A kind of preparation method of natural active polypeptide tubulysin U

Abstract

The invention provides a method for preparing a novel natural active polypeptide Tubulysin U. In the preparation method, compound 2 is dissolved in trifluoroacetic acid, heated to reflux to prepare an intermediate, and reacted with compound 3 and diisopropylethylamine to obtain The product is reacted with 2,6-lutidine and tert-butyldimethylsilyl trifluoromethanesulfonate. After the reaction, sodium hydroxide is added to treat the intermediate acid. The intermediate acid is mixed with compound 6, HATU and diiso Propylethylamine reaction, the obtained product is added with triphenylphosphine to make intermediate amine, and compound 8 and HATU are added to react, ammonium fluoride is added to make the first intermediate, and the first intermediate is added with sodium hydroxide to make the second intermediate , the second intermediate adds acetic anhydride to prepare the third intermediate, the third intermediate adds trifluoroacetic acid to obtain the fourth intermediate, and the fourth intermediate adds formaldehyde and sodium cyanoborohydride to react to produce the target product; compound 2, The structures of compound 3, compound 6 and compound 8 are:

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,...

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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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