GB2511137A - Chelator Molecule - Google Patents
Chelator Molecule Download PDFInfo
- Publication number
- GB2511137A GB2511137A GB201303405A GB201303405A GB2511137A GB 2511137 A GB2511137 A GB 2511137A GB 201303405 A GB201303405 A GB 201303405A GB 201303405 A GB201303405 A GB 201303405A GB 2511137 A GB2511137 A GB 2511137A
- Authority
- GB
- United Kingdom
- Prior art keywords
- copper
- reducing
- chelator molecule
- azide
- molecule according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000002738 chelating agent Substances 0.000 title claims abstract description 103
- 230000001603 reducing effect Effects 0.000 claims abstract description 144
- -1 copper (I) ions Chemical class 0.000 claims abstract description 77
- 235000000346 sugar Nutrition 0.000 claims abstract description 76
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 claims abstract description 62
- 150000004699 copper complex Chemical class 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 46
- 150000002772 monosaccharides Chemical class 0.000 claims abstract description 42
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 38
- 150000001345 alkine derivatives Chemical class 0.000 claims abstract description 33
- 150000001540 azides Chemical class 0.000 claims abstract description 28
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 22
- ZHOBJWVNWMQMLF-UHFFFAOYSA-N n,n-bis(prop-2-ynyl)prop-2-yn-1-amine Chemical compound C#CCN(CC#C)CC#C ZHOBJWVNWMQMLF-UHFFFAOYSA-N 0.000 claims abstract description 16
- 235000010323 ascorbic acid Nutrition 0.000 claims abstract description 11
- 239000011668 ascorbic acid Substances 0.000 claims abstract description 11
- 230000001737 promoting effect Effects 0.000 claims abstract description 11
- 229940072107 ascorbate Drugs 0.000 claims abstract description 10
- 238000010461 azide-alkyne cycloaddition reaction Methods 0.000 claims abstract description 9
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims abstract description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 7
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims abstract description 7
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 claims abstract description 6
- 229910052802 copper Inorganic materials 0.000 claims description 60
- 239000010949 copper Substances 0.000 claims description 60
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 55
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 55
- 229940108928 copper Drugs 0.000 claims description 49
- 125000001424 substituent group Chemical group 0.000 claims description 28
- 229910001431 copper ion Inorganic materials 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 18
- 239000007983 Tris buffer Substances 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- HYKCGNHOSRPGCP-UHFFFAOYSA-N 1-(2h-triazol-4-yl)-n,n-bis(2h-triazol-4-ylmethyl)methanamine Chemical group C=1NN=NC=1CN(CC=1N=NNC=1)CC1=CNN=N1 HYKCGNHOSRPGCP-UHFFFAOYSA-N 0.000 claims description 16
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 14
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 150000002500 ions Chemical class 0.000 claims description 11
- 229910052751 metal Inorganic materials 0.000 claims description 11
- 239000002184 metal Substances 0.000 claims description 11
- 229910052804 chromium Inorganic materials 0.000 claims description 10
- 229910052742 iron Inorganic materials 0.000 claims description 10
- GZCGUPFRVQAUEE-UHFFFAOYSA-N 2,3,4,5,6-pentahydroxyhexanal Chemical compound OCC(O)C(O)C(O)C(O)C=O GZCGUPFRVQAUEE-UHFFFAOYSA-N 0.000 claims description 9
- 229910052782 aluminium Inorganic materials 0.000 claims description 9
- 229910052790 beryllium Inorganic materials 0.000 claims description 9
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052749 magnesium Inorganic materials 0.000 claims description 9
- 229910052748 manganese Inorganic materials 0.000 claims description 9
- 229910052759 nickel Inorganic materials 0.000 claims description 9
- 229940088594 vitamin Drugs 0.000 claims description 9
- 229930003231 vitamin Natural products 0.000 claims description 9
- 235000013343 vitamin Nutrition 0.000 claims description 9
- 239000011782 vitamin Substances 0.000 claims description 9
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 9
- 229910052725 zinc Inorganic materials 0.000 claims description 9
- 229910019142 PO4 Inorganic materials 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 8
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 8
- 235000018417 cysteine Nutrition 0.000 claims description 8
- 239000010452 phosphate Substances 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 108010024636 Glutathione Proteins 0.000 claims description 7
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- 235000014987 copper Nutrition 0.000 claims description 7
- 229960003180 glutathione Drugs 0.000 claims description 7
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 7
- 150000005215 alkyl ethers Chemical class 0.000 claims description 6
- 150000002482 oligosaccharides Chemical class 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 150000003973 alkyl amines Chemical class 0.000 claims description 5
- 239000008103 glucose Substances 0.000 claims description 5
- 150000004676 glycans Polymers 0.000 claims description 5
- 239000005017 polysaccharide Substances 0.000 claims description 5
- WQZGKKKJIJFFOK-CBPJZXOFSA-N D-Gulose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O WQZGKKKJIJFFOK-CBPJZXOFSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-WHZQZERISA-N D-aldose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-WHZQZERISA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-IVMDWMLBSA-N D-allopyranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@@H]1O WQZGKKKJIJFFOK-IVMDWMLBSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-VSOAQEOCSA-N L-altropyranose Chemical compound OC[C@@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-VSOAQEOCSA-N 0.000 claims description 4
- 125000005907 alkyl ester group Chemical group 0.000 claims description 4
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 4
- 229930182830 galactose Natural products 0.000 claims description 4
- 235000001727 glucose Nutrition 0.000 claims description 4
- 229920001542 oligosaccharide Polymers 0.000 claims description 4
- 150000003267 reducing disaccharides Chemical class 0.000 claims description 4
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 125000005629 sialic acid group Chemical group 0.000 claims description 3
- 150000004804 polysaccharides Polymers 0.000 claims description 2
- 235000003969 glutathione Nutrition 0.000 claims 6
- 229960001031 glucose Drugs 0.000 claims 4
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 4
- 125000002951 idosyl group Chemical class C1([C@@H](O)[C@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 claims 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 1
- 241000237519 Bivalvia Species 0.000 claims 1
- 241000068587 Chelator Species 0.000 claims 1
- 235000020639 clam Nutrition 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 29
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 125000006413 ring segment Chemical group 0.000 description 6
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- WKGZJBVXZWCZQC-UHFFFAOYSA-N 1-(1-benzyltriazol-4-yl)-n,n-bis[(1-benzyltriazol-4-yl)methyl]methanamine Chemical compound C=1N(CC=2C=CC=CC=2)N=NC=1CN(CC=1N=NN(CC=2C=CC=CC=2)C=1)CC(N=N1)=CN1CC1=CC=CC=C1 WKGZJBVXZWCZQC-UHFFFAOYSA-N 0.000 description 5
- 150000001720 carbohydrates Chemical class 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- 239000002254 cytotoxic agent Substances 0.000 description 4
- 231100000599 cytotoxic agent Toxicity 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 229960005419 nitrogen Drugs 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- SQVRNKJHWKZAKO-PFQGKNLYSA-N N-acetyl-beta-neuraminic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-PFQGKNLYSA-N 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
- 229940022682 acetone Drugs 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000000562 conjugate Substances 0.000 description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 3
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 3
- 238000006352 cycloaddition reaction Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 3
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 3
- 235000010378 sodium ascorbate Nutrition 0.000 description 3
- 229960005055 sodium ascorbate Drugs 0.000 description 3
- 239000012064 sodium phosphate buffer Substances 0.000 description 3
- 239000011755 sodium-L-ascorbate Substances 0.000 description 3
- 235000019187 sodium-L-ascorbate Nutrition 0.000 description 3
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- DBJCAZPRELENEO-YOBQRZKDSA-N (2r,3s,4s,5r)-2,3,4,5,6-pentahydroxynon-8-ynal Chemical compound C#CCC(O)[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O DBJCAZPRELENEO-YOBQRZKDSA-N 0.000 description 2
- HEVMDQBCAHEHDY-UHFFFAOYSA-N (Dimethoxymethyl)benzene Chemical compound COC(OC)C1=CC=CC=C1 HEVMDQBCAHEHDY-UHFFFAOYSA-N 0.000 description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 229910052693 Europium Inorganic materials 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NYWZBRWKDRMPAS-GRRZBWEESA-N N-acetyl-9-O-acetylneuraminic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)COC(C)=O NYWZBRWKDRMPAS-GRRZBWEESA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000004450 alkenylene group Chemical group 0.000 description 2
- 125000004419 alkynylene group Chemical group 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- CLRLHXKNIYJWAW-QBTAGHCHSA-N deaminoneuraminic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@@H]1OC(O)(C(O)=O)C[C@H](O)[C@H]1O CLRLHXKNIYJWAW-QBTAGHCHSA-N 0.000 description 2
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
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- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- PWAPCRSSMCLZHG-UHFFFAOYSA-N cyclopentylidene Chemical group [C]1CCCC1 PWAPCRSSMCLZHG-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 150000008266 deoxy sugars Chemical class 0.000 description 1
- 229940120503 dihydroxyacetone Drugs 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- UQPHVQVXLPRNCX-UHFFFAOYSA-N erythrulose Chemical compound OCC(O)C(=O)CO UQPHVQVXLPRNCX-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000002256 galaktoses Chemical class 0.000 description 1
- 238000001641 gel filtration chromatography Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 239000011440 grout Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002373 hemiacetals Chemical class 0.000 description 1
- 150000002386 heptoses Chemical class 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 150000002402 hexoses Chemical class 0.000 description 1
- 150000002454 idoses Chemical class 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 125000004926 indolenyl group Chemical group 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 125000004936 isatinoyl group Chemical group N1(C(=O)C(=O)C2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical group C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical group C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 150000002584 ketoses Chemical class 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- MGLLHEBKDVYLBE-WXRYIJNVSA-N methyl (4S,5R,6R)-5-acetamido-6-[(1R,2R)-1,2-dihydroxy-3-(4-methylphenyl)sulfonyloxypropyl]-2,4-dihydroxyoxane-2-carboxylate Chemical compound S(=O)(=O)(C1=CC=C(C)C=C1)OC[C@H]([C@H]([C@H]1[C@@H]([C@H](CC(C(OC)=O)(O)O1)O)NC(C)=O)O)O MGLLHEBKDVYLBE-WXRYIJNVSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000004932 phenoxathinyl group Chemical group 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- 125000004941 pyridazin-5-yl group Chemical group N1=NC=CC(=C1)* 0.000 description 1
- 125000004942 pyridazin-6-yl group Chemical group N1=NC=CC=C1* 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- HSNZZMHEPUFJNZ-SHUUEZRQSA-N sedoheptulose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO HSNZZMHEPUFJNZ-SHUUEZRQSA-N 0.000 description 1
- 235000021309 simple sugar Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 150000003538 tetroses Chemical class 0.000 description 1
- 125000004927 thianaphthalenyl group Chemical group S1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 229930192474 thiophene Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 150000003641 trioses Chemical class 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/056—Triazole or tetrazole radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/06—Heterocyclic radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A compound of formula (I): Preferably, the reducing sugar unit is a reducing monosaccharide such as D-glucose, D-galactose or D mannose. In another aspect, a copper complex of the chelator molecule. The chelator molecule may be prepared by reacting an optionally protected azide-functionalised reducing sugar with tripropargylamine. A source of copper (I) may also be present and/or a reducing agent such as ascorbate. The reaction preferably occurs in aqueous conditions and is preferably conducted at alkaline pH. In another aspect, a method for promoting a copper (I) catalysed azide-alkyne cycloaddition reaction (CuAAC) wherein a an azide, an alkyne and a source of copper (I) ions are contacted with the chelator molecul or copper complex thereof.
Description
CELXOR MOLECULE
FIELD OF TE INVENTION
The invention relates to riovelwatersoiuble cneacor molecuies The invention also relates to a method for producing chelator md conies and a kit for use in copper (I) -caraiysed azidealkyne click conjuqa t:Lon (C:utP.C) of bioxnoieoules comprIsing copper I ligand molecules. The invention also relates to a novel method for promoting copper: cataiysed azide alkyne cyci. caddition reactions
BACKGROUND OF TEE INVENTION
Chelators for copper 1) ions such as TETA (tris[ (l-henzyllE l,2.Altriazoi--4yl)methyl]amine) 1.5 (Figure IA) , used in copper (I) catalysed azidealkvne cycloaddition reaction (CuAAC:) also referrc-d to as click conjugation, have been described e.ginChan, T.R, et al. , 2004. Org. Lett. 6:28535. The central tris (tri.azolylmethyi) amine core structure of TETA is mainly responsible for copper (I) coordination (Rodionov, V.P., et al., 2007.J, TAm, Ohe.m. Soc. l29:i2705i2) , while the side groups modulate the soluhil.ity of the complex and the reactivity of the ion. Chelators described in prior art utilize various side groups; however, marty of them may not be optimar in terms of eg. aqueous soluhility, ability to soiu--bilize copper (II:: ions and protect them from oxidation, reacL1v1.y, reaction conditions regusren for conjuga non to h.iomoiecules and ability to protect hio molecules from copperinduced damage by actively bind ing f ee copper ic.ns in the sclutxcn S UNFfl The crielator molecule accordino to the pre sent invention is characterized by what is cresented in rj aim 1 The copper complex according to the present invention is characterized by what is presented in claim 19.
The kit according to the present invention is characterized by what is presented in claim 22.
The method for preparing the chelator mole- cule according to the present invention is character-ized by what is presented in claim 27.
The method for promoting a copper (I)- catalyzed azide-alkyne cycloaddition reaction accord-ing to the present invention is characterized by what is presented in claim 34.
The use of a chelator molecule or a copper complex according to the present invention is charac-terized by what is presented in claim Ii.
BRIEF DESCRIPTION OF Tat DRAWINGS
Figure 1 shows the structures of TBTA and TGTA (tris{ [1-(6-D-galactosyl)-1B-1,2,3-triazol-4- yllmethyl}amine). A. Structure of TETA and its pro-posed copper(I) chelating mode as described in Rodionov, V.0., et al., 2007. J. Am. Chem. Soc. 129:12705-12. L represents an external ligand coordi-nating to copper. B. Structure of TGTA. TGTA has the same tris(triazolylmethyl)amine core structure as TBTA but is water-soluble due to the intrinsic hydrophilic character of the sugar units.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a chelator molecule comprising a core structure that is capable of coordinating copper(I} and side groups comprising a reducing sugar unit.
The copperCl) coordinating core structure comprises a tris(triazolylmethyl)anzine group.
The present invention relates to a chelator molecule represented by formula I
N N h
Formula I wherein each of R1, R2 and R3 is independently selected from the group consisting of a reducing sugar unit, C1-C9 alkyl, C3-C8 carbocyclyl, aryl, Ci-Ce alkyl-aryl, C1-C, alkyl-tC3-C8 carbocyclyl), heterocyclyl, C-C8 alkyl-(C3-C heterocyclyl), and 13; with the proviso that at least one substitu-ent selected from R1, R2 and It3 is a reducing sugar unit.
In this context, the term "tris(triazolylmethyl)amine group" should be under- stood as referring to a 1-(1R-triazol-4-yl}-N,N- bis (1H-triazol-4-ylmethyi)methanamine group. Substitu-ents It1, It2 and a, are thus bonded via a bond to the tris(triazolylmethyl)amine group as shown in formula I. In this context, the term "reducing sugar unit" or "reducing sugar" should be understood as re- ferring to a simple sugar moiety or a reducing mono-saccharide or a derivative thereof, or a combination of two or more sugar moieties or monosaccharides cova- lently linked to form a disaccharide, an oligosaccha-ride, or a polysaccharide, wherein the combination comprises a reducing monosaccharide.
The term "oligosaccharide" should be under-stood as referring to a saccharide comprising 2 to S monosaccharide units.
The term "polysaccharide" should be under-S stood as referring to a saccharide comprising more than 8 monosaccharide units.
A reducing sugar unit may either comprise an aldehyde or ketone group or be capable of forming one in solution. Said aldehyde or ketone group allows the sugar to act as a reducing agent4 The term "reducing sugar unit" may, in this context, also refer to a sugar unit which may be con-sidered a relatively weak reducing agent but which still displays some reducing activity.
In one embodiment, the reducing sugar unit is a group that includes an open chain or cyclized mono-mer unit based upon an open chain form of compounds having the chemical structure H(CHOH)nC(=O}(CHOH)mH, wherein the sum of n4-m is an integer in the range of 2 to 8. Thus, a monomer unit of a reducing sugar may in- clude a triose, a tetrose, a pentose, a hexose, a hep-tose, an octose, a nonose, or any mixture thereof.
In one embodiment, a hydroxyl group in the chemical structure of the reducing sugar unit is re-placed with a group such as H, amino, amine, acylamido, acetylamido, halogen, mercapto, acyl, ace-tyl, phosphate or sulphate ester, and the like.
In one embodiment, the reducing sugar unit further comprises a functional group such as carboxyl, carbonyl, hemiacetal, acetal or thio group.
In one embodiment, a hydroxyl group or an other functional group of the reducing sugar unit is protected with a protecting group such as silyl, ben-zyl, benzoyl, or the like.
The tern "alkyl" should be understood as re-ferring to a straight or branched chain saturated or unsaturated hydrocarbon having the indicated number of carbon atoms (e.g., "C-C8 alkyl" refers to an alkyl group comprising from 1 to 8 carbon atoms). When the number of carbon atoms is not indicated, the alkyl group comprises from 1 to 8 carbon atoms. Representa-tive "C1-C3 alkyl" groups include (but are not limited to) methyl (Me, CR3), ethyl (Ct, CM2CR,), 1-propyl (n-Pr, n-pzopyl, CH2CR2CH3), 2-propyl (i-Pr, isopropyl, CH(CR3)2), 1-butyl (n-Eu, n-butyl, CR2CR2CR,CR3), 2-methyl-1-propy]. (i-Eu, isobutyl, CH2CH(C113}2), 2-buty].
(s-Eu, s-butyl, CR(CM,)CR2CH,), 2-methyl-2-propyl Ct-Eu, tert-butyl, C(CH,),), 1-pentyl (n-pentyl, CM2CR2CH2CR2CH,), 2 -pentyl (CR (UI3) CH2CH2CH9), 3-pentyl (CH(CH2CH3)2), 2-methyl-2-butyl (C(CR,)2CM2CR3), 3-methyl'-2-butyl (CR (CR,) CR (CR,)2), 3-methyl-1-butyl (CR2CR2CR(CH,)2), 2-methyl-1-butyl (CH2CH(CM,)CH2CR,), 1-hexyl (CR2CH2CR2CH2CM2CH3), 2-hexyl (CH (CM,) CH2CH2CH2CH,), 3-hexyl (CH(CR2C113) (CR2CH2CR,)), 2-methyl-2-pentyl (C(CH,)2CR2CH2C11,), 3-methyl-2--pentyl (CH(CH,)CH(CR,)C}i2CR,), 4-methyl-2-pentyl (CM(CR,)CR2CM(CR,)2), 3-methyl-3-penty].
(C (CM,) (CR2C}{,) 2), 2-methyl-3-pentyl (CH(CR2CH,) CR (CR,)2), 2, 3-dimethyl-2-butyl (C(CR,)2CR(CR,)2), and 3,3-dintethyl-2-butyl (CH(CH,)C(CE3)3). An alkyl group may be unsubstituted or substituted with one or more groups including, but not limited to, OR, O(C1-C8 alkyl), aryl, COR', OCOR', CONR2, CONRR', CONR'2, NHCOR', Ski, SO2R', SOR', OSO2OH, OPO(OM)2, halogen, N,, NH2, NRR', NR'2, NHCO(C1-C8 al-kyl) or CM, wherein each TV is independently either H, C1-C0 alkyl or aryl. The term "alkyl" should also be understood as referring to an alkylene, a saturated, branched or straight chain or cyclic hydrocarbon radi-cal of 1 to 18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical such alkylenes include (but are not limited to) methylene (CR2) 1,2-ethyl (CR2CH2), 1, 3-propyl (CH2CH2CH2), 1,4-butyl (CH2CR2CH2CH2), and the like. The term "alkyl" should also be understood as referring to arylalkyl and heteroarylalkyl radicals as described below.
The term "alkenyl" should be understood as referring to a C2-C hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp2 double bond. Examples include, but are not limited to ethylene or vinyl (CR-CR2), allyl (C112CH-CH2), cyclopentenyl (C5H,), and 5-hexenyl (CH2CB2CR2CH2CHCH2).
The term "alkenyl" should also be understood as refer-ring to an alkenylene, an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical cen-ters derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent al-kene. Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (CH=CH).
The term "alkynyl" should be understood as referring to a C2-C hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond. Examples include, but are not limited to acetylenic (CCH) and propargyl (CH2CCR). The term "alkynyl" should also be understood as referring to an alkynylene, an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from carbon atoms of a parent alkyne. Typical alkynylene radicals include (but are not limited to) acetylene (n:.C), propargyl (CH2CaC), and 4-pentynyl (CH2CH2CH2CEC).
The term "aryl" should be understood as re-ferring to a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hy- drogen atom from a single carbon atom of a parent aro--matic ring system. An aryl group may be unsubstituted or substituted. Typical ary.L groups include (but are not]. imited to) radicals derived trout benrene, suhsti tuted bensene, pnenyl, napht.hale:ne anthracer-e phenyl, and the like. Anaryl nay he substituted with one or more groups including, but not limited to, OH, o (CC aikyl) aryl, COP: * COOP. , CCNH, , CONHR COUP.'2, NhCOR', PH, sC:2, SOP.', OSO,OH, CPU (OH) 2' halo-gen, N, NH7, NHR' , NP.', NHCO (OrCa aikyl) or ON, SO WktQteifl each P.' is independently either H, c:1o alkyl or aryl. The term "aryl" should also be u.nde.rsroou as referi..ing to an arylene group which is an aryl group having two covalent bonds and can he in the pare, me ta or ortho configurations, in which the phenyl group can be unsubstituted. or substituted with up to four grouns anciuding hut riot. limited to OH 0 (OC alky]. ) ary]. , COP. * DOOR, COUP.2 CONHR COUP. 2 NECOR, PH, SO,R 3CR, 05020H, CPU (OH) 2' halogen, N, NH,, NHR' Na,, NHCO(C.,CR alkyl) or ON, wherein each R isinde--pendent.ly either Ii, G1C ai.kyl or sty].
The term hi.rylaikyl" should he unders tood. as referring to an acyclic a.lkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp' carbon atom, is replaced with an ar 2.5 yl radical. Typical arylal.kyl groups include (hut are not limited to) henzyl, 2-henylethan].yl, 2 pneny1etrten1-yi, napnrr1vlmethyt, 2-naphthytethan-l yl, 2-naphthylethenl-yl, naphthobenzyi, naphthophenylethan-i--yl, and the like. The a.rylal.ky.l group may comprise 6 to 20 carbon atoms, e.g., the al-kyl moiety, includinq alkanyl, aikenyi or aikynyl groups, of the arylalkyl group:s 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms Tite term "heteroarylalkyl" should be under--stood as referring to anacyclicalky].radic in which one of the hydrocen atoms bonded to a carbon at- om, typical 117 a terminal or sp carbon atom, is re-placed with a heteroaryl radical. Typical heteroarylalky]. groups include (but are not limited to) 2-benzimidazolylmethyl, 2-furylethyl, and the like. The heteroarylalkyl group comprises 6 to 20 car-bon atoms, e.g., the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the heteroarylalkyl group is 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 ring atoms, typically 1 to 3 heteroatoms selected from N, 0, P, and 5, with the remainder being carbon atoms4 The heteroary]. moiety of the heteroarylalkyl group may be a monocyclyl having 3 to 7 ring members t2 to 6 carbon atoms) or a bicyclyl having 7 to 10 ring members (4 to 9 carbon atoms) and 1 to 3 heteroatoms selected from N, 0, B, and 8, for example a bicyclo [4,5], (5,5], (5,6], or (6,6] sys-tem.
The terms "substituted alkyl", "substituted aryl" and "substituted arylalkyl" should be understood as referring to alkyl, aryl, and arylalkyl, respec-tively, in which one or more hydrogen atoms are each independently replaced with a substituent. Typical substituents include but are not limited to X, K, -0-, OR, SR, 2, NR2, N1, NR, CX1, CN, OCN, SCN, N.C0, NCS, NO, NO2, =1429 143, NRCOR, COlt, CONK2, SO3, SO3H, 502R, OSO2OR, 30214R, 50K, OPO(OR)2, P0(0K)2, -P03-, P03H2, COlt, COX, C(=S)R, CO2R, -C02-, C(=S)0R, COSK, C(S)5R, CONK2, C(-S)NR2, and C(=NR)NR2, where each X is independently a halogen: F, Cl, Br, or I; and each P is independently H, C2-C13 alkyl, C6-C20 aryl, C3-C4 heterocyclyl or protecting group. Alkylene, alkenylene, and alkynylene groups as described above The terms "heteroaryl" and "heterocyclyl" should be understood as referring to a ring system in which one or more ring atoms is a heteroatom, e.g., nitrogen, oxygen, phosphate and sulfur. The heterocyclyl radical comprises 1 to 20 carbon atoms and 1 to 3 heteroatoms selected from N, 0, Pt and S. A heterocyclyl may be a monocyclyl having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatom.s selected from N, 0, 2, and S} or a bicyclyl having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, 0, 2, and 5), fox exam-ple: a bicyclo (4,5), (5,5], (5,6], or (6,61 system.
Reterocycles are described in Paquette, "Principles of Modern Heterocyclic Chemistry" (il. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. 82:5566 (1960).
Examples of heterocyclyls include, by way of example and not limitation, pyridyl, clihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoqui.nolinyl, benaimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2- pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis- tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 611-i, 2,5--thiadiazinyl, 2ff, 6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 311-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, plithalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4a11-carbazolyl, carbazolyl, f3-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isothromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidthyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benz isoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl.
By way of example and not limitation, carbon- bonded heterocycles may be bonded at the following po- lo sitions: position 2, 3, 4, 5, or 6 of a pyridine; po-sition 3, 4, 5, or 6 of a pyridazine; position 2, 4, 5, or 6 of a pyrimidine; position 2, 3, 5, or 6 of a pyrazine; position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole; position 2, 4, or 5 of an oxazole, imidazole or thiazole; position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole; position 2 or 3 of an aziridiie; position 2, 3, or 4 of an azetidine; position 2, 3, 4, 5, 6, 7, or 8 of a quinoline; or po- sition 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Car- bon bonded heterocyclyls may include 2-pyridyl, 3- pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3- pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-- pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl and 5-thiazolyl.
By way of example and not limitation, nitro-gen bonded heterocyclyls may be bonded at position 1.
of an aziridine, azetidine, pyrrole, pyrrolidine, 2- pyrroline, 3-pyrroline, imidazole, imidazolidine, 2- imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3--pyrazoline, piperidine, piperazine, indole, indoline, or la-indazole; position 2 of a isoindole or isoindoline; position 4 of a morpholine; and position 9 of a carbazole or 3-carboline. Still more typically, nitrogen bonded heterocyclyls include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl and 1-piperidinyl.
The term "carbocyclyl" should be understood as referring to a saturated or unsaturated ring having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle. Monocyclic carbocyclyls have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.
Sicyclic carbocyclyls have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], (5,5], [5,6] or [6,6) system, or 9 or 10 ring atoms arranged as a bicyclo 5,6) or [6,6] system. Examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cycloheptyl and cyclooctyl.
In one embodiment, at least two substituents selected from R1, R2 and R3 are reducing sugar units.
In one embodiment, each substituent selected from R, R2 and a3 is a reducing sugar unit.
In one embodiment, the reducing sugar unit comprises a reducing monosaccharide, a reducing disac-charide, a reducing oligosaccharide, or a reducing polysaccharide.
In one embodiment, the reducing sugar unit is a reducing monosaccharide, a reducing disaccharide, a reducing oI.igosaccharide, or a reducing polysaccha-ride.
In one embodiment, the reducing oligosaccha-ride comprises 2, 3, 4, 5, 6, 7 or B monosaccharides.
In one embodiment, the reducing sugar unit comprises a reducing monosaccharide.
In one embodiment, the reducing sugar unit is a reducing monosaccharide.
In one embodiment, the reducing monosaccha-ride comprises, but is not limited to, a simple aldose such as glyceraldehyde, erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose or mannoheptulose; a simple ketose such as dihydroxyacetone, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose or sedoheptulose; a deoxysugar such as fucose, 2-deoxyglucose, 2-deoxyribose or rhamnose; a sialic acid such as ketodeoxynonulosonic acid, N-acetylneuraminic acid or 9-O-acetyl-N--acetylneuraminic acid; a uronic acid such as glucuronic acid, galacturonic acid or iduronic ac-id; an amino sugar such as 2-amino-2-deoxygalactose or 2-arrtino-2-deoxyglucose; an acylamido sugar such as 2-acetamido-2-deoxygalactose, 2-acetamido-2-deoxyglucose or N-glycolylneuraminic acid; a phosphorylated sugar such as 6-phosphomannose; a sulphated sugar such as 6-sulpho-N-acetylglucosamine or 3-suiphogalactose; or any derivative or modification thereof.
The reducing monosaccharide may be a reducing monosaccharide in open-chain, pyranose or furanose form, or as the a-or -anoxner; or in any combination thereof.
Carbohydrate nomenclature in this context is essentially according to recommendations by the IUPAC- tUB Commission on Biochemical Nomenclature (e.g. Car-bohydrate Res. 1998, 312, 167; Carbohydrate Res. 1997, 297, 1; Eur. J. Biochem. 1998, 257, 293) In one embodiment, at least one substituent selected from R1, H2 and R3 comprises a reducing mono-saccharide.
In one embodiment, at least one substituent selected from R, H2 and H3 is a reducing monosaccha--ride.
In one embodiment, at least two substituents selected from K1, K2 and R3 comprise a reducing mono-saccharide.
In one embodiment, at least two substituents selected from R1, R2 and R3 are reducing monosaccha-rides.
In one embodiment, each substituent selected from R, R2 and It3 comprises a reducing monosaccharide.
In one embodiment, each substituent selected from R1, R3 and Ra is a reducing monosaccharide.
In one embodiment, the reducing monosaccha-ride is in the D-or L-configuration.
In one embodiment, the reducing monosaccha-ride is represented by formula II x5 1 >X Formula II wherein X' is either OH, H, hydroxymethyl, methyl, carboxyl, substituted carboxyl, C1-C6 alkyl or ? is either absent or CH(X4); X2, X, X4 and X5 are each independently either OH, H, amino, C1-C6 alkylamine, C1-C6 alkylether, C1-C6 alkylester, halogen, mercapto, C2-C5 acylamide, carbox-yl, substituted carboxyl, C-C6 alkyl, substituted C1-C6 alkyl, phosphate ester, sulphate ester, or a bond to the tris(triazolylrnethyl)amine group; with the proviso that one substituent se'-lected from X2, X3, X4 and X5 is a bond to the tris(triazolylmethyl)amine group, or x2, x3, x4 or x5 is bonded via a bond to the tris(triazolylmethyl)amine group.
In one embodiment, one substituent selected from X2, X3, X4 and X5 is a bond to the tris(triazolylmethyl)amine group.
in one embod.imertt X1, X, X or X is OH;, H, amino, C[CE alkvlamine C-O-. alkylether, C1C alkylester, halogen, mercapto, C2C5 acylamide, carbox yl, suhsrtuted carboxyl, OrC alk.yl, substituted CC S a.ikyl, phosphate ester, or sulphate ester; and is bonded via a bond to i.-.he tras ( tria.zolylmetnyi. ) amine group in one embodiment, Y is 011(X4) ; and X2, X and K' are each independently either OH or H, in one embodiment, Yls absent; and x2 and X3 are each independently either OH or H, in one embodi:menc., X2, H3 and K' are each:Ln.' deoendent.1. y either OH or H in one embodiment, XL, X and r are each in dependently either OH or H; X isa 01C alkyl; and X is bonded via a bond to the tris (triazolyimethyl) amine group.
in one embodiment, X is the bond to the tris (triazoly.imethvl)axrine group.
in one embodiment, the reducing monosaccha ride is an aldobexose represented. by formula Iii OH2
-OH HO)H
Eorniula 11.1 wherein OH, a bonded via a bond to the trrs (triazolyimethyl) amine group.
The wavy single bond at X' of formula II or at the OH orcup in forriul a 1i1 tndi cafes unsoecired stereochemistry of the bond due to the tact that the structure mai be an c' anomer, a 3"anomer,anopen---chain form, a pyranose or a furanose or a mixture thereof due to niutarotation. However, other carbons in formulas II and III may also be chiral and have dif-ferent relative configurations.
In one embodiment, the aldohexose is selected from the group consisting of 0-and fr-forms of allose, altrose, glucose, mannose, gulose, ictose, galactose and talose.
In one embodiment, the aldohexose is selected from the group consisting of D-glucose, D-galactose and D-mannose.
In one embodiment, the reducing monosaccha-ride is sialic acid.
In one embodiment, the sialic acid is select-ed from the group consisting of ketodeoxynonulosonic acid, N-acetylneuraminic acid and 9-O-acetyl-N-acetylneuraminic acid.
In one embodiment, the sialic acid is N-acetylneuraminic acid.
In one embodiment, K1 K2 a K3 In one embodiment, the chelator molecule is selected from the group consisting of tris(fl-(6-D-galactosyl) -lB-i, 2, 3-triazol--4-yl]methyl} amine, tris{(1-(6-D-glucosyl)-1H-1,2,3-triazol--4- yl]methyljamine and trisi [1-(6-D-mannosyl)-1H-1,2,3-triazol-4-yl]methyl) amine.
In one embodiment, the chelator molecule is selected from the group consisting of tris{(l-(6-L-galactosyl) -lB-i, 2, 3-triazol-4-yl I methyl} amine, trisj (1-(6-L-glucosyl)-1H-1,2, 3-triazol-4- yl]methyl}amine and tris{(1-(6-L-mannosyl)-tH-1,2,3-triazol-4-yljmethyl}amine.
The chelator molecule according to the inven-tion is useful as a chelating or a complexing agent for a variety of metal ions, including but not limited to copper, regardless of their efficacy for promoting a CuAAC reaction.
Copper(I} is required in a catalytic amount to catalyse a CuAAC reaction.
The present invention also relates to a cop-per complex comprising a chelator molecule according to the invention complexed with a copper ion.
In one embodiment, the copper ion is a cop-perU) ion.
In one embodiment, the copper ion is a cop-perCh) ion.
The present invention also relates to a kit comprising a chelabor molecule according to the invert-tion or a copper complex according to the invention.
In one embodiment, the kit is suitable for promoting a copper (1)-catalysed azide-alkyne cycloaddition reaction.
In one embodiment, the kit further comprises a source of copper(I). The source of copper(I) may be provided in the form of a copper (I) salt such as for example Cul, CuBr, CuOTf*C6H6 or [Cu(NCCH3)4J. The source of copper (I) may also be provided together with a co-solvent or the kit may further comprise a cc-solvent such as acetonitrile, or further agents such as a nitrogen base or amine, e.g. 2,6-lutidirie, tn-ethylamine, N, N, N-trimethylethylenediamine, diisopropylethylazuine, pyridine, proline or other au-phatic amine. Such co-solvents or further agents may assist in making the copper(I) salt soluble or prevent oxidation of copper (I) to copper (Ii). This embodiment has the added utility that copper is provided directly in the active form that is capable of catalysing a CuAAC reaction. Further reducing or oxidising agents or steps for preparing copper(I} may not be necessary.
A source of copper(I) may also comprise means for providing copperCl). Such means may comprise e.g. a source of copper(II) and a reducing agent capable of reducing copper(II) to copper(I); or copper(0) metal and an agent capable of oxidising copper (0) metal to copper(I). Such means may allow the preparation of copper(I) prior to adding the copper CI) to the chelator molecule according to the invention or to a CuAAC reaction.
In one embodiment, the kit further comprises a source of copperClt). The source of copperCil) may be e.g. a salt such as the readily available sulphate salt such as CuSO45H2O. This embodiment has the added utility that copper(II) salts may be more readily sol-uble, less costly or often purer than copper(I) salts.
The source of copper (II) may also be consid-ered to comprise means for providing copper(II).
In one embodiment, the kit comprises a source of copper(1) and a source of copper(II).
In one embodiment, the kit further comprises means for providing copper (I) and means for providing copper(II).
In one embodiment, the kit further comprises a reducing agent capable of reducing copper(II) to copper(I). A reducing agent capable of reducing cop-per(I1) to copperCl) may be e.g. ascorbate, quinone, hydroquinone, vitamin Ki, glutathione, cysteine, Fe2, or an applied electric potential. Said reducing agent may also be a metal selected from the group con-sisting of Cu, Al, Be, Co, Cr, Fe, Mg, Mn, Ni, and Zn.
The kit may optionally comprise a further component, such as a buffer, a solvent, instructions for using the kit or an agent suitable for sequester-ing or chelating copper ions to quench the reaction.
In one embodiment, the kit further comprises means for conducting the reaction in alkaline pH.
In one embodiment, the kit further comprises a buffer with alkaline pH.
The invention further relates to a method for preparing the chelator molecule according to the in-vention, which method comprises the step of reacting an azide-functionalised reducing sugar unit with tripropargylamine (N,N-di(2-propyn-1-yl)-2-propyn-1-amine).
In one embodiment, an azide-functionalised reducing sugar unit is reacted with tripropargylamine (N,N-di (2-propyn-1-yli -2-propyn-1-anine) in the pres-ence of a source of copper (I).
S The term "azide-functionalised reducing sugar unit" should be understood as referring to a reducing sugar unit which comprises an azide group.
In one embodiment, the azide-functionalised reducing sugar unit is protected by a protecting group. One or more groups in the azide-functionalised reducing sugar may be protected. Said groups may be the same or different. For instance, hydroxyl groups of a reducing sugar unit such as an aldohexose may be protected. The protecting group may be, but is not limited to, e.g. any suitable hydroxyl or diol pro-tecting group such as isopropylidene acetal, ethylidene acetal, cyclopentylidene ketal, cyclohexylidene ketal, benzylidene acetal, substituted benzylidene acetal, cyclic carbonate, an ester, ether or the like. Various protecting groups and steps of deprotecting are known in the art.
In one embodiment, the method further com- prises the step of deprotecting the azide-functionalised reducing sugar unit. The step of deprotecting the azide-functionalised reducing sugar unit may be carried out depending on the protecting group and other features of the system and may com-prise e.g. cleavage in the presence of acid.
In one embodiment, the azide-functionalised reducing sugar unit is an azide-functionalised reduc-ing monosaccharide.
In one embodiment, an azide-functionalised reducing sugar unit is reacted with tripropargylamine (N,N-di (2-propyn-1-yl) -2-propyn-1-amine) in the pres-ence of a catalytic amount of copperCl) ions.
In one embodiment, art azide-functionalised reducing sugar unit is reacted with tripropargylamine J_ 9 (N,N-di (2-propyn-l--yl)-2--prc:-pyn---l ---amine) in the pres---ence of a source of copper(1I) In one embodiment., an azide-functionaliseci reducing sugar unit: is reacted with traproparqyamne S in the presence of a source of copper (II) ions and a reducing agent capable of reducing copper (II) to cop--per(I) ]:n one emhodiment an azide-functionalised reducing sugar unit is reacted with tr ipropargylarnine (N, N-di (2-nr opyn-1 --yl --2-propyn-1-amine) in the pres--- ence of a reduc:nu agent canable of-reducing cop-per(T.l) to copner(I) In one embodiment, the reducing agent capable of reducing cop-per (II) to copper (I) is selected from the grout) cons isting of ascorbate, quinone, hydroqu i-none, vitamin Ki * glutai:hione, cyst:eine, Fe, co:*, and an applied electric potential; or is a metal selected from the group consisting of Cu, 1\l, Be, Co, Cr, Fe, Mg, Mn, Ni, and Zn The reducing agent capable of reducing cop-per ( :[I) to copper I) may ne present in order to reduce copper (11) to copper (.1) , regardless of whether a source c-f cc-poe.r (I) or a source ci: copper (II) is pre-sent. The presence of a reducing agent has the added utility that it reduces the oxidising effect of any oxygen present in the reaction system, which may cth---erwise oxidise copper 1) to copper (I I The nresent invention also relates to a math--od for promoting a copper (Ti -cata:tysed a.zide-alkyne cycloaddition reaction, wherein the methd camprises contactinc-a a aside and an alkyne with a source of copper ions in the presence of a chelatcr moiecule ac-cording to the invention or with a copper complex ac cording to the invent ion -The method shoulo'he understood as-a general method for prc-moting any copper' I) --catalysed aide-alkyne cycloaddition reaction and is therefore not limited to any particular organic azide or alkyne.
In one embodiment, the alkyne is a terminal alkyne.
The method is useful, for example, for bio-conjugation reaction conditions that may be used for preparing e.g. antibody-drug conjugates.
In one embodiment, the azide or the alkyne comprises a biomolecule.
In one embodiment, the biomolecule comprises a protein.
In one embodiment, the protein comprises an antibody.
In one embodiment, the antibody is a recombi-nant antibody.
In one embodiment, the antibody is a mono-clonal antibody4 In one embodiment, the azide or the alkyne comprises a payload molecule.
Tn this context, the term "payload molecule" should be understood as referring to any moiety that may be modified to comprise an azide or alkyne moiety.
In one embodiment of the present invention, the payload molecule is selected from the group con-sisting of a cytotoxic agent and a labelling molecule, such as a fluorescent label or a radioactive label.
In one embodiment of the present invention, the payload molecule is a cytotoxic agent.
In this context, the term "cytotoxic agent" should be understood as referring to a molecule that has the capability to affect the function or viability of a cell. The cytotoxic agent may be any compound that results in the death of a cell, or induces cell death, or in some manner decteases cell viability.
In one embodiment, an azide and an alkyne are contacted with a source of copper ions in the presence of a chelator molecule according to the invention or with a copper complex according to the invention in aqueous solution.
In this context, the term "aqueous solution" should be understood as a solution in which water is S the primary solvent. An aqueous solution may further comprise a secondary solvent.
In this context, the term "a source of copper ions" should be understood as referring to a source of copper(I) and/or a source of copper(Ir).
In one embodiment, copper(I) ions are present in a catalytic amount.
In one embodiment, an azide and an alkyne are contacted with a source of copper ions in the presence of a chelator molecule according to the invention or with a copper complex according to the invention and in the presence of a reducing agent capable of reduc-ing copper(II) to copper(I}.
The reducing agent capable of reducing cop-per (II) to copper(I) may be present in order to reduce copper(II) to copper (I), regardless of whether a source of copperCi) or a source of copper(II) is pre-sent. The presence of a reducing agent has the added utility that it reduces the oxidising effect of any oxygen present in the reaction system, which may 0th-erwise oxidise copper(t) to copperCil).
In one embodiment, an azide and an alkyne are contacted with a source of copperCil) ions in the presence of a chelator molecule according to the in- vention or with a copper complex according to the in- vention and in the presence of a reducing agent capa-ble of reducing copper(I1) to copper(I).
In one embodiment, the reducing agent capable of reducing copperClt) to copper(I) is selected from the group consisting of ascorbate, quinone, hydroqui-none, vitamin Ki, glut.athione, cysteine, Fe2, Ca24, and an applied electric potential; or is a metal selected from the group consisting of Cu, Al, Be, Co, Cr, Fe, Mg, Mn, Ni, and Zn.
However, in some embodiments of the tnven---tion, a reducing agent (other than the chelator mole cole according to the invention or the copper complex according to the invention) may not he necessary. The reducing sugar unit present in the chelator molecule or the copper complex according to the invention may function as a reducing agent. apable of reducing cop-per (II) to conper (I) or prevent oxidation of copper(I) to copper (Jfl In one embodiment the reducing sugar unit.
functions as a reducing agent in alkaline ph In one embodiment, an az:Lcie and an alkyne aie contacted with a source of coppei. ions in the presence of a chelator molecule according to the invention or with a copoer complex accordnc to the invention In alkaline p This embodiment has the added utility that reducing suqar unir..s are most effective in reducing copper in alkaline ph.
In one embodiment, the alkaline p1-i is at least 7, ox at.. least 8, or at. least 9, or a.t least 1.0, or at least 11, In one embodiment, the alkaline pH is 7 1 1, 7--lU. 7-9, 7--B, 8--il, 8'l0, 8-9, 9-ll, 9-l.0, or about 8, about 8 5, about 9, or about 95 In ccc cmbc:diment, sucn alkaline ph is se-- lec,ted that. it does not promote damage to the the as---ide and the a kyne during their contacting with a source of copper I I ions.
In one embodiment, the alkaline ph. is a slightly a±kaline nfL In one embodiment, the aikal inc ph is the highest ph that doe.s not promote damage to the the as--ide and the alkyne during their contacting with a source of copper (I) ions.
In one embodiment, an azide and an alkyne are contacted with a source of copper(I) ions in the pres-ence of a chelator molecule according to the invention or with a copper complex according to the invention.
S In one embodiment, an azide and an alkyne are contacted with a source of coppertll) in the presence of a chelator molecule according to the invention or with a copper complex according to the invention in the absence of a further reducing agent capable of re-ducing copperCil) to copper(I) In one embodiment, an azide and an alkyne are contacted with a source of coppertli) in the presence of a chelator molecule according to the invention or with a copper complex according to the invention in the absence of a reducing agent capable of reducing copper(II) to copper(I) in alkaline pH.
In one embodiments an azide and an a].kyne are contacted with a source of copper(I) in the presence of a chelator molecule according to the invention or with a copper complex according to the invention in the absence of a further reducing agent capable of re-ducing copper(II) to copper (I).
In one embodiment, an azide and an alkyne are contacted with a source of copper(I) in the presence of a che.Lator molecule according to the invention or with a copper complex according to the invention in the absence of a further reducing agent capable of re-ducing copper(tI) to copperCl) in alkaline pH.
In one embodiment, the method comprises the steps of step a) preparing a source of copperCl); and step b) contacting an azide and an alkyne with the source of copper(I) obtainable from step a) in the presence of a chelator molecule according to the invention.
Itt one embodiment, the method comprises the steps of step a) preparing a source of copper(I); step h) contacting the source of copper(I) obtainable from step a) with a chelator molecule ac-cording to the invention to prepare a copper complex; S and step c) contacting an azide and an alkyne with the copper complex obtainable from step b).
The present invention further relates to the use of a chelator molecule according to the invention or the copper complex according to the invention for promoting a copper(I)-catalysed azide-alkyne cycloaddition reaction.
The presence of reducing sugar units in the chelator molecule may provide several advantages. The chelator molecule or the copper complex according to the invention has the ability to accelerate a CuAAC reaction. The chelator molecule may modulate the reac- tivity of copper (I), and reducing sugar units may pro- vide optimal hydrophilic, steric and electronic prop-erties for chelating copper(I). Reducing sugar units also improve aqueous solubility of the chelator mole- cule and the copper complex, thus allowing CuAAC reac-tions in aqueous solutions and in conditions that ate suitable for sensitive biomolecules such as proteins.
The chelator molecule is able to effectively bind cop-per ions and remove them from the solution e.g. after CuAAC reaction in aqueous solution.
The present inventions have also surprisingly found that the chelator molecule and copper complex according to the invention have the ability to protect biomolecules from copper-induced damage in a CuAAC re-action performed in aqueous solution. The chelator molecule and copper complex according to the invention are thus well suitable for a CuAAC reaction, wherein the azide or the alkyne present in the reaction com-prises a protein or other biomolecule. Furthermore, the chelator molecule and copper complex according to the invention have the ability to reduce copper(II) ions into the catalytically active copper(I) ions and sustain reducing conditions in the solution: thereby they may be able to remove the need to use an external reducing agent such as ascorbic acid. Furthermore, re-ducing sugar units are inexpensive, non-toxic and readily available for chelator molecule synthesis.
The embodiments of the invention described hereinbefore may be used in any combination with each other. Several of the embodiments may be combined to-gether to form a further embodiment of the invention.
A product, or a use, or a method to which the inven- tion is related, may comprise at least one of the em-bodiments of the invention described hereinbefore.
Efl1WLES In the followings the present invention will be described in more detail. Reference will now be made in detail to the embodiments of the present in- vention, examples of which are illustrated in the ac-companying drawings. The description below discloses some embodiments of the invention in such detail that a person skilled in the art is able to utilize the in-vention based on the disclosure. Not all steps of the embodiments are discussed in detail, as many of the steps will be obvious for the person skilled in the
art based on this specification.
EXAMPLE 1. Synthesis of TGTA.
General experimental details: Reagents and solvents were purchased from commercial sources. Reac-tion solvents were dried and distilled prior to use when necessary. All reactions containing moisture-or air-sensitive reagents were carried out under an argon atmosphere. The preparation of 1. has been described previously and similar routes were employed in the current synthesis (see for example Yanq, 3, , et. al. 20:03. 3, 3, Orq. let:.52223--6) the NMR spectra were recorded with a Bruker hvance spectrometer operating at 600 Mi-lz(H 600 MHz, C; 150 MHz) . PulsE: secjuc.ces provided by the manufac--turer were utilized. The or abe temperature riurna the exe rinrrs was kept at 22 C unless otherwi se. inen-tioned. Chemi.ca.1 shifts are expressed on the 6 scale.
(in ppm) using TMS (tetramethyisilane) residual chio roform, acetone., 1-1,0 or methanol as internal stan---dards. Coupling constants are aiven i.n Hz and provided only once when first encountered. Coupling patterns are given as s sinolet, d, doublet, t, triplet etc. Mass spectra were obtained with a Eruker Ultraf..lex III.
MAL0.tlOF mass spectrometer operated in posi---tive/negat:i xe mode. TLC was performed on aluminium sheets precoated with silica gel $0 E254 (Merck) -Flash chromatography was carried out on silica gel 50 (0.040-0. 060:wm Aldrich) -Spot:s were visualized by [N followed by charrino with 1 5.HS0/Me0Fi and heating.
HO
N,. -N / N F 9_OH N o 4o /=\ HO'J,'° NN of r-N' HO HO " N9 2:3 Schn 1. U Tripropargylamine, 0u304, sodium L-ascorbate, DP4F:H,0-3:1, Rr, 40h, quantitative; ii) 60% TFA (in H20) $0C, 25h, quantitative.
Protected TGTA (2): To a solution containing 43mg of 1 (0.lSmmol, 5 equiv..) and 4..Bpl tripropargylamine (O.O3mmol, 1 equiv.) in 2nd of DMF:H20 (3:1) was added 2.4mg CuSO4 (O.Oi5mmol, 0.5 equiv.) and 6.4mg sodium L-ascorbate (0.O3mmol, 1 equiv.). The resulting mixture was stirred at RT for 40h (during this time a white solid precipitated from the reaction mixture). After 40h, the reaction mixture was diluted with 20m1 EtOAc transferred to a separa- tory funnel and washed with Sm! NH4C1-solution (pre-pared by dissolving a saturated NH4CI-solution with equal amount of water 1:1 v/v) and lSml brine. The or- ganic phase was dried with Na2S04, filtered and concen-trated to give the crude product. The crude product was purified by column chromatography (EtOAc-.BtOAc:MeOH 3:1) to give 2 as a colorless oil (30mg, quantitative). TLC: R, = 0.22 (EtOAc). H NMR (600MHz, COd3, 25°C): 6 8.56 Cs, 3 H, triazole-H), 5.48 (d, 3 H, J),2 = 5.0Hz, H1), 4.67 (dd, 3 H, Ga,S 3.1, Ge.Gb = 14.1Hz, H-6a), 4.65 (dd, 3 H, J31 2.5, 8.1, H-3), 4.58 (dd, 3 H, J55 = 9.0Hz, H-6b), 4.41 and 4.33 (each d, each 3 H. wcu2a,ucH2b 14.1Hz, N(C112)3), 4.32 (dd, 3 H, 13-2), 4.25 (dcl, 3 H, J4,5 1.4Hz, 13-4), 4.17 (ddd, 3 11, H-S), 1.50, 1.39, 1.37 and 1.25 (each s, each 9 13, 02C(CH,)2) ppm. HRMS: ca].cd. for C45H66N10O1Na (M+Na] 1009,46; found 1009.40.
TGTA (3): 33mg of 2 (0.O34mmol) was dissolved in 3m]. 60% TFA (in 1120) and stirred at 50°C for 1.5 hours. The reaction mixture was then diluted with Wa-ter, concentrated and dried under vacuum to give 3 as a white solid (25mg, quantitative, a: 2:3). selected NMR-data; 211 NMR (600MHz, D20, 25°C): 5 8.32 (s, 6 H (a and 13, 3 H each), triazole-if), 5.21 Cd, 3 H, J1,2= 3.9Hz, 11-la), 4.59 (a, 12 H ta and, 6 11 each), N(C112)3), 4.50 Cd, 3 H, J,,2 8.1Hz, H-1). HRt4S; ca].cd. for C27H42N10015Na (M+Na) 769.27; found 769.23.
EXAME'LE 2. Synthesis of copper chelators.
Preparation of various azide- functionalized reducing sugar units in either pro- tected or unprotected form have been described previ-ously and similar routes are employed in the synthesis of copper chelators from different reducing sugars (see e.g. 2-, 3-, 4-and 6-azidoaldohexoses: 1,3,4,6-tetra-O-acetyl-2-azido-2-deoxy-a--D-mannopyranoside, 1,2,4, 6-tetra-O-acetyl-3-azido-3-deoxy-a-D- mannopyranoside, 1,2,3, 6-tetra-O-acetyl-4-azido-4-deoxy-a-D-manno-pyranoside, 6-azido-6-deoxy-D-mannose and 1,2,3, 4-tetra-O-acetyl-6-azido-6-deoxy-a-D-mannopyranoside in Marchesan, S. and Macmillan, D., 2008. Chem. Commun. 36:4321-4323; 5-azicloaldopentoses: 5-azido-5-deoxy-D-arabinose and 1,2, 3-tri-O-acetyl-5-azido-S-deoxy-D-arabinose in Smellie, l.A., et al,., 2007. Org. Biomol. Chem. 5:2257-66; 9-azidosialic ac- ids: e.g. 5-acetamido-9--azido-3, 5, 9-trideoxy-D-glycero-D-galacto-2-nonulosonic acid in Han, S., et al., 2005. Nat. them. Biol. 1:93-7; and 6-azicloketohexoses: e.g. 6-azido-6-deoxy-D-tagatose in Jenkinson, S.F., et al., 2011. Org. Lett. 13:4064-7), Also, azido sugars such as t,3,4,6-tetra-0-acetyl-2- (2-azido) acetamido-2-deoxy-a-D-glucopyranoside and 1,3,4, 6-tetra-O-acetyl-2-(2-azido)acetamido-2-deoscy-u-D-galactopyranoside are available from e.g. Thermo Fischer Scientific (Pierce) When using a protected azide-functionalized reducing sugar unit, copper chelator is prepared ac-cording to Scheme 2:
N SA
I-
--N. N.
Z
Schete 2. 1) Couplina of protected sugar (Z SuqN3) to tr.propargylam1ne: Triproparqyiami.ne, LuSO sodium I--ascorbata, OME:.EUO 3:1, RT, 0/n; 1.1) Depro- tect±on of sugar unit: in case of acid labile protec-tire groups the following c' onditions are utilized; TEA:H,O g:.., 0°C-RT:, l-4h; :n case of base labile pro-tec tire groups the following conditions are utilized: NeOMe, MeCH, H10, PT, 4h-o/n; Sug sugar unit; 1 protected functioral groums of Sug; x unorotected runctjorAal groups of Sue.
When an unorot:ecLed azicie-functionali red re--ducing sugar unit is used, copper chelator is prepared accord.ng to Scheme 3: N.... ,Su N" K'
N
N >-)t--N Schete 3 l)T riproargy.lamine, CuSO, sodium lrasccrbate, tEuOH:H2C):OCM 3:3:1, PT, 0/n; Sug sugar unit; functional croupsof Sug.
EXAMPLE 3. Synthesis of TSTA, tris ( (1 (9 (N acetylneuraminyl) ) iHi, 2, :3triazoi---4-y:L) methyl) amine.
The preparation of 5 (Scheme 1) has been de-scribed pr:eviouslv and similar routes were employed in tecrrentsynthesJ..s (see rot example Han, S. , et al Nat. Chew, Sic!. 2005, 1, 93-97
HO
HO\ WHAc HO'K,
N -N
HO OH
H CO?H t-OH CO2H / 4 NHAt' N N JyoHJH AcHN c,. . HCi CO2H c Lb 00 H
OH
Scheme 4. ± ) 1) MeC)EU AG 50wX13 (}F form) 45C c/n, quantitative; 2) TsCI, pyridine, 0°C+RT, o/n, 67%; 3) NaN,, Acetone: H,?C 3:1, 75°C, a/n, 52%; ii) tripropa.rqv1Lar:Lne, Cu.504 * sodLum:u.ascorhate tBuC)(lcL)CM 3 3:1, RT 0/n.
5'acetamido9az.ido"3, 5, 9-trideox0-'glycer D-qa.iacto--2.--ncn.ulosoni c acid (5) : To a so1ui on corn-taming 63mg of 4 (0. 2runol) in Sm! dry MeOb (under ar gon) was added 127mg AC SOWX3 (2 weight equivalents) and the resulting m:L.xt:ure was stirred at 45°C c/n, The mixture was then filtered and concentrated to give.me--thy! I&acetyl neuraminate as a whites did (65mg, quantitatIve). TIC: Rf= 0.43 (DCM:MeOH 31) 157mg of methyl Nacetyl neuraminate (0. 49rmnoi) was dissolved in Sm! of dry pyridine (under argon) end the reaction mixture was cooled to 0°C, ISSmo Tad (0, 7mmo.1, 1.4 eauivaients) was added and the reaction mixture was slowly warmed to RT and left to stir o/nAf tar 23 nours 134mg TSC1 (0. 7zrmol, 1.4 equivalents) was added to the reaction mixture and it was stirred for an additional 2 hours at IC. The mix-ture was then cooled to 0°C and the reaction quenched with t4eOH. The mixture was concentrated and the crude product was purified by column chromatography (MeOH:DCM 1:9) to give methyl 9-O-tosyl-N-acetyl-neuraminate as a yellowish oil (159mg, 67%). TLC: R1 0.29 (DCM:MeOH 9:1). H NMR (600MHz, CD3OD, 22°C): 8 Selected NMR-data; 7.80-7.43 Cm, 4 H, CH3C6H4S02),4.28 (dd, 1 H, J = 2.2, 10.1 Hz),4.06-3.99 Un, 2 H), 3.93 (dd, 1 H, J 1.5, 10.6 Hz),3.85 (ddd, 1 H, J 2.0, 5.7, 8.5 Hz),3.77 (a, 3 H, C02C113),3.43 (dd, 1 H, J 1.5, 9.0 Hz), 2.46 Cs, 3 H, CH3C6H4SO2), 2.19 (dd, 1 H, J = 49, 12.9 Hz, H-3eq), 2.00 (a, 3 H, NHCOCE3), 1.86 (dd, 1 H, J 11.5, 12.9 Hz, H-3ax). }3RMS: calcd. for C19H27O13NNaS (M+Na]' 500.12; found 500.20.
110mg of methyl 9-O-tosyl-N-acetyl- neuraxainate (0.23cnmol) was dissolved in 2m1 ace-tone:H20 3:1 and 70mg NaN3 (1.lmmol, 4.3 equva1ents) was added. The resulting mixture was heated to 75°C and stirred o/n. The reaction mixture was then concen- trated and the crude product purified by gel filtra-tion chromatography to give 5 as a yellowish foam (40mg, 52%). Selected NMR-data; H NMR (600MHz, D20, 22°C): 5 4.03 (ddd, 1 H, J= 5.1, 10.1, 10.3 Hz), 3.99 (dd, 1 H, J = 0.9, 10.6 Hz), 3.94-3.89 Cm, 2 H), 3.61 (dd, 1 H, .J 2.8, 13.1 Hz), 3.53 Cap ci, 1 H, J = 9.4 Hz),3.49 (dd, 1 H, J' 6.0, 13.1 Hz), 2.22 (dci, 1 H, J 4.9, 12.9 Hz, H-3eq), 2.07 (a, 3 H, NHCOCK3), 1.83 (dd, 1 H, J = 11.7, 12.9 Hz, H-3ax). HRMS: calcd. for CiHxqOeN4Na [M+Nar 357.10; found 357.12; calcd. for C11H17O0N4Na2 (M+2Na-H J 379.0$; found 379.10.
TSTh (6): 18.5mg of 5 (0.O55mmol, 4 equiva-lents) was dissolved in 3m1 tBuOH:H20:DCM 3:3:1. To the mixture was next added 2jal tripropargylamine (0.Ol4mmol, 1 equivalents), 1mg Cu504 (0.OO7mmol, 0.5 equivalents) and 3mg sodium L-ascorbate (0.Ol5xvunol, 2:, I. 1 equivalents) The reaction mixture was stirred f-or n/ri at PT and concentrated to dye the or ude product.
The crude product was purlf.Led byqei. gilti-ation ch:rc matogranhy to give 6 as a yellowish oil 4.6 mc, 29%) S Selected NMR-data; H NMR (600MHz, 0,0, 22'C) 5 8.00 (s, 3d, triazol i-f),4,79 (4, 3 Hf 3 14.1 Hz),4.51 (dd, 3 H, 7.8, 14.1 hz),4.12 (Odd, 3 H, J 2.6, 8.0, 8.3Hz), 4.02 (dOd, 3 H, Jr.: 4,9, 10.2, 11,1 Hz), 3.98 (0, 3 H, 3 10.9 Hz), 3.92 (4, 3 H, J 10.2 Hzh3,Bl (hr s, 6 H), 3.40 (d, 3 H, J 9.1 Hz), 2.22 (dd, 3 H, Cr = 4.9, 13.0 Hz, H3eg), 1.99 us, 9 1-1, NHC:0C:lh), 1.134 (dO, 3 Hf J 11.1, 15.0Hz, &h-3ax).
HRMS calcd. for 0FL202,N:i [M---H] 1:1:32.40; found 3. :i. 32.47 1.5 EXAMPLE 4, Svnthes± s of: f:itroblast: growth factor con-I ustes SOpg ( Snmol) of recombinant human basic fi--nroriLast growtH rector ( eproLec:h; Eur) in 5mM sodium 2.0 phosphate buffer pH 7,3 (SOul) was incubated wit.h 1.
molar excess (l2nmoi) of NF1SPEGrN:. (Life Technolo-gies; delivered in 3h1 dimethylsulphoxide (DM30) for 3 hours at: room i:emne:rat:ure. No reacted NHS'PEGgN was separated by Amicon centrifugal filter unit (Mil-lipore; 101< cut-off) . According to MALDI-TOF mass soectr omet c an.alys.i, on average 3-4 NH.S-PEG4-N molecules were attached to one FGF molecule (average molecular weight 184000a) qalactose conjugates were made by azide-- alkyne cycloaddition reaction. Three parallel reac-Lions were per formed to comoare the performance of two copper (1) ion chelators, TGTA andi T.BTh, and 1(2055 a control 10Th (A) , TBTA (B) and H70 (C) (A) To the solution of 0. 59naiol or in 25mM sodium. phosphate buffer pH 7,3 (22.gll and 15 molar excess of EHproparayl-D-galactose in F1O (0, Spi.) , 3 molar excess of CuS0 in lUG (0,-SpI) 15 mc---- lar excess of sodium ascorbate in 1320 (0,Sul), 7,5 mo*- lar excess of TGTA in H20 (0,Spl) and ipi of 0,514 so-dium phosphate buffer pH 7.3 were added. Total volume of the reaction was 25p1.
(B) To the solution of 0.S9nmol of EGF-PEG4-N3 in 25mM sodium phosphate buffer pH 7.3 (22pl) and 15 molar excess of 6-propargyl-D-galactose in H20 (O,Sul), 3 molar excess of CuSO4 in 1320 (0,Spl), 15 no- lar excess of sodium ascorbate in (O,5p1), 7,5 no- lar excess of TBTA in DM50 (0,54) and 1.zl of 0,5t4 so-dium phosphate buffer p13 7.3 were added. Total volume of the reaction was 25111.
(C) To the solution of 0.S9nmol of FGF-PEG4-N3 in 25mM sodium phosphate buffer pH 7.3 (22il) and 15 molar excess of 6-propargyl-D-galactose in H2° (O,5il), 3 molar excess of CuSO4 in 1320 (0,54), 15 mo-lar excess of sodium ascorbate in 2° (0,Siil), 0,54 of 1320 and lii]. of 0,5M sodium phosphate buffer pH 7.3 were added. Total volume of the reaction was 254.
Reactions A, B and C were incubated at room temperature for 20 hours. In the reactions A (with TGTA) and C (20) the solutions were clear (without any visible precipitates) after 20 hour incubation, but in reaction B (with TBTA) a precipitate was de-t.ected already after 0.5 hour incubation, The reactions were stopped and the FGF-galactose conjugates purified by Amicon centrifugal filter units (101<).
Characterization of the reaction products was performed as follows: lOp! of Sx Laemmli sample buffer was added to all three 1micon-purified reactions (A, B and C, 404 each) and the samples were boiled for S win. A FGF-PEG4-N3 sample (pg) was prepared similarly.
The samples were run on 4-15% gradient SOS-PAGE gel (tliniProtean TGX gels, BioRad) using Spectra Broad Range Protein Ladder (Fermentas) as a molecular weight standard. The gel was stained with Imperial Protein Stain (Thermo Scientific) according to manufacturer's instructions. Ira the stained SOS-PAGE gel the FGF- PEG4-N3 appeared as 18.4kDa size band. The FGF-galactose conjugate from Sample A appeared as 19.1 kDa size band, showing that the reaction had proceeded as expected. No smaller size bands were detected in these two samples, showing that no degradation products were detectable in Sample A. No protein bands were detected in sample C, showing that the protein was degraded in a CuAAC reaction performed without a chelator mole- cule. These results show that the conjugation of ga- lactose to FGF-PEG4-N, was successftzl only in the pres- ence of TGTA and propargyl-modified galactose was ef-ficiently conjugated to azide-modified FGF in these conditions.
As is clear for a person skilled in the art, the invention is not limited to the examples and em-bodiments described above, but the embodiments can freely vaxy within the scope of the claims.
Claims (38)
- CLAIMS1. A chelator molecule represented by formulaIFormula I wherein each of R1, R2 and R3 is independently selected from the group consisting of a reducing sugar unit, C-C alkyl, C3C9 carbocyclyl, aryl, C-0 alkyl-aryl, alkyl-(03-08 carbocyclyl), C3C heterocyclyl, 01-08 alkyl-(03-08 heterocyclyl), and H; with the proviso that at least one substitu-ent selected from R1, R2 and R3 is a reducing sugar unit.
- 2. The chelator molecule according to claim 1, wherein at least two substituents selected from R1, R2 and R3 are reducing sugar units.
- 3. The chelator molecule according to claim 1 or 2, wherein each substituent selected from R1, R2 and R3 is a reducing sugar unit.
- 4. The chelator molecule according to any one of claims 1 -3, wherein the reducing sugar unit com- prises a reducing monosaccharide, a reducing disaccha- ride, a reducing oligosaccharide, or a reducing poly-saccharide.
- 5. The chelator molecule according to any one of claims 1 -4, wherein at least one substituent se-lected from R1, R2 and R3 is a reducing monosaccharide.
- 6. The chelator molecule according to any one of claims 1 -5, wherein at least two substituents se-lected from R1, R2 and R3 are reducing monosaccharides.
- 7. The chelator molecule according to any one of claims 1 -6, wherein each substituent selected from R1, R2 and R3 is a reducing monosaccharide.
- 8. The chelator molecule according to any one of claims 4 -7, wherein the reducing monosaccharide is in the D-or L-configuration.
- 9. The chelator molecule according to any one of claims I -8, wherein the reducing monosaccharide is represented by formula II x5 Formula II wherein X' is either OH, H, hydroxymethyl, methyl, carboxyl, substituted carboxyl, 01-06 alkyl or 1 is either absent or CH(X4); X2, X3, X4 and X5 are each independently either OH, H, amino, C1C6 alkylamine, 0106 alkylether, C1C6 alkylester, halogen, mercapto, C2C6 acylamide, carbox-yl, substituted carboxyl, C1C6 alkyl, substituted Cl-CE alkyl, phosphate ester, sulphate ester, or a bond to the tris (triazolylmethyl) amine group; with the proviso that one substituent se-lected from X2, X3, X4 and X5 is a bond to the tris(triazolylmethyl)amine group, or X2, X3, X4 or X5 is bonded via a bond to the tris(triazolylmethyl)amine group.
- 10. The chelator molecule according to claim 9, wherein X5 is OH, H, amino, Cl-CE alkylamine, 01-06 alkylether, C1C6 alkylester, halogen, mercapto, 02-CE acylamide, carboxyl, substituted carboxyl, C1C6 alkyl, substituted C1O6 alkyl, phosphate ester, or sulphate ester; and is bonded via a bond to the tris (triazolylmethyl)amine group.
- 11. The chelator molecule according to claim 9 or 10, wherein Y is CH(X4); and X2, X3 and X4 are each independently either OH or H.
- 12. The chelator molecule according to claim 9 or 10, wherein Y is absent; and X2 and X3 are each independently either OH or H.
- 13. The chelator molecule according to any one of claims 4 -11, wherein the reducing monosaccha-ride is an aldohexose represented by formula III CH2HO OHHO OHFormula III wherein OH2 is bonded via a bond to the tris (triazolylmethyl) amine group.
- 14. The chelator molecule according to claim 13, wherein the aldohexose is selected from the group consisting of 0-and L-forms of allose, altrose, glu-cose, mannose, gulose, idose, galactose and talose.
- 15. The chelator molecule according to claim 13 or 14, wherein the aldohexose is selected from the group consisting of 0-glucose, 0-galactose and 0-mannose.
- 16. The chelator molecule according to any one of claims 1 -15, wherein the chelator molecule is selected from the group consisting of tris{[l-(6-D-galactosyl) -lB-i, 2, 3-triazol-4-yl]methyl}amine, tris{ [1-(6-D-glucosyl)-1H-1,2,3-triazol-4- yl]methyl}amine and tris{[1-(6-D-mannosyl)-1H-1,2,3-triazol-4-yl] methyl} amine.
- 17. The chelator molecule according to any one of claims 4 -8, wherein the reducing monosaccha-ride is sialic acid.
- 18. The chelator molecule according to any one of claims 1 -17, wherein R1 = R2 = 19. A copper complex comprising a chelator molecule according to any one of claims 1 -18 complexed with a copper ion.20. The copper complex according to claim 19, wherein the copper ion is a copper(I) ion.21. The copper complex according to claim 19, wherein the copper ion is a copper(II) ion.22. A kit comprising a chelator molecule ac- cording to any one of claims 1 -18 or a copper com-plex according to any one of claims 19 -21.23. The kit according to claim 22, wherein the kit further comprises a source of copper(I) 24. The kit according to claim 22 or 23, wherein the kit further comprises a source of cop-per (II) 25. The kit according to any one of claims 22 -24, wherein the kit further comprises a reducing agent capable of reducing copper(II) to copper(I) 26. The kit according to claim 25, wherein the reducing agent capable of reducing copper(II) to copper(I) is selected from the group consisting of ascorbate, quinone, hydroquinone, vitamin 1<1, gluta-thione, cysteine, Fe2, Co2, and an applied electric potential; or is a metal selected from the group con-sisting of Cu, Al, Be, Co, Cr, Fe, Mg, Mn, Ni, and Zn.27. A method for preparing the chelator mole-cule according to any one of claims 1 -18, which method comprises the step of reacting an azide-functionalised reducing sugar unit with tripropargylamine.28. The method according to claim 27, wherein an azide-functionalised reducing sugar unit is reacted with tripropargylamine in the presence of a source of copper(I) 29. The method according to claim 27 or 28, wherein the azide-functionalised reducing sugar unit is protected by a protecting group.30. The method according to claim 29, wherein the method further comprises the step of deprotecting the azide-functionalised reducing sugar unit.31. The method according to any one of claims 27 -30, wherein the azide-functionalised reducing sugar unit is an azide-functionalised reducing mono-saccharide.32. The method according to any one of claims 27 -31, wherein an azide-functionalised reducing sug- ar unit is reacted with tripropargylamine in the pres-ence of a source of copper(II) ions and a reducing agent capable of reducing copper (II) to copper(I) 33. The method according to claim 32, wherein the reducing agent capable of reducing copper(II) to copperCi) is selected from the group consisting of ascorbate, quinone, hydroquinone, vitamin Ri, gluta-thione, cysteine, Fe2, Co2, and an applied electric potential; or is a metal selected from the group con-sisting of Cu, Al, Be, Co, Cr, Fe, Mg, Mn, Ni, and Zn.34. A method for promoting a copper(I)-catalysed azide-alkyne cycloaddition reaction, wherein the method comprises contacting an azide and an alkyne with a source of copper ions in the presence of a chelator molecule according to any one of claims 1 - 18 or with a copper complex according to any one of claims 19 -21.35. The method according to claim 34, wherein an azide and an alkyne are contacted with a source of copper ions in the presence of a chelator molecule ac-cording to any one of claims 1 -18 or with a copper complex according to any one of claims 19 -21 in aqueous solution.36. The method according to claim 34 or 35, wherein an azide and an alkyne are contacted with a source of copper ions in the presence of a chelator molecule according to any one of claims 1 -18 or with a copper complex according to any one of claims 19 - 21 in alkaline pH.37. The method according to any one of claims 34 -36, wherein an azide and an alkyne are contacted with a source of copper(II) ions in the presence of a chelator molecule according to any one of claims 1 - 18 or with a copper complex according to any one of claims 19 -21 and in the presence of a reducing agent capable of reducing copper(II) to copper (I) 38. The method according to claim 37, wherein the reducing agent capable of reducing copper(II) to copper(I) is selected from the group consisting of ascorbate, quinone, hydroquinone, vitamin Kl, gluta-thione, cysteine, Fe2, Co2, and an applied electric potential; or is a metal selected from the group con-sisting of Cu, Al, Be, Co, Cr, Fe, Mg, Mn, Ni, and Zn.39. The method according to any one of claims 34 -38, wherein an azide and an alkyne are contacted with a source of copper(I) ions in the presence of a chelator molecule according to any one of claims 1 - 18 or with a copper complex according to any one of claims 19 -21.40. The method according to any one of claims 34 -36 or 39, wherein an azide and an alkyne are con-tacted with a source of copper(I) or copper(II) in the presence of a chelator molecule according to any one of claims 1 -18 or with a copper complex according to any one of clams 19 -21 in the absence of a further reducing agent capable of reducing copper(II) to cop-per(I) 41. The use of a chelator molecule according to any one of claims 1 -18 or a copper complex ac-cording to any one of claims 19 -21 for promoting a copper (I) -catalysed azide-alkyne cycloaddition reac-tion.Amendments to the claims have been filed as followsCLAIMS1. A chelator molecule represented by formula E'ormula I wherein each of R, R2 and 1k3 is independently selected from the group consisting of a reducing sugar 0) 10 unit, C1*-C8 alkyl, C3-C8 carbocyclyl, aryl, Cj-C8 alkyl- aryl, Cl-Ca alkyl-(C3-C8 carbocyclyl), C3-C9 heterocy-clyl, C1-C8 alkyl-(C3-Ca heterocyclyl), and B; B with the proviso that at least one substitu-ent selected from P1, R2 and R3 is a reducing sugar unit; 0 2. The chelator molecule according to claim 1, wherein at least two substituents selected from Ri, 1k2 and R3 are reducing sugar units.3. The chelator molecule according to claim 1 or 2, wherein each substituent selected from R1, R2 and R3 is a reducing sugar unit.4. The chelator molecule according to any one of claims 1 3, wherein the reducing sugar unit com- prises a reducing monosaccharide, a reducing disaccha- ride, a reducing oligosaccharide, or a reducing poiy-saccharide.5. The chelator molecule according to any one of claims 1 -4, wherein at least one substituent se-lected from Rj, R2 and R3 is a reducing monosaccharide4 6. The chelator molecule according to any one of claims 1 -5, wherein at least two substituents se-lected from R, R and 1k3 are reducing monosaccharides.7. The chelator molecule according to any one of claims 1 -6, wherein each substituent selected from R1, R2 and R3 is a reducing monosaccharide.8. The chelator molecule according to any one of claims 4 -7, wherein the reducing monosaccharide is in the D-or L-configuration.9. The chelator molecule according to any one of claims 4 -8, wherein the reducing monosaccharide is represented by formula II xs Formula II wherein X1 is either OH, H, hydroxymethyl, O methyl, carboxyl, substituted carboxyl, C1-C6 alkyl or Y is either absent or CH(X4); X2, X3, X4 and x5 are each independently ei-ther OH, H, amino, C1-C6 alkylamine, C1-C5 alkylether, Ct-C6 alkylester, halogen, mercapto, C-C6 acylamide, carboxyl, substituted carboxyl, C1-C5 alkyl, substitut-ed C1-C6 alkyl, phosphate ester, sulphate ester, or a bond to the tris(triazolylmethyl)amine group; with the proviso that one substituent select-ed from X2, X3, X4 and X5 is a bond to the tris(triazolylmethyl)amine group, or X2, X3, X4 or is bonded via a bond to the tris(triazolylmethyl)amine group.10. The chelator molecule according to claim 9, wherein X is OH, H, amino, C1-C5 alkylamine, C1-C6 11. alkylether, CrC6 aikylester, halogen, mercapto, C2-C6 acylamide, carboxyl, substituted car-boxyl, Cs-Ce alkyl, substituted C1-C6 alkyl, phosphate ester, or sulphate ester; and is bonded via a bond to S the tris(triazolylmethyl)amine group.12. The chelator molecule according to claim 9 or 10, wherein 1 is CH(X'}; and X2, X3 and X4 are each independently either OH or H. 13. The chelator molecule according to claim 9 or 10, wherein Y is absent; and X2 and X3 are each independently either OH or H. 14. The chelator molecule according to any one of claims 4 -11, wherein the reducing monosaccha--ride is an aldohexose represented by formula III OH2COi--HO OHN-HOOM° Formula III O wherein C)!2 is bonded via a bond to the tris (triazolylmethyl) amine group.15. The chelator molecule according to claim 13, wherein the aldohexose is selected from the group consisting of D-and fr-forms of allose, altrose, glu-cose, mannose, gulose, idose, galactose and talose.16. The chelator molecule according to claim 13 or 14, wherein the aldohexose is selected from the group consisting of D-glucose, D-galactose and D-mannose.17. The chelator molecule according to any one of claims 1 -15, wherein the chelator molecule is selected from the group consisting of tris{(l-(6--D--galactosyi)-1H-1,2, 3-triazol-4-yl]methyl}amine, tris{ (l-(6-D-giucosyl)-1H-l,2,3-triazol-4- y1]methy1,amine and tris{(1-(6-D-mannosyl)-1H-1,2,3-triazol-4-yl]methyl} amine.18. The chelator molecule according to any one of claims 4 -8, wherein the reducing monosaccha-ride is sialic acid.
- 19. The chelator molecule according to any one of claims 1 -17, wherein R1 = =
- 20. A copper complex comprising a chelator molecule according to any one of claims 1 -18 corn-plexed with a copper ion.
- 21. The copper complex according to claim 19, wherein the copper ion is a copper(I) ion.
- 22. The copper complex according to claim 19, wherein the copper ion is a copper(IX) ion.
- 23. A kit comprising a chelator molecule ac- cording to any one of claims 1 -18 or a copper com- ___ plex according to any one of claims 19 -21, wherein the kit comprises a source of copper(I), wherein the kit comprises a source of copper(IT), and wherein the kit comprises a reducing agent capable of reducing copperill) to copper(t).0
- 24. The kit according to claim 22, wherein the reducing agent capable of reducing copper(tI) to copper(I) is selected from the group consisting of ascorbate, quinone, hydroquinone, vitamin Ml, gluta-thione, cysteine, Fe2, Co2, and an applied electric potential; or is a metal selected from the group con-sisting of Cu, Al, Be, Co, Cr, Fe, Mg, Mn, Ni, and Zn.
- 25. A method for preparing the chelator mole-cule according to any one of claims 1 -18, which method comprises the step of reacting an azide- functionalised reducing sugar unit with tripropargyla-mine.
- 26. The method according to claim 24, wherein an azide-functionalised reducing sugar unit is reacted with tripropargylamine in the presence of a source of copper(I).
- 27. The method according to claim 24 or 25, wherein the azide-functionalised reducing sugar unit is protected by a protecting group.
- 28. The method according to claim 26, wherein the method further comprises the step of deprotecting the azide-functionalised reducing sugar unit.
- 29. The method according to any one of claims 24 -27, wherein the azide-functionalised reducing sugar unit is an azide-functionalised reducing mono-saccharide.
- 30. The method according to any one of claims 24 -28, wherein an azide-functionalised reducing sug- ___ ar unit is reacted with tripropargylamine in the pres-C ence of a source of copper(II) ions and a reducing agent capable of reducing copper(II) to copper(t).O 20
- 31. The method according to claim 29, wherein the reducing agent capable of reducing copper(II) to O copper(I) is selected from the group consisting of ascorbate, quinone, hydroquinone, vitamin Ki, gluta-thione, cysteine, Fe2, Co2, and an applied electric potential; or is a metal selected from the group con-sisting of Cu, Al, Be, Co. Cr, Fe, Mg, Mn, Ni, and Zn.
- 32. A method for promoting a copper(I)-catalysed azide-alkyne cycloaddition reaction, wherein the method comprises contacting an azide and an alkyne with a source of copper ions in the presence of a che-lator molecule according to any one of claims 1 -18 or with a copper complex according to any one of claims 19 -21.
- 33. The method according to claim 31, wherein an azide and an alkyne are contacted with a source of copper ions in the presence of a chelator molecule ac-cording to any one of claims 1 -18 or with a copper complex according to any one of claims 19 -21 In aqueous solution.
- 34. The method according to claim 31 or 32, wherein an azide and an alkyne are contacted with a source of copper ions in the presence of a chelator molecule according to any one of claims 1 -18 or with a copper complex according to any one of claims 19 - 21 in alkaline pH.
- 35. The method according to any one of claims 31 -33, wherein an azide and an alkyne are contacted with a source of copper(II) Ions in the presence of a chelator molecule according to any one of claims 1 -CO 18 or with a copper complex according to any one of claims 19 -2]. and in the presence of a reducing agent N-capable of reducing copperClt) to copper(I).O 20
- 36. The method according to claim 34, wherein the reducing agent capable of reducing copper(II) to O copper (I) is selected from the group consisting of ascorbate, quinone, hydroquinone, vitamin Ki, gluta-thione, cysteine, Fe23, Co2, and an applied electric potential; or is a metal selected from the group con-sisting of Cu, Al, Be, Co, Cr, Fe, Mg, Mn, Ni, and Zn.
- 37. The method according to any one of claims 31 -35, wherein an azide and an alkyne are contacted with a source of copper(I) ions in the presence of a chelator molecule according to any one of claims 1 - 18 or with a copper complex according to any one of claims 19 -21.
- 38. The method according to any one of claims 31 -33 or 36, wherein an azide and an alkyne are con-tacted with a source of copper(I) or :39. copper(lI) in the presence of a chelator molecule according to any one of claims 1 -18 or with a copper complex according to any one of claims 19 - 21 in the absence of a further reducing agent capable of reducing copper(II) to copperCl).40. The use of a chelator molecule according to any one of claims 1 -lB or a copper complex ac-cording to any one of claims 19 -21 for promoting a copper(I)-catalysed azide-alkyne cycloaddition reac-tion.CON
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US10973920B2 (en) | 2014-06-30 | 2021-04-13 | Glykos Finland Oy | Saccharide derivative of a toxic payload and antibody conjugates thereof |
US10973922B2 (en) | 2013-05-02 | 2021-04-13 | Glykos Finland Oy | Glycoprotein-toxic payload conjugates |
US11548908B2 (en) | 2017-12-29 | 2023-01-10 | Glycomimetics, Inc. | Heterobifunctional inhibitors of E-selectin and galectin-3 |
US11845771B2 (en) | 2018-12-27 | 2023-12-19 | Glycomimetics, Inc. | Heterobifunctional inhibitors of E-selectin and galectin-3 |
US11873317B2 (en) | 2018-12-27 | 2024-01-16 | Glycomimetics, Inc. | Galectin-3 inhibiting c-glycosides |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US10973922B2 (en) | 2013-05-02 | 2021-04-13 | Glykos Finland Oy | Glycoprotein-toxic payload conjugates |
US10973920B2 (en) | 2014-06-30 | 2021-04-13 | Glykos Finland Oy | Saccharide derivative of a toxic payload and antibody conjugates thereof |
US11548908B2 (en) | 2017-12-29 | 2023-01-10 | Glycomimetics, Inc. | Heterobifunctional inhibitors of E-selectin and galectin-3 |
US11845771B2 (en) | 2018-12-27 | 2023-12-19 | Glycomimetics, Inc. | Heterobifunctional inhibitors of E-selectin and galectin-3 |
US11873317B2 (en) | 2018-12-27 | 2024-01-16 | Glycomimetics, Inc. | Galectin-3 inhibiting c-glycosides |
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