CA2905306A1 - Biocatalytic production of nucleoside analogues as active pharmaceutical ingredients - Google Patents
Biocatalytic production of nucleoside analogues as active pharmaceutical ingredients Download PDFInfo
- Publication number
- CA2905306A1 CA2905306A1 CA2905306A CA2905306A CA2905306A1 CA 2905306 A1 CA2905306 A1 CA 2905306A1 CA 2905306 A CA2905306 A CA 2905306A CA 2905306 A CA2905306 A CA 2905306A CA 2905306 A1 CA2905306 A1 CA 2905306A1
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- Prior art keywords
- seq
- hydrogen
- optionally substituted
- nucleotide sequence
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- Prior art date
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- 239000008186 active pharmaceutical agent Substances 0.000 title claims abstract description 63
- 229940127073 nucleoside analogue Drugs 0.000 title claims abstract description 45
- 230000002210 biocatalytic effect Effects 0.000 title claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 title claims description 37
- 239000000543 intermediate Substances 0.000 claims abstract description 59
- 238000000034 method Methods 0.000 claims abstract description 59
- 230000008569 process Effects 0.000 claims abstract description 52
- 230000001093 anti-cancer Effects 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 8
- 108020004207 Nucleoside deoxyribosyltransferase Proteins 0.000 claims description 127
- 239000002773 nucleotide Substances 0.000 claims description 82
- 125000003729 nucleotide group Chemical group 0.000 claims description 82
- 229910052739 hydrogen Inorganic materials 0.000 claims description 69
- 239000001257 hydrogen Substances 0.000 claims description 69
- 229910052736 halogen Inorganic materials 0.000 claims description 48
- 150000002367 halogens Chemical class 0.000 claims description 48
- 230000000295 complement effect Effects 0.000 claims description 44
- 125000000623 heterocyclic group Chemical group 0.000 claims description 43
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 claims description 42
- 229960000928 clofarabine Drugs 0.000 claims description 41
- 238000006243 chemical reaction Methods 0.000 claims description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 37
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 36
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 36
- 108090000790 Enzymes Proteins 0.000 claims description 35
- 102000004190 Enzymes Human genes 0.000 claims description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 32
- 239000002777 nucleoside Substances 0.000 claims description 31
- 230000000694 effects Effects 0.000 claims description 28
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 26
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 claims description 26
- 229960002555 zidovudine Drugs 0.000 claims description 26
- -1 .beta.-Thymidine Chemical compound 0.000 claims description 24
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 23
- 229960000684 cytarabine Drugs 0.000 claims description 21
- 150000002148 esters Chemical class 0.000 claims description 20
- 239000013604 expression vector Substances 0.000 claims description 19
- 239000007858 starting material Substances 0.000 claims description 17
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 claims description 16
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 238000009396 hybridization Methods 0.000 claims description 13
- 238000003259 recombinant expression Methods 0.000 claims description 13
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 12
- 238000005580 one pot reaction Methods 0.000 claims description 12
- 239000000523 sample Substances 0.000 claims description 12
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 claims description 11
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 150000007523 nucleic acids Chemical group 0.000 claims description 11
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 claims description 10
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 claims description 10
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- 229960001169 brivudine Drugs 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 229960002436 cladribine Drugs 0.000 claims description 10
- 229950011487 enocitabine Drugs 0.000 claims description 10
- 229960000961 floxuridine Drugs 0.000 claims description 10
- 229960000390 fludarabine Drugs 0.000 claims description 10
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims description 10
- ODZBBRURCPAEIQ-PIXDULNESA-N helpin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 ODZBBRURCPAEIQ-PIXDULNESA-N 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 229960004716 idoxuridine Drugs 0.000 claims description 10
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 claims description 10
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- 229960000523 zalcitabine Drugs 0.000 claims description 10
- 230000014509 gene expression Effects 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
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- 229920001184 polypeptide Polymers 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 8
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 239000012736 aqueous medium Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 229940104230 thymidine Drugs 0.000 claims description 7
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 claims description 6
- 125000004385 trihaloalkyl group Chemical group 0.000 claims description 6
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 5
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 claims description 5
- 241000186673 Lactobacillus delbrueckii Species 0.000 claims description 5
- 241000194035 Lactococcus lactis Species 0.000 claims description 5
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 5
- 229960003603 decitabine Drugs 0.000 claims description 5
- SAMRUMKYXPVKPA-UHFFFAOYSA-N n-[1-[3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]docosanamide Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1C1C(O)C(O)C(CO)O1 SAMRUMKYXPVKPA-UHFFFAOYSA-N 0.000 claims description 5
- 230000002018 overexpression Effects 0.000 claims description 5
- 229960000329 ribavirin Drugs 0.000 claims description 5
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 5
- 239000002342 ribonucleoside Substances 0.000 claims description 5
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 5
- 229960003962 trifluridine Drugs 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 235000014897 Streptococcus lactis Nutrition 0.000 claims description 4
- 125000005210 alkyl ammonium group Chemical group 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 150000002170 ethers Chemical class 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims 32
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 2
- 239000003443 antiviral agent Substances 0.000 abstract description 4
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- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 30
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- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 20
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- 125000003835 nucleoside group Chemical group 0.000 description 18
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
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- C12N9/1048—Glycosyltransferases (2.4)
- C12N9/1077—Pentosyltransferases (2.4.2)
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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
- C12P19/26—Preparation of nitrogen-containing carbohydrates
- C12P19/28—N-glycosides
- C12P19/38—Nucleosides
- C12P19/40—Nucleosides having a condensed ring system containing a six-membered ring having two nitrogen atoms in the same ring, e.g. purine nucleosides
Landscapes
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- Virology (AREA)
- Saccharide Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Enzymes And Modification Thereof (AREA)
- Physics & Mathematics (AREA)
- Biophysics (AREA)
- Plant Pathology (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201361817064P | 2013-04-29 | 2013-04-29 | |
| US61/817,064 | 2013-04-29 | ||
| PCT/EP2014/058761 WO2014177585A2 (en) | 2013-04-29 | 2014-04-29 | Biocatalytic production of nucleoside analogues as active pharmaceutical ingredients |
Publications (1)
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|---|---|
| CA2905306A1 true CA2905306A1 (en) | 2014-11-06 |
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| CA2905306A Abandoned CA2905306A1 (en) | 2013-04-29 | 2014-04-29 | Biocatalytic production of nucleoside analogues as active pharmaceutical ingredients |
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| EP (1) | EP2992107B1 (enExample) |
| JP (1) | JP2016518838A (enExample) |
| KR (1) | KR20160030876A (enExample) |
| CA (1) | CA2905306A1 (enExample) |
| WO (1) | WO2014177585A2 (enExample) |
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| EP2937420A1 (en) * | 2014-04-23 | 2015-10-28 | Synbias Pharma AG | Method for the synthesis of clofarabine |
| JP2016198075A (ja) * | 2015-04-14 | 2016-12-01 | プラズミア バイオテック，エス．エル． | シトシンヌクレオシドアナログの酵素産生 |
| CN106191172A (zh) * | 2015-05-06 | 2016-12-07 | 普拉斯米亚生物技术有限公司 | 胞嘧啶核苷类似物的酶法制备 |
| EP3115461A1 (en) * | 2015-07-07 | 2017-01-11 | Synbias Pharma AG | Method for the synthesis of pentostatin |
| BR112018002399A2 (pt) | 2015-08-06 | 2018-09-25 | Chimerix, Inc. | nucleosídeos de pirrolopirimidina e análogos dos mesmos, úteis como agentes antivirais |
| EP3684771B1 (en) | 2017-09-21 | 2024-11-27 | Chimerix, Inc. | Morphic forms of 4-amino-7-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7h-pyrrolo(2,3-d)pyrimidine-5-carboxamide and uses thereof |
| CN115109814B (zh) * | 2022-08-26 | 2022-11-29 | 常熟药明康德新药开发有限公司 | 一种制备2’-脱氧-2’-氟-β-D-阿拉伯糖腺苷类似物的方法 |
| CN116064703A (zh) * | 2022-10-21 | 2023-05-05 | 凯莱英生命科学技术(天津)有限公司 | 酶催化合成含有保护基的核苷的方法及组合物 |
| CN115725535B (zh) * | 2022-11-30 | 2023-06-06 | 杭州珲益生物科技有限公司 | 一种n-脱氧核糖转移酶及其在脱氧核苷制备中的应用 |
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| US4211773A (en) * | 1978-10-02 | 1980-07-08 | Sloan Kettering Institute For Cancer Research | 5-Substituted 1-(2'-Deoxy-2'-substituted-β-D-arabinofuranosyl)pyrimidine nucleosides |
| KR20020048930A (ko) | 1999-08-20 | 2002-06-24 | 로셰 디아그노스틱스 게엠베하 | 데옥시리보뉴클레오시드의 효소적 합성 |
| US7892838B2 (en) * | 2003-03-28 | 2011-02-22 | Institut Pasteur | Method for the in vivo modification of the synthesis activity of a metabolite by means of the modification of a gene the activity of which is not the original activity |
| EP2917341B1 (en) * | 2012-11-08 | 2017-09-27 | Centre National de la Recherche Scientifique (CNRS) | New phosphodeoxyribosyltransferase mutant enzymes and uses thereof |
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2014
- 2014-04-29 US US14/787,678 patent/US10184142B2/en not_active Expired - Fee Related
- 2014-04-29 KR KR1020157030620A patent/KR20160030876A/ko not_active Withdrawn
- 2014-04-29 JP JP2016511045A patent/JP2016518838A/ja active Pending
- 2014-04-29 CA CA2905306A patent/CA2905306A1/en not_active Abandoned
- 2014-04-29 WO PCT/EP2014/058761 patent/WO2014177585A2/en not_active Ceased
- 2014-04-29 EP EP14725646.5A patent/EP2992107B1/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| JP2016518838A (ja) | 2016-06-30 |
| EP2992107B1 (en) | 2019-12-11 |
| WO2014177585A2 (en) | 2014-11-06 |
| WO2014177585A3 (en) | 2015-01-22 |
| US20160076070A1 (en) | 2016-03-17 |
| US10184142B2 (en) | 2019-01-22 |
| EP2992107A2 (en) | 2016-03-09 |
| KR20160030876A (ko) | 2016-03-21 |
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