almost has no obvious toxicity to normal cells, and improves the safety.

The invention discloses a preparation method of intelligent hydrogel of a podophyllotoxin derivative. The method includes steps: preparing aldehyde glucan, bonding the podophyllotoxin derivative to a glucan chain through Schiff base reaction; subjecting to cross linking with carboxymethyl chitosan to form the intelligent hydrogel of the podophyllotoxin derivative. The hydrogel is capable of effectively improving water solubility of the podophyllotoxin derivative, and by a highly-hydrophilic internal structure of the hydrogel, a water-soluble anticancer drug can be further wrapped during hydrogel formation, and drug combination is realized. According to in-vitro drug release behaviors, the hydrogel has acid-base, reductant and enzyme sensitive multi-response drug release behaviors and is capable of releasing the podophyllotoxin derivative in a colon environment, thereby serving as a colon-targeted multi-drug controlled-release carrier for preparing colon-targeted controlled-release drugs.

The invention provides a podophyllotoxin lipid derivative, a nano-carrier, a preparation method thereof and an application of the podophyllotoxin lipid derivative and the nano-carrier in tumor treatment. The podophyllotoxin lipid derivative is prepared by adopting a podophyllotoxin drug mother nucleus as a hydrophobic nucleus, linking a micromolecular hydrophilic group on the podophyllotoxin drug mother nucleus to form the podophyllotoxin derivative, and introducing a highly hydrophobic long-chain fat-soluble substance to play a stabilizing role. The podophyllotoxin lipid nano-carriers with different structures can be synthesized by changing the types and sizes of the small molecules and the fat-soluble substances and the feeding ratio of the fat-soluble substances to the podophyllotoxin derivatives. The podophyllotoxin lipid derivative provided by the invention overcomes the limitations of low solubility and toxic and side effects of podophyllotoxin, and meanwhile, the podophyllotoxin lipid nano-carrier prepared by the invention has a lipid bilayer structure and an acid / enzyme sensitive connecting bond, and has the characteristic of regulating PD-L1 expression; therefore, the product has the application of tumor microenvironment response and immune escape prevention, and has a wide application prospect in the fields of chemotherapy and immunotherapy in tumor treatment.

Disclosed is the novel use of some Aza-podophyllotoxin derivatives (AZPs) for modulation of the immune system (immunomodulation), including a method for modulating an immune response comprising administering to a subject an effective amount of at least one Aza-podophyllotoxin derivative of general formula wherein A-ring is selected from the group consisting of 1,3-dioxolane, cyclopentane, 1,4-dioxane, one methoxy, two methoxys, and ethyl; and wherein E-ring is selected from the group consisting of dimethoxyanisole, veratrol, anisole, benzene, syringol, bromobenzene, chlorobenzene, 1,2-dichlorobenzene, 2,3-dimethoxybenzene, 3,4,5-trimethoxybenzene.

Formulations and uses of the formulations for treating a malignant mass in a mammal by administering an injectable formulation comprising a therapeutically effective amount of a chemotherapeutic agent dissolved or suspended in a biocompatible carrier directly into the malignant mass are disclosed. In certain preferred embodiments, the injectable formulation is a taxane (e.g. paclitaxel), a podophyllotoxin derivative (e.g., etoposide), or a camptothecin derivative (e.g., hydroxycamptothecin).

The invention discloses a prodrug of a podophyllotoxin (POD) derivative. The prodrug is formed by acid-sensitive imine bond covalent combination of a medicine molecule and hydrophilic short-chain polyethylene glycol (PEG), wherein the medicine molecule is the podophyllotoxin derivative namely amino podophyllotoxin (NPOD), and the drug loading capacity can reach over 35%. The prodrug can form a micelle with a nano structure through a self-assembly manner in a water solution. The invention further discloses application of a self-assembled prodrug micelle as a novel medicine carrier to loading hydrophobic drugs such as taxol to realize the co-therapeutic effect of the medicine. The prodrug disclosed by the invention has the advantages of simple preparation method, environmental friendliness and economical benefit, and has greater application value in the biomedical field.

The invention discloses benzenesulfonamide phenylbutyric acid podophyllotoxin carboxylic ester derivatives as well as a synthesis method and application thereof, belongs to the technical field of chemical pharmacy. The invention particularly relates to podophyllotoxin derivatives and application thereof in tumor inhibition. Corresponding benzene sulfonamide phenylbutyric acid is connected with podophyllotoxin through a synthesis means to obtain corresponding ester derivatives, and in-vitro anti-tumor activity research shows that the podophyllotoxin carboxylic ester derivatives have very strong inhibitory activity on tumor cell strains.

The invention discloses a podophyllotoxin structure modified derivative and a preparation method thereof, and belongs to the technical field of organic chemical synthesis. The derivative is an N-substituted-4[beta]-amino-4-deoxy epipodophyllotoxin derivative, the structural formula of the derivative is shown as a formula (I), and in the formula (I), R1 and R2 are independently selected from phenyl, 2-thienyl, alkyl-substituted aryl, halogen-substituted aryl, C1-C6 alkyl or camphor substituent. The preparation method of the podophyllotoxin structure modified derivative has the advantages of being mild in synthesis condition, easy to operate, high in product yield, high in atom economy and the like, has good scientific research value and application prospect, provides a brand new route for structural modification of the compound, can play an important role in the field of synthesis of drug intermediates, pesticide intermediates and the like, reduces the production cost, and has good application value and potential in industry and scientific research.

The invention discloses a novel multifunctional podophyllotoxin derivate as well as a preparation method and application thereof, and belongs to the technical field of anti-tumor active compound synthesis. The invention is characterized in that the novel multifunctional podophyllotoxin derivate has a structural formula which is shown in the description, wherein n is equal to 0 to 8. The invention also discloses the preparation method of the novel multifunctional podophyllotoxin derivative and the application of the derivative in the preparation of antitumor drugs. A kind of bifunctional inhibitor which not only can inhibit the topoisomerase of tumor cells but also can inhibit matrix metalloproteinase in microenvironment is prepared, and has excellent biological activity: (1) inhibiting liver cancer and colon cancer cell growth in vitro and in vivo; (2) inhibiting angiogenesis and inhibiting cancer cell metastasis in a very low concentration; (3) inhibiting DNA topoisomerase and matrix metalloproteinase.

The invention discloses a series of new 4alpha-acyloxy-2'(2',6'),2alpha-polyhalogenated podophyllotoxin derivatives and a preparation method thereof. The chemical general formula of the series of 4alpha-acyloxy-2'(2',6'),2alpha-polyhalogenated podophyllotoxin derivatives is shown in the specification, wherein X is Cl, Y is H, or X and Y are Cl, or X is Br and Y is H. The preparation method comprises the following steps: performing E-cyclohalogenation, C-4 hydroxy protection, C-2alpha-chloro, and C-4 deprotection on podophyllotoxin used as a raw material so as to obtain 2'(2',6'),2alpha-polyhalogenated podophyllotoxin, and finally reacting DMAP / DCC or BF3.Et2O used as a esterification reagent C-4-OH with 11 carboxylic acids so as to obtain the 4alpha-acyloxy-2'(2',6'),2alpha-polyhalogenated podophyllotoxin derivatives, wherein the C-cycloacrylated product is produced in accompanying when the BF3.Et2O is used as the esterification reagent. The test shows that the 4alpha-acyloxy-2'(2',6'),2alpha-polyhalogenated podophyllotoxin derivatives have good insecticidal activity which is partially higher than that of the podophyllotoxin, wherein the insecticidal activities of a plurality of compounds are higher than that of commercial botanical pesticide toosendanin, and a botanical insecticide with high efficiency and low toxicity can be hopefully prepared from the 4alpha-acyloxy-2'(2',6'),2alpha-polyhalogenated podophyllotoxin derivatives.

Disclosed are a 4-sulfur substituted podophyllotoxin derivative and a synthetic method therefor and the use thereof. In the present invention, introducing heteroaromatic compounds with rigidity, such as 4-trifluoromethylpyridin-2-thiol, 4-trifluoromethyl-2-mercaptopyrimidine, and para-fluorothiophenol, respectively as substituent groups to position 4 of C ring of a podophyllotoxin or 4′-demethylepipodophyllotoxin, obtaining a podophyllotoxin derivative as shown in formula (V) with a significantly improved antitumour activity and reduced toxic side effects. Experiments of in vitro tumour cell activity inhibition indicate that the antitumour activity of the compound as shown in formula (V) of the present invention is significantly improved compared to that of the podophyllotoxin or 4′-demethylepipodophyllotoxin.

Disclosed in the present invention is a podophyllotoxin derivative, and a preparation method, pharmaceutical composition and use thereof. The preparation method disclosed in the present invention comprises the following step: in an organic solvent, in the presence of a base, carrying out a condensation reaction between the compound as shown in formula II and the compound as shown in formula III under the action of a condensating agent. The pharmaceutical composition disclosed in the present invention comprises the podophyllotoxin derivative as shown in formula I and a pharmaceutically acceptable excipient. Also disclosed in the present invention is the use of the podophyllotoxin derivative as shown in formula I in the preparation of a drug for treating a cancer. The podophyllotoxin derivative of the present invention has a good tumour cell inhibitory activity, and the preparation method and post-treatment thereof are simple, with good prospects for market development.

The invention discloses a podophyllotoxin compound containing a 1,2,4-triazone structure, and an application thereof. The compound has a structure represented by general formula (I). Podophyllotoxin derivatives containing 1,2,4-triazone, represented by the general formula (I), and pharmaceutically acceptable salts thereof have antitumor effects. In-vitro cell activity experiments prove that the podophyllotoxin derivatives containing 1,2,4-triazone have a good inhibition effect on a human chronic myelocytic leukemia cell K562, a human cervical carcinoma cell Hela and a human breast cancer cellMCF-7. The compounds have a good antitumor medicine exploitation and application prospect.

The invention provides a novel etoposide derivative with a hydroxamic acid structure as showed in the general formula I, a pharmaceutically-acceptable salt of the etoposide derivative, a preparation method of the etoposide derivative and usage of the etoposide derivative. In the general formula I, X is -NH-, -O-, -S-, -NH-CH2-, -O-CH2- or -S-CH2-; Y is aromatic ring, substituted aromatic ring, aromatic hyterocyclic ring or substituted aromatic hyterocyclic ring; Z is -O-, -NHCO- or -CONH-; and B is C1-C8 alkyl, C2-C8 alkenyl, alkynyl or cycloalkyl. The compound provided by the invention has good antitumor activity and can be applied clinically by oral administration, intravenous injection or intramuscular injection.

Disclosed are a 4-sulfur substituted podophyllotoxin derivative and a synthetic method therefor and the use thereof. In the present invention, introducing heteroaromatic compounds with rigidity, such as 4-trifluoromethylpyridin-2-thiol, 4-trifluoromethyl-2-mercaptopyrimidine, and para-fluorothiophenol, respectively as substituent groups to position 4 of C ring of a podophyllotoxin or 4demethylepipodophyllotoxin, obtaining a podophyllotoxin derivative as shown in formula (V) with a significantly improved antitumour activity and reduced toxic side effects. Experiments of in vitro tumour cell activity inhibition indicate that the antitumour activity of the compound as shown in formula (V) of the present invention is significantly improved compared to that of the podophyllotoxin or 4demethylepipodophyllotoxin.

The present invention relates to a compound of general formula (A). The invention provides asynthesis of new 4β-amidotriazole linked podophyllotoxin derivatives of general formulae 8a-z to 9a-z useful as potential anticancer agents against human cancer cell lines and process for the preparation thereof. Wherein n=0, 1 and R1-R5═[H, CI, F, CH3, OCH3, 3,4(-OCH2O—), CF3, OCF3, m-OC6H5, OH]