WO2012117082A1 - Platinum complexes and their use - Google Patents
Platinum complexes and their use Download PDFInfo
- Publication number
- WO2012117082A1 WO2012117082A1 PCT/EP2012/053586 EP2012053586W WO2012117082A1 WO 2012117082 A1 WO2012117082 A1 WO 2012117082A1 EP 2012053586 W EP2012053586 W EP 2012053586W WO 2012117082 A1 WO2012117082 A1 WO 2012117082A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- absent
- nitrogen atom
- mono
- platinum
- sulfonylamino
- Prior art date
Links
- 150000003057 platinum Chemical class 0.000 title abstract description 12
- 239000012216 imaging agent Substances 0.000 claims abstract description 4
- -1 alkoxycarbonil Chemical group 0.000 claims description 106
- 229910052757 nitrogen Inorganic materials 0.000 claims description 66
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 56
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 36
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 claims description 33
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 31
- 239000003446 ligand Substances 0.000 claims description 30
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 19
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 230000007935 neutral effect Effects 0.000 claims description 17
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 16
- 125000004442 acylamino group Chemical group 0.000 claims description 16
- 125000004423 acyloxy group Chemical group 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000004986 diarylamino group Chemical group 0.000 claims description 16
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 16
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 16
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 16
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 claims description 16
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 16
- 229910052697 platinum Inorganic materials 0.000 claims description 12
- ADLVDYMTBOSDFE-UHFFFAOYSA-N 5-chloro-6-nitroisoindole-1,3-dione Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC2=C1C(=O)NC2=O ADLVDYMTBOSDFE-UHFFFAOYSA-N 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 9
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 8
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 8
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 229960002685 biotin Drugs 0.000 claims description 8
- 235000020958 biotin Nutrition 0.000 claims description 8
- 239000011616 biotin Substances 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 8
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 8
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000001188 haloalkyl group Chemical group 0.000 claims description 8
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 claims description 8
- 125000005496 phosphonium group Chemical group 0.000 claims description 8
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 8
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
- 150000003462 sulfoxides Chemical class 0.000 claims description 8
- 125000003944 tolyl group Chemical group 0.000 claims description 8
- 230000002776 aggregation Effects 0.000 claims description 7
- 238000004220 aggregation Methods 0.000 claims description 7
- 150000001721 carbon Chemical group 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims description 6
- 239000011574 phosphorus Substances 0.000 claims description 6
- 230000008859 change Effects 0.000 claims description 5
- 238000001514 detection method Methods 0.000 claims description 5
- 230000005281 excited state Effects 0.000 claims description 5
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical class OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052785 arsenic Inorganic materials 0.000 claims description 3
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000006862 quantum yield reaction Methods 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005210 alkyl ammonium group Chemical group 0.000 claims description 2
- 235000001014 amino acid Nutrition 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- 239000012491 analyte Substances 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims description 2
- 239000002777 nucleoside Substances 0.000 claims description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 2
- 239000002773 nucleotide Substances 0.000 claims description 2
- 125000003729 nucleotide group Chemical group 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 229920001184 polypeptide Polymers 0.000 claims description 2
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 2
- 235000018102 proteins Nutrition 0.000 claims description 2
- 108090000623 proteins and genes Proteins 0.000 claims description 2
- 102000004169 proteins and genes Human genes 0.000 claims description 2
- 150000003233 pyrroles Chemical class 0.000 claims description 2
- 230000008685 targeting Effects 0.000 claims description 2
- 150000003536 tetrazoles Chemical class 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 18
- 238000010186 staining Methods 0.000 abstract description 12
- 238000011503 in vivo imaging Methods 0.000 abstract description 5
- 238000000338 in vitro Methods 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 3
- 238000000429 assembly Methods 0.000 abstract description 2
- 230000000712 assembly Effects 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 64
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 63
- 238000011534 incubation Methods 0.000 description 26
- 210000004940 nucleus Anatomy 0.000 description 23
- 150000001875 compounds Chemical class 0.000 description 17
- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 230000005284 excitation Effects 0.000 description 13
- 238000005259 measurement Methods 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 229910019032 PtCl2 Inorganic materials 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 238000000295 emission spectrum Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 9
- 229940093475 2-ethoxyethanol Drugs 0.000 description 9
- 230000005526 G1 to G0 transition Effects 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 229940125782 compound 2 Drugs 0.000 description 8
- 231100000135 cytotoxicity Toxicity 0.000 description 8
- 230000003013 cytotoxicity Effects 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 239000010410 layer Substances 0.000 description 7
- 231100000331 toxic Toxicity 0.000 description 7
- 230000002588 toxic effect Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 229930040373 Paraformaldehyde Natural products 0.000 description 6
- 210000000805 cytoplasm Anatomy 0.000 description 6
- 229920002866 paraformaldehyde Polymers 0.000 description 6
- 0 CC=C(C=CC=C1)C1=* Chemical compound CC=C(C=CC=C1)C1=* 0.000 description 5
- 210000003855 cell nucleus Anatomy 0.000 description 5
- 239000000975 dye Substances 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000003833 cell viability Effects 0.000 description 4
- 210000002889 endothelial cell Anatomy 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 3
- 239000006143 cell culture medium Substances 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 238000000695 excitation spectrum Methods 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000008055 phosphate buffer solution Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000003595 spectral effect Effects 0.000 description 3
- 238000001161 time-correlated single photon counting Methods 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 241000974482 Aricia saepiolus Species 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 210000003850 cellular structure Anatomy 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 238000001218 confocal laser scanning microscopy Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000001317 epifluorescence microscopy Methods 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 238000007654 immersion Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001338 self-assembly Methods 0.000 description 2
- 239000002356 single layer Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 231100000041 toxicology testing Toxicity 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- FTYAXYWEDPWJCJ-UHFFFAOYSA-N 2-pentan-3-ylpyridine Chemical compound CCC(CC)C1=CC=CC=N1 FTYAXYWEDPWJCJ-UHFFFAOYSA-N 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- DQRKTVIJNCVZAX-UHFFFAOYSA-N 4-(2-pyridin-4-ylethyl)pyridine Chemical compound C=1C=NC=CC=1CCC1=CC=NC=C1 DQRKTVIJNCVZAX-UHFFFAOYSA-N 0.000 description 1
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical compound OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 description 1
- ABJVUPUJUGBUMM-UHFFFAOYSA-N 4-pentylpyridine Chemical compound CCCCCC1=CC=NC=C1 ABJVUPUJUGBUMM-UHFFFAOYSA-N 0.000 description 1
- DHHFGQADZVYGIE-UHFFFAOYSA-N 9h-carbazole-1-carboxylic acid Chemical compound C12=CC=CC=C2NC2=C1C=CC=C2C(=O)O DHHFGQADZVYGIE-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 238000000116 DAPI staining Methods 0.000 description 1
- XLYWRYYQVQQEOP-UHFFFAOYSA-N FC(c1n[nH]c(-c2cccc(-c3nc(C(F)(F)F)n[nH]3)n2)n1)(F)F Chemical compound FC(c1n[nH]c(-c2cccc(-c3nc(C(F)(F)F)n[nH]3)n2)n1)(F)F XLYWRYYQVQQEOP-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 239000007756 Ham's F12 Nutrient Mixture Substances 0.000 description 1
- 229910020427 K2PtCl4 Inorganic materials 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 240000007930 Oxalis acetosella Species 0.000 description 1
- 235000008098 Oxalis acetosella Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000004061 bleaching Methods 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000030570 cellular localization Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- SBOQCPPINFMCBH-UHFFFAOYSA-N diphenylphosphane;methane Chemical compound C.C=1C=CC=CC=1PC1=CC=CC=C1.C=1C=CC=CC=1PC1=CC=CC=C1 SBOQCPPINFMCBH-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002073 fluorescence micrograph Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 230000002687 intercalation Effects 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- ASRAWSBMDXVNLX-UHFFFAOYSA-N pyrazolynate Chemical compound C=1C=C(Cl)C=C(Cl)C=1C(=O)C=1C(C)=NN(C)C=1OS(=O)(=O)C1=CC=C(C)C=C1 ASRAWSBMDXVNLX-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 125000005031 thiocyano group Chemical group S(C#N)* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000001392 ultraviolet--visible--near infrared spectroscopy Methods 0.000 description 1
- 231100000925 very toxic Toxicity 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- H—ELECTRICITY
- H05—ELECTRIC TECHNIQUES NOT OTHERWISE PROVIDED FOR
- H05B—ELECTRIC HEATING; ELECTRIC LIGHT SOURCES NOT OTHERWISE PROVIDED FOR; CIRCUIT ARRANGEMENTS FOR ELECTRIC LIGHT SOURCES, IN GENERAL
- H05B33/00—Electroluminescent light sources
- H05B33/12—Light sources with substantially two-dimensional radiating surfaces
- H05B33/14—Light sources with substantially two-dimensional radiating surfaces characterised by the chemical or physical composition or the arrangement of the electroluminescent material, or by the simultaneous addition of the electroluminescent material in or onto the light source
-
- H—ELECTRICITY
- H10—SEMICONDUCTOR DEVICES; ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
- H10K—ORGANIC ELECTRIC SOLID-STATE DEVICES
- H10K85/00—Organic materials used in the body or electrodes of devices covered by this subclass
- H10K85/30—Coordination compounds
- H10K85/341—Transition metal complexes, e.g. Ru(II)polypyridine complexes
- H10K85/346—Transition metal complexes, e.g. Ru(II)polypyridine complexes comprising platinum
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1059—Heterocyclic compounds characterised by ligands containing three nitrogen atoms as heteroatoms
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/18—Metal complexes
- C09K2211/185—Metal complexes of the platinum group, i.e. Os, Ir, Pt, Ru, Rh or Pd
-
- H—ELECTRICITY
- H10—SEMICONDUCTOR DEVICES; ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
- H10K—ORGANIC ELECTRIC SOLID-STATE DEVICES
- H10K2101/00—Properties of the organic materials covered by group H10K85/00
- H10K2101/10—Triplet emission
-
- H—ELECTRICITY
- H10—SEMICONDUCTOR DEVICES; ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
- H10K—ORGANIC ELECTRIC SOLID-STATE DEVICES
- H10K50/00—Organic light-emitting devices
- H10K50/10—OLEDs or polymer light-emitting diodes [PLED]
- H10K50/11—OLEDs or polymer light-emitting diodes [PLED] characterised by the electroluminescent [EL] layers
Definitions
- the invention relates to platinum complexes and their use in biomedical applications, like in vitro and in vivo imaging and cell staining.
- Cell staining is a technique that can be used to better visualize cells and cell components under a microscope. By using different stains, one can preferentially stain certain cell components, such as a nucleus or a cell-membrane, or the entire cell. Most stains can be used on fixed, or non-living cells, while only some can be used on living cells.
- Electroluminescent compounds like platinum(II)complexes gained more and more attention recently.
- WO 2009/111299 discloses a platinum(II)complex in which three aromatic systems together form a tridentate ligand coordinated to a platinum ion through atoms X, Y and Z.
- the complexes are asymmetric and emit in the UV to near IR range. They are intended for use in organic light emitting devices.
- Platinum complexes are also used in tumour therapy as they intercalate with DNA. This means that those complexes are toxic, which is a problem for their use in cell staining, especially in in vivo staining of cells.
- the object of the present invention is to provide novel platinum(II)complexes which are either toxic or not toxic and suitable to stain cells or cell compartments.
- Yi, Y 2 , Y 3 Y 4 , Y5, Y 6 , Y 7 , Y 8 and Y9 can be independently either carbon or nitrogen with the proviso
- R 2 , R3 , R19, R20, R21, R28, R29, and R 3 0 are selected from the group comprising H, F, CI, Br, I, CH 3 , CF 3 , N0 2 , OH, tiocyanate, isotiocyanate, -NCO, -CN, CHO, COOH, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, linear or branched, chiral or achiral, from 1 till
- a platinum(II) complex wherein Xi, X 2 , X 3 X 7i X 8 , X9, X 1 0, Xn, X12, Xi 3> Xi 45 Xi 5> Xi 6 , Xn and X 18 represent independently from each other a carbon atom and R 4 _ 9,, R 22 - 2 7 or R 3 i- 36 , respectively, are selected from the group comprising H, F, CI, Br, I, CH 3 , CF 3 , N0 2 , OH, tiocyanate, isotiocyanate, -NCO, -CN, CHO, COOH, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamo
- the tridentate ligand of the platinum(II)complex is dianionic and L is a neutral monodentate ligand coordinating through nitrogen, phosphorus, carbon, sulphur, arsenic.
- Rio, Rn, Ri 2 , Ri 3 , Ri 4 , R15, Ri6, R17 and Ri 8 are selected independently from the group comprising H, F, CI, Br, I, CH 3 , CF 3 , N0 2 , OH, tiocyanate, isotiocyanate, -NCO, -CN, CHO, COOH, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, linear or branched, chiral or achiral, from 1 till 18 carbon atom containing any combination of the following groups: CF 3 , N0 2 , OH, CHO, COOH, tiocyanate,
- L may coordinate through phosphorus and L is PAr 3 , PR 3 , P(OR) 3 or L may coordinate through carbon, wherein L is a N-heterocyclic carbene, carbonyl, or L may coordinate through As, wherein L is AsR 3 , AsAr 3
- the tridentate ligand can be mono-anionic and L can be a mono-anionic ligand selected from the group comprising -CI, -Br, -I, -CN, -NCS, -NSC, -NCO, -SR, -SAr, -OR, - OAr, pyrazolate, pyrrolate, carbazolate and azolates.
- the tridentate ligand may also be dianionic and L may be a neutral monodentate ligand according to formula (II), coordinating through nitrogen, phosphorus or carbon, wherein the link between L and L' is selected from the group comprising
- Z9_ 2 o represent independently carbon or nitrogen with the proviso
- R 4 i_5 8 are selected independently from the group comprising H, F, CI, Br, I, CH 3 ,
- CF 3 N0 2 , OH, tiocyanate, isotiocyanate, -NCO, -CN, CHO, COOH, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, linear or branched, chiral or achiral, from 1 till 18 carbon atomcontainingany combination of the following groups: CF 3 , N0 2 , OH, CHO, COOH, tiocyanate, isotiocyanate, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy
- a platinum complex is provided, wherein the ligand can be covalently bound to biomolecules selected from the group comprising a polypeptide or protein, a nucleoside or a nucleotide chain and a sugar or sugar moiety.
- the platinum(II)complex can also be in the aggregate form wherein the photophysical properties changes upon aggregation of the complex. [0017] It is also envisaged that the platinum(II)complex is coupled to a targeting agent.
- Another object of the invention is a use of a platinum(II) as imaging agent in vitro or in vivo. Further the platinum(II)complex can be used in therapeutic or diagnostic applications. In particular the loss of aggregation can be used to liberate toxic monomers in a detection method. The platinum(II)complex according to the invention is also intended for the detection of an analyte.
- Platinum(II)complexes PtLl capable of self-assembly in the nucleus, PtL2 unable to form aggregates and staining the cytoplasm, PtL3 analogous to PtLl but completely soluble in water.
- Fig. 2 Normalized excitation and emission spectra for monomeric PtLl (upper) and its aggregated form (lower).
- Fig. 6 Emission spectra of platinum(II)complexes with different incubation times in the cell: a. 30 min, b. 4h
- Figure 1 shows examples of molecules according to the disclosure, which can be uptaken by cells.
- PtLl is able to self-assemble within the nucleus, while PtL2 stains only the cytoplasm.
- PtL3 which is completely water-soluble enters into the nucleus and forms aggregates.
- Figure 2 shows normalized excitation and emission spectra in 2MeTHF at 77K for PtLl.
- Sample concentrations were l.OxlO 4 M (solid line) and l.OxlO 5 M (dotted line).
- the samples were excited at 300 nm (upper) and 350 (lower) for the emission spectra and for excitation the spectra were acquired at 580 nm.
- the upper spectra show emission bands at 450 nm (upper) and the aggregated platinum complexes in cell culture medium.
- the emission quantum yields for a series of platinum complexes possessing the same tridentate is comparable and can be as high as 74%.
- Figure 3 shows the uptake of PtLl and its aggregates formation inside the nucleus after 2h incubation.
- Figure 3 a shows excitation at 360-370 nm and figure 3 b shows excitation at 460-490 nm of PtLl.
- Figure 4 shows uptake kinetic of PtLl at the indicated incubation times. After 4h a maximum uptake into the nucleus can be observed. Longer incubation times result in a decrease of staining.
- Figure 5 shows in a) and b) excitation at different excitation ranges.
- a excitation at 360-370 nm is shown, while figure 5 b) shows excitation at 460-490 nm.
- Figure 5c shows an overlay at both excitation ranges. The specific accumulation in the nucleus is clearly visible.
- FIG. 6 shows emission spectra of the platinum complexes in cell.
- Figure 7 shows the cell uptake of the water-soluble platinum complex PtL3. The increased water solubility results in a longer time until the complex is accumulated in the nucleus. After 30 minutes (a) or 2h (b) no staining of nuclei is visible. Weak fluorescence is visible after 4h incubation (c) and after 8h (d) the nuclei are clearly and specifically stained.
- Figure 9 shows endothelial cell uptake kinetics of PtLl.
- Fig 9 a, b show 30 min incubation, figure 9 c, d 2h incubation and figure 9 e, f 4 h of incubation.
- the upper row shows fluorescence of PtLl, whereas the lower row shows DAPI-staining of the nuclei.
- FIG. 10 shows cytotoxicity results of different DMSO concentrations after 24h incubation.
- the used complex PtLl was solved in DMSO and to exclude a toxic effect by DMSO in Hela-S3 cells viability studies were investigated by using a Casy-1 device. Different concentrations had to be checked in case of cytotoxicity and especially the best concentration of DMSO for ongoing experiments had to be determined The cytotoxicity experiments showed clearly that a DMSO concentration from 10 % down to 5 % is extremely toxic for the cells. Nearly no viable cells could be detected. A concentration of 2,5 % DMSO showed already a high amount of viable Hela-S3 cells but still some dead cells were detected. Below 1,8 % DMSO no toxic effect was detectable for Hela-S3 cells after 24 h incubation. For safety reasons in case of cytotoxicity the following experiments were performed at a concentration of 1 % DMSO.
- Figure 11 shows cell viability after 24h incubation with complex PtLl (OH), PtL2 (PPH) and PTL3 (PEG) .
- the performed experiments highlighted clearly that the incubation with complex PtLl reduced the cell viability only about 26 %. This gives us a serious consideration that this complex did not induce rapid cell death after 24 h. Additional experiments with complex PtL2 showed after a 24 h incubation a decreased viability of around 28 % (see figure 11).
- Figure 12 shows an epifluorescence image of the aggregates formed in acetone of the PtLl.
- Figure 13 shows the red emission of dinuclear compounds 12 and 13, when they are aggregated.
- This invention deals with the use of metal complexes and in particular, Pt ions coordinated to tridentate ligands coordinated via N-N-N.
- a fourth ligand is coordinated which could be e.g. pyridine, pyrazine, diazine, azoles, carbenes, phosphine, thiocyano, carboxylate, thiol, (di)sulfide, isotiocyanate, cyanate, carbonyl, halogens.
- the invention focuses on the materials and on the emission properties of the metal complexes as well as the change in the emission properties, colour, excited state lifetimes, emission quantum yields, reactivity - including toxicity-, upon aggregation/disaggregation of the Pt complexes.
- the aggregation can be independently controlled either with the tridentate ligand or with the ancillary ligand. Furthermore functionalization of one or more of the ligands leads to the localization of the Pt complexes in a desired part of the cell.
- the assembly to form aggregates is caused by the tendency of the platinum complexes to interact via the dz orbitals and can be modulated by the ligands coordinated to the Pt ion.
- the assembly can be induced by the solvent, the interaction with biomolecules or by the template effect of DNA or RNA.
- the complexes can be hydrophilic or hydrophobic (on the metal moiety).
- the Pt units stay in the interior part of the aggregate, which can self-assemble in water or in the cell.
- Such localization determines a lack of sensitivity towards oxygen and possible quenchers in solution.
- their interaction with DNA, RNA or other vital parts of the cell is inhibited and therefore their toxicity is switched off. Imaging of portion or of the entire cell is possible and the brightness of the complexes is better than any existing molecular probe so far used for the imaging e.g. of the nucleus.
- the present invention discloses new materials and their use as imaging agent.
- the formation of luminescent aggregates can allow an enhancement or a change in colour of the emission leading to a dynamic label and on the formation of soft assemblies, which, in some cases, are even more emissive than the isolated corresponding species.
- the disclosed complexes are suitable for uptake by cells, and their internalization.
- a platinum complex with a similar structure to those used for tumor therapy is able to be uptaken as monomeric species, emitting blue light, by the cell and selectively accumulate into the nucleus.
- the complexes can accumulate in the e.g. nucleus of cancer cells (figure 3, 4, 5, 7) or other type (e.g. epithelial or endothelial, figure 9) of cells and form luminescent aggregates.
- the process can be followed by simple epifluorescence microscopy since the platinum complex as monomeric species is a blue emitter and the aggregates are orange.
- Organometallic complexes capable of self-assembly in cells in vivo have not been disclosed previously and it is the first time that any aggregate forms specifically inside the nucleus. Furthermore the formation of the aggregate leads to a turn off of the toxicity of the platinum complexes, which in principle should exert its toxicity upon intercalation into the DNA.
- the complexes are suitable as dynamic labels for cells and can stain different part of the cell.
- nucleus staining with visible emitters and long excited state lifetimes has been demonstrated.
- nucleus dyes There are only very few nucleus dyes and they are all very toxic and short live.
- the colour of the emission of the aggregate is very suitable for microscopy and in vivo studies and many other colors can be developed with simple modification of the ligand. This allows having a completely new family of dyes for cell staining, covering the spectrum from ultraviolet to near- infrared (NIR).
- NIR near- infrared
- NIR Pt emitters either as monomers or aggregates can be used for in vivo imaging. - The excited state lifetime of the emitter is extremely long compared with the existing dyes and therefore the measurements are easy and interference from biomolecules is avoided.
- the stability of the aggregate is very high and photo bleaching is less than for any other organic dye allowing longer observation time.
- the disclosed complexes are intended for their use in in vitro and in vivo imaging. In vivo imaging comprises staining of living cells in cell culture or even the uptake of the platinum complexes via endovenous injection in animals.
- HeLa cells derived from cervical cancer
- the cells were incubated at 37 °C under a 5% C0 2 atmosphere for 24 h. After that the culture medium was removed and replaced with 2 ml medium containing the platinum complex (PtLl or PtL2: 50 ⁇ in l%DMSO containing media or PtL3: 50 ⁇ in 1%THF containing media) which was filtered with 0.2 ⁇ membrane filter before used.
- PtLl or PtL2 50 ⁇ in l%DMSO containing media
- PtL3 50 ⁇ in 1%THF containing media
- the samples were excited with a 375 nm laser 40 kHz for lifetime measurements and for spectral measurements.
- the spectra were recorded on the same setup using a fibre-coupled spectrometer (Shamrock 163, Andor) and a back-illuminated CCD camera (Newton DU970N).
- Endothelial cell uptake kinetics Approximately 50.000 endothelial cells were seeded as a monolayer onto gelatine coated glass cover slips in a 6-well plate in Dulbecco's modified Eagle's medium with 2% fetal bovine serum. The cells were incubated at 37 °C under a 5% C0 2 atmosphere for 24 h. After that the culture medium was removed and replaced with 2 ml medium containing the platinum complex PtLl, (50 ⁇ in l%DMSO containing media) which was filtered with 0.2 ⁇ membrane filter before used.
- Cytotoxicity experiments HeLa S3 cells were seeded intol2-well tissue culture dishes in a density of approximately 80000 cells per well. The logarithmically growing cells were cultured for 24 h in Ham's F12 nutrient mixture containing 10% fetal bovine serum, 100 U penicillin per mL and 100 mg streptomycin per mL and incubated at 37 °C with 5% C02 in air and 100% humidity until the Pt-complexes were added. The cytotoxicity of thePt- complexes was elucidated by quantifying the percentage of viable cells.
- Cell viability was measured after 24 h Pt-complexincubation and trypsinizing of cells, by an automatic cell counter (Casy-1, Roche Innovatis AG). These measurements are based on non-invasive (dye- free) electrical current exclusion with signal evaluation via pulse area analysis and allow the structural integrity of cells (membrane integrity and cell death).
- the lifetime and emission spectra of the Pt complex in the cell nucleus were recorded by using a confocal fluorescence microscopy with a lOOx oil immersion objective.
- the samples were excited with a 375 nm laser 2.5 kHz for lifetime measurements and for spectral measurements.
- the spectra were recorded on the same setup using a fibre-coupled spectrometer and a back-illuminated CCD camera.
- the lifetime measurements showed that the monomeric Pt-complex has a short lifetime, on the contrary the aggregate Pt-complex in [0051] the cell nucleus has a long lifetime (Table 1). Similar result was also shown by the measurement of the same Pt-complex (1.0* 10 "5 M) in cell culture media.
- Table 1 The lifetime values of platinum complex PtLl with different incubation times in cells 5a: 5 x 10 "5 M for 30min; 5b 5 x 10 "5 M for 4h sample hex Lifetime
- Time resolved measurements were performed using the multichannel scaling (MCS) single-photon-counting or time-correlated single-photon-counting (TCSPC) option on the Horiba Jobin-Yvone IBH FL-322 Fluorolog 3.
- MCS multichannel scaling
- TCSPC time-correlated single-photon-counting
- a pulsed xenon lamp was used to excite the sample in the case of MCS setup, while a pulsed NanoLED at 402 nm in the case of TCSPC.
- the excitation sources were mounted directly on the sample chamber at 90° to a double-grating emission monochromator (2.1 nm/mm dispersion, 1200 grooves/mm) and collected by a TBX-4-X single-photon- counting detector.
- the photons collected at the detector are correlated by a time-to-amplitude converter (TAC) to the excitation pulse.
- TAC time-to-amplitude converter
- Signals were collecter using an IBH Data Station Hub photon-counting module, and data analysis was performed using the commercially available DAS6 software (HORIBA Jobin-Yvon IBH). The quality of the fit was assessed by minimizing the reduced ⁇ function and by visual inspection of the weighted residuals. All solvent used for spectroscopical characterization were spectrometric grade and purchased by VWR.
- the desired compound (3), PtL2 was purified on column chromatography using as silica gel as stationary phase and 2:3 THF:n-hexane mixture as eluent and obtained as pale yellow solid (634 mg, 0.79 mmol, yield 22%).
- the desired compound (4) was purified on column chromatography using as silica gel as stationary phase and 1: 1 THF:n-hexane mixture as eluent and obtained as yellowish-orange solid (166 mg, 0.24 mmol, yield 30.0%).
- PtCl 2 (DMSO) 2 368.0 mg, 0.87 mmol, 1.0 eq.
- 4-(l,l-dibutyl)pentylpyridine 200 ⁇ , 0.87 mmol, 1.0 eq.
- the reaction mixture was overnight heated at 85°C. Rapidly, a plentiful green precipitate appeared.
- the desired compound (6) was purified on column chromatography using as silica gel as stationary phase and 1:2 THF:n-hexane mixture as eluent, and obtained as green solid (340.0 mg, 0.43 mmol, yield 44.0%).
- the desired compound (7) was purified on column chromatography using as silica gel as stationary phase and a gradient 1: 1.5— > 2: 1 of THF:n-hexane mixture as eluent, and obtained as green solid (383.0 mg, 0.617 mmol, yield 56.6%).
- the desired compound (8) was purified on column chromatography using as silica gel as stationary phase and a gradient 2: 1— > 1: 1 of THF:n-hexane mixture as eluent, and obtained as pale yellow solid (124.0 mg, 0.08 mmol, yield 14.6%).
- the desired compound (9) was purified on column chromatography using as silica gel as stationary phase and a 1: 1 THF:n-hexane mixture as eluent, and obtained as pale yellow solid
- the compound 10, PtL3, was prepared accordingly to the same synthetic procedure used for the compounds 3-7, where the compound 11 was used as ancillary neutral ligand in order to increase the water-solubility of the final complex.
- the desired compound (9) was purified on column chromatography using as silica gel as stationary phase and acetone as eluent, and obtained as pale yellow solid (yield 76%).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Crystallography & Structural Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention relates to platinum complexes and their use in biomedical applications, like in vitro and in vivo imaging and cell staining. The present invention provides new materials and their use as imaging agent. The formation of luminescent aggregates can allow a switch of the emission leading to a dynamic label and on the formation of soft assemblies, which, in some cases, are even more emissive than the isolated corresponding species.
Description
Platinum Complexes and Their Use
Description CROSS REFERENCES WITH OTHER APPLICATIONS
[0001] This application claims priority of German application DE 10 2011 001 007.6 filed March 1, 2011, which is incorporated by reference herein.
FILED OF THE INVENTION
[0002] The invention relates to platinum complexes and their use in biomedical applications, like in vitro and in vivo imaging and cell staining.
BACKGROUND
[0003] Cell staining is a technique that can be used to better visualize cells and cell components under a microscope. By using different stains, one can preferentially stain certain cell components, such as a nucleus or a cell-membrane, or the entire cell. Most stains can be used on fixed, or non-living cells, while only some can be used on living cells.
[0004] Electroluminescent compounds like platinum(II)complexes gained more and more attention recently. WO 2009/111299 discloses a platinum(II)complex in which three aromatic systems together form a tridentate ligand coordinated to a platinum ion through atoms X, Y and Z. The complexes are asymmetric and emit in the UV to near IR range. They are intended for use in organic light emitting devices. [0005] Platinum complexes are also used in tumour therapy as they intercalate with DNA. This means that those complexes are toxic, which is a problem for their use in cell staining, especially in in vivo staining of cells.
BRIEF SUMMARY OF THE INVENTION
[0006] The object of the present invention is to provide novel platinum(II)complexes which are either toxic or not toxic and suitable to stain cells or cell compartments.
wherein Yi, Y2 , Y3 Y4, Y5, Y6, Y7, Y8and Y9 can be independently either carbon or nitrogen with the proviso
- if Y1 or Y4 are a nitrogen atom, then Ri or R 9 are absent;
-if Y2 or Y5 are a nitrogen atom, then R2 or R2o are absent;
-if Y3 or Y6 are a nitrogen atom, then R3 or R2i are absent;
- if Y7 is a nitrogen atom, then R28 is absent;
-if Y8 is a nitrogen atom, then R29 is absent;
-if Y9 is a nitrogen atom, then R30 is absent,
and if Yi, Y2 , Y3 Y4, Y5, Υό, Y7, Y8and Y9 represent a carbon Ri, R2 , R3 , R19, R20, R21, R28, R29, and R30 are selected from the group comprising H, F, CI, Br, I, CH3, CF3, N02, OH, tiocyanate, isotiocyanate, -NCO, -CN, CHO, COOH, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, linear or branched, chiral or achiral, from 1 till 18 carbon atom containing any combination of the following groups: CF3, N02, OH, CHO, COOH, tiocyanate, isotiocyanate, keto, amine, mono- or di- alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, aliphatic or alicyclic alkyl, alkenyl, alkynyl, aryl, ester, carboxy, amine, sulfoxide, amide, phosphine or neutral heterocyclic moieties such as ethyl,, n-propyl, phosphine, n-Butyl, t- Butyl, iso-Propyl, Hexyl, F(CF2)m(CH2)n- (m= 1-10, n= 0-4), F(CF2)m(CH2)nC6H4- (m= 1-10, n= 0-4), 0(CH2CH20)nCH3 (n = 0 - 10000),haloalkyl, mono- or, disulfide, natural or synthetic sugar residuals, biotin, phosphonium moiety, aminoacidic residual, antibody,Phenyl, Chlorophenyl, Tolyl, Anisyl, Trifluoromethylphenyl, Benzyl, Fluorenyl, Carbazolyl, Cyclohexyl, Menthyl, Allyl, Hydroxyphenyl, Pentaflurophenyl, Carboxyphenyl, Naphthyl, Pyridyl, Furyl, Bis-(trifluoromethyl)-phenyl, Carbene, N-heterocyclic Carbene, Imidazolyl, Pyridazinyl, Pyrazinyl, Pyrimidyl, Phosphinyl, any aromatic rings fused with the central N- containing esatomic ring, such as
and wherein Xi, X2, X3 X7i X8, X9, X10, Xn, X12, Xi3> Xi4> Xi5> X½, X17 and X18 are carbon and nitrogen atoms, that independently combine in such a way to have heterocycles selected from the group comprising pyrroles, diazoles, triazoles, tetrazoles, and wherein R4 - 9, R22-27 or R3i-36 are selected from the group of mono- or polyatomic substituents, and wherein the platinum ion is coordinated to a ligand L and/or L' which is neutral, mono- or multi- either positively or negatively charged to yield a neutral-core complex, wherein the molecule is either fully neutral or either positively or negatively charged. [0008] It is intended that L and/or L' comprise on remote sites -S03 ", -OS03 ", - phosphonium, -COO", alkylammonium, aminoacid, phosphate.
[0009] Further a platinum(II) complex is provided, wherein Xi, X2, X3 X7i X8, X9, X10, Xn, X12, Xi3> Xi45 Xi5> Xi6, Xn and X18 represent independently from each other a carbon atom and R4 _ 9,, R22-27 or R3i-36, respectively, are selected from the group comprising H, F, CI, Br, I, CH3, CF3, N02, OH, tiocyanate, isotiocyanate, -NCO, -CN, CHO, COOH, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, linear or branched, chiral or achiral, from 2 till 18 carbon atom containing any combination of the following groups: CF3, N02, OH, CHO, COOH, tiocyanate, isotiocyanate, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, aliphatic or alicyclic alkyl, alkenyl, alkynyl, aryl, ester, carboxy, amine, sulfoxide, amide, phosphine or neutral heterocyclic moieties such as ethyl,, n-propyl, phosphine, n-Butyl, t-Butyl, iso-Propyl, Hexyl, F(CF2)m(CH2)n- (m= 1-10, n= 0-4), F(CF2)m(CH2)nC6H4- (m= 1-10, n= 0-4), 0(CH2CH20)nCH3 (n = 0 - 10000), haloalkyl, mono- or, disulfide, natural or synthetic sugar residuals, biotin, phosphonium moiety, aminoacidic residual, antibody, Phenyl, Chlorophenyl, Tolyl, Anisyl, Trifluoromethylphenyl, Benzyl, Fluorenyl, Carbazolyl, Cyclohexyl, Menthyl, Allyl, Hydroxyphenyl, Pentaflurophenyl, Carboxyphenyl, Naphthyl, Pyridyl, Furyl, Bis-(trifluoromethyl)-phenyl, Carbene, N- heterocyclic Carbene, Imidazolyl, Pyridazinyl, Pyrazinyl, Pyrimidyl, Phosphinyl, any aromatic rings fused with the central N-containing esatomic ring, such as
[0010] In a further embodiment the tridentate ligand of the platinum(II)complex is dianionic and L is a neutral monodentate ligand coordinating through nitrogen, phosphorus, carbon, sulphur, arsenic.
[0011] In a platinum(II)complex according to formula (I) L may coordinate through nitrogen and corresponds to formula (III) or (IV)
(III) (IV)
wherein Zi, Z2, Z3, Z4, Z5, Z6, Z7, Z8 and Z9 represent independently carbon or nitrogen with the provisio
- if Zi is a nitrogen atom, then Rio is absent;
-if Z2 is a nitrogen atom, then Rn is absent;
-if Z3 is a nitrogen atom, then Ri2 is absent;
-if Z4 is a nitrogen atom, then Ri3 is absent;
-if Z5 is a nitrogen atom, then Ri4 is absent;
-if Z6 is a nitrogen atom, then R15 is absent;
-if Z7 is a nitrogen atom, then R½ is absent;
-if Z8 is a nitrogen atom, then Ri7 is absent;
-if Z9 is a nitrogen atom, then Ri8 is absent;
wherein Rio, Rn, Ri2, Ri3, Ri4, R15, Ri6, R17 and Ri8 are selected independently from the group comprising H, F, CI, Br, I, CH3, CF3, N02, OH, tiocyanate, isotiocyanate, -NCO, -CN, CHO, COOH, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, linear or branched, chiral or achiral, from 1 till 18 carbon atom containing any combination of the following groups: CF3, N02, OH, CHO, COOH, tiocyanate, isotiocyanate, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, aliphatic or alicyclic alkyl, alkenyl, alkynyl, aryl, ester, carboxy, amine, sulfoxide, amide, phosphine or neutral heterocyclic moieties such as ethyl, n-propyl, phosphine, n-Butyl, t-Butyl, iso-Propyl, Hexyl, F(CF2)m(CH2)n- (m= 1-10, n= 0-4), F(CF2)m(CH2)„C6H4- (m= 1-10, n= 0-4), 0(CH2CH20)„CH3 (n = 0 - 10000), haloalkyl, mono- or, disulfide, natural or synthetic sugar residual, biotin, phosphonium moiety, aminoacidic residual, antibody, Phenyl, Chlorophenyl, Tolyl, Anisyl, Trifluoromethylphenyl, Benzyl, Fluorenyl, Carbazolyl, Cyclohexyl, Menthyl, Allyl, Hydroxyphenyl, Pentaflurophenyl, Carboxyphenyl, Naphthyl, Pyridyl, Furyl, Bis- (trifluoromethyl)-phenyl, Carbene, N-heterocyclic Carbene, Imidazolyl, Pyridazinyl, Pyrazinyl, Pyrimidyl, Phosphinyl, any aromatic rings fused with the central N-containing Pt- coordinating ring, such as
[0012] It is further intended that L may coordinate through phosphorus and L is PAr3, PR3, P(OR)3 or L may coordinate through carbon, wherein L is a N-heterocyclic carbene, carbonyl, or L may coordinate through As, wherein L is AsR3, AsAr3
[0013] The tridentate ligand can be mono-anionic and L can be a mono-anionic ligand selected from the group comprising -CI, -Br, -I, -CN, -NCS, -NSC, -NCO, -SR, -SAr, -OR, - OAr, pyrazolate, pyrrolate, carbazolate and azolates.
[0014] The tridentate ligand may also be dianionic and L may be a neutral monodentate ligand according to formula (II), coordinating through nitrogen, phosphorus or carbon, wherein the link between L and L' is selected from the group comprising
- if Z9 is a nitrogen atom, then R37 is absent;
-if Z10 is a nitrogen atom, then R38 is absent;
-if Z11 is a nitrogen atom, then R 9 is absent;
-if Z12 is a nitrogen atom, then R4o is absent;
-if Zi3 is a nitrogen atom, then R4i is absent;
-if Zi4 is a nitrogen atom, then R42 is absent;
-if Zi5 is a nitrogen atom, then R43 is absent;
-if Zi6 is a nitrogen atom, then R44 is absent;
-if Zi7 is a nitrogen atom, then R45 is absent;
-if Zis is a nitrogen atom, then R46 is absent;
-if Z19 is a nitrogen atom, then R47 is absent;
-if Z2o is a nitrogen atom, then R48 is absent;
wherein R4i_58 are selected independently from the group comprising H, F, CI, Br, I, CH3,
CF3, N02, OH, tiocyanate, isotiocyanate, -NCO, -CN, CHO, COOH, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, linear or branched, chiral or achiral, from 1 till 18 carbon atomcontainingany combination of the following groups: CF3, N02, OH, CHO, COOH, tiocyanate, isotiocyanate, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl,
sulfinyl, aliphatic or alicyclic alkyl, alkenyl, alkynyl, aryl, ester, carboxy, amine, sulfoxide, amide, phosphine or neutral heterocyclic moieties such as ethyl, n-propyl, phosphine, n-Butyl, t-Butyl, iso-Propyl, Hexyl, F(CF2)m(CH2)„- (m= 1-10, n= 0-4), F(CF2)m(CH2)„C6H4- (m= 1- 10, n= 0-4), 0(CH2CH20)nCH3 (n = 0 - 10000), haloalkyl, mono- or, disulfide, natural or synthetic sugar residual, biotin, phosphonium moiety, aminoacidic residual, antibody, Phenyl, Chlorophenyl, Tolyl, Anisyl, Trifluoromethylphenyl, Benzyl, Fluorenyl, Carbazolyl, Cyclohexyl, Menthyl, Allyl, Hydroxyphenyl, Pentaflurophenyl, Carboxyphenyl, Naphthyl, Pyridyl, Furyl, Bis-(trifluoromethyl)-phenyl, Carbene, N-heterocyclic Carbene, Imidazolyl, Pyridazinyl, Pyrazinyl, Pyrimidyl, Phosphinyl, any aromatic rings fused with the central N- containing Pt-coordinating ring, such as
[0015] A platinum complex is provided, wherein the ligand can be covalently bound to biomolecules selected from the group comprising a polypeptide or protein, a nucleoside or a nucleotide chain and a sugar or sugar moiety.
[0016] The platinum(II)complex can also be in the aggregate form wherein the photophysical properties changes upon aggregation of the complex.
[0017] It is also envisaged that the platinum(II)complex is coupled to a targeting agent.
[0018] Another object of the invention is a use of a platinum(II) as imaging agent in vitro or in vivo. Further the platinum(II)complex can be used in therapeutic or diagnostic applications. In particular the loss of aggregation can be used to liberate toxic monomers in a detection method. The platinum(II)complex according to the invention is also intended for the detection of an analyte. BRIEF DESCRIPTION OF THE FIGURES
Fig. 1 Platinum(II)complexes: PtLl capable of self-assembly in the nucleus, PtL2 unable to form aggregates and staining the cytoplasm, PtL3 analogous to PtLl but completely soluble in water.
Fig. 2 Normalized excitation and emission spectra for monomeric PtLl (upper) and its aggregated form (lower).
Fig. 3 Uptake of the complex PtLl and its aggregates formation inside the nucleus after 2 hours incubation
Fig. 4 Cell uptake kinetics of PtLl at indicated time-points
Fig. 5 Fluorescence microscopy images of cell uptake of PtLl after 4h incubation time
Fig. 6 Emission spectra of platinum(II)complexes with different incubation times in the cell: a. 30 min, b. 4h
Fig. 7 Cell uptake PtL3
Fig. 8 Cell uptake PtL2
Fig. 9 Endothelial cell uptake kinetics of PtLl
Fig. 10 Cytotoxicity results of different DMSO concetrations after 24 h incubation
Fig. 11 Cell viability after incubation with complex PtL2 and PtLl
Fig. 12 Aggregate formation for PtLl
Fig. 13 Red emission of aggregate complexes
DETAILED DESCRIPTION OF THE FIGURES
[0019] Figure 1 shows examples of molecules according to the disclosure, which can be uptaken by cells. PtLl is able to self-assemble within the nucleus, while PtL2 stains only the
cytoplasm. Also PtL3, which is completely water-soluble enters into the nucleus and forms aggregates.
[0020] The examples demonstrate that the choice of ligands and substituents is critical for the respective application of the disclosed platinum(II)complexes.
[0021] Figure 2 shows normalized excitation and emission spectra in 2MeTHF at 77K for PtLl. Sample concentrations were l.OxlO 4 M (solid line) and l.OxlO 5 M (dotted line). The samples were excited at 300 nm (upper) and 350 (lower) for the emission spectra and for excitation the spectra were acquired at 580 nm.
[0022] The upper spectra show emission bands at 450 nm (upper) and the aggregated platinum complexes in cell culture medium. The emission quantum yields for a series of platinum complexes possessing the same tridentate is comparable and can be as high as 74%.
[0023] Figure 3 shows the uptake of PtLl and its aggregates formation inside the nucleus after 2h incubation. Figure 3 a shows excitation at 360-370 nm and figure 3 b shows excitation at 460-490 nm of PtLl. [0024] Figure 4 shows uptake kinetic of PtLl at the indicated incubation times. After 4h a maximum uptake into the nucleus can be observed. Longer incubation times result in a decrease of staining.
[0025] Figure 5 shows in a) and b) excitation at different excitation ranges. In figure 5 a excitation at 360-370 nm is shown, while figure 5 b) shows excitation at 460-490 nm. Figure 5c shows an overlay at both excitation ranges. The specific accumulation in the nucleus is clearly visible.
[0026] Figure 6 shows emission spectra of the platinum complexes in cell. The monomeric platinum complex displayed after 30 minutes incubation in the cells very weak emission (a), while the aggregates of the platinum complex show a very intense emission after 4h of incubation emission around Xem = 580 nm as depicted in figure 6 b.
[0027] Figure 7 shows the cell uptake of the water-soluble platinum complex PtL3. The increased water solubility results in a longer time until the complex is accumulated in the nucleus. After 30 minutes (a) or 2h (b) no staining of nuclei is visible. Weak fluorescence is visible after 4h incubation (c) and after 8h (d) the nuclei are clearly and specifically stained.
[0028] The same experimental setup was performed using complex PtL2. The results are shown in figure 8 and the time points correspond to figure 7. Obviously PtL2 enters the cells, but fails to aggregate in the nucleus. Due to the bulky phosphine ligand the complex seems not to be able to enter the nucleus so that no orange emission was detected. The compound stains only the cytoplasm.
[0029] Figure 9 shows endothelial cell uptake kinetics of PtLl. Fig 9 a, b show 30 min incubation, figure 9 c, d 2h incubation and figure 9 e, f 4 h of incubation. The upper row shows fluorescence of PtLl, whereas the lower row shows DAPI-staining of the nuclei.
[0030] Figure 10 shows cytotoxicity results of different DMSO concentrations after 24h incubation. The used complex PtLl was solved in DMSO and to exclude a toxic effect by DMSO in Hela-S3 cells viability studies were investigated by using a Casy-1 device. Different concentrations had to be checked in case of cytotoxicity and especially the best concentration of DMSO for ongoing experiments had to be determined The cytotoxicity experiments showed clearly that a DMSO concentration from 10 % down to 5 % is extremely toxic for the cells. Nearly no viable cells could be detected. A concentration of 2,5 % DMSO showed already a high amount of viable Hela-S3 cells but still some dead cells were detected. Below 1,8 % DMSO no toxic effect was detectable for Hela-S3 cells after 24 h incubation. For safety reasons in case of cytotoxicity the following experiments were performed at a concentration of 1 % DMSO.
[0031] Figure 11 shows cell viability after 24h incubation with complex PtLl (OH), PtL2 (PPH) and PTL3 (PEG) . The performed experiments highlighted clearly that the incubation with complex PtLl reduced the cell viability only about 26 %. This gives us a serious consideration that this complex did not induce rapid cell death after 24 h. Additional experiments with complex PtL2 showed after a 24 h incubation a decreased viability of around 28 % (see figure 11).
[0032] Figure 12 shows an epifluorescence image of the aggregates formed in acetone of the PtLl. [0033] Figure 13 shows the red emission of dinuclear compounds 12 and 13, when they are aggregated.
DETAILLED DESCRIPTION OF THE INVENTION
[0034] This invention deals with the use of metal complexes and in particular, Pt ions coordinated to tridentate ligands coordinated via N-N-N. To fill the coordination sphere a fourth ligand is coordinated which could be e.g. pyridine, pyrazine, diazine, azoles, carbenes, phosphine, thiocyano, carboxylate, thiol, (di)sulfide, isotiocyanate, cyanate, carbonyl, halogens.
[0035] The invention focuses on the materials and on the emission properties of the metal complexes as well as the change in the emission properties, colour, excited state lifetimes, emission quantum yields, reactivity - including toxicity-, upon aggregation/disaggregation of the Pt complexes.
[0036] The aggregation can be independently controlled either with the tridentate ligand or with the ancillary ligand. Furthermore functionalization of one or more of the ligands leads to the localization of the Pt complexes in a desired part of the cell. The assembly to form aggregates is caused by the tendency of the platinum complexes to interact via the dz orbitals and can be modulated by the ligands coordinated to the Pt ion. The assembly can be induced by the solvent, the interaction with biomolecules or by the template effect of DNA or RNA.
[0037] The general formulas of the complexes investigated are shown below where their synthesis is reported. The compounds are taken up by different type of cells and they are at the beginning localized in the cytoplasm as mononuclear species. Migration of the complexes in different part of the cell determines an increase of the local concentration of the Pt compounds leading to aggregates, if the case, which possess different photophysical and/or cytotoxicity properties.
[0038] Thus, the disclosed platinum complexes represent dynamic labels, because the monomeric species in the cytoplasm show e.g. blue emission, while the aggregates in the nucleus show orange emission due to the aggregated form. It is not only completely surprising that the complexes are able to stain the nucleus without being toxic, but also that the color depends on the cellular localization of the complexes.
[0039] It was demonstrated that imaging of the cytoplasm, and even more interesting of the nucleus, can occur (figures 3, 4, 5, 7, 8, 9). The complexes can be hydrophilic or hydrophobic (on the metal moiety). In this last case the Pt units stay in the interior part of the aggregate, which can self-assemble in water or in the cell. Such localization determines a lack of sensitivity towards oxygen and possible quenchers in solution. Furthermore, their interaction with DNA, RNA or other vital parts of the cell is inhibited and therefore their toxicity is switched off. Imaging of portion or of the entire cell is possible and the brightness of the complexes is better than any existing molecular probe so far used for the imaging e.g. of the nucleus.
[0040] The present invention discloses new materials and their use as imaging agent. The formation of luminescent aggregates (see figurel2) can allow an enhancement or a change in colour of the emission leading to a dynamic label and on the formation of soft assemblies, which, in some cases, are even more emissive than the isolated corresponding species. The disclosed complexes (see e.g. figure 1) are suitable for uptake by cells, and their internalization. In particular a platinum complex with a similar structure to those used for tumor therapy is able to be uptaken as monomeric species, emitting blue light, by the cell and selectively accumulate into the nucleus. The complexes can accumulate in the e.g. nucleus of cancer cells (figure 3, 4, 5, 7) or other type (e.g. epithelial or endothelial, figure 9) of cells and form luminescent aggregates. The process can be followed by simple epifluorescence microscopy since the platinum complex as monomeric species is a blue emitter and the aggregates are orange.
[0041] Organometallic complexes capable of self-assembly in cells in vivo have not been disclosed previously and it is the first time that any aggregate forms specifically inside the nucleus. Furthermore the formation of the aggregate leads to a turn off of the toxicity of the
platinum complexes, which in principle should exert its toxicity upon intercalation into the DNA.
[0042] Toxicity studies showed on the other hand that the toxicity is very minor even after 48 hours of incubation.
[0043] Toxicity studies show that the toxicity can be modulated using different ligands (see figure 11) [0044] The disclosed platinum(II)complexes provide several advantages:
The complexes are suitable as dynamic labels for cells and can stain different part of the cell. In particular nucleus staining with visible emitters and long excited state lifetimes has been demonstrated. There are only very few nucleus dyes and they are all very toxic and short live.
- The colour of the emission of the aggregate is very suitable for microscopy and in vivo studies and many other colors can be developed with simple modification of the ligand. This allows having a completely new family of dyes for cell staining, covering the spectrum from ultraviolet to near- infrared (NIR).
NIR Pt emitters either as monomers or aggregates can be used for in vivo imaging. - The excited state lifetime of the emitter is extremely long compared with the existing dyes and therefore the measurements are easy and interference from biomolecules is avoided.
The stability of the aggregate is very high and photo bleaching is less than for any other organic dye allowing longer observation time.
- By choosing appropriate tridentate and/or ancillary ligands it is possible to change solubility in organic solvents and/or water or modulate the degree of aggregation By choosing appropriate tridentate and/or ancillary ligands it is possible to influence the degree of aggregation, solubility in organic and/or aqueous solvents or to change the excited state properties and color of emission.
- Dinuclear or multinuclear complexes (figure 12) are used for the same purposes.
[0045] The disclosed complexes are intended for their use in in vitro and in vivo imaging. In vivo imaging comprises staining of living cells in cell culture or even the uptake of the platinum complexes via endovenous injection in animals.
EXPERIMENTAL PROCEDURES
[0046] Cell uptake kinetics with HeLa cells: Approximately 50.000 HeLa cells (derived from cervical cancer) were seeded as a monolayer onto glass cover slips in a 6-well plate in Dulbecco's modified Eagle's medium Ham's F-12 supplement with 2% fetal bovine serum. The cells were incubated at 37 °C under a 5% C02 atmosphere for 24 h. After that the culture medium was removed and replaced with 2 ml medium containing the platinum complex (PtLl or PtL2: 50 μΜ in l%DMSO containing media or PtL3: 50 μΜ in 1%THF containing media) which was filtered with 0.2 μιη membrane filter before used. After incubation at 37 °C or 4 °C for 30 min, 2 h, 4 h, 8 h, and 24 h the medium was removed, and the cell layer was washed gently with phosphate buffer solution (PBS, lmL x 3) and fixed with 4% paraformaldehyde (PFA) solution for 10 min. Subsequently, cell layer was washed with PBS x 2 and with water x 3. Finally the cover slips were mounted onto glass slides for measurements. Observations were performed using a fluorescence microscopy (Microtime 200 - PicoQuant GmbH, Germany) with a lOOx oil immersion objective (Planapochromat, NA 1.4). The samples were excited with a 375 nm laser 40 kHz for lifetime measurements and for spectral measurements. The spectra were recorded on the same setup using a fibre-coupled spectrometer (Shamrock 163, Andor) and a back-illuminated CCD camera (Newton DU970N).
[0047] Endothelial cell uptake kinetics: Approximately 50.000 endothelial cells were seeded as a monolayer onto gelatine coated glass cover slips in a 6-well plate in Dulbecco's modified Eagle's medium with 2% fetal bovine serum. The cells were incubated at 37 °C under a 5% C02 atmosphere for 24 h. After that the culture medium was removed and replaced with 2 ml medium containing the platinum complex PtLl, (50 μΜ in l%DMSO containing media) which was filtered with 0.2 μιη membrane filter before used. After incubation at 37 °C for 30 min, 2 h, and 4 h the medium was removed, and the cell layer was washed gently with phosphate buffer solution (PBS, lmL x 3) and fixed with 4% paraformaldehyde (PFA) solution for 10 min. Subsequently, cell layer was washed with PBS x 2 and with water x 3. Finally, the fixed cell nucleus was stained with 4',6-diamidino-2-
phenylindole (DAPI). The images were recorded with epifluorescence microscopy to follow the kinetics of uptake and formation of the Pt complex aggregates inside the cells.
[0048] Cytotoxicity experiments: HeLa S3 cells were seeded intol2-well tissue culture dishes in a density of approximately 80000 cells per well. The logarithmically growing cells were cultured for 24 h in Ham's F12 nutrient mixture containing 10% fetal bovine serum, 100 U penicillin per mL and 100 mg streptomycin per mL and incubated at 37 °C with 5% C02 in air and 100% humidity until the Pt-complexes were added. The cytotoxicity of thePt- complexes was elucidated by quantifying the percentage of viable cells. Cell viability was measured after 24 h Pt-complexincubation and trypsinizing of cells, by an automatic cell counter (Casy-1, Roche Innovatis AG). These measurements are based on non-invasive (dye- free) electrical current exclusion with signal evaluation via pulse area analysis and allow the structural integrity of cells (membrane integrity and cell death). [0049] Co-staining experiments: After incubation for 30 min, 2 h, 4 h, 8 h, and 24 h the medium was removed, and the cell layer was washed gently with phosphate buffer solution (PBS, lmL x 3) and cell membrane was stained with red-fluorescent FM® 4-64 dyes (5 μg/ml in ice cold Hanks' balanced salt solution (HBSS) without magnesium or calcium) for 1 min. Then cell layer was fixed with 4% paraformaldehyde (PFA) solution for 10 min in ice. Subsequently, cell layer was washed with HBSS x 2 and with water x 3 and cell nucleus was stained with 4',6-diamidino-2-phenylindole (DAPI). Finally the cover slips were mounted onto glass slides for measurements. Observations were performed using a confocal fluorescence microscopy (Leica). [0050] The lifetime and emission spectra of the Pt complex (PtLl) in the cell nucleus:
The lifetime and emission spectra of the Pt complex in the cell nucleus were recorded by using a confocal fluorescence microscopy with a lOOx oil immersion objective. The samples were excited with a 375 nm laser 2.5 kHz for lifetime measurements and for spectral measurements. The spectra were recorded on the same setup using a fibre-coupled spectrometer and a back-illuminated CCD camera. The lifetime measurements showed that the monomeric Pt-complex has a short lifetime, on the contrary the aggregate Pt-complex in
[0051] the cell nucleus has a long lifetime (Table 1). Similar result was also shown by the measurement of the same Pt-complex (1.0* 10"5 M) in cell culture media.
[0052] Table 1: The lifetime values of platinum complex PtLl with different incubation times in cells 5a: 5 x 10"5 M for 30min; 5b 5 x 10"5 M for 4h sample hex Lifetime
[nm] [ns]
5a 375 4.8
5b 375 1 98
[0053] The spectral measurements were also in agreement with the emission spectra of the Pt-complex in cell culture media. The monomeric Pt-complex (after 30 min incubation period in the cells) showed very weak emission and the Pt-complex as aggregates (after 4h incubation period in the cells) showed emission around Xem = 580 nm (Figure 6).
[0054] Synthesis. All the reactions were carried out under nitrogen atmosphere. All the solvents and reagents are used as received from Aldrich, Fluka, TCI and VWR without further purification. K2PtCl4 was purchased from Precious Metal Online. PtCl2(DMSO)2 was prepared by following already reported synthetic procedures (R. Romeo, L. M. Scolaro Inorg. Synth. 1998, 32, 153). Column chromatography was performed with silica gel 60 (particle size 63-200 μιη, 230-400 mesh, Merk). High-resolution electron spray ionization mass spectrometry (HR-ESI-MS) was performed on a Bruker Daltonics (Bremen, Germany) MicroToF with loop injection. 1H- 19F and 31P-NMR were carried out on an ARX 300 from Bruker Analytische Messtechnik (Karlsruhe, Germany). All these facilities were available at the Department of Chemistry, University of Muenster, Germany.
[0055] Photophysics. Absorption spectra were measured on a Varian Cary 5000 double- beam UV-vis-NIR spectrometer and baseline corrected. Steady-state emission spectra were recorded on an Edimburgh FS920 spectrometer equipped with a 450 W xenon-arc lamp, excitation and emission monochromators (1.8 nm/mm dispersion, 1800 grooves/mm blazed at 500 nm), and a Hamamatsu R928 photomultiplier tube. Emission and excitation spectra were corrected for sourse intensity (lamp and grating) by standard correction curves. Time resolved
measurements were performed using the multichannel scaling (MCS) single-photon-counting or time-correlated single-photon-counting (TCSPC) option on the Horiba Jobin-Yvone IBH FL-322 Fluorolog 3. A pulsed xenon lamp was used to excite the sample in the case of MCS setup, while a pulsed NanoLED at 402 nm in the case of TCSPC. The excitation sources were mounted directly on the sample chamber at 90° to a double-grating emission monochromator (2.1 nm/mm dispersion, 1200 grooves/mm) and collected by a TBX-4-X single-photon- counting detector. The photons collected at the detector are correlated by a time-to-amplitude converter (TAC) to the excitation pulse. Signals were collecter using an IBH Data Station Hub photon-counting module, and data analysis was performed using the commercially available DAS6 software (HORIBA Jobin-Yvon IBH). The quality of the fit was assessed by minimizing the reduced χ function and by visual inspection of the weighted residuals. All solvent used for spectroscopical characterization were spectrometric grade and purchased by VWR. [0056] Synthesis of compound 1
[0057] In a 500 mL round bottom flask 2,6-dicarbonitrile (20.0 g, 154.9 mmol, 1.0 eq.) and MeONa (1.67 g, 30.98 mmol, 0.2 eq) were dissolved in 180 mL of dry methanol. After refluxing for 6 h, ammonium chloride (12.8 g, 340.8 mmol, 2.2 eq.) was added to the reaction mixture and kept overnight under reflux. After cooling, the solid was filtered over a Buchner, washed with Et20, dried and collected as pure compound 1 (30.6 g, 130.2 mmol, yield 84.0%) 1H NMR (D20, ppm) δ: 8.43 (1H, m)
HR-ESI-MS (positive scan): calcd. 235.04 uma; found 164.0903 [M-C1-HC1]+
[0058] Synthesis of compound 2
[0059] In a 500 mL round-bottom flask, ethyltrifluoroacetate (13.7 mL, 114.4 mmol, 2.2 eq.) was dissolved in 150 mL of THF and hydrazine monohydrate (6.15 mL, 126.7 mmol, 2.2 eq.) was added. The reaction mixture was refluxed for 2 h, then compound 1 (15.0 g, 63.5 mmol, 1 eq.) and sodium methoxide (2.54 g, 63.5 mmol, 1 eq.) were added. The reaction mixture was kept overnight refluxing under N2. After cooling, the desired product (2) was purified from the crude on column chromatography by using silica gel as stationary phase and dichloromethane and acetone 9: 1 as eluent (2.04 g, 5.84 mmol, yield 9.2%).
1H NMR (CD2C12, ppm) δ: 13.82 (2H), 8.21 (2H), 8.06 (1H); 19F{!H} NMR (CD2C12, ppm) δ: -65.61 (IF)
HR-ESI-MS (negative scan): calcd. 349.05 uma [M]; found 348.0457[M-H]~
[0060] Synthesis of compound 3, PtL2
[0061] In a 250 mL round-bottom flask, compound 2 (1.40 g, 4.01 mmol, 1.1 eq.), PtCl2(DMSO)2 (1.54 g, 3.65 mmol, 1.0 eq.), triphenylphosphine (956 mg, 3.65 mmol, 1.0 eq.) were suspended in 130 mL of a 3: 1 2-ethoxyethanol and water mixture. The reaction mixture was overnight heated at 85°C. Rapidly, a greenish-blue precipitate appeared. The desired compound (3), PtL2, was purified on column chromatography using as silica gel as stationary
phase and 2:3 THF:n-hexane mixture as eluent and obtained as pale yellow solid (634 mg, 0.79 mmol, yield 22%).
1H NMR (CD2C12, ppm) δ: 8.08 (1H), 7.83 (2H), 7.72-7.64 (6H), 7.51-7.44 (3H), 7.40- 7.34 (6H); 19F{!H} NMR (CD2C12, ppm) δ: -65.06 (IF); 31P{!H} NMR (CD2C12, ppm) δ: 10.76 (IP)
HR-ESI-MS (positive scan): calcd. 804.09 uma [M]; found 805.0973 [M+H]+; 827.0793
[M+Na]+.
[0062] Synthesis of compound 4
4
[0063] In a 50 mL round-bottom flask, compound 2 (280 mg, 0.80 mmol, 1.0 eq.), PtCl2(DMSO)2 (339 mg, 0.80 mmol, 1.0 eq.), 4-amylpyridine (145 μί, 0.80 mmol, 1.0 eq.) and triethylamine (100 μί) were suspended in 20 mL of a 3: 1 2-ethoxyethanol and water mixture. The reaction mixture was overnight heated at 85°C. Rapidly, a yellowish-orange precipitate appeared. The desired compound (4) was purified on column chromatography using as silica gel as stationary phase and 1: 1 THF:n-hexane mixture as eluent and obtained as yellowish-orange solid (166 mg, 0.24 mmol, yield 30.0%).
1H NMR (CD2C12, ppm) δ: 9.36 (2H), 7.98 (1H), 7.72 (2H), 7.35 (2H), 2.69 (2H), 1.66
(2H), 0.87-0.72 (7H); 19F{!H} NMR (CD2C12, ppm) δ: -64.81 (IF).
HR-ESI-MS (positive scan): calcd. 804.09 uma [M]; found 805.0973 [M+H]+; 827.0793
[M+Na]+.
[0064] Synthesis of compound 5, PtLl
5
[0065] In a 50 mL round-bottom flask, compound 2 (230.0 mg, 0.660 mmol, 1.0 eq.), PtCl2(DMSO)2 (306.0 mg, 0.73 mmol, 1.1 eq.), 4-hydroxypyridine (63 \iL, 0.660 mmol, 1.0 eq.) were suspended in 20 mL of a 3: 1 2-ethoxyethanol and water mixture. The reaction mixture was overnight heated at 85°C. Rapidly, a yellowish-green precipitate appeared. The desired compound (5), PtLl was purified on column chromatography using as silica gel as stationary phase and 3: 1 THF:n-hexane mixture as eluent, and obtained as yellow solid (66.1 mg, 0.104 mmol, yield 15.7%).
1H NMR (THF- S, ppm) δ: 9.31 (2H), 8.14 (1H), 8.72 (2H), 6.95 (2H); 19F{!H} NMR (THF- d8, ppm) δ: -65.10 (IF).
HR-ESI-MS (negative scan): calcd. 636.03246 uma [M] ; found 636.03002 [M-H]~.
[0066] Synthesis of compound 6
PtCl2(DMSO)2 (368.0 mg, 0.87 mmol, 1.0 eq.), 4-(l,l-dibutyl)pentylpyridine (200 μί, 0.87 mmol, 1.0 eq.) were suspended in 25 mL of a 3: 1 2-ethoxyethanol and water mixture. The reaction mixture was overnight heated at 85°C. Rapidly, a plentiful green precipitate appeared. The desired compound (6) was purified on column chromatography using as silica gel as stationary phase and 1:2 THF:n-hexane mixture as eluent, and obtained as green solid (340.0 mg, 0.43 mmol, yield 44.0%).
1H NMR (CD2C12, ppm) δ: 9.56 (2H), 8.03 (1H), 7.80 (2H), 7.52 (2H), 1.66 (6H), 1.21 (6H), 0.97 (6H), 0.80 (9H); 19F{!H} NMR (CD2C12, ppm) δ: -64.58 (IF).
HR-ESI-MS (positive scan): calcd. 804.25330 uma [M+H]; found 804.25251 [M-H]+.
[0068] Synthesis of compound 7
[0069] In a 100 mL round-bottom flask, compound 2 (381.8 mg, 1.09 mmol, 1.1 eq.), PtCl2(DMSO)2 (419.7 mg, 0.99 mmol, 1.0 eq.), and pyridine (80 μί, 0.99 mmol, 1.0 eq.) were suspended in 33 mL of a 3: 1 mixture of 2-ethoxyethanol and water. The reaction mixture was overnight heated at 85°C. Rapidly, a plentiful greenish-yellow precipitate appeared. The desired compound (7) was purified on column chromatography using as silica gel as stationary phase and a gradient 1: 1.5— > 2: 1 of THF:n-hexane mixture as eluent, and obtained as green solid (383.0 mg, 0.617 mmol, yield 56.6%).
1H NMR (CD2C12, ppm) δ: 9.61 (2H), 8.05 (2H), 7.80 (2H), 7.62 (2H); 19F{!H} NMR (CD2C12, ppm) δ: -64.62.
HR-ESI-MS (positive scan): calcd. 621.04 uma [M+H]; found 622.04932 [M+H]+.
[0070] Synthesis of compound 8
1H NMR (CD2C12, ppm) δ: 8.11 (1H), 7.84 (2H), 7.63 (4H), 7.51 (2H), 7.35 (4H), 3.68 (2H); 19F{!H} NMR (CD2C12, ppm) δ: -64.90 (1H), 31P{!H} NMR (CD2C12, ppm) δ: 6.56 (IP).
HR-ESI-MS (positive scan): calcd. 1482.14 uma [M]; found 1505.1224 [M+Na]+. [0072] Synthesis of compound 9
[0073] In a 100 mL round-bottom flask, compound 2 (264.0 mg, 0.76 mmol, 1.0 eq.), PtCl2(DMSO)2 (320.0 mg, 0.76 mmol, 1.0 eq.), bis-(diphenylphosphine)-methane (145.7 mg,
0.38 mmol, 0.5 eq.) and triethylamine (264 μί, 2.5 eq.) were suspended in 20 mL of a 3: 1 mixture of 2-ethoxyethanol and water. The reaction mixture was overnight heated at 85°C.
Rapidly, the reaction mixture turned yellow and a plentiful pale yellow precipitate appeared.
The desired compound (9) was purified on column chromatography using as silica gel as stationary phase and a 1: 1 THF:n-hexane mixture as eluent, and obtained as pale yellow solid
(338.0 mg, 0.23 mmol, yield 30.2%).
1H NMR (CD2C12, ppm) δ: 8.17 (IH), 7.86 (2H), 7.77 (4H), 7.21 (6H), 5.54 (IH); 19F{!H} NMR (CD2CI2, ppm) δ: -64.92 (IH), 31P{!H} NMR (CD2C12, ppm) δ: -3.21 (IP).
HR-ESI-MS (positive scan): calcd. 1468.12 uma [M]; found 1469.12200 [M+H]+. [0074] Synthesis of compound 10, PtL3
11
[0075] The compound 10, PtL3, was prepared accordingly to the same synthetic procedure used for the compounds 3-7, where the compound 11 was used as ancillary neutral ligand in order to increase the water-solubility of the final complex. The desired compound (9) was purified on column chromatography using as silica gel as stationary phase and acetone as eluent, and obtained as pale yellow solid (yield 76%).
[0076] Synthesis of compound 12
12
[0077] In a 100 mL round-bottom flask, compound 2 (1 eq.), PtCl2(DMSO)2(1.0 eq.), pyridazine (0.5 eq.) and triethylamine (2.5 eq.) were suspended in 16 mL of a 3: 1 mixture of 2-ethoxyethanol and water. The reaction mixture was overnight heated at 85°C. Rapidly, the reaction mixture turned yellow-orange and a plentiful orange precipitate appeared, corresponding to the desired compound 12 (yield 28%).
[0078] Synthesis of compound 13
[0079] In a 100 mL round-bottom flask, compound 2 (1 eq.), PtCl2(DMSO)2 (1.0 eq.), 1,2- Bis(4-pyridyl)ethane (0.5 eq.) and triethylamine (2.5 eq.) were suspended in 16 mL of a 3: 1 mixture of 2-ethoxyethanol and water. The reaction mixture was overnight heated at 85°C. Rapidly, the reaction mixture turned yellow-orange and a plentiful red precipitate appeared, corresponding to the desired compound 13.
Claims
28
- if Yi or Y4 are a nitrogen atom, then Ri or R 9 are absent;
-if Y2 or Y5 are a nitrogen atom, then R2 or R2o are absent;
-if Y3 or Y6 are a nitrogen atom, then R3 or R2i are absent;
- if Y7 is a nitrogen atom, then R28 is absent;
-if Y8 is a nitrogen atom, then R¾ is absent;
-if Y9 is a nitrogen atom, then R3o is absent,
and if Yi, Y2 , Y3 Y4, Y5, Y6, Y7, Y8and Y9 represent a carbon Ri, R2 , R3 , R19, R2o, R21 , R28, R29, and R3o are selected from the group comprising H, F, CI, Br, I, CH3, CF3, N02, OH, tiocyanate, isotiocyanate, -NCO, -CN, CHO, COOH, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, linear or branched, chiral or achiral, from 2 till 18 carbon atom containing any combination of the following groups: CF3, N02, OH, CHO, COOH, tiocyanate, isotiocyanate, keto, amine, mono- or di-alkylamino, mono- or diaryl- amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, aliphatic or alicyclic alkyl, alkenyl, alkynyl, aryl, ester, carboxy, amine, sulfoxide, amide, phosphine or neutral heterocyclic moieties such as ethyl,, n-propyl, phosphine, n- Butyl, t-Butyl, iso-Propyl, Hexyl, F(CF2)m(CH2)n- (m= 1-10, n= 0-4), F(CF2)m(CH2)nC6H4- (m= 1-10, n= 0-4), 0(CH2CH20)nCH3 (n = 0 - 10000), haloalkyl, mono- or, disulfide, natural or synthetic sugar residuals, biotin, phosphonium moiety, aminoacidic residual, antibody,Phenyl, Chlorophenyl, Tolyl, Anisyl, Trifluoromethylphenyl, Benzyl, Fluorenyl, Carbazolyl, Cyclohexyl, Menthyl, Allyl, Hydroxyphenyl, Pentaflurophenyl, Carboxyphenyl, Naphthyl, Pyridyl, Furyl, Bis- (trifluoromethyl)-phenyl, Carbene, N-heterocyclic Carbene, Imidazolyl, Pyridazinyl, Pyrazinyl, Pyrimidyl, Phosphinyl, any aromatic rings fused with the central N- containing esatomic ring, such as
Xi, X2, X3 X7, Xs, X9, X10, X11, X12, Xi3, Xi4, Xi5, Xi6, Xi7 and Xi8 are carbon and nitrogen atoms, that independently combine in such a way to have heterocycles selected from the group comprising pyrroles, diazoles, triazoles, tetrazoles, and wherein R4 _ 9, R22-27 or R3i-36 are selected from the group of mono- or polyatomic substituents, and wherein
the platinum ion is coordinated to a ligand L and/or L' which is neutral, mono- or multi- either positively or negatively charged to yield a neutral-core complex, wherein the molecule is either fully neutral or either positively or negatively charged.
2. The platinum(II)complex according to claim 1, wherein L and/or L' comprise on remote sites -S03 ", -OS03 ", -phosphonium, -COO", alkylammonium, aminoacid, phosphate.
3. The platinum(II) complex according to any of the preceding claims, wherein Xi, X2, X3 X7, X8, X9, X10, X11, X12, Xi3, Xi4, Xi5, Xi6, Xi7 and X18 represent independently from each other a carbon atom and R4 _ 9,, R22-27 or R3i-36, respectively, are selected from the group comprising H, F, CI, Br, I, CH3, CF3, N02, OH, tiocyanate,
isotiocyanate, -NCO, -CN, CHO, COOH, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, linear or branched, chiral or achiral, from 2 till 18 carbon atom containing any combination of the following groups: CF3, N02, OH, CHO, COOH, tiocyanate, isotiocyanate, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, aliphatic or alicyclic alkyl, alkenyl, alkynyl, aryl, ester, carboxy, amine, sulfoxide, amide, phosphine or neutral heterocyclic moieties such as ethyl,, n-propyl, phosphine, n-Butyl, t-Butyl, iso-Propyl, Hexyl, F(CF2)m(CH2)n- (m= 1-10, n= 0-4), F(CF2)m(CH2)nC6H4- (m= 1-10, n= 0-4), 0(CH2CH20)nCH3 (n = 0 - 10000), haloalkyl, mono- or, disulfide, natural or synthetic sugar residuals, biotin, phosphonium moiety, aminoacidic residual, antibody, Phenyl, Chlorophenyl, Tolyl, Anisyl, Trifluoromethylphenyl, Benzyl, Fluorenyl, Carbazolyl, Cyclohexyl, Menthyl, Allyl, Hydroxyphenyl, Pentaflurophenyl, Carboxyphenyl, Naphthyl, Pyridyl, Furyl, Bis-(trifluoromethyl)-phenyl, Carbene, N-heterocyclic Carbene, Imidazolyl, Pyridazinyl, Pyrazinyl, Pyrimidyl, Phosphinyl, any aromatic rings fused with the central N-containing esatomic ring, such as
The platinum(II)complex according to formula (I) of any of the preceding claims, wherein L coordinates through nitrogen and corresponds to formula (III) or (IV)
(III) (IV)
wherein Zi, Z2, Z3, Z4, Z5, Z6, Z7, Z8 and Z9 represent independently carbon or nitrogen with the proviso
- if Zi is a nitrogen atom, then Rio is absent;
-if Z2 is a nitrogen atom, then Rn is absent;
-if Z3 is a nitrogen atom, then Ri2 is absent;
-if Z4 is a nitrogen atom, then Ri3 is absent;
-if Z5 is a nitrogen atom, then Ri4 is absent;
-if Z6 is a nitrogen atom, then R15 is absent;
-if Z7 is a nitrogen atom, then Ri6 is absent;
-if Z8 is a nitrogen atom, then Ri7 is absent;
-if Z9 is a nitrogen atom, then Ri8 is absent;
wherein Rio, Rn, Ri2, Ri3, Ri4, R15, R½, R17 and Ri8 are selected independently from the group comprising H, F, CI, Br, I, CH3, CF3, N02, OH, tiocyanate, isotiocyanate, - NCO, -CN, CHO, COOH, keto, amine, mono- or di-alkylamino, mono- or diaryl- amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto,
sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, linear or branched, chiral or achiral, from 2 till 18 carbon atomcontainingany combination of the following groups: CF3, N02, OH, CHO, COOH, tiocyanate, isotiocyanate, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, aliphatic or alicyclic alkyl, alkenyl, alkynyl, aryl, ester, carboxy, amine, sulfoxide, amide, phosphine or neutral heterocyclic moieties such as ethyl,, n-propyl, phosphine, n-Butyl, t-Butyl, iso-Propyl, Hexyl, F(CF2)m(CH2)n- (m= 1-10, n= 0-4), F(CF2)m(CH2)nC6H4- (m= 1-10, n= 0-4), 0(CH2CH20)nCH3 (n = 0 - 10000), haloalkyl, mono- or, disulfide, natural or synthetic sugar residual, biotin, phosphonium moiety, aminoacidic residual, antibody, Phenyl, Chlorophenyl, Tolyl, Anisyl, Trifluoromethylphenyl, Benzyl, Fluorenyl, Carbazolyl, Cyclohexyl, Menthyl, Allyl, Hydroxyphenyl, Pentaflurophenyl, Carboxyphenyl, Naphthyl, Pyridyl, Furyl, Bis-(trifluoromethyl)-phenyl, Carbene, N-heterocyclic Carbene, Imidazolyl, Pyridazinyl, Pyrazinyl, Pyrimidyl, Phosphinyl, any aromatic rings fused with the central N-containing Pt-coordinating ring, such as
6. The platinum(II)complex according to formula (I) of any of the preceding claims, wherein L coordinates through phosphorus and L is PAr3, PR3, P(OR)3.
7. The platinum(II)complex according to formula (I) of any of the preceding claims, wherein L coordinates through arsenic and L is AsAr3, AsR3.
8. The platinum(II)complex according to formula (I) of any of the preceding claims, wherein L coordinates through carbon and L is a N-heterocyclic carbene, carbonyl.
9. The platinum(II)complex according to formula (I) of any of the preceding claims, wherein the tridentate ligand is mono-anionic and L is a mono-anionic ligand selected from the group comprising -CI, -Br, -I, -CN, -NCS, -NSC, -NCO, -SR, -SAr, -OR, NaHP04, HC03, carboxylate, -OAr, azolates, pyrrolates, ArO .
10. The platinum(II)complex according to formula (II) of any of the preceding claims, wherein the tridentate ligand is dianionic and L is a neutral monodentate ligand coordinating through nitrogen, phosphorus or carbon, wherein the link between L and L' is selected from the group comprising
- if Z9 is a nitrogen atom, then R37 is absent;
-if Zio is a nitrogen atom, then R38 is absent;
-if Zii is a nitrogen atom, then R 9 is absent;
-if Z12 is a nitrogen atom, then R4o is absent;
-if Zi3 is a nitrogen atom, then R4i is absent;
-if Zi4 is a nitrogen atom, then R42 is absent;
-if Zi5 is a nitrogen atom, then R43 is absent;
-if Zi6 is a nitrogen atom, then R44 is absent;
-if Zi7 is a nitrogen atom, then R45 is absent;
-if Zi8 is a nitrogen atom, then R46 is absent;
-if Z19 is a nitrogen atom, then R47 is absent;
-if Z2o is a nitrogen atom, then R48 is absent; wherein R4i_58 are selected independently from the group comprising H, F, CI, Br, I, CH3, CF3, N02, OH, tiocyanate, isotiocyanate, -NCO, -CN, CHO, COOH, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, linear or branched, chiral or achiral, from 2 till 18 carbon atomcontainingany combination of the following groups: CF3, N02, OH, CHO, COOH, tiocyanate, isotiocyanate, keto, amine, mono- or di-alkylamino, mono- or diaryl-amino, alkoxy, heteroaryloxy, alkoxycarbonil, acyloxy, acylamino, mercapto, sulfonylamino, cyano, carbamoyl, sulfonylamino, sulfamoyl, sulfinyl, aliphatic or alicyclic alkyl, alkenyl, alkynyl, aryl, ester, carboxy, amine, sulfoxide, amide, phosphine or neutral heterocyclic moieties such as ethyl,, n-propyl, phosphine, n- Butyl, t-Butyl, iso-Propyl, Hexyl, F(CF2)m(CH2)n- (m= 1-10, n= 0-4), F(CF2)m(CH2)nC6H4- (m= 1-10, n= 0-4), 0(CH2CH20)nCH3 (n = 0 - 10000), haloalkyl, mono- or, disulfide, natural or synthetic sugar residual, biotin, phosphonium moiety, aminoacidic residual, antibody, Phenyl, Chlorophenyl, Tolyl, Anisyl, Trifluoromethylphenyl, Benzyl, Fluorenyl, Carbazolyl, Cyclohexyl, Menthyl, Allyl, Hydroxyphenyl, Pentaflurophenyl, Carboxyphenyl, Naphthyl, Pyridyl, Furyl, Bis- (trifluoromethyl)-phenyl, Carbene, N-heterocyclic Carbene, Imidazolyl, Pyridazinyl, Pyrazinyl, Pyrimidyl, Phosphinyl, any aromatic rings fused with the central N- containing Pt-coordinating ring, such as
11. The platinum(II)complex according to any of the preceding claims, wherein the ligand is covalently bound to biomolecules selected from the group comprising a polypeptide or protein, a nucleoside or a nucleotide chain and a sugar or sugar moiety.
12. The platinum(II)complex according to any of the preceding claims, wherein the complex is in the aggregated form.
13. The platinum(II)complex according to claim 11, wherein the emission colour or the emission quantum yield or the excited state lifetime change upon aggregation of the complex.
14. The platinum(II) complex according to claim 11, wherein the complex is coupled to a targeting agent.
15. A use of a platinum(II) complex according to any of the preceding claims as imaging agent.
16. A use of a platinum(II) complex according to any of the preceding claims in therapeutic and/or diagnostic applications.
17. A use of a platinum(II) complex according to any of the preceding claims in a detection method.
18. A use of a platinum(II) complex according to any of the preceding claims for the detection of an analyte.
19. A use of a platinum(II) complex according to any of the preceding claims for the detection of cell evolution.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP12707291.6A EP2681228B1 (en) | 2011-03-01 | 2012-03-01 | Platinum complexes and their use |
| US14/002,637 US8962838B2 (en) | 2011-03-01 | 2012-03-01 | Platinum complexes and their use |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102011001007.6 | 2011-03-01 | ||
| DE102011001007A DE102011001007A1 (en) | 2011-03-01 | 2011-03-01 | New platinum (II) complexes as triplet emitters for OLED applications |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2012117082A1 true WO2012117082A1 (en) | 2012-09-07 |
Family
ID=45808881
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2012/053586 WO2012117082A1 (en) | 2011-03-01 | 2012-03-01 | Platinum complexes and their use |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US8962838B2 (en) |
| EP (1) | EP2681228B1 (en) |
| DE (1) | DE102011001007A1 (en) |
| WO (1) | WO2012117082A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2873711A1 (en) * | 2013-11-18 | 2015-05-20 | Centre National de la Recherche Scientifique (C.N.R.S.) | Platinum complexes |
| EP2920186A4 (en) * | 2012-11-19 | 2016-04-20 | Univ Hong Kong | Novel gold(iii) complexes containing n-heterocyclic carbene ligand, synthesis, and their applications in cancer treatment and thiol detection |
| US10529935B2 (en) | 2016-02-11 | 2020-01-07 | Samsung Electronics Co., Ltd. | Organometallic compound, organic light emitting device, and composition for diagnosing including organometallic compound |
| CN112778375A (en) * | 2021-01-08 | 2021-05-11 | 陕西师范大学 | Amphiphilic chiral platinum complex, self-assembled temperature-sensitive single-component luminescent material thereof and application |
| DE102020110305A1 (en) | 2020-04-15 | 2021-10-21 | Bundesanstalt Für Materialforschung Und -Prüfung | Use of d8 metal complex compounds with ligand-controlled aggregation and luminescence properties |
| JP2021181455A (en) * | 2015-08-13 | 2021-11-25 | 三星電子株式会社Samsung Electronics Co., Ltd. | Organometallic compound, and organic light-emitting device and diagnosis composition that include the same |
| WO2023121258A1 (en) * | 2021-12-22 | 2023-06-29 | Samsung Display Co., Ltd. | A ligand for complexes for use in optoelectronic devices |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3130595B1 (en) * | 2015-08-13 | 2018-10-17 | Samsung Electronics Co., Ltd. | Organometallic compound, organic light-emitting device including the organometallic compound, and diagnosis composition including the organometallic compound |
| KR102527229B1 (en) * | 2017-05-10 | 2023-05-02 | 삼성디스플레이 주식회사 | Organometallic compound and organic light emitting device comprising the same |
| CN109503667B (en) * | 2018-12-28 | 2020-09-08 | 西安交通大学 | Three-ligand synergistic enhanced aggregation-induced emission organometallic platinum complex luminescent material |
| CN110699069B (en) * | 2019-10-17 | 2020-09-04 | 华中科技大学 | Light response type luminescent material and application thereof |
| CN113683645B (en) * | 2021-09-02 | 2023-11-07 | 湖北科技学院 | Binuclear Pt (II) complex with anti-tumor activity and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007169541A (en) * | 2005-12-26 | 2007-07-05 | Konica Minolta Holdings Inc | Material for organic electroluminescent element, organic electroluminescent element, display device and illuminating device |
| WO2007133349A2 (en) * | 2006-04-10 | 2007-11-22 | The Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Las Vegas | Fluorous 2,2'-bipyridines and fluorinated biphasic systems for ligand design |
| WO2009111299A2 (en) | 2008-02-29 | 2009-09-11 | Arizona Board Of Regents For And On Behalf Of Arizona State University | Tridentate platinum (ii) complexes |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006069936A (en) | 2004-08-31 | 2006-03-16 | Fuji Photo Film Co Ltd | Metal complex, luminescent solid, organic el device and organic el display |
| US8057989B2 (en) | 2006-02-10 | 2011-11-15 | The University Of Hong Kong | Label-free optical sensing and characterization of biomolecules by d8 or d10 metal complexes |
| US9023490B2 (en) * | 2007-06-15 | 2015-05-05 | Versitech Limited | Extended pi-conjugated platinum (II) complexes |
| GB0818151D0 (en) | 2008-10-03 | 2008-11-12 | Central Lab Innovation And Knowledge Transf Ltd | Imaging techniques |
| US20100314994A1 (en) * | 2009-06-16 | 2010-12-16 | Chi Ming Che | Platinum (II) Isoqulinoline-Pyridine-Benzene Based Complexes, Methods for Making Same, and Organic Light-Emitting Diodes Including Such Complexes |
| US8530659B2 (en) | 2009-10-28 | 2013-09-10 | The University Of Hong Kong | Pharmaceutical composition containing cyclometalated N-heterocyclic carbene complexes for cancer treatment |
-
2011
- 2011-03-01 DE DE102011001007A patent/DE102011001007A1/en not_active Withdrawn
-
2012
- 2012-03-01 WO PCT/EP2012/053586 patent/WO2012117082A1/en active Application Filing
- 2012-03-01 EP EP12707291.6A patent/EP2681228B1/en not_active Not-in-force
- 2012-03-01 US US14/002,637 patent/US8962838B2/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007169541A (en) * | 2005-12-26 | 2007-07-05 | Konica Minolta Holdings Inc | Material for organic electroluminescent element, organic electroluminescent element, display device and illuminating device |
| WO2007133349A2 (en) * | 2006-04-10 | 2007-11-22 | The Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Las Vegas | Fluorous 2,2'-bipyridines and fluorinated biphasic systems for ligand design |
| WO2009111299A2 (en) | 2008-02-29 | 2009-09-11 | Arizona Board Of Regents For And On Behalf Of Arizona State University | Tridentate platinum (ii) complexes |
Non-Patent Citations (5)
| Title |
|---|
| CRISTIAN A. STRASSERT ET AL: "Switching On Luminescence by the Self-Assembly of a Platinum(II) Complex into Gelating Nanofibers and Electroluminescent Films", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 50, no. 4, 27 December 2010 (2010-12-27), pages 946 - 950, XP055023592, ISSN: 1433-7851, DOI: 10.1002/anie.201003818 * |
| DUATI MARCO ET AL: "Enhancement of Luminescence Lifetimes of Mononuclear Ruthenium(II)-Terpyridine Complexes by Manipulation of the .sigma.-Donor Strength of Ligands", INORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, EASTON, US, vol. 42, no. 25, 1 January 2003 (2003-01-01), pages 8377 - 8384, XP002486394, ISSN: 0020-1669, DOI: 10.1021/IC034691M * |
| R. ROMEO; L. M. SCOLARO, INORG. SYNTH., vol. 32, 1998, pages 153 |
| RUBINO S ET AL: "Synthesis, structural characterisation and biological studies of new mononuclear platinum(II) complexes with sterically hindered heterocyclic ligands", INORGANICA CHIMICA ACTA, ELSEVIER BV, NL, vol. 370, no. 1, 18 January 2011 (2011-01-18), pages 207 - 214, XP028191308, ISSN: 0020-1693, [retrieved on 20110131], DOI: 10.1016/J.ICA.2011.01.047 * |
| SCHNEIDER JACOB ET AL: "Cyclometalated 6-phenyl-2,2'-bipyridyl (CNN) platinum(II) acetylide complexes: structure, electrochemistry, photophysics, and oxidative- and reductive-quenching studies", INORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, EASTON, US, vol. 48, no. 10, 24 April 2009 (2009-04-24), pages 4306 - 4316, XP009153248, ISSN: 0020-1669 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2920186A4 (en) * | 2012-11-19 | 2016-04-20 | Univ Hong Kong | Novel gold(iii) complexes containing n-heterocyclic carbene ligand, synthesis, and their applications in cancer treatment and thiol detection |
| EP2873711A1 (en) * | 2013-11-18 | 2015-05-20 | Centre National de la Recherche Scientifique (C.N.R.S.) | Platinum complexes |
| JP2021181455A (en) * | 2015-08-13 | 2021-11-25 | 三星電子株式会社Samsung Electronics Co., Ltd. | Organometallic compound, and organic light-emitting device and diagnosis composition that include the same |
| JP7214800B2 (en) | 2015-08-13 | 2023-01-30 | 三星電子株式会社 | Organometallic compounds, organic light-emitting devices containing the same, and diagnostic compositions |
| US11737350B2 (en) | 2015-08-13 | 2023-08-22 | Samsung Electronics Co., Ltd. | Organometallic compound, organic light-emitting device including the organometallic compound, and diagnosis composition including the organometallic compound |
| US10529935B2 (en) | 2016-02-11 | 2020-01-07 | Samsung Electronics Co., Ltd. | Organometallic compound, organic light emitting device, and composition for diagnosing including organometallic compound |
| DE102020110305A1 (en) | 2020-04-15 | 2021-10-21 | Bundesanstalt Für Materialforschung Und -Prüfung | Use of d8 metal complex compounds with ligand-controlled aggregation and luminescence properties |
| CN112778375A (en) * | 2021-01-08 | 2021-05-11 | 陕西师范大学 | Amphiphilic chiral platinum complex, self-assembled temperature-sensitive single-component luminescent material thereof and application |
| CN112778375B (en) * | 2021-01-08 | 2024-03-01 | 陕西师范大学 | Amphiphilic chiral platinum complex, self-assembled temperature-sensitive single-component luminescent material and application thereof |
| WO2023121258A1 (en) * | 2021-12-22 | 2023-06-29 | Samsung Display Co., Ltd. | A ligand for complexes for use in optoelectronic devices |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2681228B1 (en) | 2016-12-21 |
| DE102011001007A1 (en) | 2012-09-06 |
| US8962838B2 (en) | 2015-02-24 |
| EP2681228A1 (en) | 2014-01-08 |
| US20140088307A1 (en) | 2014-03-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8962838B2 (en) | Platinum complexes and their use | |
| Septiadi et al. | Bio-imaging with neutral luminescent Pt (II) complexes showing metal⋯ metal interactions | |
| Lo | Luminescent rhenium (I) and iridium (III) polypyridine complexes as biological probes, imaging reagents, and photocytotoxic agents | |
| Colombo et al. | Neutral N^ C^ N terdentate luminescent Pt (II) complexes: their synthesis, photophysical properties, and bio-imaging applications | |
| Shaikh et al. | Phosphorescent Ir (III) complexes as cellular staining agents for biomedical molecular imaging | |
| Steunenberg et al. | Phosphorescence imaging of living cells with amino acid-functionalized tris (2-phenylpyridine) iridium (III) complexes | |
| Li et al. | A nonemissive iridium (III) complex that specifically lights-up the nuclei of living cells | |
| Yoshihara et al. | Mitochondria-targeted oxygen probes based on cationic iridium complexes with a 5-amino-1, 10-phenanthroline ligand | |
| Mauro et al. | Aggregation induced colour change for phosphorescent iridium (iii) complex-based anionic surfactants | |
| Alam et al. | Facile tuning of the aggregation-induced emission wavelength in a common framework of a cyclometalated iridium (iii) complex: micellar encapsulated probe in cellular imaging | |
| Palmioli et al. | Glyco-functionalized dinuclear rhenium (i) complexes for cell imaging | |
| Zhang et al. | Mitochondria-targeting phosphorescent iridium (III) complexes for living cell imaging | |
| Solomatina et al. | Water-soluble cyclometalated platinum (II) and iridium (III) complexes: Synthesis, tuning of the photophysical properties, and in vitro and in vivo phosphorescence lifetime imaging | |
| Sathish et al. | Photoswitchable alkoxy-bridged binuclear rhenium (I) complexes–a potential probe for biomolecules and optical cell imaging | |
| Berenguer et al. | Luminescent pentafluorophenyl-cycloplatinated complexes: synthesis, characterization, photophysics, cytotoxicity and cellular imaging | |
| Natrajan et al. | Two-photon luminescence from polar bis-terpyridyl-stilbene derivatives of Ir (III) and Ru (II) | |
| Nie et al. | Two novel six-coordinated cadmium (II) and zinc (II) complexes from carbazate β-diketonate: crystal structures, enhanced two-photon absorption and biological imaging application | |
| WO2016136718A1 (en) | Super-resolution fluorescent imaging probe | |
| François et al. | A functionalized heterobimetallic 99m Tc/Re complex as a potential dual-modality imaging probe: synthesis, photophysical properties, cytotoxicity and cellular imaging investigations | |
| Sarkar et al. | Remarkable visible light-triggered cytotoxicity of mitochondria targeting mixed-ligand cobalt (III) complexes of curcumin and phenanthroline bases binding to human serum albumin | |
| CN114729199A (en) | Compound and fluorescent-labeled biological substance using same | |
| Aikman et al. | Highly-fluorescent BODIPY-functionalised metallacages as drug delivery systems: synthesis, characterisation and cellular accumulation studies | |
| JP6485799B2 (en) | Luminescent composition that emits light by three-photon excitation | |
| Ding et al. | Imaging of the nuclei of living tumor cells by novel ruthenium (II) complexes coordinated with 6-chloro-5-hydroxylpyrido [3, 2-a] phenazine | |
| Koenig et al. | Polyamine-modified near-infrared cyanine dyes for targeting the nuclei and nucleoli of cells |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12707291 Country of ref document: EP Kind code of ref document: A1 |
|
| REEP | Request for entry into the european phase |
Ref document number: 2012707291 Country of ref document: EP |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2012707291 Country of ref document: EP |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 14002637 Country of ref document: US |