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Production of polyketides

A compound, polyketone technology, applied in the fields of chemistry, medicinal chemistry, molecular biology and pharmacy, medicine, agriculture, and can solve the problems of laborious, impractical and expensive chemical synthesis of epothilone

Inactive Publication Date: 2004-07-07
KOSAN BIOSCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite the success of these attempts, the chemical synthesis of epothilone is laborious, time-consuming and expensive
Indeed, these approaches are considered impractical for large-scale drug development of any epothilone for use as an anticancer agent

Method used

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Experimental program
Comparison scheme
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Embodiment 8

[0075]A large number of promoters are available for the preferred Myxococcus expression vectors of the invention. See Example 8 below. For example, the promoter of the S. cellulosus epothilone PKS gene (see PCT Publication No. 00 / 031247, incorporated herein by reference) functions in Myxococcus xanthus host cells. The epothilone PKS gene promoter can drive the expression of one or more epothilone PKS genes or other PKS gene products in recombinant host cells. Another preferred promoter for expressing the recombinant PKS of the present invention in Myxococcus xanthus host cells is the pilA gene promoter of Myxococcus xanthus. This promoter and two strains of Myxococcus xanthus have been described in Wu and Kaiser, December 1997, the expression regulation of pilA gene in Myxococcus xanthus, Journal of Bacteriology 179 (24): 7748-7758, and here Cited for reference, the above two strains of Myxococcus xanthus are pilA-deleted strains and pilS-deleted strains, which can express h...

Embodiment 16

[0351] Example 16 describes this synthesis in more detail.

[0352] In another embodiment, the macrolides of the invention can be converted into the macrolides of the invention. As depicted in Scheme 3, the deoxymacrolides of the present invention are epoxidized with dimethyldioxirane as previously described in Scheme 2 to provide the oxygen-containing counterparts.

[0353] Diagram 3

[0354]

[0355] The oxygenated macrolide is treated with sodium azide and tetrakis(triphenylphosphine)palladium to open the ring and form the azido acid. The azide is then reduced with trimethylphosphine to form the aminocarboxylic acid.

[0356] The epoxy compounds with NH at the W position of the present invention can be produced by macrolactamization of aminocarboxylic acids.

[0357] Diagram 4

[0358]

[0359] As shown in Scheme 4, aminocarboxylic acids are treated with 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide and 1-hydr...

Embodiment 1

[0389] Construction of Expression Vector of Myxococcus xanthus

[0390] DNA from phage Mx8, which provides integration and attachment functions, was inserted into commercially available pACYC184 (New England Biolabs). The ~2360 bp MfeI-SmaI fragment was isolated from plasmid pPLH343 (see Salmi et al., Feb. 1998, J. Bacteriology 180(3):614-621) and ligated into the large EcoRI-XmnI restriction fragment of plasmid pACYC184. The circular DNA thus formed was ~6 kb in size and was named plasmid pKOS35-77.

[0391] Plasmid pKOS35-77 is used as a convenient vector for expressing the recombinant PKS gene of the present invention under the control of the epothilone PKS gene promoter. In an example embodiment, the complete epothilone PKS gene with its cognate promoter is inserted into a plasmid in one or more fragments to generate the expression vector of the invention.

[0392] The present invention also provides such an expression vector, wherein the recombinant PK...

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Abstract

Recombinant Myxococcus host cells can be used to produce polyketides, including epothilone and epothilone analogs that can be purified from the fermentation broth and crystallized.

Description

field of invention [0001] The present invention provides recombinant methods and materials for producing polyketides in recombinant host cells; provides recombinant host cells producing polyketides; and provides novel polyketides structurally related to epothilones ; a method for purifying epothilones is provided; and a crystalline form of epothilone D is provided. In a preferred embodiment, the recombinant host cell of the present invention is from the Suborder Cystobacterineae, preferably from the genera Myxococcus (Myxococcus) and Stigmatella, which have been encoded with the Modular or iterative polyketide synthase (PKS) gene transformation with the recombinant DNA expression vector of the present invention. Recombinant host cells produce known and novel polyketides including, but not limited to, epothilones and epothilone derivatives. The present invention relates to the fields of agriculture, chemistry, medicinal chemistry, medicine, molecular biology and pharmacy. B...

Claims

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Application Information

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IPC IPC(8): C07D313/00C07D405/06C07D413/06C07D417/06C07D491/04C12N1/20C12N1/21C12N9/00C12N15/52C12N15/74C12P17/16C12P17/18C12R1/01
CPCC07D417/06C07D407/06C12N9/00C07D409/06C12P17/16C07D413/06C12N1/20C07D405/06C12R1/01C12P17/181C07D491/04C07D493/04C07D313/00C12N15/74C12N15/52C12R2001/01C12N1/205C12N5/10
Inventor R·L·阿尔斯拉尼安G·阿什利S·弗吕克曼B·朱利恩L·卡茨C·科斯拉J·劳P·J·利卡里R·雷根廷D·桑蒂L·唐
Owner KOSAN BIOSCI
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