- CONJUGATES OF A CELL-BINDING MOLECULE WITH CAMPTOTHECIN ANALOGS
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Provided are conjugates of camptothecin analogs with a cell-binding molecule of formula (I), wherein R1, R2, R3, R4, R5, X, L, n, m, T and ----- are defined herein. It also provides methods of making the conjugates of camptothecin analogs to a cell-binding agent, as well as methods of using the conjugates in targeted treatment of cancer, infection, and immunological disorders.
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- CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES
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A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.
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- CONJUGATION LINKERS CONTAINING 2,3-DIAMINOSUCCINYL GROUP
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Provided is a conjugate of a cytotoxic drug/molecule to a cell-binding molecule with a bis-linker (adual-linker) containing a 2, 3-diaminosuccinyl group. It also relates to preparation of the conjugate of a cytotoxic drug/molecule to a cell-binding molecule with the bis-linker, particularly when the drug having functional groups of amino, hydroxyl, diamino, amino-hydroxyl, dihydroxyl, carboxyl, hydrazine, aldehyde and thiol for conjugation with the bis-linker in a specific manner, as well as the therapeutic use of the conjugates.
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- A CONJUGATE OF AN AMANITA TOXIN WITH BRANCHED LINKERS
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Provided herein is the conjugation of an amanita toxin compound to a cell-binding molecule with branched linkers for having better targeted treatment of abnormal cells. It also relates to a branched-linkage method of conjugation of an amanita molecule to a cell-binding ligand, as well as methods of using the conjugate in targets treatment of cancer, infection and autoimmune disease.
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- A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS
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Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.
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- A CONJUGATE OF A TUBULYSIN ANALOG WITH BRANCHED LINKERS
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The present invention relates to the conjugation of a tubulysin analog compound to a cell-binding molecule with branched/side-chain linkers for having better delivery of the conjugate compound and targeted treatment of abnormal cells. It also relates to a branched-linkage method of conjugation of a tubulysin analog molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and autoimmune disease.
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- CONJUGATION OF A CYTOTOXIC DRUG WITH BIS-LINKAGE
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What provided is the conjugation of cytotoxic to a cell-binding molecule with a bis-linker(dual-linker) as shown in Formula (I). It provides bis-linkage methods of making a conjugate of a cytotoxic drug molecule to a cell-binding agent in a specific manner. It also relates to application of the conjugates for the treatment of a cancer, or an autoimmune disease, or an infectious disease.
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- Identification of New Small-Molecule Inducers of Estrogen-related Receptor α (ERRα) Degradation
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A series of (E)-3-(4-((2,4-bis(trifluoromethyl)benzyl)oxy)-3-methoxyphenyl)-2-cyanoacrylamide derivatives were designed and synthesized as new estrogen-related receptor α (ERRα) degraders based on the proteolysis targeting chimera (PROTAC) concept. One of the representative compounds 6c is capable of specifically degrading ERRα protein by >80% at a relatively low concentration of 30 nM, becoming one of the most potent and selective ERRα degraders to date. Compound 6c could be utilized as a new powerful research tool for further biological investigation of ERRα.
- Peng, Lijie,Zhang, Zhensheng,Lei, Chong,Li, Shan,Zhang, Zhang,Ren, Xiaomei,Chang, Yu,Zhang, Yan,Xu, Yong,Ding, Ke
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p. 767 - 772
(2019/05/08)
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- A CONJUGATE OF A TUBULYSIN ANALOG WITH BRANCHED LINKERS
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The present invention relates to the conjugation of a tubulysin analog compound to a cell-binding molecule with branched/side-chain linkers for having better delivery of the conjugate compound and targeted treatment of abnormal cells. It also relates to a branched-linkage method of conjugation of a tubulysin analog molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and autoimmune disease.
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- Preparation method of amino polyethylene glycol propionic acid
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The invention relates to the field of organic synthesis, in particular to a preparation method of amino polyethylene glycol propionic acid. The preparation method comprises the steps that catalytic hydrogenation is carried out on dibenzyl amino polyethylene glycol tert-butyl propionate shown in formula I-2 to obtain amino polyethylene glycol tert-butyl propionate shown in formula I-3; (2) the amino polyethylene glycol tert-butyl propionate shown in formula I-3 is hydrolyzed under the acidic condition to obtain amino polyethylene glycol propionic acid shown in formula I. The preparation methodof the amino polyethylene glycol propionic acid has the advantages that the defects in the prior art that the yield is low, the dangerousness is high, and the enlargement of production is difficult are overcome, the reaction conditions are mild, the operation is simple, an intermediate does not to be purified, the next reaction can be directly carried out, the whole yield reaches up to 87-92%, thepurity of end products reaches up to 97-99.5%, and a safe and efficient synthetic route is provided for the preparation of amino polyethylene glycol propionic acid.
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- CONJUGATION LINKERS, CELL BINDING MOLECULE-DRUG CONJUGATES CONTAINING THE LIKERS, METHODS OF MAKING AND USES SUCH CONJUGATES WITH THE LINKERS
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The present invention relates to linkers having a group of propiolyl, substituted acryl (acryloyl), or disubstituted propanoyl, and using such linkers for the conjugation of compounds, in particular, cytotoxic agents to a cell-binding molecule.
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- Target Identification of Yaku'amide B and Its Two Distinct Activities against Mitochondrial FoF1-ATP Synthase
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Yaku'amide B (1b) is a structurally unique tetradecapeptide bearing four β,β-dialkylated α,β-unsaturated amino acid residues. Growth-inhibitory profile of 1b against a panel of 39 human cancer cell lines is distinct from those of clinically used anticancer drugs, suggesting a novel mechanism of action. We achieved total syntheses of chemical probes based on 1b and elucidated the cellular target and mode of action of 1b. Fluorescent (3, 4) and biotinylated (5, 6) derivatives of 1b were prepared for cell imaging studies and pull-down assays, respectively. In addition, the unnatural enantiomer of 1b (ent-1b) and its fluorescent probe (ent-3) were synthesized for control experiments. Subcellular localization analysis using 3 and 4 showed that 1b selectively accumulates in the mitochondria of MCF-7 human breast cancer cells. Pull-down assays with 6 revealed FoF1-ATP synthase as the major target protein of 1b. Consistent with these findings, biochemical activity assays showed that 1b inhibits ATP production catalyzed by mitochondrial FoF1-ATP synthase. Remarkably, 1b was also found capable of enhancing the ATP hydrolytic activity of FoF1-ATP synthase. On the other hand, ent-1b inhibits ATP synthesis more weakly than does 1b and does not affect ATP hydrolysis, suggesting the stereospecific requirement for the characteristic multimodal functions of 1b. These findings corroborate that 1b causes growth arrest in MCF-7 cells by inhibiting ATP production and enhancing ATP hydrolysis, thereby depleting the cellular ATP pool. This study provides, for the first time, a structural basis for the design and development of anticancer agents exploiting the novel mode of action of 1b.
- Kitamura, Kai,Itoh, Hiroaki,Sakurai, Kaori,Dan, Shingo,Inoue, Masayuki
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p. 12189 - 12199
(2018/09/25)
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- DERIVATIVES OF AMANITA TOXINS AND THEIR CONJUGATION TO A CELL BINDING MOLECULE
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Derivatives of Amernita toxins of Formula (I), wherein, formula (a) R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X, L, m, n and Q are defined herein. The preparation of the derivatives. The therapeutic use of the derivatives in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.
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- SPECIFIC CONJUGATION LINKERS, SPECIFIC IMMUNOCONJUGATES THEREOF, METHODS OF MAKING AND USES SUCH CONJUGATES THEREOF
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The present invention relates to novel linkers containing a 2,3-disubstituted succinic group, or 2-monosubstituted, or 2,3-disubstituted fumaric or maleic (trans (E)- or cis (Z)- butenedioic), or acetylenedicarboxyl group for conjugation of a cytotoxic agent, and/or one or more different functional molecules per linker to a cell-binding molecule, through bridge linking pairs of thiols on the cell-binding molecule specifically. The invention also relates to methods of making such linkers, and of using such linkers in making homogeneous conjugates, as well as of application of the conjugates in treatment of cancers, infections and autoimmune disorders.
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- Synthesis of tumor-associated MUC1-glycopeptides and their multivalent presentation by functionalized gold colloids
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The mucin MUC1 is a glycoprotein involved in fundamental biological processes, which can be found over-expressed and with a distinctly altered glycan pattern on epithelial tumor cells; thus it is a promising target structure in the quest for effective carbohydrate-based cancer vaccines and immunotherapeutics. Natural glycopeptide antigens indicate only a low immunogenicity and a T-cell independent immune response; however, this major drawback can be overcome by coupling of glycopeptide antigens multivalently to immunostimulating carrier platforms. In particular, gold nanoparticles are well suited as templates for the multivalent presentation of glycopeptide antigens, due to their remarkably high surface-to-volume ratio in combination with their high biostability. In this work the synthesis of novel MUC1-glycopeptide antigens and their coupling to gold nanoparticles of different sizes are presented. In addition, the development of a new dot-blot immunoassay to test the potential antigen-antibody binding is introduced.
- Tavernaro, Isabella,Hartmann, Sebastian,Sommer, Laura,Hausmann, Heike,Rohner, Christian,Ruehl, Martin,Hoffmann-Roeder, Anja,Schlecht, Sabine
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- SYNTHESIS OF NOVEL ASYMMETRIC BOW-TIE PAMAM DENDRIMER-BASED CONJUGATES FOR TUMOR-TARGETING DRUG DELIVERY
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The present disclosure relates to a dendrimer-based conjugate of the formula Vm-D-C-D'-(T-F)n, which is useful for tumor targeting drug delivery. The use of asymmetric dendrimers allow for specific targeting as well as synthetic reproducibility.
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- Probing the Anticancer Mechanism of (-)-Ainsliatrimer A through Diverted Total Synthesis and Bioorthogonal Ligation
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Herein, we report an efficient approach for exploring the novel anticancer mechanism of (-)-ainsliatrimer A, a structurally complex and unique trimeric sesquiterpenoid, through a combined strategy of diverted total synthesis (DTS) and bioorthogonal ligation (TQ ligation), which allowed us to visualize the subcellular localization of this natural product in live cells. Further biochemical studies facilitated by pretarget imaging revealed that PPARγ, a nucleus receptor, was a functional cellular target of ainsliatrimer A. We also confirmed that the anticancer activity of ainsliatrimer A was caused by the activation of PPARγ.
- Li, Chao,Dong, Ting,Li, Qiang,Lei, Xiaoguang
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supporting information
p. 12111 - 12115
(2016/02/23)
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- Dendrimers of vaccines consisting of tumor-associated glycopeptide antigens and T cell epitope peptides
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According to the principle of multiple antigen presentation (MAP), a di-lysyl lysine core was used for the synthesis of tetramers of a glycododecapeptide antigen from the tandem-repeat sequence of the tumor-associated mucin, MUC1, which carries a sialyl TN-antigen saccharide side chain. The methodology was extended to the analogous construction of a tetrameric vaccine consisting of a T cell epitope from tetanus toxoid and the sialyl TN-glycododecapeptide of MUC1. Georg Thieme Verlag Stuttgart.
- Keil, Stefanie,Kaiser, Anton,Syed, Fauziya,Kunz, Horst
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experimental part
p. 1355 - 1369
(2010/03/01)
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- GLUCAGON-LIKE PROTEIN-1 RECEPTOR (GLP-1R) AGONIST COMPOUNDS
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The present invention provides GA targeting compounds which comprise GA targeting agent-linker conjugates linked to a combining site of an antibody. Various uses of the compounds are provided, including methods to prevent or treat diabetes or diabetes-related conditions.
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- ANTI-ANGIOGENIC COMPOUNDS
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The present invention provides AA targeting compounds which comprise AA targeting agent-linker conjugates which are linked to a combining site of an antibody. Various uses of the compounds are provided, including methods to treat disorders connected to abnormal angiogenesis.
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Page/Page column 106-107
(2008/12/06)
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- Anti-angiogenic compounds
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The present invention provides AA targeting compounds which comprise AA targeting agent-linker conjugates which are linked to a combining site of an antibody. Various uses of the compounds are provided, including methods to treat disorders connected to abnormal angiogenesis.
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Page/Page column 105
(2008/06/13)
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