132202-92-7

Upstream product

• 133645-50-8 (3R,4S,5S)-4-((tert-butoxycarbonyl)amino)-3-hydroxy-5-methyl-heptanoic acid 
• 77-78-1 dimethyl sulfate 
• 333-27-7 methyl trifluoromethanesulfonate 
• 1565-80-6 (2S)-2-methyl-1-butanol 
• 1350919-88-8 (3R,4S,5S)-4-(tert-butoxycarbonyl)(methyl)amino-1-((S)-4-isopropyl-2-oxazolidinone-3-yl)-3-methoxy-5-methyl-1-oxoheptanone 
• 133645-49-5 (3R,4S,5S )-ethyl 4-((tert-butoxycarbonyl)amino)-3-hydroxy-5-methyl-heptanoate 
• 133565-39-6 (4S,5S)-ethyl 4-((tert-butoxycarbonyl)amino)-5-methyl-3-oxo-heptanoate 
• 13139-16-7 N-(tert-butyloxycarbonyl)-L-isoleucine 
• 944728-66-9 ethyl (3R,4S,5S)-4-(N-tert-butoxycarbonyl-N-methylamino)-3-methoxy-5-methyl-heptanoate 
• 74-88-4 methyl iodide 
• 132149-80-5 (3S,4S,5R)-N-methyl-N-(tert-butoxycarbonyl)-(3-methyl-5-methoxy-7-octen-4-yl)amine 

Downstream Products

• 669074-47-9 methyl (S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-amino-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoate 
• 474645-27-7 [3H]-Vedotin 
• 646502-53-6 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl((S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate 
• 1415246-55-7 (S)-methyl 2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)-pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoate 

Relevant academic research and scientific papers

Samarium iodide-mediated Reformatsky reactions for the stereoselective preparation of β-hydroxy-γ-amino acids: Synthesis of isostatine and dolaisoleucine

The synthesis of β-hydroxy-γ-amino acids via SmI 2-mediated Reformatsky reactions of α- chloroacetyloxazolidinones with aminoaldehydes is reported. Diastereoselective coupling is demonstrated to depend on the absolute configuration of the Evans chiral auxiliary employed in the reaction, allowing erythro or threo products to be obtained selectively. The potential utility of the methodology is exemplified by the facile synthesis of biologically relevant N-Boc-isostatine (2b) and N-Boc-dolaisoleucine (3c). This article not subject to U.S. Copyright. Published 2011 by the American Chemical Society.

EFFICIENT PREPARATION OF DOLASTATIN AND AURISTATIN ANALOGS THROUGH A COMMON INTERMEDIATE

Methods for making a dolastatin, auristatin or related compounds comprising the steps of providing a universal dolastatin core of Formula (I) reacting the C-terminal carboxylic acid group with an amine (A) to form an amide bond and reacting the N-terminal amine with a carboxylic acid (CA) to form an amide bond, wherein the steps can be performed in either order. Also provided are an isolated salt of the universal dolastatin core for use in preparation of dolastatins, auristatins and related compounds. Also provided are a number of intermediates and process steps which are useful for the preparation of high purity dolastatin core and high purity dolastatin and auristatin compounds.

NOVEL CONNECTED BODY AND USE THEREOF IN SPECIFIC CONJUGATION BETWEEN BIOMOLECULE AND DRUG

PROBLEM TO BE SOLVED: To provide: a method for producing a connected body; a method for using the connected body in the production of a uniform conjugate; and a method for applying the conjugate in the treatment of cancer, infectious diseases, and autoimmune diseases. SOLUTION: A novel connected body is provided that includes a 2,3-di-substituted succinic acid group or a 2-mono-substituted or 2,3-di-substituted fumaric acid or maleic acid (trans (E)- or cis (Z)-butenedioic acid) group for conjugating 2 or more compounds/cytotoxic agents per connected body with a cell-binding molecule by specifically bridge-linking to a pair of thiol on the cell-binding molecule. The connected body is exemplified by the following general formula. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT

CONJUGATION LINKERS CONTAINING 2,3-DIAMINOSUCCINYL GROUP

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.

CONJUGATION OF A CYTOTOXIC DRUG WITH BIS-LINKAGE

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.

CONJUGATION LINKERS, CELL BINDING MOLECULE-DRUG CONJUGATES CONTAINING THE LIKERS, METHODS OF MAKING AND USES SUCH CONJUGATES WITH THE LINKERS

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.

Preparation method for antitumor active compound dolastatin 10 Dil fragment

The invention belongs to the field of chemical synthesis, and relates to a preparation method for an antitumor active compound dolastatin 10 Dil fragment. The method for preparing the dolastatin 10 Dil fragment comprises the steps of performing conversion from an intermediate 1 to Dil, and synthesizing the compound according to steps 1-6. The method provided by the invention has the advantages ofa simple route, simple operation and a higher yield, and reagents used in the method are all common reagents; and in particular, the preparation costs of the technical route of the preparation methodare obviously reduced, the stereoselectivity is high, and the reaction conditions are mild.

Synthesis and biological activity evaluation of dolastatin 10 analogues with N-terminal modifications

We have described the synthesis of the two complex units (2R,3R,4S)-dolaproine (Dap) and (3R,4S,5S)-dolaisoleuine (Dil) of dolastatin 10 from natural amino acids. The stereoselective syntheses of N-Boc-Dap (4a) and N-Boc-(2S)-iso-Dap (4b) were performed by employing crotylation of N-Boc-L-prolinal as a key step. Barbier-type allylation of N-Boc-L-isoleucinal provided a mild and convenient approach for the synthesis of N-Boc-Dil (5a) and N-Boc-(3S)-iso-Dil (5b). Ten dolastatin 10 analogues have been designed and synthesized with N-terminal modifications based on the known compound monomethylauristatin F (MMAF, 3). In comparison with MMAF (3), four of the compounds showed enhanced potency against HCT 116 human colon cancer cells in?vitro.

SPECIFIC CONJUGATION LINKERS, SPECIFIC IMMUNOCONJUGATES THEREOF, METHODS OF MAKING AND USES SUCH CONJUGATES THEREOF

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.

AURISTATIN ANALOGUES AND THEIR CONJUGATES WITH CELL-BINDING MOLECULES

This invention relates to analogues of auristatins, in particular monomethyl auristatin F (MMAF), as cytotoxic agents, conjugates of such cytotoxic agents with a cell-binding agent, the preparation and the therapeutic uses of these cytotoxic agents and conjugates thereof to arrest or retard abnormal cell growth and /or proliferation.