WO2023120292A1 - Light sulfonamide synthesis reaction - Google Patents
Light sulfonamide synthesis reaction Download PDFInfo
- Publication number
- WO2023120292A1 WO2023120292A1 PCT/JP2022/045786 JP2022045786W WO2023120292A1 WO 2023120292 A1 WO2023120292 A1 WO 2023120292A1 JP 2022045786 W JP2022045786 W JP 2022045786W WO 2023120292 A1 WO2023120292 A1 WO 2023120292A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- general formula
- producing
- compound
- light irradiation
- Prior art date
Links
- 229940124530 sulfonamide Drugs 0.000 title description 8
- 150000003456 sulfonamides Chemical class 0.000 title description 7
- 238000003786 synthesis reaction Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 69
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract description 46
- 238000004519 manufacturing process Methods 0.000 claims abstract description 39
- HFFXLYHRNRKAPM-UHFFFAOYSA-N 2,4,5-trichloro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC(Cl)=C(Cl)C=2)Cl)=N1 HFFXLYHRNRKAPM-UHFFFAOYSA-N 0.000 claims abstract description 35
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 36
- 239000003607 modifier Substances 0.000 claims description 34
- 239000000758 substrate Substances 0.000 claims description 16
- 235000018102 proteins Nutrition 0.000 claims description 15
- 108090000623 proteins and genes Proteins 0.000 claims description 15
- 102000004169 proteins and genes Human genes 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 235000000346 sugar Nutrition 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 102000039446 nucleic acids Human genes 0.000 claims description 9
- 108020004707 nucleic acids Proteins 0.000 claims description 9
- 150000007523 nucleic acids Chemical class 0.000 claims description 9
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 230000001678 irradiating effect Effects 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 238000003506 protein modification method Methods 0.000 claims description 5
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 230000009145 protein modification Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 60
- -1 sulfonic acid halides Chemical class 0.000 description 22
- 239000000243 solution Substances 0.000 description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 125000002947 alkylene group Chemical group 0.000 description 6
- 238000007865 diluting Methods 0.000 description 6
- 125000004430 oxygen atom Chemical group O* 0.000 description 6
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 125000006850 spacer group Chemical group 0.000 description 6
- 125000004434 sulfur atom Chemical group 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 238000012650 click reaction Methods 0.000 description 5
- 125000004862 thiobutyl group Chemical group 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 4
- 150000008163 sugars Chemical class 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- YKFROQCFVXOUPW-UHFFFAOYSA-N 4-(methylthio) aniline Chemical compound CSC1=CC=C(N)C=C1 YKFROQCFVXOUPW-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- SMTOKHQOVJRXLK-UHFFFAOYSA-N butane-1,4-dithiol Chemical compound SCCCCS SMTOKHQOVJRXLK-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000017 hydrogel Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 125000000565 sulfonamide group Chemical group 0.000 description 3
- NEZGPRYOJVPJKL-UHFFFAOYSA-N 1-methylsulfanyl-4-nitrobenzene Chemical compound CSC1=CC=C([N+]([O-])=O)C=C1 NEZGPRYOJVPJKL-UHFFFAOYSA-N 0.000 description 2
- GFVKZOWOILTVEW-UHFFFAOYSA-N 4-dodecylsulfanylaniline Chemical compound CCCCCCCCCCCCSC1=CC=C(N)C=C1 GFVKZOWOILTVEW-UHFFFAOYSA-N 0.000 description 2
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 150000004662 dithiols Chemical class 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229960005404 sulfamethoxazole Drugs 0.000 description 2
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 1
- 238000006596 Alder-ene reaction Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- WMPXPUYPYQKQCX-UHFFFAOYSA-N Sulfamonomethoxine Chemical compound C1=NC(OC)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 WMPXPUYPYQKQCX-UHFFFAOYSA-N 0.000 description 1
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 1
- PJSFRIWCGOHTNF-UHFFFAOYSA-N Sulphormetoxin Chemical compound COC1=NC=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1OC PJSFRIWCGOHTNF-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004999 nitroaryl group Chemical group 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- BSFJGCCAXDCMOX-UHFFFAOYSA-N sodium;(4-aminophenyl)sulfonyl-(4-methylpyrimidin-2-yl)azanide Chemical compound [Na+].CC1=CC=NC([N-]S(=O)(=O)C=2C=CC(N)=CC=2)=N1 BSFJGCCAXDCMOX-UHFFFAOYSA-N 0.000 description 1
- ODWMXYHUKDMPTR-UHFFFAOYSA-N sodium;(4-aminophenyl)sulfonyl-(6-chloropyridazin-3-yl)azanide Chemical compound [Na+].C1=CC(N)=CC=C1S(=O)(=O)[N-]C1=CC=C(Cl)N=N1 ODWMXYHUKDMPTR-UHFFFAOYSA-N 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004306 sulfadiazine Drugs 0.000 description 1
- ZZORFUFYDOWNEF-UHFFFAOYSA-N sulfadimethoxine Chemical compound COC1=NC(OC)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 ZZORFUFYDOWNEF-UHFFFAOYSA-N 0.000 description 1
- 229960000973 sulfadimethoxine Drugs 0.000 description 1
- 229960004673 sulfadoxine Drugs 0.000 description 1
- 229960000654 sulfafurazole Drugs 0.000 description 1
- 229960003618 sulfamerazine sodium Drugs 0.000 description 1
- 229950003874 sulfamonomethoxine Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/06—Compounds containing nitro groups bound to a carbon skeleton having nitro groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
- C07C319/12—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols by reactions not involving the formation of mercapto groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/33—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring
- C07C323/35—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group
- C07C323/36—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group the sulfur atom of the sulfide group being further bound to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
- C07C323/67—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfonamide groups, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G75/00—Macromolecular compounds obtained by reactions forming a linkage containing sulfur with or without nitrogen, oxygen, or carbon in the main chain of the macromolecule
- C08G75/30—Polysulfonamides; Polysulfonimides
Definitions
- the present invention relates to a method for producing a sulfonamide derivative, a modifier for a thiol group, a method for producing a biomolecule chip, a method for modifying a protein, and a method for producing a polysulfonamide derivative.
- Sulfonamides form the backbone of many pharmaceuticals and are characterized by their stability and biocompatibility (S. Mondal, S. Malakar, Tetrahedron 2020, 76, 131662).
- sulfonamides are mostly synthesized from amino groups and sulfonic acid halides or their analogues, but synthetic methods using compounds with thiol groups (Non-Patent Document 1) and compounds with nitro groups are used.
- a synthetic method (Non-Patent Document 2) is also known.
- Non-Patent Document 1 is a method of reacting RSH and H 2 NR' in the presence of an oxidizing agent
- the synthesis method of Non-Patent Document 2 is a method of reacting RNO 2 and NaO 2 SR' in the presence of a reducing agent. is a method of reacting
- the photo-click reaction is expected to bind biomolecules and physiologically active molecules only to the light-irradiated part, so there are great expectations in the field of bio-nanotechnology (B. D. Fairbanks, et al. Chem. Rev. 2021, 121, 6915).
- B. D. Fairbanks, et al. Chem. Rev. 2021, 121, 6915 there has been no report of a photoclick reaction forming a sulfonamide bond, which is known to be stable and highly biocompatible.
- a thiol-ene reaction is known as a photo-click reaction for thiols (M. Ahangarpour, et al. Chem. Soc. Rev. 2021, 50, 898). It is necessary to use it, and there may be cases where it is difficult to apply it depending on the target biomolecule.
- the present invention was made against this background, and aims to provide a novel means of synthesizing sulfonamides by a photoclick reaction.
- a sulfonamide can be synthesized from a compound having a nitro group and a compound having a thiol group by a photo-click reaction. completed.
- a synthesis method using a compound having a thiol group Non-Patent Document 1
- a synthesis method using a compound having a nitro group Non-Patent Document 2
- no method for synthesizing sulfonamides from has been reported.
- the present invention provides the following [1] to [15].
- a method for producing a sulfonamide derivative comprising the step of reacting a compound having a nitro group and a compound having a thiol group under light irradiation to produce a sulfonamide derivative.
- X 1 , X 2 , X 3 , X 4 and X 5 are each independently a hydrogen atom, a straight or branched chain alkyl group having 1 to 3 carbon atoms, a straight chain having 1 to 3 carbon atoms, It represents a chain or branched chain alkylthio group, a straight or branched chain alkoxy group having 1 to 3 carbon atoms, a group derived from a sugar, a group derived from a peptide, or a group derived from a nucleic acid.
- the wavelength of the light to be irradiated is 200 to 600 nm, the light irradiation time is 1 to 48 hours, and the light irradiation intensity is 1 to 500 mW/cm 2 [1] to [ 3]
- a modifier for binding a modifier to a thiol group which has the following general formula (I) [Wherein, X 1 , X 2 , X 3 , X 4 and X 5 each independently represent a hydrogen atom or a group derived from a modifier (provided that X 1 , X 2 , X 3 , At least one of X4 and X5 represents a group derived from a modifier.).
- a thiol group modifier comprising a compound represented by:
- a method for producing a biomolecule chip comprising the following steps (1) to (3): (1)
- a substrate having a thiol group on its surface is represented by the following general formula (I) [Wherein, X 1 , X 2 , X 3 , X 4 and X 5 each independently represent a hydrogen atom or a group derived from a biomolecule (provided that X 1 , X 2 , X 3 , X 4 and X 5 represent a group derived from a biomolecule).
- the step of contacting with a compound represented by (2) A step of irradiating light onto a site on the substrate where the biomolecule is to be immobilized to bond the compound represented by the general formula (I) to the thiol group on the substrate surface; (3) A step of removing the compound represented by general formula (I) that has not bonded to the thiol group on the substrate surface.
- the wavelength of the light to be irradiated is 200 to 600 nm, the light irradiation time is 1 to 48 hours, and the light irradiation intensity is 1 to 500 mW/cm 2 [7] or [ 8].
- a method for modifying a protein by binding a modifier to a protein containing a cysteine residue comprising the following steps (1) and (2): (1) protein represented by the following general formula (I) [Wherein, X 1 , X 2 , X 3 , X 4 and X 5 each independently represent a hydrogen atom or a group derived from a modifier (provided that X 1 , X 2 , X 3 , At least one of X4 and X5 represents a group derived from a modifier.). ]
- the step of contacting with a compound represented by (2) A step of irradiating the protein and the compound represented by the general formula (I) with light.
- the wavelength of the light to be irradiated is 200 to 600 nm, the light irradiation time is 1 to 48 hours, and the light irradiation intensity is 1 to 500 mW/cm 2 [10] or [ 11], the protein modification method.
- a method for producing a polysulfonamide derivative comprising the step of reacting a compound having two nitro groups and a compound having two thiol groups under light irradiation to produce a polysulfonamide derivative.
- the wavelength of the light to be irradiated is 200 to 600 nm, the light irradiation time is 1 to 48 hours, and the light irradiation intensity is 1 to 500 mW/cm 2 [13] or [ 14].
- the present invention provides a novel method for producing sulfonamide derivatives.
- a sulfonamide derivative is generated by a photo-click reaction, so biomolecules and physiologically active molecules can be bound only to the light-irradiated portions, and applications such as biomolecular microarray fabrication technology are expected.
- no radical initiator is required, it can be applied to a wide range of biomolecules.
- the method for producing a sulfonamide derivative of the present invention is characterized by including a step of reacting a compound having a nitro group and a compound having a thiol group under light irradiation to produce a sulfonamide derivative.
- the compound having a nitro group is not particularly limited, and nitroaryl, nitroalkene, etc. can be used.
- the compound having a thiol group is also not particularly limited, and thiol, dithiol, etc. can be used.
- the wavelength of light to be irradiated is not particularly limited as long as it can generate a sulfonamide derivative, and can be, for example, 200 to 600 nm, preferably 300 to 500 nm.
- Irradiation time is not particularly limited as long as it can generate a sulfonamide derivative, and can be, for example, 1 to 48 hours, preferably 2 to 36 hours.
- the irradiation intensity of light is also not particularly limited as long as it is an intensity capable of generating a sulfonamide derivative, and can be, for example, 1 to 500 mW/cm 2 , preferably 5 to 300 mW/cm 2 , More preferably, it can be 10 to 100 mW/cm 2 .
- the reaction to produce a sulfonamide derivative is usually carried out in a solvent.
- the solvent is not particularly limited as long as it does not inhibit the reaction, and N,N-dimethylformamide (DMF), toluene, dimethylsulfoxide (DMSO), dichloromethane, water, or a mixed solvent thereof can be used.
- the amount of the compound having a thiol group to be used is not particularly limited.
- the temperature during the reaction is not particularly limited, and can be, for example, 10 to 40°C, preferably 20 to 30°C.
- the method for producing a sulfonamide derivative of the present invention includes the step of producing the sulfonamide derivative described above, but also includes other steps, for example, a step of separating and purifying the produced sulfonamide derivative from other products. You can
- X 1 , X 2 , X 3 , X 4 and X 5 each independently represent a hydrogen atom, an alkyl group, an alkylthio group, an alkoxy group or a group derived from sugar. , represents a group derived from a peptide or a group derived from a nucleic acid.
- the alkyl group is generally a linear or branched alkyl group having 1 to 3 carbon atoms, preferably a methyl group.
- the alkylthio group is generally a linear or branched alkylthio group having 1 to 3 carbon atoms, preferably a methylthio group.
- the alkoxy group is generally a linear or branched alkoxy group having 1 to 3 carbon atoms, preferably a methoxy group.
- a group derived from sugar means, for example, a group obtained by removing one hydrogen atom or one hydroxy group in a sugar molecule, or a group obtained by removing one hydrogen atom or one hydroxy group in a sugar molecule. and a sulfur atom, an oxygen atom, and/or a divalent group (for example, an alkylene group or a phenylene group) as a spacer is bonded thereto.
- Sugars may be monosaccharides, disaccharides, oligosaccharides, or polysaccharides, and hydroxy groups in sugar molecules may be protected by protective groups.
- a "group derived from a peptide” is, for example, a group obtained by removing one hydrogen atom or one hydroxy group in a peptide molecule, or removing one hydrogen atom or one hydroxy group in a peptide molecule. and a sulfur atom, an oxygen atom, and/or a divalent group (for example, an alkylene group or a phenylene group) as a spacer is bonded thereto.
- Group derived from nucleic acid means, for example, a group obtained by removing one hydrogen atom or one hydroxy group in the nucleic acid molecule, or removing one hydrogen atom or one hydroxy group in the nucleic acid molecule.
- X 1 , X 2 , X 3 , X 4 and X 5 may be the same group or different groups.
- X 1 , X 2 , X 3 , X 4 and X 5 may be the groups described above, but X 4 and X 5 are preferably hydrogen atoms.
- X 1 , X 2 , X 3 , X 4 and X 5 are X 1 , X 3 , X 4 and X 5 are hydrogen atoms and X 2 is a hydrogen atom, a methyl group or a methylthio group. , a methoxy group, or a group derived from a sugar.
- a more preferred combination is a combination in which X 1 , X 3 , X 4 and X 5 are hydrogen atoms, and X 2 is a methyl group or A combination that is a methylthio group can be mentioned.
- R 1 represents an optionally substituted alkyl group.
- a thiol group can be mentioned as a substituent.
- the alkyl group optionally substituted with a substituent is generally a straight or branched alkyl group having 1 to 14 carbon atoms, preferably a straight chain alkyl group having 1 to 12 carbon atoms, and more Preferred are n-dodecanyl group, ethyl group and 4-mercaptobutyl group.
- R 1 may be any of the groups described above, preferably an n-dodecanyl group, an ethyl group, or a 4-mercaptobutyl group.
- the method for producing a sulfonamide derivative of the present invention includes, for example, (A) a thiol group modifier, (B) a method for producing a biomolecule chip, (C) a method for modifying a protein, and (D) a method for producing a polysulfonamide derivative. can be applied to These inventions are described below.
- the thiol group modifier of the present invention is a modifier for binding a modifier to a thiol group, and has the following general formula (I).
- X 1 , X 2 , X 3 , X 4 and X 5 each independently represent a hydrogen atom or a group derived from a modifier (provided that X 1 , X 2 , X 3 , At least one of X4 and X5 represents a group derived from a modifier.).
- It is characterized by containing a compound represented by.
- a group derived from a modifier means, for example, a group obtained by removing one hydrogen atom or one hydroxy group in the molecule of the modifier, or one hydrogen atom or one hydroxyl group in the molecule of the modifier. It is a group in which a group is removed and a sulfur atom, an oxygen atom and/or a divalent group serving as a spacer (for example, an alkylene group or a phenylene group) is bonded thereto.
- Modifications can be anything, for example, biomolecules such as sugars, peptides, nucleic acids, or bioactive low-molecular-weight compounds.
- the thiol group to be modified may be the thiol group of a cysteine residue in a protein or the thiol group of a low-molecular-weight compound.
- a substrate having a thiol group on its surface is represented by the following general formula (I) [Wherein, X 1 , X 2 , X 3 , X 4 and X 5 each independently represent a hydrogen atom or a group derived from a biomolecule (provided that X 1 , X 2 , X 3 , X 4 and X 5 represent a group derived from a biomolecule).
- a group derived from a biomolecule means, for example, a group obtained by removing one hydrogen atom or one hydroxy group in a biomolecule, or one hydrogen atom or one hydroxy group in a biomolecule. It is a group obtained by removing a sulfur atom, an oxygen atom, and/or a divalent group (for example, an alkylene group or a phenylene group) serving as a spacer.
- Biomolecules can include sugars, peptides, nucleic acids, and the like.
- reaction between the compound represented by the general formula (I) and the thiol group is a photo-click reaction, it is possible to immobilize biomolecules at any position on the substrate by precisely controlling the site irradiated with light. can.
- the protein modification method of the present invention is a protein modification method for binding a modification product to a protein containing a cysteine residue, comprising the following steps (1) and (2). It is characterized.
- (1) protein represented by the following general formula (I) [Wherein, X 1 , X 2 , X 3 , X 4 and X 5 each independently represent a hydrogen atom or a group derived from a modifier (provided that X 1 , X 2 , X 3 , At least one of X4 and X5 represents a group derived from a modifier.). ]
- the step of contacting with a compound represented by (2) A step of irradiating the protein and the compound represented by the general formula (I) with light.
- a group derived from a modifier means, for example, a group obtained by removing one hydrogen atom or one hydroxy group in the molecule of the modifier, or one hydrogen atom or one hydroxyl group in the molecule of the modifier. It is a group in which a group is removed and a sulfur atom, an oxygen atom and/or a divalent group serving as a spacer (for example, an alkylene group or a phenylene group) is bonded thereto.
- Modifications can be anything, for example, biomolecules such as sugars, peptides, nucleic acids, or bioactive low-molecular-weight compounds.
- the method for producing a polysulfonamide derivative of the present invention comprises a step of reacting a compound having two nitro groups and a compound having two thiol groups under light irradiation to produce a polysulfonamide derivative. It is characterized by including
- the compound having two nitro groups is not particularly limited, and dinitroaryl, dinitroalkene, etc. can be used.
- the nitro group is preferably in the para position.
- the compound having two thiol groups is also not particularly limited, and dithiol and the like can be used.
- the thiol group is preferably present at the terminal carbon.
- a compound having a sulfonamide structure can be synthesized. They are commonly called sulfa drugs and are used as medicines. Therefore, the method for producing a sulfonamide derivative of the present invention can also be used for producing pharmaceuticals.
- Sulfa drugs include sulfamethoxazole, sulfadimethoxine, sulfamonomethoxine, sulfisoxazole, sulfadoxine, sulfamethoxazole, sulfadiazine, sulfachlorpyridazine sodium, and sulfamerazine sodium.
- the method for producing a sulfonamide derivative of the present invention can be used for these productions.
- Some compounds with a sulfonamide structure are known to exhibit herbicidal action. For example, Penokislam. Therefore, the method for producing a sulfonamide derivative of the present invention can also be used for producing agricultural chemicals such as herbicides.
- the method for producing a sulfonamide derivative of the present invention can form a crosslinked structure between nitro groups and thiol groups to create a three-dimensional network structure, so it can also be used for producing hydrogels.
- the produced hydrogels can be used in various applications such as artificial cartilage, artificial joints, artificial organs, cell culture substrates, and drug delivery systems. Recently, attention has been focused on organ printing, in which hydrogels containing cells are used as "ink” to fabricate artificial organs using 3D printers. .
- silica gel (C-300 Wakogel (registered trademark)) column (ethyl acetate/hexane 1%-50%) was performed to obtain N-[4-(methylthio)phenyl]ethylsulfonamide 3[SCH 3 ; C2H5 ] : 71 mg (26%), 4-methylthioaniline 4[ SCH3 ]: 20 mg (12%), 2 -ethylsulfonyl-4-methylthioaniline 5[ SCH3 ; C2H5 ]: 8 mg (3%) was obtained.
- Xe ( _ Hg) lamp 200 W; CuSO 4 aqueous solution filter
- Heating was performed with a dryer immediately after the start of light irradiation.
- After diluting the reaction solution with CH 2 Cl 2 it was washed twice with water, once with saturated aqueous sodium bicarbonate solution and once with saturated brine, and the organic layer was dried over MgSO 4 .
- Xe(Hg) was added to a solution of 4-nitrobenzene (1[H]: 17 ⁇ L, 0.166 mmol) and 1,4-butanedithiol (2[C 4 H 8 SH]: 380 ⁇ L, 3.24 mmol) in DMSO (1 mL).
- a lamp 200 W; CuSO 4 aqueous solution filter
- Heating was performed with a dryer immediately after the start of light irradiation.
- After diluting the reaction solution with CH 2 Cl 2 it was washed twice with water, once with saturated aqueous sodium bicarbonate solution and once with saturated brine, and the organic layer was dried over MgSO 4 .
- the sulfonamide produced by the present invention forms the backbone of many pharmaceuticals. Therefore, the present invention can be used in industrial fields related to pharmaceuticals.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Provided is a method for producing a sulfonamide derivative, the method being characterized by including a step of causing a compound having a nitro group to react with a compound having a thiol group under light irradiation, and forming a sulfonamide derivative.
Description
本発明は、スルホンアミド誘導体の製造方法、チオール基の修飾剤、生体分子チップの作製方法、タンパク質の修飾方法、及びポリスルホンアミド誘導体の製造方法に関する。
The present invention relates to a method for producing a sulfonamide derivative, a modifier for a thiol group, a method for producing a biomolecule chip, a method for modifying a protein, and a method for producing a polysulfonamide derivative.
スルホンアミドは多くの医薬品の骨格を形成しており、その安定性や生体適合性が特長となっている（S. Mondal, S. Malakar, Tetrahedron 2020, 76, 131662）。通常、スルホンアミドはアミノ基とスルホン酸ハライド又はその類縁体から合成される場合がほとんどであるが、チオール基を有する化合物を使用した合成法（非特許文献１）やニトロ基を有する化合物を使用した合成法（非特許文献２）も知られている。非特許文献１の合成法は、酸化剤の存在下、RSHとH2NR’を反応させる方法であり、非特許文献２の合成法は、還元剤の存在下、RNO2とNaO2SR’を反応させる方法である。
Sulfonamides form the backbone of many pharmaceuticals and are characterized by their stability and biocompatibility (S. Mondal, S. Malakar, Tetrahedron 2020, 76, 131662). Usually, sulfonamides are mostly synthesized from amino groups and sulfonic acid halides or their analogues, but synthetic methods using compounds with thiol groups (Non-Patent Document 1) and compounds with nitro groups are used. A synthetic method (Non-Patent Document 2) is also known. The synthesis method of Non-Patent Document 1 is a method of reacting RSH and H 2 NR' in the presence of an oxidizing agent, and the synthesis method of Non-Patent Document 2 is a method of reacting RNO 2 and NaO 2 SR' in the presence of a reducing agent. is a method of reacting
光クリック反応は、光照射した部分にだけ生体分子や生理活性分子を結合させることができることから、バイオナノテクノロジーの分野で大きな期待が持たれている（B. D. Fairbanks, et al. Chem. Rev. 2021, 121, 6915）。しかし、安定で生体適合性が高いことで知られるスルホンアミド結合を形成させる光クリック反応は本発明者の知る限り報告されていない。また、チオールに対する光クリック反応としては、チオール・エン反応が知られているが（M. Ahangarpour, et al. Chem. Soc. Rev. 2021, 50, 898）、この反応には、ラジカル開始剤の使用が必要であり、対象とする生体分子によっては応用が困難なケースも予想される。
The photo-click reaction is expected to bind biomolecules and physiologically active molecules only to the light-irradiated part, so there are great expectations in the field of bio-nanotechnology (B. D. Fairbanks, et al. Chem. Rev. 2021, 121, 6915). However, as far as the present inventors know, there has been no report of a photoclick reaction forming a sulfonamide bond, which is known to be stable and highly biocompatible. A thiol-ene reaction is known as a photo-click reaction for thiols (M. Ahangarpour, et al. Chem. Soc. Rev. 2021, 50, 898). It is necessary to use it, and there may be cases where it is difficult to apply it depending on the target biomolecule.
本発明は、このような背景の下になされたものであり、光クリック反応によりスルホンアミドを合成する新規な手段を提供することを目的とする。
The present invention was made against this background, and aims to provide a novel means of synthesizing sulfonamides by a photoclick reaction.
本発明者は、上記課題を解決するため鋭意検討を重ねた結果、光クリック反応により、ニトロ基を有する化合物とチオール基を有する化合物からスルホンアミドを合成できることを見出し、この知見に基づき、本発明を完成した。上述したように、チオール基を有する化合物を使用した合成法（非特許文献１）やニトロ基を有する化合物を使用した合成法（非特許文献２）は知られていたが、これら二種類の化合物からスルホンアミドを合成する方法は、本発明者の知る限り報告されていない。
本発明は、以下の〔１〕～〔１５〕を提供する。 As a result of intensive studies to solve the above problems, the present inventor found that a sulfonamide can be synthesized from a compound having a nitro group and a compound having a thiol group by a photo-click reaction. completed. As described above, a synthesis method using a compound having a thiol group (Non-Patent Document 1) and a synthesis method using a compound having a nitro group (Non-Patent Document 2) were known, but these two types of compounds To the present inventors' knowledge, no method for synthesizing sulfonamides from has been reported.
The present invention provides the following [1] to [15].
本発明は、以下の〔１〕～〔１５〕を提供する。 As a result of intensive studies to solve the above problems, the present inventor found that a sulfonamide can be synthesized from a compound having a nitro group and a compound having a thiol group by a photo-click reaction. completed. As described above, a synthesis method using a compound having a thiol group (Non-Patent Document 1) and a synthesis method using a compound having a nitro group (Non-Patent Document 2) were known, but these two types of compounds To the present inventors' knowledge, no method for synthesizing sulfonamides from has been reported.
The present invention provides the following [1] to [15].
〔１〕ニトロ基を有する化合物とチオール基を有する化合物を光照射下で反応させ、スルホンアミド誘導体を生成させる工程を含むことを特徴とするスルホンアミド誘導体の製造方法。
[1] A method for producing a sulfonamide derivative, comprising the step of reacting a compound having a nitro group and a compound having a thiol group under light irradiation to produce a sulfonamide derivative.
〔２〕ニトロ基を有する化合物とチオール基を有する化合物を光照射下で反応させ、スルホンアミド誘導体を生成させる工程が、下記の一般式(I)
〔式中、X1、X2、X3、X4、及びX5は、それぞれ独立して、水素原子、炭素数1～3の直鎖若しくは分岐鎖アルキル基、炭素数1～3の直鎖若しくは分岐鎖アルキルチオ基、炭素数1～3の直鎖若しくは分岐鎖アルコキシ基、糖から誘導される基、ペプチドから誘導される基、又は核酸から誘導される基を表す。〕
で表される化合物と下記の一般式(II)
〔式中、R1は、置換基で置換されていてもよい炭素数1～14の直鎖若しくは分岐鎖アルキル基を表す。〕
で表される化合物を反応させ、下記の一般式(III)
〔式中、X1、X2、X3、X4、X5、及びR1は上記と同じ意味である。〕
で表されるスルホンアミド誘導体を生成させる工程であることを特徴とする〔１〕に記載のスルホンアミド誘導体の製造方法。 [2] The step of reacting a compound having a nitro group and a compound having a thiol group under light irradiation to produce a sulfonamide derivative is represented by the following general formula (I)
[Wherein, X 1 , X 2 , X 3 , X 4 and X 5 are each independently a hydrogen atom, a straight or branched chain alkyl group having 1 to 3 carbon atoms, a straight chain having 1 to 3 carbon atoms, It represents a chain or branched chain alkylthio group, a straight or branched chain alkoxy group having 1 to 3 carbon atoms, a group derived from a sugar, a group derived from a peptide, or a group derived from a nucleic acid. ]
and a compound represented by the following general formula (II)
[In the formula, R 1 represents a linear or branched alkyl group having 1 to 14 carbon atoms which may be substituted with a substituent. ]
By reacting the compound represented by the following general formula (III)
[In the formula, X 1 , X 2 , X 3 , X 4 , X 5 and R 1 have the same meanings as above. ]
The method for producing a sulfonamide derivative according to [1], which is a step of producing a sulfonamide derivative represented by:
で表される化合物と下記の一般式(II)
で表される化合物を反応させ、下記の一般式(III)
で表されるスルホンアミド誘導体を生成させる工程であることを特徴とする〔１〕に記載のスルホンアミド誘導体の製造方法。 [2] The step of reacting a compound having a nitro group and a compound having a thiol group under light irradiation to produce a sulfonamide derivative is represented by the following general formula (I)
and a compound represented by the following general formula (II)
By reacting the compound represented by the following general formula (III)
The method for producing a sulfonamide derivative according to [1], which is a step of producing a sulfonamide derivative represented by:
〔３〕一般式(I)及び(III)におけるX4及びX5が、水素原子であることを特徴とする〔２〕に記載のスルホンアミド誘導体の製造方法。
[3] The method for producing a sulfonamide derivative according to [2], wherein X 4 and X 5 in general formulas (I) and (III) are hydrogen atoms.
〔４〕照射する光の波長が200～600nmであり、光の照射時間が1～48時間であり、光の照射強度が1～500mW/cm2であることを特徴とする〔１〕乃至〔３〕のいずれかに記載のスルホンアミド誘導体の製造方法。
[4] The wavelength of the light to be irradiated is 200 to 600 nm, the light irradiation time is 1 to 48 hours, and the light irradiation intensity is 1 to 500 mW/cm 2 [1] to [ 3] The method for producing the sulfonamide derivative according to any one of the above.
〔５〕チオール基に修飾物を結合させるための修飾剤であって、下記の一般式(I)
〔式中、X1、X2、X3、X4、及びX5は、それぞれ独立して、水素原子又は修飾物から誘導される基を表す（但し、X1、X2、X3、X4、及びX5少なくとも一つは修飾物から誘導される基を表す。）。〕
で表される化合物を含有することを特徴とするチオール基の修飾剤。 [5] A modifier for binding a modifier to a thiol group, which has the following general formula (I)
[Wherein, X 1 , X 2 , X 3 , X 4 and X 5 each independently represent a hydrogen atom or a group derived from a modifier (provided that X 1 , X 2 , X 3 , At least one of X4 and X5 represents a group derived from a modifier.). ]
A thiol group modifier comprising a compound represented by:
で表される化合物を含有することを特徴とするチオール基の修飾剤。 [5] A modifier for binding a modifier to a thiol group, which has the following general formula (I)
A thiol group modifier comprising a compound represented by:
〔６〕一般式(I)におけるX4及びX5が、水素原子であることを特徴とする〔５〕に記載のチオール基の修飾剤。
[6] The thiol group modifier of [5], wherein X 4 and X 5 in general formula (I) are hydrogen atoms.
〔７〕下記の工程（１）～（３）を含むことを特徴とする生体分子チップの作製方法、
（１）表面にチオール基を有する基板を下記の一般式(I)
〔式中、X1、X2、X3、X4、及びX5は、それぞれ独立して、水素原子、又は生体分子から誘導される基を表す（但し、X1、X2、X3、X4、及びX5の少なくとも一つは生体分子から誘導される基を表す。）。〕
で表される化合物と接触させる工程、
（２）基板上の生体分子を固定したい部位に光を照射し、基板表面のチオール基に一般式(I)で表される化合物を結合させる工程、
（３）基板表面のチオール基に結合しなかった一般式(I)で表される化合物を除去する工程。 [7] A method for producing a biomolecule chip, comprising the following steps (1) to (3):
(1) A substrate having a thiol group on its surface is represented by the following general formula (I)
[Wherein, X 1 , X 2 , X 3 , X 4 and X 5 each independently represent a hydrogen atom or a group derived from a biomolecule (provided that X 1 , X 2 , X 3 , X 4 and X 5 represent a group derived from a biomolecule). ]
The step of contacting with a compound represented by
(2) A step of irradiating light onto a site on the substrate where the biomolecule is to be immobilized to bond the compound represented by the general formula (I) to the thiol group on the substrate surface;
(3) A step of removing the compound represented by general formula (I) that has not bonded to the thiol group on the substrate surface.
（１）表面にチオール基を有する基板を下記の一般式(I)
で表される化合物と接触させる工程、
（２）基板上の生体分子を固定したい部位に光を照射し、基板表面のチオール基に一般式(I)で表される化合物を結合させる工程、
（３）基板表面のチオール基に結合しなかった一般式(I)で表される化合物を除去する工程。 [7] A method for producing a biomolecule chip, comprising the following steps (1) to (3):
(1) A substrate having a thiol group on its surface is represented by the following general formula (I)
The step of contacting with a compound represented by
(2) A step of irradiating light onto a site on the substrate where the biomolecule is to be immobilized to bond the compound represented by the general formula (I) to the thiol group on the substrate surface;
(3) A step of removing the compound represented by general formula (I) that has not bonded to the thiol group on the substrate surface.
〔８〕一般式(I)におけるX4及びX5が、水素原子であることを特徴とする〔７〕に記載の生体分子チップの作製方法。
[8] The method for producing a biomolecule chip according to [7], wherein X4 and X5 in general formula (I) are hydrogen atoms.
〔９〕照射する光の波長が200～600nmであり、光の照射時間が1～48時間であり、光の照射強度が1～500mW/cm2であることを特徴とする〔７〕又は〔８〕に記載の生体分子チップの作製方法。
[9] The wavelength of the light to be irradiated is 200 to 600 nm, the light irradiation time is 1 to 48 hours, and the light irradiation intensity is 1 to 500 mW/cm 2 [7] or [ 8].
〔１０〕システイン残基を含むタンパク質に修飾物を結合させるタンパク質の修飾方法であって、下記の工程（１）及び（２）を含むことを特徴とするタンパク質の修飾方法、
（１）タンパク質を下記の一般式(I)
〔式中、X1、X2、X3、X4、及びX5は、それぞれ独立して、水素原子又は修飾物から誘導される基を表す（但し、X1、X2、X3、X4、及びX5の少なくとも一つは修飾物から誘導される基を表す。）。〕
で表される化合物と接触させる工程、
（２）タンパク質及び一般式(I)で表される化合物に光を照射する工程。 [10] A method for modifying a protein by binding a modifier to a protein containing a cysteine residue, comprising the following steps (1) and (2):
(1) protein represented by the following general formula (I)
[Wherein, X 1 , X 2 , X 3 , X 4 and X 5 each independently represent a hydrogen atom or a group derived from a modifier (provided that X 1 , X 2 , X 3 , At least one of X4 and X5 represents a group derived from a modifier.). ]
The step of contacting with a compound represented by
(2) A step of irradiating the protein and the compound represented by the general formula (I) with light.
（１）タンパク質を下記の一般式(I)
で表される化合物と接触させる工程、
（２）タンパク質及び一般式(I)で表される化合物に光を照射する工程。 [10] A method for modifying a protein by binding a modifier to a protein containing a cysteine residue, comprising the following steps (1) and (2):
(1) protein represented by the following general formula (I)
The step of contacting with a compound represented by
(2) A step of irradiating the protein and the compound represented by the general formula (I) with light.
〔１１〕一般式(I)におけるX4及びX5が、水素原子であることを特徴とする〔１０〕に記載のタンパク質の修飾方法。
[11] The method for modifying a protein of [10], wherein X4 and X5 in general formula (I) are hydrogen atoms.
〔１２〕照射する光の波長が200～600nmであり、光の照射時間が1～48時間であり、光の照射強度が1～500mW/cm2であることを特徴とする〔１０〕又は〔１１〕に記載のタンパク質の修飾方法。
[12] The wavelength of the light to be irradiated is 200 to 600 nm, the light irradiation time is 1 to 48 hours, and the light irradiation intensity is 1 to 500 mW/cm 2 [10] or [ 11], the protein modification method.
〔１３〕二つのニトロ基を有する化合物と二つのチオール基を有する化合物を光照射下で反応させ、ポリスルホンアミド誘導体を生成させる工程を含むことを特徴とするポリスルホンアミド誘導体の製造方法。
[13] A method for producing a polysulfonamide derivative, comprising the step of reacting a compound having two nitro groups and a compound having two thiol groups under light irradiation to produce a polysulfonamide derivative.
〔１４〕二つのニトロ基を有する化合物と二つのチオール基を有する化合物を光照射下で反応させ、ポリスルホンアミド誘導体を生成させる工程が、下記の一般式(IVa)、(IVb)、又は(IVc)
〔式中、Xは、O、S、又は-CH2-を表し、mは0～2の整数を表す。〕
で表される化合物と下記の一般式(V)
〔式中、nは、2～8の整数を表す。〕
で表される化合物を反応させ、下記の一般式(VIa)、(VIb)、又は (VIc)
〔式中、X、m、及びnは上記と同じ意味である。〕
で表される繰り返し単位を有するポリスルホンアミド誘導体を生成させる工程であることを特徴とする〔１３〕に記載のポリスルホンアミド誘導体の製造方法。 [14] The step of reacting a compound having two nitro groups and a compound having two thiol groups under light irradiation to produce a polysulfonamide derivative is represented by the following general formula (IVa), (IVb), or (IVc )
[In the formula, X represents O, S, or -CH 2 -, and m represents an integer of 0 to 2. ]
and the compound represented by the following general formula (V)
[In the formula, n represents an integer of 2 to 8. ]
By reacting the compound represented by the following general formula (VIa), (VIb), or (VIc)
[In the formula, X, m and n have the same meanings as above. ]
The method for producing a polysulfonamide derivative according to [13], which is a step of producing a polysulfonamide derivative having a repeating unit represented by:
で表される化合物と下記の一般式(V)
で表される化合物を反応させ、下記の一般式(VIa)、(VIb)、又は (VIc)
で表される繰り返し単位を有するポリスルホンアミド誘導体を生成させる工程であることを特徴とする〔１３〕に記載のポリスルホンアミド誘導体の製造方法。 [14] The step of reacting a compound having two nitro groups and a compound having two thiol groups under light irradiation to produce a polysulfonamide derivative is represented by the following general formula (IVa), (IVb), or (IVc )
and the compound represented by the following general formula (V)
By reacting the compound represented by the following general formula (VIa), (VIb), or (VIc)
The method for producing a polysulfonamide derivative according to [13], which is a step of producing a polysulfonamide derivative having a repeating unit represented by:
〔１５〕照射する光の波長が200～600nmであり、光の照射時間が1～48時間であり、光の照射強度が1～500mW/cm2であることを特徴とする〔１３〕又は〔１４〕に記載のポリスルホンアミド誘導体の製造方法。
[15] The wavelength of the light to be irradiated is 200 to 600 nm, the light irradiation time is 1 to 48 hours, and the light irradiation intensity is 1 to 500 mW/cm 2 [13] or [ 14].
本明細書は、本願の優先権の基礎である日本国特許出願、特願2021-206935の明細書及び／又は図面に記載される内容を包含する。
This specification includes the contents described in the specification and/or drawings of the Japanese patent application, Japanese Patent Application No. 2021-206935, which is the basis of the priority of this application.
本発明は、スルホンアミド誘導体の新規な製造方法を提供する。この方法は、光クリック反応によってスルホンアミド誘導体を生成させるので、光照射した部分にだけ生体分子や生理活性分子を結合させることができ、生体分子マイクロアレイ作製技術などに応用が期待される。また、ラジカル開始剤は不要であることから、広範な生体分子に適用可能である。
The present invention provides a novel method for producing sulfonamide derivatives. In this method, a sulfonamide derivative is generated by a photo-click reaction, so biomolecules and physiologically active molecules can be bound only to the light-irradiated portions, and applications such as biomolecular microarray fabrication technology are expected. Moreover, since no radical initiator is required, it can be applied to a wide range of biomolecules.
以下、本発明を詳細に説明する。
本発明のスルホンアミド誘導体の製造方法は、ニトロ基を有する化合物とチオール基を有する化合物を光照射下で反応させ、スルホンアミド誘導体を生成させる工程を含むことを特徴とするものである。 The present invention will be described in detail below.
The method for producing a sulfonamide derivative of the present invention is characterized by including a step of reacting a compound having a nitro group and a compound having a thiol group under light irradiation to produce a sulfonamide derivative.
本発明のスルホンアミド誘導体の製造方法は、ニトロ基を有する化合物とチオール基を有する化合物を光照射下で反応させ、スルホンアミド誘導体を生成させる工程を含むことを特徴とするものである。 The present invention will be described in detail below.
The method for producing a sulfonamide derivative of the present invention is characterized by including a step of reacting a compound having a nitro group and a compound having a thiol group under light irradiation to produce a sulfonamide derivative.
ニトロ基を有する化合物は特に限定されず、ニトロアリール、ニトロアルケンなどを使用することができる。
The compound having a nitro group is not particularly limited, and nitroaryl, nitroalkene, etc. can be used.
チオール基を有する化合物も特に限定されず、チオール、ジチオールなどを使用することができる。
The compound having a thiol group is also not particularly limited, and thiol, dithiol, etc. can be used.
照射する光の波長はスルホンアミド誘導体を生成させ得る波長であれば特に限定されず、例えば、200～600nmとすることができ、好ましくは、300～500nmとすることができる。照射時間もスルホンアミド誘導体を生成させ得る時間であれば特に限定されず、例えば、1～48時間とすることができ、好ましくは、2～36時間とすることができる。光の照射強度もスルホンアミド誘導体を生成させ得る強度であれば特に限定されず、例えば、1～500mW/cm2とすることができ、好ましくは、5～300mW/cm2とすることができ、より好ましくは、10～100mW/cm2とすることができる。
The wavelength of light to be irradiated is not particularly limited as long as it can generate a sulfonamide derivative, and can be, for example, 200 to 600 nm, preferably 300 to 500 nm. Irradiation time is not particularly limited as long as it can generate a sulfonamide derivative, and can be, for example, 1 to 48 hours, preferably 2 to 36 hours. The irradiation intensity of light is also not particularly limited as long as it is an intensity capable of generating a sulfonamide derivative, and can be, for example, 1 to 500 mW/cm 2 , preferably 5 to 300 mW/cm 2 , More preferably, it can be 10 to 100 mW/cm 2 .
スルホンアミド誘導体を生成させる反応は、通常、溶媒中で行われる。溶媒は、反応を阻害しないものであれば特に限定されず、N,N-ジメチルホルムアミド（DMF）、トルエン、ジメチルスルホキシド（DMSO）、ジクロロメタン、水、又はこれらの混合溶媒を使用することができる。使用するチオール基を有する化合物の量は特に限定されないが、ニトロ基を有する化合物1 molに対し、例えば、1～30molとすることができ、好ましくは、5～20molとすることができる。反応時の温度は特に限定されず、例えば、10～40℃とすることができ、好ましくは、20～30℃とすることができる。
The reaction to produce a sulfonamide derivative is usually carried out in a solvent. The solvent is not particularly limited as long as it does not inhibit the reaction, and N,N-dimethylformamide (DMF), toluene, dimethylsulfoxide (DMSO), dichloromethane, water, or a mixed solvent thereof can be used. The amount of the compound having a thiol group to be used is not particularly limited. The temperature during the reaction is not particularly limited, and can be, for example, 10 to 40°C, preferably 20 to 30°C.
本発明のスルホンアミド誘導体の製造方法は、上述したスルホンアミド誘導体を生成させる工程を含むが、他の工程、例えば、生成したスルホンアミド誘導体を他の生成物から分離し、精製する工程を含んでいてもよい。
The method for producing a sulfonamide derivative of the present invention includes the step of producing the sulfonamide derivative described above, but also includes other steps, for example, a step of separating and purifying the produced sulfonamide derivative from other products. You can
上述したスルホンアミド誘導体を生成させる工程の具体例としては、下記の一般式(I)
で表される化合物と下記の一般式(II)
で表される化合物を反応させ、下記の一般式(III)
で表されるスルホンアミド誘導体を生成させる工程を例示できる。
As a specific example of the step of producing the sulfonamide derivative described above, the following general formula (I)
and a compound represented by the following general formula (II)
By reacting the compound represented by the following general formula (III)
A step of producing a sulfonamide derivative represented by can be exemplified.
一般式(I)及び(III)においてX1、X2、X3、X4、及びX5は、それぞれ独立して、水素原子、アルキル基、アルキルチオ基、アルコキシ基、糖から誘導される基、ペプチドから誘導される基、又は核酸から誘導される基を表す。アルキル基は、通常、炭素数1～3の直鎖若しくは分岐鎖のアルキル基であり、好ましくは、メチル基である。アルキルチオ基は、通常、炭素数1～3の直鎖若しくは分岐鎖のアルキルチオ基であり、好ましくは、メチルチオ基である。アルコキシ基は、通常、炭素数1～3の直鎖若しくは分岐鎖のアルコキシ基であり、好ましくは、メトキシ基である。「糖から誘導される基」とは、例えば、糖分子中の一つの水素原子又は一つのヒドロキシ基を除去することによって得られる基や糖分子中の一つの水素原子又は一つのヒドロキシ基を除去し、そこに硫黄原子、酸素原子、及び／又はスペーサとなる二価の基（例えば、アルキレン基、フェニレン基）を結合させた基である。糖は、単糖、二糖、オリゴ糖、多糖のいずれであってもよく、糖分子中のヒドロキシ基は保護基によって保護されていてもよい。「ペプチドから誘導される基」とは、例えば、ペプチド分子中の一つの水素原子又は一つのヒドロキシ基を除去することによって得られる基やペプチド分子中の一つの水素原子又は一つのヒドロキシ基を除去し、そこに硫黄原子、酸素原子、及び／又はスペーサとなる二価の基（例えば、アルキレン基、フェニレン基）を結合させた基である。「核酸から誘導される基」とは、例えば、核酸分子中の一つの水素原子又は一つのヒドロキシ基を除去することによって得られる基や核酸分子中の一つの水素原子又は一つのヒドロキシ基を除去し、そこに硫黄原子、酸素原子、及び／又はスペーサとなる二価の基（例えば、アルキレン基、フェニレン基）を結合させた基である。X1、X2、X3、X4、及びX5は同一の基であってもよく、異なる基であってもよい。X1、X2、X3、X4、及びX5は、前記した基であればよいが、X4及びX5は水素原子であることが好ましい。X1、X2、X3、X4、及びX5の好ましい組み合わせとしては、X1、X3、X4、及びX5が水素原子であり、X2が水素原子、メチル基、メチルチオ基、メトキシ基、又は糖から誘導される基である組み合わせを挙げることができ、より好ましい組み合わせとしては、X1、X3、X4、及びX5が水素原子であり、X2がメチル基又はメチルチオ基である組み合わせを挙げることができる。
In general formulas (I) and (III), X 1 , X 2 , X 3 , X 4 and X 5 each independently represent a hydrogen atom, an alkyl group, an alkylthio group, an alkoxy group or a group derived from sugar. , represents a group derived from a peptide or a group derived from a nucleic acid. The alkyl group is generally a linear or branched alkyl group having 1 to 3 carbon atoms, preferably a methyl group. The alkylthio group is generally a linear or branched alkylthio group having 1 to 3 carbon atoms, preferably a methylthio group. The alkoxy group is generally a linear or branched alkoxy group having 1 to 3 carbon atoms, preferably a methoxy group. "A group derived from sugar" means, for example, a group obtained by removing one hydrogen atom or one hydroxy group in a sugar molecule, or a group obtained by removing one hydrogen atom or one hydroxy group in a sugar molecule. and a sulfur atom, an oxygen atom, and/or a divalent group (for example, an alkylene group or a phenylene group) as a spacer is bonded thereto. Sugars may be monosaccharides, disaccharides, oligosaccharides, or polysaccharides, and hydroxy groups in sugar molecules may be protected by protective groups. A "group derived from a peptide" is, for example, a group obtained by removing one hydrogen atom or one hydroxy group in a peptide molecule, or removing one hydrogen atom or one hydroxy group in a peptide molecule. and a sulfur atom, an oxygen atom, and/or a divalent group (for example, an alkylene group or a phenylene group) as a spacer is bonded thereto. "Group derived from nucleic acid" means, for example, a group obtained by removing one hydrogen atom or one hydroxy group in the nucleic acid molecule, or removing one hydrogen atom or one hydroxy group in the nucleic acid molecule. and a sulfur atom, an oxygen atom, and/or a divalent group (for example, an alkylene group or a phenylene group) as a spacer is bonded thereto. X 1 , X 2 , X 3 , X 4 and X 5 may be the same group or different groups. X 1 , X 2 , X 3 , X 4 and X 5 may be the groups described above, but X 4 and X 5 are preferably hydrogen atoms. Preferred combinations of X 1 , X 2 , X 3 , X 4 and X 5 are X 1 , X 3 , X 4 and X 5 are hydrogen atoms and X 2 is a hydrogen atom, a methyl group or a methylthio group. , a methoxy group, or a group derived from a sugar. A more preferred combination is a combination in which X 1 , X 3 , X 4 and X 5 are hydrogen atoms, and X 2 is a methyl group or A combination that is a methylthio group can be mentioned.
一般式(II)及び(III)においてR1は、置換基で置換されていてもよいアルキル基を表す。置換基としては、チオール基を挙げることができる。置換基で置換されていてもよいアルキル基は、通常、炭素数1～14の直鎖若しくは分岐鎖のアルキル基であり、好ましくは、炭素数1～12の直鎖のアルキル基であり、より好ましくは、n-ドデカニル基、エチル基、4-メルカプトブチル基である。R1は、前記した基であればよいが、好ましくは、n-ドデカニル基、エチル基、又は4-メルカプトブチル基である。
In general formulas (II) and (III), R 1 represents an optionally substituted alkyl group. A thiol group can be mentioned as a substituent. The alkyl group optionally substituted with a substituent is generally a straight or branched alkyl group having 1 to 14 carbon atoms, preferably a straight chain alkyl group having 1 to 12 carbon atoms, and more Preferred are n-dodecanyl group, ethyl group and 4-mercaptobutyl group. R 1 may be any of the groups described above, preferably an n-dodecanyl group, an ethyl group, or a 4-mercaptobutyl group.
本発明のスルホンアミド誘導体の製造方法は、例えば、（Ａ）チオール基の修飾剤、（Ｂ）生体分子チップの作製方法、（Ｃ）タンパク質の修飾方法、及び（Ｄ）ポリスルホンアミド誘導体の製造方法に応用することができる。以下、これらの発明について説明する。
The method for producing a sulfonamide derivative of the present invention includes, for example, (A) a thiol group modifier, (B) a method for producing a biomolecule chip, (C) a method for modifying a protein, and (D) a method for producing a polysulfonamide derivative. can be applied to These inventions are described below.
（Ａ）チオール基の修飾剤
本発明のチオール基の修飾剤は、チオール基に修飾物を結合させるための修飾剤であって、下記の一般式(I)
〔式中、X1、X2、X3、X4、及びX5は、それぞれ独立して、水素原子又は修飾物から誘導される基を表す（但し、X1、X2、X3、X4、及びX5の少なくとも一つは修飾物から誘導される基を表す。）。〕
で表される化合物を含有することを特徴とするものである。 (A) Thiol Group Modifier The thiol group modifier of the present invention is a modifier for binding a modifier to a thiol group, and has the following general formula (I).
[Wherein, X 1 , X 2 , X 3 , X 4 and X 5 each independently represent a hydrogen atom or a group derived from a modifier (provided that X 1 , X 2 , X 3 , At least one of X4 and X5 represents a group derived from a modifier.). ]
It is characterized by containing a compound represented by.
本発明のチオール基の修飾剤は、チオール基に修飾物を結合させるための修飾剤であって、下記の一般式(I)
で表される化合物を含有することを特徴とするものである。 (A) Thiol Group Modifier The thiol group modifier of the present invention is a modifier for binding a modifier to a thiol group, and has the following general formula (I).
It is characterized by containing a compound represented by.
「修飾物から誘導される基」とは、例えば、修飾物分子中の一つの水素原子又は一つのヒドロキシ基を除去することによって得られる基や修飾物分子中の一つの水素原子又は一つのヒドロキシ基を除去し、そこに硫黄原子、酸素原子、及び／又はスペーサとなる二価の基（例えば、アルキレン基、フェニレン基）を結合させた基である。
"A group derived from a modifier" means, for example, a group obtained by removing one hydrogen atom or one hydroxy group in the molecule of the modifier, or one hydrogen atom or one hydroxyl group in the molecule of the modifier. It is a group in which a group is removed and a sulfur atom, an oxygen atom and/or a divalent group serving as a spacer (for example, an alkylene group or a phenylene group) is bonded thereto.
修飾物はどのようなものでもよく、例えば、糖、ペプチド、核酸などの生体分子であってもよく、生理活性を持つ低分子化合物であってもよい。
Modifications can be anything, for example, biomolecules such as sugars, peptides, nucleic acids, or bioactive low-molecular-weight compounds.
修飾対象とするチオール基は、タンパク質中のシステイン残基のチオール基であってもよく、低分子化合物のチオール基であってもよい。
The thiol group to be modified may be the thiol group of a cysteine residue in a protein or the thiol group of a low-molecular-weight compound.
（Ｂ）生体分子チップの作製方法
本発明の生体分子チップの作製方法は、下記の工程（１）～（３）を含むことを特徴とするものである、
（１）表面にチオール基を有する基板を下記の一般式(I)
〔式中、X1、X2、X3、X4、及びX5は、それぞれ独立して、水素原子、又は生体分子から誘導される基を表す（但し、X1、X2、X3、X4、及びX5の少なくとも一つは生体分子から誘導される基を表す。）。〕
表される化合物と接触させる工程、
（２）基板上の生体分子を固定したい部位に光を照射し、基板表面のチオール基に一般式(I)で表される化合物を結合させる工程、
（３）基板表面のチオール基に結合しなかった一般式(I)で表される化合物を除去する工程。 (B) Method for producing a biomolecule chip The method for producing a biomolecule chip of the present invention is characterized by including the following steps (1) to (3):
(1) A substrate having a thiol group on its surface is represented by the following general formula (I)
[Wherein, X 1 , X 2 , X 3 , X 4 and X 5 each independently represent a hydrogen atom or a group derived from a biomolecule (provided that X 1 , X 2 , X 3 , X 4 and X 5 represent a group derived from a biomolecule). ]
contacting with a compound represented;
(2) A step of irradiating light onto a site on the substrate where the biomolecule is to be immobilized to bond the compound represented by the general formula (I) to the thiol group on the substrate surface;
(3) A step of removing the compound represented by general formula (I) that has not bonded to the thiol group on the substrate surface.
本発明の生体分子チップの作製方法は、下記の工程（１）～（３）を含むことを特徴とするものである、
（１）表面にチオール基を有する基板を下記の一般式(I)
表される化合物と接触させる工程、
（２）基板上の生体分子を固定したい部位に光を照射し、基板表面のチオール基に一般式(I)で表される化合物を結合させる工程、
（３）基板表面のチオール基に結合しなかった一般式(I)で表される化合物を除去する工程。 (B) Method for producing a biomolecule chip The method for producing a biomolecule chip of the present invention is characterized by including the following steps (1) to (3):
(1) A substrate having a thiol group on its surface is represented by the following general formula (I)
contacting with a compound represented;
(2) A step of irradiating light onto a site on the substrate where the biomolecule is to be immobilized to bond the compound represented by the general formula (I) to the thiol group on the substrate surface;
(3) A step of removing the compound represented by general formula (I) that has not bonded to the thiol group on the substrate surface.
「生体分子から誘導される基」とは、例えば、生体分子中の一つの水素原子又は一つのヒドロキシ基を除去することによって得られる基や生体分子中の一つの水素原子又は一つのヒドロキシ基を除去し、そこに硫黄原子、酸素原子、及び／又はスペーサとなる二価の基（例えば、アルキレン基、フェニレン基）を結合させた基である。生体分子としては、糖、ペプチド、核酸などを挙げることができる。
"A group derived from a biomolecule" means, for example, a group obtained by removing one hydrogen atom or one hydroxy group in a biomolecule, or one hydrogen atom or one hydroxy group in a biomolecule. It is a group obtained by removing a sulfur atom, an oxygen atom, and/or a divalent group (for example, an alkylene group or a phenylene group) serving as a spacer. Biomolecules can include sugars, peptides, nucleic acids, and the like.
一般式(I)で表される化合物とチオール基との反応は、光クリック反応なので、光を照射する部位を精密に制御することにより、基板上の任意の位置に生体分子を固定することができる。
Since the reaction between the compound represented by the general formula (I) and the thiol group is a photo-click reaction, it is possible to immobilize biomolecules at any position on the substrate by precisely controlling the site irradiated with light. can.
上記の（１）～（３）の工程を1回行うことにより、基板上に1種類の生体分子を固定できる。（１）～（３）の工程を何度も繰り返すことにより、基板上に多数の生体分子を固定できる。
By performing the above steps (1) to (3) once, one type of biomolecule can be immobilized on the substrate. By repeating the steps (1) to (3) many times, a large number of biomolecules can be immobilized on the substrate.
（Ｃ）タンパク質の修飾方法
本発明のタンパク質の修飾方法は、システイン残基を含むタンパク質に修飾物を結合させるタンパク質の修飾方法であって、下記の工程（１）及び（２）を含むことを特徴とするものである。
（１）タンパク質を下記の一般式(I)
〔式中、X1、X2、X3、X4、及びX5は、それぞれ独立して、水素原子又は修飾物から誘導される基を表す（但し、X1、X2、X3、X4、及びX5の少なくとも一つは修飾物から誘導される基を表す。）。〕
で表される化合物と接触させる工程、
（２）タンパク質及び一般式(I)で表される化合物に光を照射する工程。 (C) Protein Modification Method The protein modification method of the present invention is a protein modification method for binding a modification product to a protein containing a cysteine residue, comprising the following steps (1) and (2). It is characterized.
(1) protein represented by the following general formula (I)
[Wherein, X 1 , X 2 , X 3 , X 4 and X 5 each independently represent a hydrogen atom or a group derived from a modifier (provided that X 1 , X 2 , X 3 , At least one of X4 and X5 represents a group derived from a modifier.). ]
The step of contacting with a compound represented by
(2) A step of irradiating the protein and the compound represented by the general formula (I) with light.
本発明のタンパク質の修飾方法は、システイン残基を含むタンパク質に修飾物を結合させるタンパク質の修飾方法であって、下記の工程（１）及び（２）を含むことを特徴とするものである。
（１）タンパク質を下記の一般式(I)
で表される化合物と接触させる工程、
（２）タンパク質及び一般式(I)で表される化合物に光を照射する工程。 (C) Protein Modification Method The protein modification method of the present invention is a protein modification method for binding a modification product to a protein containing a cysteine residue, comprising the following steps (1) and (2). It is characterized.
(1) protein represented by the following general formula (I)
The step of contacting with a compound represented by
(2) A step of irradiating the protein and the compound represented by the general formula (I) with light.
「修飾物から誘導される基」とは、例えば、修飾物分子中の一つの水素原子又は一つのヒドロキシ基を除去することによって得られる基や修飾物分子中の一つの水素原子又は一つのヒドロキシ基を除去し、そこに硫黄原子、酸素原子、及び／又はスペーサとなる二価の基（例えば、アルキレン基、フェニレン基）を結合させた基である。
"A group derived from a modifier" means, for example, a group obtained by removing one hydrogen atom or one hydroxy group in the molecule of the modifier, or one hydrogen atom or one hydroxyl group in the molecule of the modifier. It is a group in which a group is removed and a sulfur atom, an oxygen atom and/or a divalent group serving as a spacer (for example, an alkylene group or a phenylene group) is bonded thereto.
修飾物はどのようなものでもよく、例えば、糖、ペプチド、核酸などの生体分子であってもよく、生理活性を持つ低分子化合物であってもよい。
Modifications can be anything, for example, biomolecules such as sugars, peptides, nucleic acids, or bioactive low-molecular-weight compounds.
（Ｄ）ポリスルホンアミド誘導体の製造方法
本発明のポリスルホンアミド誘導体の製造方法は、二つのニトロ基を有する化合物と二つのチオール基を有する化合物を光照射下で反応させ、ポリスルホンアミド誘導体を生成させる工程を含むことを特徴とするものである。 (D) Method for producing a polysulfonamide derivative The method for producing a polysulfonamide derivative of the present invention comprises a step of reacting a compound having two nitro groups and a compound having two thiol groups under light irradiation to produce a polysulfonamide derivative. It is characterized by including
本発明のポリスルホンアミド誘導体の製造方法は、二つのニトロ基を有する化合物と二つのチオール基を有する化合物を光照射下で反応させ、ポリスルホンアミド誘導体を生成させる工程を含むことを特徴とするものである。 (D) Method for producing a polysulfonamide derivative The method for producing a polysulfonamide derivative of the present invention comprises a step of reacting a compound having two nitro groups and a compound having two thiol groups under light irradiation to produce a polysulfonamide derivative. It is characterized by including
二つのニトロ基を有する化合物は特に限定されず、ジニトロアリール、ジニトロアルケンなどを使用することができる。二つのニトロ基を有する化合物が二つのニトロ基を有するベンゼンである場合、ニトロ基はパラ位に存在することが好ましい。
The compound having two nitro groups is not particularly limited, and dinitroaryl, dinitroalkene, etc. can be used. When the compound with two nitro groups is benzene with two nitro groups, the nitro group is preferably in the para position.
二つのチオール基を有する化合物も特に限定されず、ジチオールなどを使用することができる。二つのチオール基を有する化合物が二つのチオール基を有する直鎖のアルカンである場合、チオール基は末端の炭素に存在することが好ましい。
The compound having two thiol groups is also not particularly limited, and dithiol and the like can be used. When the compound having two thiol groups is a straight-chain alkane having two thiol groups, the thiol group is preferably present at the terminal carbon.
上述したポリスルホンアミド誘導体を生成させる工程の具体例としては、下記の一般式(IVa)、(IVb)、又は(IVc)
〔式中、Xは、O、S、又は-CH2-を表し、mは0～2の整数を表す。〕
で表される化合物と下記の一般式(V)
〔式中、nは、2～8の整数を表す。〕
で表される化合物を反応させ、下記の一般式(VIa)、(VIb)、又は (VIc)
〔式中、X、m、及びnは上記と同じ意味である。〕
で表される繰り返し単位を有するポリスルホンアミド誘導体を生成させる工程を例示できる。なお、一般式(IVc)及び (VIc)においてmが0であるとは、一般式(IVc)及び (VIc)中の多環式芳香族環がナフタレン環であることを意味する。 As a specific example of the step of producing the polysulfonamide derivative described above, the following general formula (IVa), (IVb), or (IVc)
[In the formula, X represents O, S, or -CH 2 -, and m represents an integer of 0 to 2. ]
and the compound represented by the following general formula (V)
[In the formula, n represents an integer of 2 to 8. ]
By reacting the compound represented by the following general formula (VIa), (VIb), or (VIc)
[In the formula, X, m and n have the same meanings as above. ]
A process of producing a polysulfonamide derivative having a repeating unit represented by can be exemplified. In general formulas (IVc) and (VIc), m being 0 means that the polycyclic aromatic ring in general formulas (IVc) and (VIc) is a naphthalene ring.
で表される化合物と下記の一般式(V)
で表される化合物を反応させ、下記の一般式(VIa)、(VIb)、又は (VIc)
で表される繰り返し単位を有するポリスルホンアミド誘導体を生成させる工程を例示できる。なお、一般式(IVc)及び (VIc)においてmが0であるとは、一般式(IVc)及び (VIc)中の多環式芳香族環がナフタレン環であることを意味する。 As a specific example of the step of producing the polysulfonamide derivative described above, the following general formula (IVa), (IVb), or (IVc)
and the compound represented by the following general formula (V)
By reacting the compound represented by the following general formula (VIa), (VIb), or (VIc)
A process of producing a polysulfonamide derivative having a repeating unit represented by can be exemplified. In general formulas (IVc) and (VIc), m being 0 means that the polycyclic aromatic ring in general formulas (IVc) and (VIc) is a naphthalene ring.
（Ｅ）その他の応用例
本発明のスルホンアミド誘導体の製造方法により、スルホンアミド構造を持つ化合物を合成することができるが、このような構造を持つ化合物は抗菌作用を示すものが多く、それらは一般にサルファ剤と呼ばれ、医薬品として使用されている。従って、本発明のスルホンアミド誘導体の製造方法は、医薬品の製造にも利用できる。サルファ剤としては、スルファメトキサゾール、スルファジメトキシン、スルファモノメトキシン、スルフイソキサゾール、スルファドキシン、スルファメトキサゾール、スルファジアジン、スルファクロルピリダジンナトリウム、スルファメラジンナトリウムなどが知られているが、これらの製造に本発明のスルホンアミド誘導体の製造方法を利用可能である。 (E) Other application examples By the method for producing a sulfonamide derivative of the present invention, a compound having a sulfonamide structure can be synthesized. They are commonly called sulfa drugs and are used as medicines. Therefore, the method for producing a sulfonamide derivative of the present invention can also be used for producing pharmaceuticals. Sulfa drugs include sulfamethoxazole, sulfadimethoxine, sulfamonomethoxine, sulfisoxazole, sulfadoxine, sulfamethoxazole, sulfadiazine, sulfachlorpyridazine sodium, and sulfamerazine sodium. However, the method for producing a sulfonamide derivative of the present invention can be used for these productions.
本発明のスルホンアミド誘導体の製造方法により、スルホンアミド構造を持つ化合物を合成することができるが、このような構造を持つ化合物は抗菌作用を示すものが多く、それらは一般にサルファ剤と呼ばれ、医薬品として使用されている。従って、本発明のスルホンアミド誘導体の製造方法は、医薬品の製造にも利用できる。サルファ剤としては、スルファメトキサゾール、スルファジメトキシン、スルファモノメトキシン、スルフイソキサゾール、スルファドキシン、スルファメトキサゾール、スルファジアジン、スルファクロルピリダジンナトリウム、スルファメラジンナトリウムなどが知られているが、これらの製造に本発明のスルホンアミド誘導体の製造方法を利用可能である。 (E) Other application examples By the method for producing a sulfonamide derivative of the present invention, a compound having a sulfonamide structure can be synthesized. They are commonly called sulfa drugs and are used as medicines. Therefore, the method for producing a sulfonamide derivative of the present invention can also be used for producing pharmaceuticals. Sulfa drugs include sulfamethoxazole, sulfadimethoxine, sulfamonomethoxine, sulfisoxazole, sulfadoxine, sulfamethoxazole, sulfadiazine, sulfachlorpyridazine sodium, and sulfamerazine sodium. However, the method for producing a sulfonamide derivative of the present invention can be used for these productions.
スルホンアミド構造を持つ化合物の中には、除草作用を示すものも知られている。例えば、ペノキススラムなどである。従って、本発明のスルホンアミド誘導体の製造方法は、除草剤などの農薬の製造にも利用できる
Some compounds with a sulfonamide structure are known to exhibit herbicidal action. For example, Penokislam. Therefore, the method for producing a sulfonamide derivative of the present invention can also be used for producing agricultural chemicals such as herbicides.
本発明のスルホンアミド誘導体の製造方法は、ニトロ基とチオール基との間に架橋構造を形成させ、三次元網目構造を作ることができるので、ハイドロゲルの製造にも利用できる。製造されたハイドロゲルは、様々な用途、例えば、人工軟骨、人工関節、人工臓器、細胞培養基材、ドラッグデリバリーシステムなどに利用できる。最近、細胞を含むハイドロゲルを「インク」とし、3Dプリンターによって人工臓器を作製する臓器プリンティングが注目されているが、上記方法によって製造されたハイドロゲルは、この臓器プリンティングの「インク」として使用できる。
The method for producing a sulfonamide derivative of the present invention can form a crosslinked structure between nitro groups and thiol groups to create a three-dimensional network structure, so it can also be used for producing hydrogels. The produced hydrogels can be used in various applications such as artificial cartilage, artificial joints, artificial organs, cell culture substrates, and drug delivery systems. Recently, attention has been focused on organ printing, in which hydrogels containing cells are used as "ink" to fabricate artificial organs using 3D printers. .
以下に、実施例により本発明を更に詳細に説明するが、本発明はこれらの実施例に限定されるものではない。
EXAMPLES The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.
〔実施例１〕 X = SCH3; R = C12H25
[Example 1] X = SCH3 ; R = C12H25
4-ニトロチオアニソール（1[SCH3]: 203 mg, 1.20 mmol）と1-ドデカンチオール（2[C12H25]: 2.00 mL, 8.35 mmol）のDMF（1 mL）溶液にLED（365 nm）を4 cm先から24時間照射した（52.5 mW/cm2）。反応溶液をCH2Cl2で希釈した後、水で2回、飽和重曹水で１回、飽和食塩水で１回洗浄し、有機層をMgSO4で乾燥した。有機層を濃縮後、シリカゲル（C-300 Wakogel（登録商標））カラム（ethyl acetate/hexane 1%-50%）を行い3分画に分取したもの各々についてさらにシリカゲル（C-300 Wakogel（登録商標））カラム（toluene/hexane 50%-99%）を行い、N-[4-(メチルチオ)フェニル]ドデシルスルホンアミド3[SCH3;C12H25]: 214 mg（48%）、N-[4-(ドデシルチオ)フェニル]ドデシルスルホンアミド3[S C12H25;C12H25]: 31 mg（5%）、4-メチルチオアニリン4[SCH3]: 23 mg（14%）、 4-ドデシルチオアニリン4[SC12H25]: 14 mg（4%）、2-ドデシルスルホニル-4-メチルチオアニリン5[SCH3;C12H25]: 31 mg（7%）、N-[4-(メチルチオ)フェニル]ドデシルスルフィンアミド6[S6CH3;C12H25]: 8 mg（2%）を得た。
LED ( 365 nm ) was irradiated from 4 cm ahead for 24 hours (52.5 mW/cm 2 ). After diluting the reaction solution with CH 2 Cl 2 , it was washed twice with water, once with saturated aqueous sodium bicarbonate solution and once with saturated brine, and the organic layer was dried over MgSO 4 . After concentrating the organic layer, it was subjected to a silica gel (C-300 Wakogel (registered trademark)) column (ethyl acetate/hexane 1%-50%) and separated into three fractions. Trademark)) column (toluene/hexane 50%-99%) gave N-[4-(methylthio)phenyl]dodecylsulfonamide 3[SCH 3 ;C 12 H 25 ]: 214 mg (48%), N- [4-(dodecylthio )phenyl]dodecylsulfonamide 3[SC12H25;C12H25 ] : 31 mg (5%), 4-methylthioaniline 4[ SCH3 ]: 23 mg (14%), 4- Dodecylthioaniline 4[ SC12H25 ]: 14 mg (4%), 2 - dodecylsulfonyl-4-methylthioaniline 5[ SCH3 ; C12H25 ]: 31 mg (7%), N-[4- (Methylthio)phenyl]dodecylsulfinamide 6 [ S6CH3 ; C12H25 ]: Obtained 8 mg (2%).
3[SCH3;C12H25](Mw 371.608): Rf 0.42 (20% ethyl acetate/hexane); 1H NMR (500 MHz, CDCl3, 298K) δ (ppm) 0.876 (t, 3H, J = 6.8Hz, -CH3), 1.229 (m, 16H, -(CH2)3(CH2)8CH3), 1.356 (quin, 2H, J = 7.0 Hz, -SO2(CH2)2CH2-), 1.796 (quin, 2H, J = 7.8 Hz, -SO2CH2CH2-), 2.471 (s, 3H, -SCH3), 3.052 (t, 2H, J = 8.0 Hz, -SO2CH2-), 6.597 (br, 1H, -NH-), 7.154 (d, 2H, J = 8.5 Hz, Ar-H), 7.236 (d, 2H, J = 8.5 Hz, Ar-H); HRMS (ESI): m/z calcd for C19H32NO2S2 [M-H]:370.1876; found: 370.1878.
3[SCH 3 ;C 12 H 25 ](Mw 371.608): Rf 0.42 (20% ethyl acetate/hexane); 1 H NMR (500 MHz, CDCl 3 , 298K) δ (ppm) 0.876 (t, 3H, J = 6.8Hz, -CH3 ) , 1.229 (m, 16H, -( CH2 ) 3 ( CH2 ) 8CH3 ), 1.356 (quin, 2H, J = 7.0Hz, -SO2 ( CH2 ) 2CH2 -), 1.796 (quin, 2H, J = 7.8 Hz, -SO2CH2CH2- ), 2.471 (s, 3H, -SCH3 ), 3.052 (t , 2H , J = 8.0 Hz, -SO2CH 2 -), 6.597 (br, 1H, -NH-), 7.154 (d, 2H, J = 8.5 Hz, Ar-H), 7.236 (d, 2H, J = 8.5 Hz, Ar-H); HRMS (ESI ): m / z calcd for C19H32NO2S2 [ MH ]: 370.1876; found: 370.1878.
3[SC12H25;C12H25](Mw 525.904): Rf 0.56 (20% ethyl acetate/hexane); 1H NMR (500 MHz, CDCl3, 298K) δ (ppm) 0.876 (t, 6H, J = 6.8Hz, -CH3 x 2), 1.252 (m, 32H, -(CH2)3(CH2)8CH3 x 2), 1.380 (m, 4H, -S(CH2)2CH2-, -SO2(CH2)2CH2-), 1.620 (quin, 2H, J = 7.5 Hz, -SCH2CH2-), 1.797 (quin, 2H, J = 7.5 Hz, -SO2CH2CH2-), 2.878 (t, 2H, J = 7.3 Hz, -SCH2-), 3.060 (t, 2H, J = 7.5 Hz, -SO2CH2-), 6.519 (br, 1H, -NH-), 7.130 (d, 2H, J = 8.5 Hz, Ar-H), 7.292 (d, 2H, J = 8.5 Hz, Ar-H); HRMS (ESI): m/z calcd for C30H54NO2S2 [M-H]:524.3596; found: 524.3587.
3[SC 12 H 25 ;C 12 H 25 ](Mw 525.904): Rf 0.56 (20% ethyl acetate/hexane); 1 H NMR (500 MHz, CDCl 3 , 298K) δ (ppm) 0.876 (t, 6H, J = 6.8Hz, -CH 3 x 2), 1.252 (m, 32H, -(CH 2 ) 3 (CH 2 ) 8 CH 3 x 2), 1.380 (m, 4H, -S(CH 2 ) 2 CH 2 -, -SO2 ( CH2 ) 2CH2- ) , 1.620 (quin, 2H, J = 7.5 Hz , -SCH2CH2- ), 1.797 (quin , 2H, J = 7.5 Hz, -SO2CH2 CH2- ), 2.878 (t, 2H, J = 7.3 Hz, -SCH2- ), 3.060 (t, 2H, J = 7.5 Hz, -SO2CH2- ), 6.519 (br, 1H , -NH- ), 7.130 (d, 2H, J = 8.5 Hz, Ar -H), 7.292 (d, 2H, J = 8.5 Hz , Ar-H); HRMS (ESI): m/z calcd for C30H54NO2 S2 [MH]:524.3596; found: 524.3587.
4[SCH3](Mw 139.221): Rf 0.21 (20% ethyl acetate/hexane); 1H NMR (500 MHz, CDCl3, 298K) δ (ppm) 2.412 (s, 3H, -SCH3), 3.658 (br, 2H, -NH2), 6.636 (d, 2H, J = 8.5 Hz, Ar-H), 7.182 (d, 2H, J = 8.5 Hz, Ar-H). lit (G. D. Vo; J. F. Hartwig, J. Am. Chem. Soc. 2009, 131, 11049-11061). δ (ppm) 2.42 (s, 3H, -SCH3), 3.66 (br, 2H, -NH2), 6.62 (d, 2H, J = 8.6 Hz, Ar-H), 7.18 (d, 2H, J = 8.6 Hz, Ar-H).
4[SCH 3 ](Mw 139.221): Rf 0.21 (20% ethyl acetate/hexane); 1 H NMR (500 MHz, CDCl 3 , 298K) δ (ppm) 2.412 (s, 3H, -SCH 3 ), 3.658 ( br, 2H, -NH 2 ), 6.636 (d, 2H, J = 8.5 Hz, Ar-H), 7.182 (d, 2H, J = 8.5 Hz, Ar-H). lit (G. D. Vo; J. F. Hartwig, J Am. Chem . Soc. 2009, 131, 11049-11061). 8.6 Hz, Ar-H), 7.18 (d, 2H, J = 8.6 Hz, Ar-H).
4[SC12H25] (Mw 293.517): Rf 0.47 (20% ethyl acetate/hexane); 1H NMR (500 MHz, CDCl3, 298K) δ (ppm) 0.877 (t, 3H, J = 7.0Hz, -CH3), 1.244 (m, 16H, -(CH2)3(CH2)8CH3), 1.362 (quin, 2H, J = 7.5 Hz, -S(CH2)2CH2-), 1.566 (m, 2H, -SCH2CH2-), 2.756 (t, 2H, J = 7.5 Hz, -SCH2-), 3.685 (br, 2H, -NH2), 6.619 (d, 2H, J = 8.5 Hz, Ar-H), 7.227 (d, 2H, J = 8.5 Hz, Ar-H); HRMS (ESI): m/z calcd for C18H31NS [M+]:293.2177; found: 293.2172.
4[SC 12 H 25 ] (Mw 293.517): Rf 0.47 (20% ethyl acetate/hexane); 1 H NMR (500 MHz, CDCl 3 , 298K) δ (ppm) 0.877 (t, 3H, J = 7.0Hz, -CH3 ), 1.244 (m , 16H, -(CH2)3(CH2)8CH3 ) , 1.362 ( quin, 2H, J = 7.5 Hz, -S( CH2 ) 2CH2- ), 1.566 (m, 2H, -SCH2CH2- ), 2.756 (t, 2H, J = 7.5 Hz, -SCH2- ), 3.685 (br, 2H, -NH2 ), 6.619 (d, 2H, J = 8.5 Hz, Ar-H), 7.227 (d, 2H, J = 8.5 Hz, Ar - H); HRMS (ESI): m/z calcd for C18H31NS [M+]:293.2177; found: 293.2172.
5[SCH3;C12H25] (Mw 371.608): Rf 0.35 (20% ethyl acetate/hexane); 1H NMR (500 MHz, CDCl3, 298K) δ (ppm) 0.875 (t, 3H, J = 6.8Hz, -CH3), 1.230 (m, 16H, -(CH2)3(CH2)8CH3), 1.349 (quin, 2H, J = 7.8 Hz, -SO2(CH2)2CH2-), 1.712 (quin, 2H, J = 7.8 Hz, -SO2CH2CH2-), 2.438 (s, 3H, -SCH3), 3.127 (t, 2H, J = 8.0 Hz, -SO2CH2-), 4.992 (br, 2H, -NH2), 6.693 (d, 1H, J = 8.5 Hz, Ar-H), 7.349 (dd, 1H, J = 8.5, 2.0 Hz, Ar-H), 7.658 (d, 1H, J = 2.0 Hz, Ar-H); HRMS (ESI): m/z calcd for C19H32NO2S2 [M-H]:370.1876; found: 370.1889.
5[SCH 3 ;C 12 H 25 ] (Mw 371.608): Rf 0.35 (20% ethyl acetate/hexane); 1 H NMR (500 MHz, CDCl 3 , 298K) δ (ppm) 0.875 (t, 3H, J = 6.8Hz, -CH3 ) , 1.230 (m, 16H, -( CH2 ) 3 ( CH2 ) 8CH3 ), 1.349 (quin, 2H, J = 7.8Hz, -SO2 ( CH2 ) 2CH2 -), 1.712 (quin, 2H, J = 7.8 Hz, -SO2CH2CH2- ), 2.438 (s, 3H, -SCH3 ), 3.127 (t , 2H , J = 8.0 Hz, -SO2CH 2 -), 4.992 (br, 2H, -NH 2 ), 6.693 (d, 1H, J = 8.5 Hz, Ar-H), 7.349 (dd, 1H, J = 8.5, 2.0 Hz, Ar-H), 7.658 (d, 1H, J = 2.0 Hz, Ar-H); HRMS ( ESI ) : m/z calcd for C19H32NO2S2 [ MH ]: 370.1876; found: 370.1889.
6[SCH3;C12H25] (Mw 355.609): Rf 0.10 (20% ethyl acetate/hexane); 1H NMR (500 MHz, CDCl3, 298K) δ (ppm) 0.881 (t, 3H, J = 7.0Hz, -CH3), 1.261 (m, 16H, -(CH2)3(CH2)8CH3), 1.451 (m, 2H, -SO(CH2)2CH2-), 1.763 (quin, 2H, J = 7.8 Hz, -SOCH2CH2-), 2.453 (s, 3H, -SCH3), 2.908 (m, 2H, -SOCH2-), 5.717 (br, 1H, -NH-), 7.003 (d, 2H, J = 8.5 Hz, Ar-H), 7.231 (d, 2H, J = 8.5 Hz, Ar-H); HRMS (ESI): m/z calcd for C19H33NOS2Na [M+Na]:378.1903; found: 378.1903.
6[SCH 3 ;C 12 H 25 ] (Mw 355.609): Rf 0.10 (20% ethyl acetate/hexane); 1 H NMR (500 MHz, CDCl 3 , 298K) δ (ppm) 0.881 (t, 3H, J = 7.0Hz, -CH3 ) , 1.261 (m, 16H, -(CH2)3(CH2)8CH3 ) , 1.451 ( m , 2H, -SO(CH2)2CH2- ) , 1.763 (quin , 2H, J = 7.8 Hz, -SOCH2CH2- ) , 2.453 (s, 3H, -SCH3 ), 2.908 (m, 2H, -SOCH2- ), 5.717 (br, 1H, -NH-), 7.003 (d, 2H, J = 8.5 Hz, Ar-H), 7.231 (d, 2H, J = 8.5 Hz, Ar-H); HRMS (ESI): m/z calcd for C19H33NOS2Na [ M+Na]: 378.1903; found: 378.1903.
〔実施例２〕 X = SCH3; R = C2H5
[Example 2] X = SCH3 ; R = C2H5
4-ニトロチオアニソール（1[SCH3]: 200 mg, 1.18 mmol）とエタンチオール（2[C2H5]: 440 μL, 5.94 mmol）のトルエン（3 mL）溶液にLED（365 nm）を4 cm先から24時間照射した（48.5 mW/cm2）。反応溶液をCH2Cl2で希釈した後、水で2回、飽和重曹水で１回、飽和食塩水で１回洗浄し、有機層をMgSO4で乾燥した。有機層を濃縮後、シリカゲル（C-300 Wakogel（登録商標））カラム（ethyl acetate/hexane 1%-50%）を行い、N-[4-(メチルチオ)フェニル]エチルスルホンアミド3[SCH3;C2H5]: 71 mg（26%）、4-メチルチオアニリン4[SCH3]: 20 mg（12%）、2-エチルスルホニル-4-メチルチオアニリン5[SCH3;C2H5]: 8 mg（3%）を得た。
An LED (365 nm) was placed in a toluene (3 mL) solution of 4-nitrothioanisole (1[SCH 3 ]: 200 mg, 1.18 mmol) and ethanethiol (2[C 2 H 5 ]: 440 μL, 5.94 mmol). Irradiated from 4 cm ahead for 24 hours (48.5 mW/cm 2 ). After diluting the reaction solution with CH 2 Cl 2 , it was washed twice with water, once with saturated aqueous sodium bicarbonate solution and once with saturated brine, and the organic layer was dried over MgSO 4 . After concentrating the organic layer, silica gel (C-300 Wakogel (registered trademark)) column (ethyl acetate/hexane 1%-50%) was performed to obtain N-[4-(methylthio)phenyl]ethylsulfonamide 3[SCH 3 ; C2H5 ] : 71 mg (26%), 4-methylthioaniline 4[ SCH3 ]: 20 mg (12%), 2 -ethylsulfonyl-4-methylthioaniline 5[ SCH3 ; C2H5 ]: 8 mg (3%) was obtained.
3[SCH3;C2H5] (Mw 231,340): Rf 0.32 (20% ethyl acetate/hexane); 1H NMR (500 MHz, CDCl3, 298K) δ (ppm) 1.362 (t, 3H, J = 7.5Hz, -CH3), 2.466 (s, 3H, -SCH3), 3.104 (q, 2H, J = 7.0 Hz, -SO2CH2-), 7.166 (d, 2H, J = 8.5 Hz, Ar-H), 7.234 (d, 2H, J = 8.5 Hz, Ar-H).
3[SCH 3 ;C 2 H 5 ] (Mw 231,340): Rf 0.32 (20% ethyl acetate/hexane); 1 H NMR (500 MHz, CDCl 3 , 298K) δ (ppm) 1.362 (t, 3H, J = 7.5Hz, -CH3 ), 2.466 (s, 3H, -SCH3 ), 3.104 (q, 2H, J = 7.0 Hz, -SO2CH2- ), 7.166 (d , 2H, J = 8.5 Hz, Ar -H), 7.234 (d, 2H, J = 8.5 Hz, Ar-H).
5[SCH3;C2H5] (Mw 231,340): Rf 0.28 (20% ethyl acetate/hexane); 1H NMR (500 MHz, CDCl3, 298K) δ (ppm) 1.274 (t, 3H, J = 9.3Hz, -CH3) , 2.435 (s, 3H, -SCH3), 3.173 (q, 2H, J = 7.5 Hz, -SO2CH2-), 5.010 (br, 2H, -NH2), 6.697 (d, 1H, J = 8.5 Hz, Ar-H), 7.351 (dd, 1H, J = 8.5 Hz, 2.0 Hz, Ar-H), 7.655 (d, 1H, J = 2.0 Hz, Ar-H).
5[SCH 3 ;C 2 H 5 ] (Mw 231,340): Rf 0.28 (20% ethyl acetate/hexane); 1 H NMR (500 MHz, CDCl 3 , 298K) δ (ppm) 1.274 (t, 3H, J = 9.3Hz, -CH3 ), 2.435 (s, 3H, -SCH3 ) , 3.173 (q, 2H, J = 7.5 Hz, -SO2CH2- ), 5.010 (br, 2H, -NH2 ), 6.697 (d, 1H, J = 8.5 Hz, Ar-H), 7.351 (dd, 1H, J = 8.5 Hz, 2.0 Hz, Ar-H), 7.655 (d, 1H, J = 2.0 Hz, Ar-H).
〔実施例３〕 X = SCH3; R = C4H8SH
[ Example 3] X = SCH3 ; R = C4H8SH
4-ニトロチオアニソール（1[SCH3]: 13.5 mg, 0.0798 mmol）と1,4-ブタンジチオール（2[C4H8SH]: 185 μL, 1.58 mmol）のDMSO（1 mL）溶液にXe(Hg)ランプ（200 W; CuSO4水溶液フィルター）を4 cm先から5時間照射した（36 mW/cm2）。光照射開始2時間後からはドライヤーにより加熱を行った。反応溶液をCH2Cl2で希釈した後、水で2回、飽和重曹水で１回、飽和食塩水で１回洗浄し、有機層をMgSO4で乾燥した。有機層を濃縮後、シリカゲル（Biotage）カラム（ethyl acetate/hexane 5%-33%）を行い、4-メルカプトブチル-N-[4-(メチルチオ)フェニル]スルホンアミド3[SCH3;C4H8SH]: 7 mg（30%）、4-メチルチオアニリン4[SCH3]: 2 mg（18%）、2-(4-メルカプトブチル)-4-メチルチオアニリン5[SCH3;C4H8SH]: 1 mg（4%）を得た。
Xe was added to a solution of 4-nitrothioanisole (1[SCH 3 ]: 13.5 mg, 0.0798 mmol) and 1,4-butanedithiol (2[C 4 H 8 SH]: 185 μL, 1.58 mmol) in DMSO (1 mL). A (Hg) lamp (200 W; CuSO 4 aqueous solution filter) was irradiated from 4 cm ahead for 5 hours (36 mW/cm 2 ). Two hours after the start of light irradiation, heating was performed with a dryer. After diluting the reaction solution with CH 2 Cl 2 , it was washed twice with water, once with saturated aqueous sodium bicarbonate solution and once with saturated brine, and the organic layer was dried over MgSO 4 . After concentrating the organic layer, it was subjected to a silica gel (Biotage) column (ethyl acetate/hexane 5%-33%) to obtain 4-mercaptobutyl-N-[4-(methylthio)phenyl]sulfonamide 3[SCH 3 ;C 4 H 8SH ]: 7 mg (30%), 4 - methylthioaniline 4[ SCH3 ]: 2 mg (18%), 2-(4-mercaptobutyl)-4-methylthioaniline 5[ SCH3 ; C4H8 SH]: 1 mg (4%) was obtained.
3[SCH3;C4H8SH] (Mw 291.459): Rf 0.20 (20% ethyl acetate/hexane); 1H NMR (500 MHz, CDCl3, 298K) δ (ppm) 1.331 (t, 1H, -SH), 1.717 (quin, 2H, J = 7.3 Hz, -SCH2CH2-), 1.942 (quin, 2H, J = 7.3 Hz, -SO2CH2CH2-), 2.474 (s, 3H, -SCH3), 2.517 (m, 2H, -CH2SH), 3.067 (t, 2H, J = 7.8 Hz, -SO2CH2-), 6.407 (br, 1H, -NH-), 7.156 (d, 2H, J = 7.8 Hz, Ar-H), 7.234 (d, 2H, Ar-H).
3[SCH 3 ;C 4 H 8 SH] (Mw 291.459): Rf 0.20 (20% ethyl acetate/hexane); 1 H NMR (500 MHz, CDCl 3 , 298K) δ (ppm) 1.331 (t, 1H, - SH), 1.717 (quin, 2H, J = 7.3 Hz, -SCH2CH2- ), 1.942 ( quin , 2H, J = 7.3 Hz, -SO2CH2CH2-), 2.474 (s, 3H , - SCH3 ), 2.517 (m, 2H, -CH2SH ), 3.067 (t, 2H, J = 7.8 Hz, -SO2CH2-), 6.407 (br, 1H , -NH- ), 7.156 (d, 2H, J = 7.8 Hz, Ar-H), 7.234 (d, 2H, Ar-H).
5[SCH3;C4H8SH] (Mw 291.459): Rf 0.17 (20% ethyl acetate/hexane); 1H NMR (500 MHz, CDCl3, 298K) δ (ppm) 1.331 (t, 1H, -SH), 1.717 (quin, 2H, J = 7.3 Hz, -SCH2CH2-), 1.853 (m, 2H, -SO2CH2CH2-), 2.442 (s, 3H, -SCH3), 2.517 (m, 2H, -CH2SH), 3.153 (t, 2H, J = 7.8 Hz, -SO2CH2-), 4.998 (br, 2H, -NH2), 6.704 (d, 1H, J = 8.5 Hz, Ar-H), 7.361 (dd, 1H, J = 8.5, 2.2 Hz, Ar-H HHH), 7.659 (br, 1H, J = 2.2 Hz, Ar-H).
5[SCH 3 ;C 4 H 8 SH] (Mw 291.459): Rf 0.17 (20% ethyl acetate/hexane); 1 H NMR (500 MHz, CDCl 3 , 298K) δ (ppm) 1.331 (t, 1H, - SH), 1.717 (quin, 2H, J = 7.3 Hz, -SCH2CH2- ), 1.853 (m, 2H , -SO2CH2CH2- ), 2.442 (s, 3H, -SCH3 ), 2.517 (m, 2H, -CH2SH ), 3.153 (t, 2H, J = 7.8 Hz, -SO2CH2- ), 4.998 (br, 2H , -NH2 ), 6.704 (d, 1H, J = 8.5 Hz, Ar-H), 7.361 (dd, 1H, J = 8.5, 2.2 Hz, Ar-H HHH), 7.659 (br, 1H, J = 2.2 Hz, Ar-H).
〔実施例４〕 X = OCH3; R = C4H8SH
[Example 4] X = OCH3 ; R = C4H8SH
4-ニトロアニソール（1[OCH3]: 16 mg, 0.104 mmol）と1,4-ブタンジチオール（2[C4H8SH]: 200 μL, 1.70 mmol）のDMSO（1 mL）溶液にXe(Hg)ランプ（200 W; CuSO4水溶液フィルター）を4 cm先から5時間照射した（17 mW/cm2）。光照射開始直後からドライヤーにより加熱を行った。反応溶液をCH2Cl2で希釈した後、水で2回、飽和重曹水で１回、飽和食塩水で１回洗浄し、有機層をMgSO4で乾燥した。有機層を濃縮後、シリカゲル（Biotage）カラム（ethyl acetate/hexane 5%-33%）を行い、4-メルカプトブチル-N-[4-(メトキシ)フェニル]スルホンアミド3[OCH3;C4H8SH]: 7 mg（25%）、2-(4-メルカプトブチル)-4-メトキシアニリン5[OCH3;C4H8SH]: 1 mg（3%）を得た。
Xe ( _ Hg) lamp (200 W; CuSO 4 aqueous solution filter) was irradiated from 4 cm ahead for 5 hours (17 mW/cm 2 ). Heating was performed with a dryer immediately after the start of light irradiation. After diluting the reaction solution with CH 2 Cl 2 , it was washed twice with water, once with saturated aqueous sodium bicarbonate solution and once with saturated brine, and the organic layer was dried over MgSO 4 . After concentrating the organic layer, it was subjected to a silica gel (Biotage) column (ethyl acetate/hexane 5%-33%) and 4-mercaptobutyl-N-[4-(methoxy)phenyl]sulfonamide 3[OCH 3 ;C 4 H 8 SH]: 7 mg (25%), 2-(4-mercaptobutyl)-4-methoxyaniline 5[OCH 3 ;C 4 H 8 SH]: 1 mg (3%).
3[OCH3;C4H8SH] (Mw 275.393): Rf 0.39 (33% ethyl acetate/hexane); 1H NMR (500 MHz, CDCl3, 298K) δ (ppm) 1.339 (t, 1H, J = 8.8 Hz, -SH), 1.720 (quin, 2H, J = 7.5 Hz, -SCH2CH2-), 1.949 (quin, 2H, J = 7.8 Hz, -SO2CH2CH2-), 2.521 (q, 2H, J = 7.3 Hz, -CH2SH), 3.028 (t, 2H, J = 8.0 Hz, -SO2CH2-), 3.803 (s, 3H, -OCH3), 6.000-6.250 (br, 1H, -NH-), 6.883 (d, 2H, J = 9.0 Hz, Ar-H), 7.184 (d, 2H, J = 9.0 Hz Ar-H HHH)
3[OCH 3 ;C 4 H 8 SH] (Mw 275.393): Rf 0.39 (33% ethyl acetate/hexane); 1 H NMR (500 MHz, CDCl 3 , 298K) δ (ppm) 1.339 (t, 1H, J = 8.8 Hz, -SH), 1.720 (quin, 2H, J = 7.5 Hz, -SCH 2 CH 2 -), 1.949 (quin, 2H, J = 7.8 Hz, -SO 2 CH 2 CH 2 -), 2.521 ( q, 2H, J = 7.3 Hz, -CH2SH ), 3.028 (t, 2H, J = 8.0 Hz, -SO2CH2- ), 3.803 (s, 3H , -OCH3 ), 6.000-6.250 (br , 1H, -NH-), 6.883 (d, 2H, J = 9.0 Hz, Ar-H), 7.184 (d, 2H, J = 9.0 Hz Ar-H HHH)
5[OCH3;C4H8SH] (Mw 275.393): Rf 0.39 (33% ethyl acetate/hexane); 1H NMR (500 MHz, CDCl3, 298K) δ (ppm) 1.339 (t, 1H, J = 8.8 Hz, -SH), 1.720 (quin, 2H, J = 7.5 Hz, -SCH2CH2-), 1.852 (quin, 2H, J = 8.0 Hz, -SO2CH2CH2-), 2.521 (q, 2H, J = 7.3 Hz, -CH2SH), 3.190 (t, 2H, J = 7.8 Hz, -SO2CH2-), 3.780 (s, 3H, CH3O-), 4.672 (br, 1H, -NH-), 6.714 (d, 1H, J = 8.5 Hz, Ar-H), 7.009 (dd, 1H, J = 9.0 Hz, 3.0 Hz, Ar-H HHH), 7.218 (d, 1H, J = 2.5 Hz, Ar-H)
5[OCH 3 ;C 4 H 8 SH] (Mw 275.393): Rf 0.39 (33% ethyl acetate/hexane); 1 H NMR (500 MHz, CDCl 3 , 298K) δ (ppm) 1.339 (t, 1H, J = 8.8 Hz, -SH), 1.720 (quin, 2H, J = 7.5 Hz, -SCH 2 CH 2 -), 1.852 (quin, 2H, J = 8.0 Hz, -SO 2 CH 2 CH 2 -), 2.521 ( q, 2H, J = 7.3 Hz, -CH2SH ), 3.190 (t, 2H, J = 7.8 Hz, -SO2CH2- ), 3.780 (s, 3H, CH3O- ), 4.672 (br, 1H, -NH-), 6.714 (d, 1H, J = 8.5 Hz, Ar-H), 7.009 (dd, 1H, J = 9.0 Hz, 3.0 Hz, Ar-H HHH), 7.218 (d, 1H, J = 2.5 Hz, Ar-H)
〔実施例５〕 X = H; R = C4H8SH
[Example 5] X=H; R = C4H8SH
4-ニトロベンゼン（1[H]: 17 μL, 0.166 mmol）と1,4-ブタンジチオール（2[C4H8SH]: 380 μL, 3.24 mmol）のDMSO（1 mL）溶液にXe(Hg)ランプ（200 W; CuSO4水溶液フィルター）を4 cm先から5時間照射した（16.5 mW/cm2）。光照射開始直後からドライヤーにより加熱を行った。反応溶液をCH2Cl2で希釈した後、水で2回、飽和重曹水で１回、飽和食塩水で１回洗浄し、有機層をMgSO4で乾燥した。有機層を濃縮後、シリカゲル（Biotage）カラム（ethyl acetate/hexane 5%-33%）を行い、4-メルカプトブチル-N-フェニルスルホンアミド3[H;C4H8SH]: 10 mg（24%）を得た。
Xe(Hg) was added to a solution of 4-nitrobenzene (1[H]: 17 μL, 0.166 mmol) and 1,4-butanedithiol (2[C 4 H 8 SH]: 380 μL, 3.24 mmol) in DMSO (1 mL). A lamp (200 W; CuSO 4 aqueous solution filter) was irradiated from 4 cm ahead for 5 hours (16.5 mW/cm 2 ). Heating was performed with a dryer immediately after the start of light irradiation. After diluting the reaction solution with CH 2 Cl 2 , it was washed twice with water, once with saturated aqueous sodium bicarbonate solution and once with saturated brine, and the organic layer was dried over MgSO 4 . After concentrating the organic layer, it was subjected to a silica gel (Biotage) column (ethyl acetate/hexane 5%-33%) to give 4-mercaptobutyl-N-phenylsulfonamide 3[H;C 4 H 8 SH]: 10 mg (24 %) was obtained.
3[H;C4H8SH] (Mw 245.367): Rf 0.43 (33% ethyl acetate/hexane); 1H NMR (500 MHz, CDCl3, 298K) δ (ppm) 1.321 (t, 1H, J = 8.0 Hz, -SH), 1.714(quin, 2H, J = 7.5 Hz, -SCH2CH2-), 1.950 (quin, 2H, J = 7.8 Hz, -SO2CH2CH2-), 2.509 (q, 2H, J = 7.0 Hz, -CH2SH), 3.099 (t, 2H, J = 7.8 Hz, -SO2CH2-), 5.009 (br, 1H, -NH-), 7.187 (t, 1H, Ar-H), 7.213 (d, 2H, J = 8.5 Hz Ar-H HHH), 7.355 (t, 2H, J = 7.8 Hz Ar-H HHH).
3[H;C 4 H 8 SH] (Mw 245.367): Rf 0.43 (33% ethyl acetate/hexane); 1 H NMR (500 MHz, CDCl 3 , 298K) δ (ppm) 1.321 (t, 1H, J = 8.0 Hz, -SH ), 1.714(quin, 2H, J = 7.5 Hz, -SCH2CH2- ) , 1.950 (quin, 2H , J = 7.8 Hz, -SO2CH2CH2-), 2.509 ( q , 2H, J = 7.0 Hz, -CH 2 SH), 3.099 (t, 2H, J = 7.8 Hz, -SO 2 CH 2 -), 5.009 (br, 1H, -NH-), 7.187 (t, 1H, Ar-H), 7.213 (d, 2H, J = 8.5 Hz Ar-H HHH), 7.355 (t, 2H, J = 7.8 Hz Ar-H HHH).
〔実施例６〕 X = Me6GlcSPh; R = C4H8SH
[Example 6] X = Me6GlcSPh ; R = C4H8SH
[4-(4-ニトロフェニル)-フェニル] 2,3,4,6-テトラ-O-メチル-1-チオ-β-D-グルコピラノシド（1[Me6GlcSPh]: 10.3 mg, 0.0229 mmol）と1,4-ブタンジチオール（2[C4H8SH]: 50 μL, 0.426 mmol）のDMSO（1 mL）溶液にXe(Hg)ランプ（200 W; CuSO4水溶液フィルター）を4 cm先から6時間照射した（17 mW/cm2）。光照射中にドライヤーにより３時間30分加熱を行った。反応溶液をCH2Cl2で希釈した後、水で2回、飽和重曹水で１回、飽和食塩水で１回洗浄し、有機層をMgSO4で乾燥した。有機層を濃縮後、シリカゲル（Biotage）カラム（ethyl acetate/hexane 0%-100%）を行い、さらに主画分についてPTLC（ethyl acetate/hexane 33%で2回上げ）を行い、N-[4-[4-(2,3,4,6-テトラ-O-メチル-β-D-グルコピラノシルチオ)フェニル]フェニル]-4-メルカプトブチルスルホンアミド3[Me6GlcSPh;C4H8SH]: 3 mg（23%）、4-[4-(2,3,4,6-テトラ-O-メチル-β-D-グルコピラノシルチオ)フェニル]アニリン4[Me6GlcSPh]: 1 mg（10%）を得た。
[4-(4-Nitrophenyl)-phenyl]2,3,4,6-tetra-O-methyl-1-thio-β-D-glucopyranoside (1[ Me6GlcSPh ]: 10.3 mg, 0.0229 mmol) and A solution of 1,4-butanedithiol (2[C 4 H 8 SH]: 50 μL, 0.426 mmol) in DMSO (1 mL) was illuminated with a Xe(Hg) lamp (200 W; CuSO 4 aqueous filter) from 4 cm away. time irradiation (17 mW/cm 2 ). Heating was performed for 3 hours and 30 minutes with a dryer during the light irradiation. After diluting the reaction solution with CH 2 Cl 2 , it was washed twice with water, once with saturated aqueous sodium bicarbonate solution and once with saturated brine, and the organic layer was dried over MgSO 4 . After concentrating the organic layer, it was subjected to a silica gel (Biotage) column (ethyl acetate/hexane 0%-100%). -[4- ( 2,3,4,6-tetra-O-methyl-β-D-glucopyranosylthio)phenyl]phenyl]-4-mercaptobutylsulfonamide 3[ Me6GlcSPh ; C4H8SH ]: 3 mg (23%), 4-[4-(2,3,4,6-tetra-O-methyl-β-D-glucopyranosylthio)phenyl]aniline 4[ Me6GlcSPh ]: 1 mg (10%) was obtained.
3[Me6GlcSPh;C4H8SH] (Mw 571.780): Rf 0.12 (33% ethyl acetate/hexane); 1H NMR (500 MHz, CDCl3, 298K) δ (ppm) 1.334 (t, 1H, J = 7.8 Hz, -SH), 1.738 (quin, 2H, J = 7.5 Hz, -SCH2CH2-), 1.978 (quin, 2H, J = 7.8 Hz, -SO2CH2CH2-), 2.536 (q, 2H, J = 7.8 Hz, -CH2SH), 3.074 (t, 1H, J = 9.0 Hz, H2’), 3.137 (t, 2H, J = 7.8 Hz, -SO2CH2-), 3.191 (t, 1H, J = 9.0 Hz, H3’), 3.213 (t, 1H, J = 9.0 Hz, H4’), 3.313 (m, 1H, H5’), 3.403 (s, 3H, -OCH3), 3.538 (s, 3H, -OCH3), 3.579 (dd, 1H, J = 11.0 Hz, 4.5 Hz, H6a’), 3.617 (s, 3H, -OCH3), 3.627 (m, 1H, H6b’), 3.657 (s, 3H, -OCH3), 4.517 (d, 1H, J = 10.0 Hz, H1’), 6.374 (br, 1H, -NH-), 7.284 (d, 2H, Ar-H), 7.477 (d, 2H, J = 8.5 Hz Ar-H HHH), 7.557 (d, 2H, J = 8.5 Hz Ar-H), 7.595 (d, 2H, J = 8.5 Hz, Ar-H); HRMS (ESI): m/z calcd for C26H37NO7S3Na [M+Na]: 594.1631; found: 594.1646.
3[Me 6 GlcSPh;C 4 H 8 SH] (Mw 571.780): Rf 0.12 (33% ethyl acetate/hexane); 1 H NMR (500 MHz, CDCl 3 , 298K) δ (ppm) 1.334 (t, 1H, J = 7.8 Hz , -SH ) , 1.738 (quin, 2H , J = 7.5 Hz, -SCH2CH2-), 1.978 (quin, 2H, J = 7.8 Hz, -SO2CH2CH2- ), 2.536 (q, 2H, J = 7.8 Hz, -CH2SH ), 3.074 (t, 1H, J = 9.0 Hz, H2'), 3.137 (t, 2H , J = 7.8 Hz, -SO2CH2- ) , 3.191 (t, 1H, J = 9.0 Hz, H3'), 3.213 (t, 1H, J = 9.0 Hz, H4'), 3.313 (m, 1H, H5'), 3.403 (s, 3H, -OCH3 ) , 3.538 (s, 3H, -OCH 3 ), 3.579 (dd, 1H, J = 11.0 Hz, 4.5 Hz, H6a'), 3.617 (s, 3H, -OCH 3 ), 3.627 (m, 1H, H6b') , 3.657 (s, 3H, -OCH 3 ), 4.517 (d, 1H, J = 10.0 Hz, H1'), 6.374 (br, 1H, -NH-), 7.284 (d, 2H, Ar-H), 7.477 (d, 2H, J = 8.5 Hz Ar-H HHH), 7.557 (d, 2H, J = 8.5 Hz Ar-H), 7.595 (d, 2H, J = 8.5 Hz, Ar-H); HRMS (ESI) : m / z calcd for C26H37NO7S3Na [M+Na]: 594.1631; found : 594.1646.
4[Me6GlcSPh] (Mw 419.542): Rf 0.18 (33% ethyl acetate/hexane); 1H NMR (500 MHz, CDCl3, 298K) δ (ppm) 3.060 (t, 1H, J = 9.3 Hz, H2’), 3.166 (t, 1H, J = 9.0 Hz, H3’), 3.219 (t, 1H, J = 8.5 Hz, H4’), 3.288 (m, 1H, H5’), 3.398 (s, 3H, -OCH3), 3.531 (s, 3H, -OCH3), 3.580 (dd, 1H, J = 11.0Hz, 4.5 Hz, H6a’), 3.615 (s, 3H, -OCH3), 3.635 (m, 1H, H6b’), 3.651 (s, 3H, -OCH3), 3.742 (br, 1H, -NH-), 4.477 (d, 1H, J = 10.0 Hz, H1’), 6.749 (d, 2H, J = 8.0 Hz, Ar-H), 7.396 (d, 2H, J = 8.0 Hz Ar-H HHH), 7.454 (d, 2H, J = 8.0 Hz Ar-H), 7.557 (d, 2H, J = 8.0 Hz, Ar-H).
4[Me 6 GlcSPh] (Mw 419.542): Rf 0.18 (33% ethyl acetate/hexane); 1 H NMR (500 MHz, CDCl 3 , 298K) δ (ppm) 3.060 (t, 1H, J = 9.3 Hz, H2 '), 3.166 (t, 1H, J = 9.0 Hz, H3'), 3.219 (t, 1H, J = 8.5 Hz, H4'), 3.288 (m, 1H, H5'), 3.398 (s, 3H, - OCH3 ), 3.531 (s, 3H, -OCH3 ), 3.580 (dd, 1H, J = 11.0Hz, 4.5Hz, H6a'), 3.615 (s, 3H, -OCH3 ), 3.635 (m, 1H, H6b'), 3.651 (s, 3H, -OCH3 ), 3.742 (br, 1H, -NH-), 4.477 (d, 1H, J = 10.0 Hz, H1'), 6.749 (d, 2H, J = 8.0 Hz, Ar-H), 7.396 (d, 2H, J = 8.0 Hz Ar-H HHH), 7.454 (d, 2H, J = 8.0 Hz Ar-H), 7.557 (d, 2H, J = 8.0 Hz, Ar -H).
本明細書で引用した全ての刊行物、特許及び特許出願をそのまま参考として本明細書にとり入れるものとする。
All publications, patents and patent applications cited herein are incorporated herein by reference.
本発明により製造されるスルホンアミドは、多くの医薬品の骨格を形成している。従って、本発明は、医薬品に関連する産業分野において利用可能である。
The sulfonamide produced by the present invention forms the backbone of many pharmaceuticals. Therefore, the present invention can be used in industrial fields related to pharmaceuticals.
Claims (15)
- ニトロ基を有する化合物とチオール基を有する化合物を光照射下で反応させ、スルホンアミド誘導体を生成させる工程を含むことを特徴とするスルホンアミド誘導体の製造方法。 A method for producing a sulfonamide derivative, comprising a step of reacting a compound having a nitro group and a compound having a thiol group under light irradiation to produce a sulfonamide derivative.
- ニトロ基を有する化合物とチオール基を有する化合物を光照射下で反応させ、スルホンアミド誘導体を生成させる工程が、下記の一般式(I)
で表される化合物と下記の一般式(II)
で表される化合物を反応させ、下記の一般式(III)
で表されるスルホンアミド誘導体を生成させる工程であることを特徴とする請求項１に記載のスルホンアミド誘導体の製造方法。 The step of reacting a compound having a nitro group and a compound having a thiol group under light irradiation to produce a sulfonamide derivative is represented by the following general formula (I)
and a compound represented by the following general formula (II)
By reacting the compound represented by the following general formula (III)
2. The method for producing a sulfonamide derivative according to claim 1, which is a step of producing a sulfonamide derivative represented by: - 一般式(I)及び(III)におけるX4及びX5が、水素原子であることを特徴とする請求項２に記載のスルホンアミド誘導体の製造方法。 3. The method for producing a sulfonamide derivative according to claim 2, wherein X4 and X5 in general formulas (I) and (III) are hydrogen atoms.
- 照射する光の波長が200～600nmであり、光の照射時間が1～48時間であり、光の照射強度が1～500mW/cm2であることを特徴とする請求項１乃至３のいずれか一項に記載のスルホンアミド誘導体の製造方法。 The wavelength of the light to be irradiated is 200 to 600 nm, the light irradiation time is 1 to 48 hours, and the light irradiation intensity is 1 to 500 mW/cm 2 . A method for producing the sulfonamide derivative according to item 1.
- チオール基に修飾物を結合させるための修飾剤であって、下記の一般式(I)
で表される化合物を含有することを特徴とするチオール基の修飾剤。 A modifier for binding a modifier to a thiol group, which has the following general formula (I)
A thiol group modifier comprising a compound represented by: - 一般式(I)におけるX4及びX5が、水素原子であることを特徴とする請求項５に記載のチオール基の修飾剤。 6. The thiol group modifier according to claim 5, wherein X4 and X5 in general formula (I) are hydrogen atoms.
- 下記の工程（１）～（３）を含むことを特徴とする生体分子チップの作製方法、
（１）表面にチオール基を有する基板を下記の一般式(I)
で表される化合物と接触させる工程、
（２）基板上の生体分子を固定したい部位に光を照射し、基板表面のチオール基に一般式(I)で表される化合物を結合させる工程、
（３）基板表面のチオール基に結合しなかった一般式(I)で表される化合物を除去する工程。 A method for producing a biomolecule chip, comprising the following steps (1) to (3):
(1) A substrate having a thiol group on its surface is represented by the following general formula (I)
The step of contacting with a compound represented by
(2) A step of irradiating light onto a site on the substrate where the biomolecule is to be immobilized to bond the compound represented by the general formula (I) to the thiol group on the substrate surface;
(3) A step of removing the compound represented by general formula (I) that has not bonded to the thiol group on the substrate surface. - 一般式(I)におけるX4及びX5が、水素原子であることを特徴とする請求項７に記載の生体分子チップの作製方法。 8. The method for producing a biomolecule chip according to claim 7, wherein X4 and X5 in general formula (I) are hydrogen atoms.
- 照射する光の波長が200～600nmであり、光の照射時間が1～48時間であり、光の照射強度が1～500mW/cm2であることを特徴とする請求項７又は８に記載の生体分子チップの作製方法。 9. The method according to claim 7 or 8, wherein the wavelength of light to be irradiated is 200 to 600 nm, the light irradiation time is 1 to 48 hours, and the light irradiation intensity is 1 to 500 mW/cm 2 . A method for producing a biomolecule chip.
- システイン残基を含むタンパク質に修飾物を結合させるタンパク質の修飾方法であって、下記の工程（１）及び（２）を含むことを特徴とするタンパク質の修飾方法、
（１）タンパク質を下記の一般式(I)
で表される化合物と接触させる工程、
（２）タンパク質及び一般式(I)で表される化合物に光を照射する工程。 A protein modification method for binding a modifier to a protein containing a cysteine residue, comprising the following steps (1) and (2):
(1) protein represented by the following general formula (I)
The step of contacting with a compound represented by
(2) A step of irradiating the protein and the compound represented by the general formula (I) with light. - 一般式(I)におけるX4及びX5が、水素原子であることを特徴とする請求項１０に記載のタンパク質の修飾方法。 11. The method for modifying a protein according to claim 10, wherein X4 and X5 in general formula (I) are hydrogen atoms.
- 照射する光の波長が200～600nmであり、光の照射時間が1～48時間であり、光の照射強度が1～500mW/cm2であることを特徴とする請求項１０又は１１に記載のタンパク質の修飾方法。 12. The method according to claim 10 or 11, wherein the wavelength of the irradiated light is 200-600 nm, the light irradiation time is 1-48 hours, and the light irradiation intensity is 1-500 mW/cm 2 . Methods of protein modification.
- 二つのニトロ基を有する化合物と二つのチオール基を有する化合物を光照射下で反応させ、ポリスルホンアミド誘導体を生成させる工程を含むことを特徴とするポリスルホンアミド誘導体の製造方法。 A method for producing a polysulfonamide derivative, comprising a step of reacting a compound having two nitro groups and a compound having two thiol groups under light irradiation to produce a polysulfonamide derivative.
- 二つのニトロ基を有する化合物と二つのチオール基を有する化合物を光照射下で反応させ、ポリスルホンアミド誘導体を生成させる工程が、下記の一般式(IVa)、(IVb)、又は(IVc)
で表される化合物と下記の一般式(V)
で表される化合物を反応させ、下記の一般式(VIa)、(VIb)、又は (VIc)
で表される繰り返し単位を有するポリスルホンアミド誘導体を生成させる工程であることを特徴とする請求項１３に記載のポリスルホンアミド誘導体の製造方法。 The step of reacting a compound having two nitro groups and a compound having two thiol groups under light irradiation to produce a polysulfonamide derivative is represented by the following general formula (IVa), (IVb), or (IVc)
and the compound represented by the following general formula (V)
By reacting the compound represented by the following general formula (VIa), (VIb), or (VIc)
14. The method for producing a polysulfonamide derivative according to claim 13, which is a step of producing a polysulfonamide derivative having a repeating unit represented by: - 照射する光の波長が200～600nmであり、光の照射時間が1～48時間であり、光の照射強度が1～500mW/cm2であることを特徴とする請求項１３又は１４に記載のポリスルホンアミド誘導体の製造方法。 15. The method according to claim 13 or 14, wherein the wavelength of the light to be irradiated is 200 to 600 nm, the light irradiation time is 1 to 48 hours, and the light irradiation intensity is 1 to 500 mW/cm 2 . A method for producing a polysulfonamide derivative.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2021206935 | 2021-12-21 | ||
| JP2021-206935 | 2021-12-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2023120292A1 true WO2023120292A1 (en) | 2023-06-29 |
Family
ID=86902418
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2022/045786 WO2023120292A1 (en) | 2021-12-21 | 2022-12-13 | Light sulfonamide synthesis reaction |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2023120292A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014210754A (en) * | 2013-04-22 | 2014-11-13 | 国立大学法人富山大学 | Sulfonyl azide derivative and manufacturing method of acylsulfonamide derivative and use thereof |
| WO2017061561A1 (en) * | 2015-10-08 | 2017-04-13 | 日本化薬株式会社 | Novel polysulfone amide compound, and resin composition containing same |
| WO2017175598A1 (en) * | 2016-04-05 | 2017-10-12 | 富士フイルム株式会社 | Gas separation membrane, gas separation module, gas separation device, and gas separation method |
| CN112939822A (en) * | 2021-02-09 | 2021-06-11 | 浙江理工大学 | Quantum dot and method for preparing sulfonamide derivative by using same |
-
2022
- 2022-12-13 WO PCT/JP2022/045786 patent/WO2023120292A1/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014210754A (en) * | 2013-04-22 | 2014-11-13 | 国立大学法人富山大学 | Sulfonyl azide derivative and manufacturing method of acylsulfonamide derivative and use thereof |
| WO2017061561A1 (en) * | 2015-10-08 | 2017-04-13 | 日本化薬株式会社 | Novel polysulfone amide compound, and resin composition containing same |
| WO2017175598A1 (en) * | 2016-04-05 | 2017-10-12 | 富士フイルム株式会社 | Gas separation membrane, gas separation module, gas separation device, and gas separation method |
| CN112939822A (en) * | 2021-02-09 | 2021-06-11 | 浙江理工大学 | Quantum dot and method for preparing sulfonamide derivative by using same |
Non-Patent Citations (3)
| Title |
|---|
| BAO ZHAOWEI, ZOU JUAN, MOU CHENGLI, JIN ZHICHAO, REN SHI-CHAO, CHI YONGGUI ROBIN: "Direct Reaction of Nitroarenes and Thiols via Photodriven Oxygen Atom Transfer for Access to Sulfonamides", ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 24, no. 48, 9 December 2022 (2022-12-09), US , pages 8907 - 8913, XP093075573, ISSN: 1523-7060, DOI: 10.1021/acs.orglett.2c03770 * |
| FLEMING STEVEN A., RAWLINS DAVID B., SAMANO VICENTE, ROBINS MORRIS J.: "Photochemistry of nucleoside transport inhibitor 6-S-benzylated thiopurine ribonucleosides. Implications for a new class of photoaffinity labels", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 57, no. 22, 1 October 1992 (1992-10-01), pages 5968 - 5976, XP093075562, ISSN: 0022-3263, DOI: 10.1021/jo00048a034 * |
| GOVINDARAJU THIMMAIAH, JONKHEIJM PASCAL, GOGOLIN LARS, SCHROEDER HENDRIK, BECKER CHRISTIAN F. W., NIEMEYER CHRISTOF M., WALDMANN H: "Surface immobilization of biomolecules by click sulfonamide reaction", CHEMICAL COMMUNICATIONS, ROYAL SOCIETY OF CHEMISTRY, UK, no. 32, 15 July 2008 (2008-07-15), UK , pages 3723, XP093075569, ISSN: 1359-7345, DOI: 10.1039/b806764c * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| SU1093247A3 (en) | Process for preparing substituted isothiazole-1,1-dioxides | |
| US20190112328A1 (en) | Diarylsulfide backbone containing photolabile protecting groups | |
| Wallace et al. | Mild, selective deprotection of thioacetates using sodium thiomethoxide | |
| CN110156646B (en) | Method for synthesizing difluoroalkyl or difluoromethyl sulfur (selenium) -containing compound | |
| WO2023120292A1 (en) | Light sulfonamide synthesis reaction | |
| Yang et al. | Simple synthesis of sulfonyl chlorides from thiol precursors and derivatives by NaClO2-mediated oxidative chlorosulfonation | |
| WO2004048320A1 (en) | Biguanide and dihydrotriazine derivatives | |
| Rajeshkumar et al. | A one-pot metal-free protocol for the synthesis of chalcogenated furans from 1, 4-enediones and thiols | |
| ES2794832T3 (en) | Process for the preparation of Enzalutamide | |
| CN112321477B (en) | 3, 5-dimethyl-4-sulfuryl-1H-pyrrole compound, preparation method and application | |
| Jansa et al. | A conversion of aromatic thiocyanates into sulfothioates: new synthetic route to aromatic Bunte salts | |
| CN110938027B (en) | Synthetic method of indole derivatives | |
| Badali et al. | Nitroepoxide ring opening with thionucleophiles in water: synthesis of α-xanthyl ketones, β-keto sulfones and β-keto sulfonic acids | |
| Arslan | Synthesis and characterisation of new sulfonamide chalcones containing an azo group | |
| JP2009505997A (en) | Preparation of thioalkylamines in high yield | |
| CN113880737A (en) | Application of novel persulfur reagent in synthesis of asymmetric persulfur | |
| CN114163313A (en) | Method for selectively synthesizing EZ-stilbene by coupling aryl diazonium salt and cinnamic acid under catalysis of ruthenium | |
| US9908846B2 (en) | Composition, synthesis, and use of new arylsulfonyl isonitriles | |
| WO2022025117A1 (en) | Fluorinating agent and method for producing fluorine-containing compounds | |
| CN115197118B (en) | Synthesis method of 3, 3-disubstituted vulcanized oxindole derivative | |
| CN115850208B (en) | Method for synthesizing S-aryl dithio carbamate compound by visible light induction | |
| RU2223952C2 (en) | Derivatives of n,s-substituted n'-1-[(hetero)aryl]-n'-[(hetero)aryl]- methylisothioureas or their salts and bases, pharmaceutical composition, method for treatment and method for study of glutamatergic system | |
| KR20190095441A (en) | Functionalized Cyclic Dithiocarbamate Synthesis Method | |
| CA1335204C (en) | Aminoacetonitrile derivatives | |
| RU2819608C1 (en) | Method of producing thiomethylated derivatives of pyrrole and 2-(benzpyrrol-3-yl)acetic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22911000 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |