Preparation method of natural active polypeptide Tubulysin U

Abstract

The invention provides a preparation method of a novel natural active polypeptide Tubulysin U. The preparation method comprises the following steps: dissolving a compound 2 in trifluoroacetic acid, heating under reflux to prepare an intermediate, reacting with a compound 3 and diisopropylethylamine to obtain a product, reacting the product with 2, 6-dimethylpyridine and tert-butyldimethylsilyltrifluoromethanesulfonate, adding sodium hydroxide after the reaction to prepare an intermediate acid, reacting the intermediate acid with a compound 6, HATU and diisopropylethylamine to obtain a product,adding triphenylphosphine to prepare an intermediate amine, adding a compound 8 and HATU to react, adding ammonium fluoride to prepare a first intermediate, adding sodium hydroxide to the first intermediate to prepare a second intermediate, adding acetic anhydride to the second intermediate to prepare a third intermediate, adding trifluoroacetic acid to the third intermediate to prepare a fourthintermediate, and adding formaldehyde and sodium cyanoborohydride to the fourth intermediate to react, thereby obtaining the target product. The structures of the compound 2, compound 3, compound 6 and compound 8 are disclosed in the specification.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of natural active polypeptide Tubulysin U. Background technique [0002] The tetrapeptide compound Tubulysins was extracted from myxobacteria by Hofle et al. in 2000, but its crystal structure was not determined until 2004. Tubulysin A-Z is a family of compounds (see Table 1), and they all belong to natural products, which can be represented by the following chemical structural formula: [0003] [0004] Table 1 Structural formulas of Tubulysins family compounds [0005] [0006] [0007] Studies have found that Tubulysin U exhibits extremely potent cytotoxic activity in mammalian cells, including multidrug-resistant cell lines, IC 50 Values ​​are in the lower nanomolar range (see Table 2). Tubulysin U is a cytotoxic active tubulysin that inhibits tubulin polymerization and leads to cell cycle arrest and apoptosis. In addition,...

AI Technical Summary

Problems solved by technology

However, in the prior art, its synthesis is not ideal. So far, there are dozens of documents reported on the chemical synthesis of Tubulysin U and its analogues, and most of the synthetic routes are not perfect, and there is a lot of room for further exploration.

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