27 results about "Anti proliferative" patented technology

The invention belongs to the technical field of biological medicine, and particularly relates to an N-aryl substituted amide as a novel HDAC6 (histone deacetylase 6) inhibitor and application of the N-aryl substituted amide in preparation of antitumor drugs. A compound shown as a formula (I) is screened and synthesized on the basis of an artificial intelligence technology; the compound shows excellent inhibitory activity on HDAC6, and can be used for efficiently inhibiting HDAC6 and / or HDAC1; in addition, anti-tumor cell proliferation evaluation further reveals that the compound can significantly inhibit proliferation of tumor cells. Based on the excellent enzyme inhibition activity and the cellular level anti-proliferation effect, the compound can be used for preparing medicines for treating tumors, autoimmune diseases, inflammation or Alzheimer's disease, and has a wide development prospect.

The invention discloses a formamide pyrazole compound as well as a pharmaceutical composition and application thereof. The compound has a structure as shown in a formula (I), has relatively strong anti-proliferative activity on a TRK xDFG mutation drug-resistant cell strain Ba / F3-LMNA-NTRK1-G667C, can effectively down-regulate the TRKAG667C protein level in a Ba / F3-LMNA-NTRK1-G667C cell, has an application value as a TRK degradation agent, is used for preparing an anti-tumor drug, and particularly provides a new drug molecule for treating mutation drug-resistant cancers.

The invention relates to the field of medicinal chemistry, and particularly discloses an mTOR / GLS1 double-target inhibitor as well as a preparation method and medical application thereof. The compound is based on a rapamycin structure, an amide side chain containing pyridopyrimidine-thiadiazole substitution is introduced to a 42-O site, and through reasonable Linker connection, double-target synergistic inhibition on mammal rapamycin target protein (mTOR) and glutaminase 1 (GLS1) is realized. The compound can block glycometabolism and glutamine metabolism reprogramming of tumor cells at the same time, so that proliferation and metastasis of the tumor cells are remarkably inhibited, and drug resistance is reduced. In-vivo and in-vitro experiment results show that the compounds show excellent anti-proliferative activity in various breast cancer cell lines, and the representative compound I-4 has a relatively strong inhibition effect on mTOR and GLS1, can significantly inhibit tumor metastasis in an animal model, and has no obvious toxic or side effect. The mTOR / GLS1 double-target inhibitor provided by the invention can be used as an important candidate for developing novel efficient and low-toxicity antitumor drugs.

The invention discloses an antiproliferative synergistic antifungal drug composition based on a notopterygium incisum source, and relates to the technical field of drug preparation, the antiproliferative synergistic antifungal drug composition comprises a first active component and a second active component, the first active component is an anti-proliferative active component and is selected from at least one of the following two compounds: class A: giant column alkane sesquiterpenoids; the class B is a cycloartane type triterpenoid compound; the second active component is a synergistic antifungal active component and is composed of an active component A and an active component B; the pharmaceutical composition takes a specific active component from notopterygium incisum as a core, and can accurately induce apoptosis of target cells, efficiently inhibit proliferation of the target cells, remarkably enhance the antibacterial activity of the antifungal drug and greatly reduce the clinical dosage and toxic risk of the antifungal drug; the natural active components are excellent in biocompatibility and high in medication safety, and can synchronously realize dual effects of disease treatment and infection protection.

The present invention relates to the field of medical technology, and specifically discloses a near-infrared fluorescent diagnostic and therapeutic probe that can monitor ERα protein degradation in real time, as well as its preparation method and application. The highly ERα-targeting fluorophore 2-(6-hydroxy-2-(4-hydroxystyryl)-4H-benzopyran-4-subunit) malononitrile is used as a warhead that specifically binds to the target protein, methyl VHL is used as a ligand to recruit E3 ligase, and carbon chains of different lengths are used as linkers to design and synthesize a series of near-infrared fluorescent diagnostic and therapeutic probes that can monitor ERα protein degradation in real time. The diagnostic and therapeutic NIR probe of the present invention can not only effectively degrade ERα protein, but also exhibit excellent anti-proliferative activity. This innovative study successfully integrated PROTAC technology with a fluorescent probe targeting ERα for the first time, realizing real-time visualization of ERα protein degradation in MCF-7 cells. These results provide strong support for the potential application prospects of this type of compound in the treatment of breast cancer and expand the application field of PROTAC technology.

The invention discloses a targeted protein degradation agent utilizing a ubiquitin-proteasome pathway as well as a preparation method and application of the targeted protein degradation agent, and belongs to the technical field of biological medicines. On the basis of a PROTAC (protein targeted degradation chimera) strategy and on the basis of imatinib, different Linkers are introduced to be connected with an E3 ubiquitin enzyme ligand Nutlin-3 derivative, a degradation tag is labeled on BCR-ABL cancer protein, and the degradation agent with the Bcr-Abl protein targeting capacity is constructed. A Western blot experiment shows that the targeted protein degradation agent shows a good degradation effect on the Bcr-Abl protein in K562 cells, and the compound WP shows a degradation effect on concentration dependence and time dependence of the Bcr-Abl protein. Tumor cell proliferation experiments show that the compound has certain inhibitory activity on K562 cells. Wherein when the Linker is dodecane-1, 12-diketone, the anti-proliferative activity is the best. An apoptosis experiment and a period experiment show that the targeted protein degradation agent can realize concentration-dependent promotion of cell apoptosis and retard cells in S and G1 / G0 periods.

The present application provides a fused ring diimide derivative, which has a chemical structure described in formula I. The present application also provides a preparation method thereof. The fused ring diimide derivative of the present application has excellent anti-tumor activity, and the anti-proliferation activity on various cancer cells is significantly better than that of similar compounds.

The present invention discloses a stereoselective synthesis method and application of α-2′-deoxynucleosides, which utilizes a phosphine oxide group on a glycosyl donor as a remote directing group. By anti-selectivity, the sugar ring β face is shielded so that the glycosyl acceptor can only carry out nucleophilic attack on the anomeric position of the glycosyl donor from the sugar ring α face, thereby achieving stereoselective glycosidation of the opposite side. This method can efficiently control the stereoselectivity and regioselectivity of the glycosidation reaction, especially for the synthesis of nucleoside derivatives in which C-2′ does not have an adjacent group participating group, showing great advantages. The method has mild reaction conditions and is easy to operate. At the same time, anti-proliferation experiments show that the preferred compounds of α-2′-deoxynucleosides have good inhibitory activity against tumor cells such as SH-SY5Y and LN229, and have good application prospects in the anti-tumor field. The present invention is of great help in exploring the potential value of α-configuration nucleosides, nucleotides and even nucleic acids in drug development.

This invention discloses a KRAS protein degrader modified with norbornene as a hydrophobic group, its preparation method, and its applications. This invention provides a protein degrader with norbornene as the hydrophobic group and MRTX1133 as the KRAS ligand terminus, capable of selectively binding to KRAS (preferably the G12D mutant) and inducing its degradation within cells through a hydrophobic tag, thereby inhibiting downstream oncogenic signaling pathways and suppressing tumor cell proliferation. One objective of this invention is to provide a general synthetic route for this type of degrader and several preferred compound examples (denoted as P1~P7), and to demonstrate methods for detecting its KRAS degradation ability and antiproliferative activity in cell biology experiments (WB, cell viability assays, etc.).

The present invention relates to a kind of HER2 targeting platinum-based antibody conjugate and its synthesis method and tumor treatment application, the HER2 targeting platinum-based antibody conjugate of the present invention is formed by connecting an anti-HER2 monoclonal antibody and a cyclometallated N-heterocyclic carbene platinum (II) complex via a linker, and the linker is a self-eliminating linker including a maleimide linker connecting the antibody and the cyclometallated N-heterocyclic carbene platinum (II) complex. The present invention combines a cyclometallated N-heterocyclic carbene platinum (II) complex with antiproliferative activity with a monoclonal antibody with a specific recognition function as a carrier to improve the tumor targeting of the platinum complex, improve its distribution in the body, and achieve efficient delivery of platinum drugs to tumor tissue, thereby improving cancer treatment effect; can effectively reduce the accumulation of drugs in non-tumor sites, reduce toxic and side effects; can effectively reduce the amount of platinum metal used, reduce toxic and side effects; can also achieve efficient, low-toxic tumor treatment effect by effectively killing tumor cells.

Devices, systems, and methods are provided including a structure having one or more surfaces configured for internal use within a patient's body and one or more therapeutic compositions comprising one or more active substances including a direct factor Xa inhibitor, and a direct factor IIa inhibitor disposed in or on the structure. The structure is configured to be positioned adjacent an injury site in the patient's body. The one or more active substances optionally include an anti-proliferative agent. The therapeutic composition is formulated to release the one or more active substances to the injury site to provide one or more of inhibit clot formation, promote clot dissolution, inhibit or dissolute inflammation, inhibit vessel injury, increase time before clotting, and / or inhibit cell proliferation.

The invention belongs to the technical field of organic electrochemical synthesis, and particularly discloses a phosphine-containing pyridino-phenanthridine ketone derivative as well as an electrochemical synthesis method and application of the phosphine-containing pyridino-phenanthridine ketone derivative. The preparation method comprises the following steps: mixing an N-aryl acrylamide compound, a symmetric phosphonyl compound, an electrolyte, an additive, alkali and an organic solvent, and electrifying to react, so as to obtain the phosphine-containing pyridino-phenanthridine ketone derivative. According to the method, a metal catalyst is not needed, only the ferrocene oxidation substrate is catalyzed through electric induction circulation, a by-product is hydrogen, and the method has the advantages that raw materials are easy to obtain, operation is easy, electrolyte and a solvent can be used mechanically, and the method has high implementation value and social and economic benefits. The synthesized compound has an inhibition effect on proliferation of breast cancer cells. Experimental results show that a plurality of compound examples show remarkable anti-proliferative activity on the tumor cell line under low micromolar concentration, important candidate molecules are provided for developing novel anti-tumor drugs, and potential clinical application value is achieved.

The present invention relates to the field of natural medicine technology, and specifically to a caged ketone compound extracted from Garcinia macrobracte leaves, as well as a preparation method and use thereof. An insulin resistance model was established by inducing HepG2 cells with palmitic acid, and the hypoglycemic activity of the compound was tested using an in vitro glucose oxidase method. The results showed that the caged ketone compound could significantly increase glucose consumption in HepG2-IR cells and improve the insulin resistance state of HepG2-IR cells to varying degrees. In vitro anti-proliferative activity experiments showed that the caged ketone compound had significant anti-A549 cell proliferation activity. The present invention provides alternative compounds for the development of new hypoglycemic and anti-tumor drugs, which is of great significance to the comprehensive development and utilization of Garcinia macrobracte leaves.

The invention relates to a BRD4 and p300 / CBP double-target degradation agent as well as a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The compound has the following general formula: BRD4 and p300 / CBP protein can be efficiently degraded at the same time in a concentration-dependent and time-dependent manner, the compound shows remarkable anti-tumor activity on a PC-3 cell line in vitro, and IC50 is lower than 30 nM. The overall activity is superior to that of positive control drugs NEO2734, paclitaxel and ARV-771, and the anti-proliferation effect is remarkably superior to that of existing control drugs. The compound can be used as a candidate or lead compound for the development of antitumor drugs, is simple and convenient in synthesis method, and has good development and application prospects.

The invention provides a benzoheterocycle compound, a pharmaceutical composition containing the benzoheterocycle compound and application of the benzoheterocycle compound, and particularly relates to a compound shown in the following formula I, pharmaceutically acceptable salt, stereoisomer, deuterated compound, solvate, prodrug or metabolite of the benzoheterocycle compound, a pharmaceutical composition containing the benzoheterocycle compound and application of the benzoheterocycle compound. The compound disclosed by the invention is a WRN regulating agent with a novel structure, has strong WRN inhibitory activity and MSI HCT116 cell proliferation inhibitory activity, shows excellent selectivity in anti-proliferation activity evaluation of MSI cells HCT116 and MSS cells SW620, shows relatively good stability in in-vitro human liver microsome, has better druggability, and can be applied to preparation of anti-proliferative drugs of human liver microsome, such as liver microsome anti-proliferative drugs, liver microsome anti-proliferative drugs, liver microsome anti-proliferative drugs, liver microsome anti-proliferative drugs, liver microsome anti-proliferative drugs and liver microsome anti-proliferative drugs. The compound can be used as a WRN regulating agent for preparing medicines for preventing or treating diseases related to WRN.

The application discloses a STAT3 / HDAC dual-target inhibitor, a composition and application thereof. A variety of biological experiments prove that the compound has excellent anti-proliferation activity on a variety of cancer cells, has STAT3 and HDAC dual inhibition activity, and has the functions of regulating Ser727 and Tyr705 phosphorylation, and can be used as a STAT3 / HDAC dual-target inhibitor to prepare an anti-tumor and other STAT3 related disease treatment, and has a good application prospect.

The invention belongs to the technical field of medicinal chemistry, and particularly discloses a platinum (IV) prodrug with a small molecule TrxR inhibitor as a ligand and a preparation method and application of the platinum (IV) prodrug, the synthesized platinum (IV) prodrug shows good anti-proliferative activity on cancer cells such as MDA-MB-231, MCF-7, 4T1 and MDA-MB-231 / CDDP, and the anticancer activity of a compound 6b is optimal. In an in-vivo anti-tumor activity test, the compound 6b can effectively inhibit proliferation of cis-platinum sensitive and cis-platinum drug-resistant triple negative breast cancer xenotransplantation tumors, the tumor inhibition rates of the compound 6b are 73.8% and 66.3%, and the curative effect of the compound 6b is superior to that of a positive drug cis-platinum. In addition, the compound 6b can effectively inhibit proliferation of homotransplantation tumors of mouse breast cancer cells 4T1, and the tumor inhibition rate of the compound 6b is 76.8% and is obviously higher than that of a cis-platinum treatment group. And the compound 6b shows a powerful immunoregulation effect in vivo, which indicates that the design successfully realizes effective combination of chemotherapy and immunotherapy, and the compound disclosed by the invention has potential application prospects in treatment of triple negative breast cancer.

The invention relates to an aryl amide compound with a structure as shown in a formula I, a formula II, a formula III or a formula IV, or pharmaceutically acceptable salt or stereoisomer thereof, and application thereof. The aryl amide compound provided by the invention is a molecular glue degradation agent aiming at Bcr-AblT315I, can effectively degrade wild type Bcr-Abl kinase and mutant type Bcr-AblT315I kinase, can effectively inhibit the kinase activity of Bcr-Abl and Bcr-AblT315I mutants, and has a relatively good anti-proliferation effect on tumor cells carrying Bcr-Abl and Bcr-AblT315I; the selectivity is good, toxic and side effects are small, and the safety is good.

The present invention discloses a dihydropyrazole-azepine compound, a pharmaceutical composition containing the same, and its use in anti-tumor treatment. The structure of the dihydropyrazole-azepine compound is shown in Formula I. The inventors of the present invention have confirmed through multiple experiments that the compound of the present invention has a significant inhibitory effect on AKT1, exhibiting a potent anti-proliferative effect on tumor cell lines such as mouse neuroblastoma Neuro2a cells and a potent differentiation-inducing effect on Neuro2a cell lines. Therefore, the compound of the present invention can be used as a differentiation-inducing regulator and / or AKT inhibitor in drugs for treating solid tumors or blood cancers associated with cell proliferation and differentiation abnormalities in humans or animals.

The present invention discloses a rosin acid derivative, a preparation method, and an application thereof. The rosin acid derivative has significant anti-proliferative activity against glioma cells, can achieve a significant anti-glioma proliferation effect at relatively low concentrations, and has good tumor treatment effects. The compound with outstanding activity has low hepatotoxicity and exerts an anti-proliferative effect on glioma cells in a time- and concentration-dependent manner. In addition, the representative rosin acid derivative has a pKa value within the range of 6.2 to 7.2, has good blood-brain barrier permeability, and is conducive to entering the brain to exert its medicinal effect.

The invention provides application of a persimmon leaf flavonoid compound in preparation of a drug for enhancing cis-platinum sensitivity, and belongs to the technical field of biological medicine. The invention provides a nanoparticle formed by self-assembly of a persimmon leaf flavonoid compound and a platinum drug. In-vivo and in-vitro experiment results show that when the persimmon leaf flavonoid compound and the cis-platinum are combined for administration, the killing ability of the cis-platinum to tumor cells can be improved, and when the persimmon leaf flavonoid compound and the cis-platinum are prepared into the nanoparticles (PLF-Cis NPs), the toxicity, the anti-proliferation property and the anti-migration property of the cis-platinum to cancer cells can be greatly further improved. The PLF-Cis NPs can improve the killing effect, promote cell apoptosis and induce cell immunogenic death. According to the invention, the persimmon leaf flavonoid compound is used as the sensitizer for the first time, so that the tumor killing property of platinum drugs can be greatly improved, and a new means is provided for treating tumors or cancers with poor cis-platinum sensitivity.

Copper chelators of the tetradentate monoquinoline (TDMQ) series are highly efficient against several cancer cell lines. One of these selective copper chelators, TDMQ20, is highly cytotoxic on the non-small cell lung carcinoma (A549), the cervix cancer HeLa and the hepatocarcinoma HepG2 cell cultures, with IC50 values ranging from 14 to 16 μM in vitro, lower than those obtained with the reference drug 5-fluorouracil (5-FU). TDMQ20 also exhibits a significant antiproliferative activity on HeLa cells in vitro. The mechanism of its cytotoxicity and antiproliferative activity involved intracellular production of reactive oxygen species, drastic mitochondrial damages and induction of apoptosis. The selectivity of TDMQ20 for cancer cells with respect to non-cancer human cells is higher than that of 5-FU, the reference drug. These data strongly support the selection of TDMQ20 as drug-candidate to treat several human cancers.

The invention discloses application of pinoresinol in treatment of rectal cancer, it is found for the first time that the pinoresinol can inhibit expression of CaLM1, then CaLM1 / CaMKII / CREB signaling pathways can be inhibited by reducing expression levels of CAMKII and p-CREB, and on the basis of the inhibition of the expression levels of CAMKII and p-CREB, the application of the pinoresinol in treatment of rectal cancer is achieved. The pinoresinol is used as an inhibitor of a CaLM1 / CaMKII / CREB signal channel for the first time, in-vitro and in-vivo effects on rectal cancer cells and solid tumors thereof are experimented, and it is found that in-vitro pinoresinol dose dependence reduces expression of CaLM1, CaMKII and p-CREB, proliferation of cancer cells is remarkably inhibited, apoptosis of the cancer cells is promoted, and the tumor cell cycle is retarded in the G0 / G1 phase. In-vivo experiments show that the volume and weight of tumors are reduced by dosages of the pinoresinol, and the experiments find that the rectal cancer inhibition effect of the high-concentration pinoresinol (20.0 mg / kg) is close to that of a known chemotherapeutic drug cis-platinum (8.0 mg / kg) with a curative effect; in addition, the TUNEL experiment and the immunohistochemical analysis further support the apoptosis promoting and anti-proliferation effects of the pinoresinol by inhibiting the CaLM1 / CaMKII / CREB signal channel.

Disclosed is a cohort of anti-proliferative microRNAs (miRs) wherein each member of the cohort (or combinations thereof) represent a target for modulating cell proliferation (and migration), influencing (or modulating) vascular remodelling and the treatment of various vascular complications, vascular injury vascular disease and (for example) disorders, diseases, syndromes and / or conditions which affect vessels and / or vascular systems of the human or animal body.

Copper chelators of the tetradentate monoquinoline (TDMQ) series are highly efficient against several cancer cell lines. One of these selective copper chelators, TDMQ20, is highly cytotoxic on the non-small cell lung carcinoma (A549), the cervix cancer HeLa and the hepatocarcinoma HepG2 cell cultures, with IC 50 values ranging from 14 to 16 mM in vitro, lower than those obtained with the reference drug 5-fluorouracil (5-FU). TDMQ20 also exhibits a significant antiproliferative activity on HeLa cells in vitro. The mechanism of its cytotoxicity and antiproliferative activity involved intracellular production of reactive oxygen species, drastic mitochondrial damages and induction of apoptosis. The selectivity of TDMQ20 for cancer cells with respect to non-cancer human cells is higher than that of 5-FU, the reference drug. These data strongly support the selection of TDMQ20 as drug-candidate to treat several human cancers.

This invention discloses a CDK8 / BRD4 dual-target inhibitor, its preparation method, pharmaceutical composition, and applications, relating to the field of medicinal chemistry. The multi-target inhibitory compound designed and synthesized in this invention can effectively inhibit BET and kinase protein activity. The preferred compound has an IC50 value of [missing information]. 50 The concentration can reach nanomolar levels and has excellent anti-proliferative activity against colorectal cancer cells, achieving excellent therapeutic effects at the molecular level, with a very wide range of application prospects; at the same time, the compound preparation method provided by this invention is highly versatile and suitable for various structural types.

The invention discloses a copper (II) complex with anticancer activity as well as a preparation method and application thereof, and belongs to the technical field of complexes. According to the preparation method, CuCl22H2O, CuBr2 or Cu (NO3) 2.3 H2O is subjected to a reaction with benzoyl hydrazone 3-acetyl-7-N, N-diethylamino coumarin respectively, and the complex is obtained. The obtained complex has certain anti-proliferative activity to four cell lines, namely HeLa, MCF-7, A549 and HepG-2, and the anti-proliferative activity is obviously superior to that of a ligand, particularly, the complex shows relatively excellent anti-proliferative activity to the MCF-7 cell line, and the toxicity to normal HUVEC cells is also obviously lower than that of cis-platinum. The copper (II) complex provided by the invention has good anti-cancer activity, the preparation method is simple, the toxicity is small, and a new thought is provided for the development of anti-cancer drugs.