WO2010028667A1 - Genetically modified strains for biotransformations in anthracycline production - Google Patents
Genetically modified strains for biotransformations in anthracycline production Download PDFInfo
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- WO2010028667A1 WO2010028667A1 PCT/EP2008/007460 EP2008007460W WO2010028667A1 WO 2010028667 A1 WO2010028667 A1 WO 2010028667A1 EP 2008007460 W EP2008007460 W EP 2008007460W WO 2010028667 A1 WO2010028667 A1 WO 2010028667A1
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- 0 CI(C(C(C1)N)O)OC1OC(C[C@@](Cc1c(c(C(C2*3=C(*)C=CC2=C)=O)c2C3=O)O)(*(**)=O)O)c1c2O Chemical compound CI(C(C(C1)N)O)OC1OC(C[C@@](Cc1c(c(C(C2*3=C(*)C=CC2=C)=O)c2C3=O)O)(*(**)=O)O)c1c2O 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/44—Preparation of O-glycosides, e.g. glucosides
- C12P19/56—Preparation of O-glycosides, e.g. glucosides having an oxygen atom of the saccharide radical directly bound to a condensed ring system having three or more carbocyclic rings, e.g. daunomycin, adriamycin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/36—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Actinomyces; from Streptomyces (G)
Definitions
- the present invention relates to improved microbial strains and to their use in a biotransformation process for improving the yields of anthracycline antitumor antibiotics, particularly epirubicin and idarubicin.
- Daunomycins are a group of antitumor antibiotics produced by several Streptomyces sp., such as S. peucetius, S. coerulorubidus, S. griseus, Streptomyces sp. C5, S. peucetius var. caesius, and S. bifurcus.
- the basic compound of the group is daunomycin (DiMarco et al., 1964). Daunomycins may be described by the general formula I
- R 13 OH ldarubicin H H 58957-92-9
- Epirubicin Semisynthetic derivatives of daunorubicin, epirubicin and idarubicin could be classified as unnatural anthracycline antibiotics as the natural occuring strains do not produce these anthracyclines.
- Epirubicin is clinically used for many types of cancer. The market is growing as it competes with doxorubicin. New formulations, conjugates and new combinations with other cancer drugs also expand the usage of epirubicin.
- Epirubicin is manufactured by a process which comprises producing daunorubicin by fermentation and synthetically modifying the aglycone and sugar moiety, disclosed e.g. in US Patent 5,874,550.
- Idarubicin (4-demethoxy-daunorubicin) is used to treat certain types of cancer, including leukemia, lymphoma, and other diseases of the bone marrow. It is claimed to cause less side effects than doxorubicin.
- the global annual market for idarubicin is, however, no more than 20 kg, presumably because of its exceptionally high price, which is due to a very complicated manufacturing process, ldarubicinone is manufactured started from daunomycinone, obtained from fermentation of daunorubicin with subsequent acidic hydrolysis. Daunorubicinone is further synthetically modified to idarubicinone. A sugar resi- due, daunosamine, is attached by a complicated synthetic reaction series, as described in e.g. US Patent No. 4,325,946.
- Figure 1 is a schematic presentation of the biosynthetic pathway for daunomycin class of anthracyclines.
- Figure 2 is a schematic presentation of the process for production of epirubicin and idarubicin according to this invention.
- Figure 3 is a chromatogram showing the production profile of a biotransformation strain according to the present invention after feeding with 4-deoxy- ⁇ -rhodomycinone.
- Rt 6.0 : 13-dihydro-idarubicin
- Rt 6.9 : Idarubicin
- Rt 8.1 : 13-deoxy-ldarubicin
- Rt 11.0 : 4-deoxy- ⁇ -rhodomycinone.
- the present invention relates to a microbial strain, which converts anthracycline metabo- lites, such as epidaunorubicin, 13-dihydroepidauno-rubicin, 4'-epi-feudomycin and ⁇ - rhodomycinone, into non-natural anthracyline antibiotics, such as epirubicin and idarubicin.
- anthracycline metabo- lites such as epidaunorubicin, 13-dihydroepidauno-rubicin, 4'-epi-feudomycin and ⁇ - rhodomycinone
- non-natural anthracyline antibiotics such as epirubicin and idarubicin.
- such strains are selected from the genera Streptomyces, more preferably from the species Streptomyces peucetius, and most preferably from the subspecies Streptomyces peucetius var. ca
- the present invention also relates to a process for converting anthracycline metabolites such as 13-dihydroepidaunorubicin, and ⁇ -rhodomycinone, into non-natural anthracyline antibiotics, such as epirubicin and idarubicin using a microbial strain according to the present invention.
- a resin preferably selected from the group consisting of ionic and non-ionic adsorbents, more preferably from polystyrenes, and most preferably from the group consisting of XAD-7 and Diaion HP-20, is used at any time to adsorb the anthracycline metabo- lites or anthracycline antibiotics.
- the present invention relates to improved Streptomyces strains, which are able to convert modified anthracycline intermediates into important antitumor anthracycline drugs, idaru- bicin and epirubicin. Said strains are useful in a process for converting anthracycline metabolites into the final products.
- the gene snorO was isolated from S. nogalater (ATCC 27952) and is suggested to be responsible for the resistance to nogalamycin (Torkkell 2001 ). Based on sequence analysis, the gene product, SnorO is a multifunction gene product for resistance, with domains for the excision repair protein UvrA, and ABC transporter ATP-binding protein. Heterologous expression of snorO in S. lividans TK24 showed that the gene protected the strain from all tested different anthracyclines, nogalamycin, aclarubicin and daunorubicin.
- Introduction of the gene snorO into the improved strain derived from G001 provided a new biotransformation strain, which exhibits increased resistance to idarubicin.
- snorO when introduced into improved strain derived from G001 in the E. coli vector, improved the conversion rate and stabilized the strain to maintain the conversion within ⁇ 10%, even in six sequences of cultivations.
- Said new biotransformation strain may be fed by natural anthracycline intermediates such as aklavinone and ⁇ -rhodomycinone and natural anthracyclines, daunomycins are formed.
- natural anthracycline intermediates such as aklavinone and ⁇ -rhodomycinone and natural anthracyclines, daunomycins are formed.
- the strain is able to carry out conversion of unnatural metabolites and feeding with un-natural 4-deoxy- ⁇ -rhodomycinone resulted in formation of idarubicin. Additionally, the strain is able to convert 13-DHED into epidaunorubicin. Synthetic conversion of ⁇ - rhodomycinone into 4-deoxy- ⁇ -rhodomycinone is presented. In accordance with the present invention 4-deoxy- ⁇ -rhodomycinone is subsequently biotransformed into idarubicin by the above mentioned new biotransformation strain, which does not produce daunomycin metabolites. 13-DHED was further converted into epidaunorubicin by biotransformation using the same mutant strain.
- biotransformation strain suitable for use in the present invention are:
- any suitable strain can be used for biotransformation of the 4-deoxy-semisynthetic intermediate into idarubicin. Nevertheless, it is critical that the strain has either endogenous or transferred expressible genes for the following reactions: modifications of glucose to form daunosamine, 10-esterase activity to remove a methyl group with the connected 10- decarboxylase activity, 13-oxygenase and the suitable glycosyl transferase activity. Furthermore, the downstream process after biotransformation is cost-effective only if no or minor amounts of natural anthracycline metabolites are accumulated by the strain used as a host in biotransformation.
- S. peucetius var. caesius mutant blocked in the early stage of daunomycin biosynthesis; preferably a mutant blocked in minimal PKS (minimal PoIy- KetideSynthase catalyzes the first reactions, polyketide assembly in anthracyline and other Type Il polyketide pathway).
- the new biotransformation strain derived from wild type Streptomyces peucetius var. caesius ATCC 27952 as described above is a highly preferred strain, but any strain sharing the following characteristics is suitable for the conversion process according to the pre- sent invention.
- the present invention further relates to a process for production of un-natural anthracy- cline antibiotics, epirubicin and idarubicin by exploiting the shunt products, ⁇ - rhodomycinone formed in the fermentation production of daunorubicin and epidaunorubi- cin, and 13-DHED formed in the fermentation production of epidaunorubicin.
- a host strain is the new biotransformation strain described above, derived from genus Strepto- myces, preferably derived from S. peucetius var. caesius.
- idarubicinone can be converted into idarubicin by a complicated chemical synthesis series, as described in e.g. US Patent No. 7,053,191.
- an endogenous biosynthetic reaction series of a bacterial strain to convert 4-deoxy- ⁇ -rhodomycinone into idarubicin is preferably used. It is known that biosynthesis proceeds in the sequence shown in Fig. 1.
- Aklavinone a typical precursor for several anthracyclines, is 11-hydroxylated to form ⁇ -rhodomycinone, which is glycosylated.
- ⁇ -rhodomycinone obtained as a shunt product by a fermentation process of daunomycin metabolites, is processed into 4-deoxy- ⁇ -rhodomycinone by synthetic chemistry.
- Various synthetic paths are possible to remove a hydroxyl group from position 4 of ⁇ -rhodo- mycinone.
- we prefer to carry out the four reaction series starting by protection of C7 and C9-hydroxyl groups by totalization. After that, trifylation of the OH-group at C4 takes place following by reduction to remove the substituent at C4.
- the product is isolated or purified by precipitation/crystallization and the overall yield of > 20 %, preferably > 30 %, most preferably > 40 % is obtained.
- the purity of 4-deoxy- ⁇ - rhodomycinone obtained in this process is > 60 %, preferably > 80 %, most preferably > 90 % being a suitable substrate for biotransformation.
- ⁇ -rhodomycinone is typically accumulated in the fermentation broth in large quantities and purification by conventional methods is successful.
- Synthetic conversion of ⁇ -rhodomycinone provides > 20 %, preferably > 30 %, most preferably > 40 % of pure 4-deoxy- ⁇ - rhodomycinone, which is fed to the non-producing mutant strain of S. peucetius var. cae- sius.
- the efficiency of biotransformation of 4-deoxy- ⁇ -rhodomycinone into idarubicin was > 20 %, preferably > 30 %, most preferably > 40 %.
- More than 100 mg of the semisynthetic intermediate could be fed to a litre of the culture of the biotransformation strain.
- the timing to feed the intermediate is not critical. Any fermentation conditions allowing growth of streptomycetes and secondary metabolism could be used whereas it is advantageous to use E1 -medium and temperature range of 25-35 0 C in pH between 6 to 8.
- idarubicin is carried out with any suitable method, such as centrifuging, filtration or by a suitable ionic or non-ionic adsorbent.
- any water-soluble organic solvent could be used, whilst acidic alcohols are preferred.
- Aglycones are removed with acidic extraction after which glycosides are extracted back from water phase to chloroform phase in high pH.
- idarubicin is finally purified by crystallization or, preferably, by chromatography and crystallization. It is advantageous to use a silica column for purification.
- 13-DHED could be adsorbing to a resin added to the culture broth of Strepto- myces strain with capabilities for daunomycin synthesis and especially the late steps. Even though any strain is suitable, it is advantageous to use the strain which is blocked in early biosynthetic pathway and unable to accumulate daunomycin metabolites.
- the new biotransformation strain derived from genus Streptomyces, preferably derived from S. peucetius var. caesius is used for biotransformation to convert 13-DHED to epidaunorubicin.
- Conversion rates in the conditions described for production of epidaunomycins according to the present invention are > 20 %, preferably > 30 %, most preferably > 40 %.
- Epidaunorubicin obtained in this way may be purified from other metabolites bound to the resin by any conventional methods used for anthracyclines recovery whereas chromatography and especially reverse-phase chromatography is preferably used to provide adequately purified epidaunorubicin for synthesis.
- epidaunorubicin (purity > 60 %, preferably > 80 %, most preferably > 90 %) is used as a starting material for synthetic chemistry to obtain epirubicin, which is a frequently used cancer drug. Any synthetic or biocatalytic reaction series may be used for the 14- hydroxylation.
- Figure 1 a discloses a biosynthetic pathway for daunorubicin. Baumycins are formed from daunorubicin. The biosynthetic pathway is branched to (i)doxorubicin and to (ii)baumycin after daunorubicin. These steps are not shown in the figure.
- Figure 1 b discloses a biosynthetic pathway for dTDP-daunosamine, which is used for the C-7-glycosylation in Fig. 1a.
- Figure 2 discloses a scheme for a biotransformation process.
- Figure 3 discloses a chromatogram showing the production profile of biotransformation strain after feeding with 4-deoxy- ⁇ -rhodomycinone.
- mutagenization strain G001 derived from wild type S. peucetius var. caesius ATCC 27952 by mutagenization was cultured in 50 ml TSB-medium in 250 ml Erlenmeyer flask. All the flasks for mutagenesis contained a string in the bottom of the flask to disperse my- celia during cultivation. Cultivation was carried out for two days at 30 0 C and 330 rpm in a shaker. One ml of the culture was further inoculated to the next bottle containing 50 ml TSB and cultivation was continued for one day (30 0 C, 330 rpm).
- This younger culture was adapted to alkaline pH with NaOH and NTG was added to act on the cells for 20 minutes at > 30 0 C.
- the mutagenized culture of said strain was divided into two tubes and pelleted by centrifugation (300 rpm, 10 minutes). Combined pellets were used to inoculate 50 ml of TSB medium. After one day (30 0 C, 330 rpm), the titre of the cell suspension was determined by plating suitable dilutions, said 1 :10 - 1:100000 on ISP4-plates. Colonies of mutagenized cultures were compared to the wild type and those exhibiting distinct features from the wild type were selected for further characterization.
- the mutants were selected based on pale colour from the dark red-pigmented wild type on the ISP4 -agar plate.
- the gene snorO (Torkkell, 2001 ) was introduced into the mutants with E. coli vector, pCNB3033. Integration was suggested to occur by a#P-site.
- the obtained improved biotransformation strain gave repeated conversion rates for > 20 %, preferably > 30 %, most preferably > 40 % of fed 4-deoxy- ⁇ -rhodomycinone into idarubicin metabolites as is detailed described in Example 5.
- Suitable mutants selected as described in example 1 were cultivated in 50 ml of E1- medium supplemented with adsorbent resin (15 g/l).
- E1 Per litre of tap water: glucose 20 g; soluble starch 20 g; Peptide 5 g; Yeast extract 2.5 g; K 2 HPO 4 ⁇ H 2 O 1.3 g; MgSO 4 « 7H 2 0 1 g; NaCI 3 g; CaCO 3 3 g; pH 7-7.5).
- the compounds were extracted at the tenth day of incubation.
- the adsorbent resin was decanted with water from one cultivation flask and washed resin was extracted with 40 ml of acidic alcohol shaking for at least 30 min.
- the HPLC was used for analysing the samples.
- the use of adsorbent resin in E1 -medium was known to increase production of anthracycline metabolites in said conditions.
- mutant strains have the functional biosynthetic genes for the glycosylation and modification of aglycones according to biosynthesis pathway of Figure 1 and as was demonstrated by feeding experiments.
- the natural aglycones, ⁇ -rhodomycinone and aklavi- none were fed to the mutant strains (at least 100 mg of the aglycone per 1 litre of the culture broth) and the fed aglycone was converted into daunomycin metabolites in two days.
- feeding the mutant strains with 4-deoxy- ⁇ -rhodomycinone failed to give repeated conversion to idarubicin metabolites. The reason for the failure was suggested to be caused by a poor resistance against fed or formed product.
- the improved biotransformation strain was able to convert natural aglycones, ⁇ - rhodomycinone and aklavinone as was expected. It also converted un-natural analogous biosynthetic intermediate, 4-deoxy- ⁇ -rhodomycinone and 13-DHED to idarubicin and to epidaunorubicin, as is described in the example 4 below.
- ⁇ -rhodomycinone of > 60 %, preferably > 80 %, most preferably > 90 % chroma- tographic purity was in use for synthesis of 4-deoxy- ⁇ -rhodomycinone.
- the synthesis of 4-deoxy- ⁇ -rhodomycinone consists of four steps: A) protection, B) trifylation, C) reduction and D) deprotection.
- a starting material from protection step was dissolved in chloroform.
- NMP N-methyl pyr- rolidone
- DIPEA di-isopropylethylamine
- Reaction was monitored with TLC.
- the compound was precipitated by adding water and citric acid to mixture. Precipitate was filtered and washed with KHSO 4 . Crystals were filtered and dried under vacuum.
- a deprotection reaction mixture (CHCI 3 / TsOH x H 2 O) was diluted with chloroform, and washed with 1M NaHCO 3 .
- the chloroform fraction was dried with anhydrous MgSO4, filtered and evaporated to dryness. Crystallization was done from chloroform-methanol. Crystals were filtered and dried under vacuum.
- Example 4 Recovery of 13-DHED from culture broth of a epidaunorubicin- producing mutant strain derived from Streptomyces peucetius var. caesius Fermentation broth for production of epidaunorbicin contains three major metabolites in this order: Epidaunorubicin, 13-DHED and epi-feudomycin (Ref. epi-patent application).
- the substituents adsorbed to a resin were decanted from the 20 litre culture broth obtained from fermentation. The resin was washed to remove cell debris by water. Pellet was extracted with alcohol for one to five times. The aglycones were extracted with chlo- roform by adding chloroform to the combined alcohol extracts.
- Seed culture was made by cultivating a biotransformation strain in two flasks of 400 ml of the E1 medium for three days. The cultures were combined and the 800 ml of the culture broth were used to inoculate a 20 litre E1 -medium supplemented with XAD-7. Fermenta- tion was carried out in 20 litres volume for 8 days at the temperature of 30 0 C, 350 rpm with the aeration of 10 l/min. pH has to be kept slightly acid, which ensures more stable conversion of fed 4-deoxy- ⁇ -rhodomycinone into idarubicin.
- 4-deoxy- ⁇ -rhodomycinone is feeded continously 4 days started 24 hours after inoculation with at least 5 mg/ml 4- deoxy- ⁇ -rhodomycinone in EtOH. Feeded 4-deoxy- ⁇ -rhodomycinone amount is at least 100 mg/l.
- Example 6 Biosynthetic conversion of 13-DHED into epidaunorubicin Pre-cultivation of biotransformation strain was done as detailed described in Example 5. 13-DHED adsorbed to resin corresponding to at least 50 mg/ 1 of the culture broth was added to the cultivation after one day and cultivation was continued for four days. Fermentations were carried out in flasks containing 50 ml E1-medium, at 34 0 C 1 300 rpm.
- Engwall K, Otten SL and Hutchinson CR Biosynthesis of natural and hybrid polyketides by anthracycline-producing streptomycetes.
- Torkkell S 1 Kunnari T 1 Palmu K, Mantsala P, Hakala J and Ylihonko K The entire nogala- mycin biosynthetic gene cluster of Streptomyces nogalater: characterization of a 20-kb DNA region and generation of hybrid structures. (2001) Molecular Genetics and Genomics 266:276-288. Torkkell S: Anthracycline antibiotics: Biosynthetic pathway and molecular genetics of no- galamycin, a product of Streptomyces nogalater. (2001) Publications in Annales Universitatis Turkuensis-series nr: 275.
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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JP2011526375A JP2012501663A (en) | 2008-09-11 | 2008-09-11 | Genetically modified strains for biotransformation in anthracycline production |
US13/063,297 US20110171691A1 (en) | 2008-09-11 | 2008-09-11 | Genetically modified strains for biotransformations in anthracycline production |
AU2008361598A AU2008361598B2 (en) | 2008-09-11 | 2008-09-11 | Genetically modified strains for biotransformations in anthracycline production |
PCT/EP2008/007460 WO2010028667A1 (en) | 2008-09-11 | 2008-09-11 | Genetically modified strains for biotransformations in anthracycline production |
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PCT/EP2008/007460 WO2010028667A1 (en) | 2008-09-11 | 2008-09-11 | Genetically modified strains for biotransformations in anthracycline production |
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US (1) | US20110171691A1 (en) |
JP (1) | JP2012501663A (en) |
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WO (1) | WO2010028667A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015166016A1 (en) | 2014-04-30 | 2015-11-05 | Heraeus Deutschland GmbH & Co. KG | Purification of epidaunorubicin |
CN110819561A (en) * | 2019-11-08 | 2020-02-21 | 中国科学院东北地理与农业生态研究所 | Actinomycete TL-007 and application thereof |
CN112010913A (en) * | 2019-05-31 | 2020-12-01 | 南京正大天晴制药有限公司 | Preparation method of 4-deoxy daunorubicin |
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- 2008-09-11 AU AU2008361598A patent/AU2008361598B2/en not_active Ceased
- 2008-09-11 US US13/063,297 patent/US20110171691A1/en not_active Abandoned
- 2008-09-11 WO PCT/EP2008/007460 patent/WO2010028667A1/en active Application Filing
- 2008-09-11 JP JP2011526375A patent/JP2012501663A/en active Pending
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CN112010913A (en) * | 2019-05-31 | 2020-12-01 | 南京正大天晴制药有限公司 | Preparation method of 4-deoxy daunorubicin |
WO2020237836A1 (en) * | 2019-05-31 | 2020-12-03 | 南京正大天晴制药有限公司 | Preparation method for 4-idarubicin hydrochloride |
CN110819561A (en) * | 2019-11-08 | 2020-02-21 | 中国科学院东北地理与农业生态研究所 | Actinomycete TL-007 and application thereof |
CN110819561B (en) * | 2019-11-08 | 2021-06-11 | 中国科学院东北地理与农业生态研究所 | Actinomycete TL-007 and application thereof |
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JP2012501663A (en) | 2012-01-26 |
AU2008361598B2 (en) | 2015-02-12 |
AU2008361598A1 (en) | 2010-03-18 |
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