Fermentation process of preparing demethyl maytansinoids

• US 4,361,650 A
• Filed: 08/07/1981
• Issued: 11/30/1982
• Est. Priority Date: 03/24/1978
• Status: Expired due to Fees

• Current Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Inventors: Nakahama, Kazuo, Izawa, Motowo, Asai, Mitsuko
• Primary Examiner(s): Tanenholtz, Alvin E.
• Application Number:
  US06/290,943
• Time in Patent Office: 480 Days
• Field of Search: 435/119
• US Class Current: 435/119
• CPC Class Codes: C07D 498/16 Peri-condensed systems
• CPC Class Codes: C12N 1/205 Bacterial isolates
• CPC Class Codes: C12P 17/188 Heterocyclic compound containing in the condensed system at least one hetero ring having nitrogen atoms and oxygen atoms as the only ring heteroatoms ergot-alcaloids C12P17/183
• CPC Class Codes: C12R 2001/04 Actinomyces
• CPC Class Codes: C12R 2001/11 Bacillus megaterium
• CPC Class Codes: C12R 2001/465 Streptomyces
• CPC Class Codes: C12R 2001/585 Streptomyces platensis

Abstract

Novel demethylmaytansinoids representable by the formula: ##STR1## (wherein X is Cl or H; R₁ is H or acyl group) are produced from maytansinoids by means of enzymic transformation. The demethylmaytansinoids are useful as antifungal, antiprotozoal or antitumor agents.

Claims

1. A method for producing a demethylmaytansinoid compound of the formula:

##STR23## (wherein X is Cl or H;

R₁ is H or acyl) characterized in that a maytansinoid compound of the formula;

##STR24## (wherein X and R₁ are as respectively defined above) is contacted with a culture broth, inclusive of a processed matter of the culture broth, of a microorganism belonging to the genus Bacillus, the genus Streptomyces or the genus Actinomyces which is able to transform the 20-methoxy group of said maytansinoid compound into a hydroxy group.

2. A method as claimed in claim 1, wherein the microorganism is Bacillus megaterium, Streptomyces flavotricini, Streptomyces platensis, Streptomyces libani or Actinomyces nigrescens.

3. A method as claimed in claim 2, wherein the microorganism is Bacillus megaterium IFO 12108 Streptomyces flavotricini IFO 12770, Streptomyces platensis IFO 12901, Streptomyces libani IFO 13452 or Actinomyces nigrescens IFO 12894.

4. A method for producing a demethylmaytansinoid compound of the formula:

##STR25## (wherein X is Cl or H) characterized in that a maytansinoid compound of the formula;

##STR26## (wherein X is as defined above;

R₁ '"'"' is acyl group) is contacted with a culture broth, inclusive of a processed matter of the culture broth, of a microorganism of the genus Bacillus, the genus Streptomyces or the genus Actinomyces which is able to transform the 20-methoxy group of said maytansinoid compound into a hydroxy group to obtain a compound of the formula;

##STR27## (wherein X and R₁ '"'"' are as respectively defined above) and this latter compound is then subjected to deacylation.

5. A method as claimed in claim 4, wherein the microorganism is Bacillus megaterium, Streptomyces flavotricini, Streptomyces platensis, Streptomyces libani or Actinomyces nigrescens.

6. A method as claimed in claim 5, wherein the microorganism is Bacillus megaterium IFO 12108, Streptomyces flavotricini IFO 12770, Streptomyces platensis IFO 12901, Streptomyces libani IFO 13452 or Actinomyces nigrescens IFO 12894.

7. A method as claimed in claim 4, wherein the deacylation is conducted by employing a complex metal hydride.

8. A method as claimed in claim 7, wherein the complex metal hydride is lithium aluminum hydride.