CN104327156B - Dihydro porphin light, sound sensitiser and preparation method and application - Google Patents
Dihydro porphin light, sound sensitiser and preparation method and application Download PDFInfo
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- 231100000489 sensitizer Toxicity 0.000 title claims abstract description 20
- RKCAIXNGYQCCAL-UHFFFAOYSA-N porphin Chemical compound N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 RKCAIXNGYQCCAL-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 101
- 239000000126 substance Substances 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 41
- 239000000243 solution Substances 0.000 claims description 36
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 29
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 26
- 239000011259 mixed solution Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 229940125782 compound 2 Drugs 0.000 claims description 17
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 15
- 108010024636 Glutathione Proteins 0.000 claims description 15
- 235000018417 cysteine Nutrition 0.000 claims description 15
- 229960003180 glutathione Drugs 0.000 claims description 15
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims description 14
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims description 14
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 14
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 14
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 12
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- 239000012317 TBTU Substances 0.000 claims description 10
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 10
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 9
- 239000002994 raw material Substances 0.000 claims description 9
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 8
- 229940126214 compound 3 Drugs 0.000 claims description 8
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 6
- -1 reacts 1~4 hour Chemical compound 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 229940125904 compound 1 Drugs 0.000 claims description 5
- ZENKESXKWBIZCV-UHFFFAOYSA-N 2,2,4,4-tetrafluoro-1,3-benzodioxin-6-amine Chemical group O1C(F)(F)OC(F)(F)C2=CC(N)=CC=C21 ZENKESXKWBIZCV-UHFFFAOYSA-N 0.000 claims description 4
- 230000000118 anti-neoplastic effect Effects 0.000 claims description 4
- 238000011938 amidation process Methods 0.000 claims description 2
- 239000001569 carbon dioxide Substances 0.000 claims description 2
- 230000004044 response Effects 0.000 claims description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 claims 2
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 claims 2
- 150000003923 2,5-pyrrolediones Chemical class 0.000 claims 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- 241000432767 Asparagus setaceus Species 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 230000008685 targeting Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 16
- 238000002428 photodynamic therapy Methods 0.000 abstract description 14
- 238000009214 sonodynamic therapy Methods 0.000 abstract description 8
- 239000003795 chemical substances by application Substances 0.000 abstract description 7
- 201000007270 liver cancer Diseases 0.000 abstract description 5
- 208000014018 liver neoplasm Diseases 0.000 abstract description 5
- 230000001235 sensitizing effect Effects 0.000 abstract description 5
- UJKPHYRXOLRVJJ-MLSVHJFASA-N CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C Chemical compound CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C UJKPHYRXOLRVJJ-MLSVHJFASA-N 0.000 abstract description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 abstract description 4
- 229960003569 hematoporphyrin Drugs 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 4
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 3
- 239000013641 positive control Substances 0.000 abstract description 3
- 238000011156 evaluation Methods 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 58
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
- 239000012043 crude product Substances 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 229910052757 nitrogen Inorganic materials 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000012544 monitoring process Methods 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 235000011181 potassium carbonates Nutrition 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- 231100000419 toxicity Toxicity 0.000 description 7
- 230000001988 toxicity Effects 0.000 description 7
- 235000011054 acetic acid Nutrition 0.000 description 6
- 150000001243 acetic acids Chemical class 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 239000010410 layer Substances 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 150000002240 furans Chemical class 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229910001510 metal chloride Inorganic materials 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NHSVUOMBUHCTCB-LBPRGKRZSA-N 3-o-tert-butyl 1-o-methyl (2s)-2-amino-2-(4-aminobutyl)propanedioate Chemical compound CC(C)(C)OC(=O)[C@@](N)(C(=O)OC)CCCCN NHSVUOMBUHCTCB-LBPRGKRZSA-N 0.000 description 1
- 101000905241 Mus musculus Heart- and neural crest derivatives-expressed protein 1 Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000005842 biochemical reaction Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 150000001945 cysteines Chemical class 0.000 description 1
- 239000008232 de-aerated water Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- BYHXBBOSJKPUJL-BYPYZUCNSA-N dimethyl (2s)-2-aminobutanedioate Chemical compound COC(=O)C[C@H](N)C(=O)OC BYHXBBOSJKPUJL-BYPYZUCNSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 208000007578 phototoxic dermatitis Diseases 0.000 description 1
- 231100000018 phototoxicity Toxicity 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to a class dihydro porphin light, the preparation method of sound sensitiser and application, belong to chemical medicine.The compound has below formula:
Description
Technical field
The present invention relates to a class dihydro porphin light, the preparation method of sound sensitiser and application, belong to chemical medicine.
Background technology
Photodynamic therapy (Photodynamic therapy, PDT) and Sonodynamic therapy (Sonodynamic
Therapy, SDT), be respectively by sensitising agent (photosensitizer) or sensitising agent (sonosensitizer) in light or
Ultrasonic excitation issues biochemical reaction and kills tumour cell to reach a kind of medical technology of therapeutic purposes.Wherein photodynamics
It is using sensitising agent and visible ray in the environment with the presence of oxygen, by anti-to treat (Photodynamic therapy, PDT)
Should produce singlet oxygen (1O2) and free radical have very big lethality to tumour cell.With surgical operation, chemotherapy, radiation
Traditional treatment methods such as treatment are compared, and PDT has to target tissue selectivity height, Small side effects, excellent to internal organs not damaged etc.
Point；Sonodynamic therapy (Sonodynamic therapy, SDT), then be in photodynamic therapy (Photodynamic
Therapy, PDT) on the basis of grow up it is a kind of can be used for pernicious, advanced tumors clinical treatment new method.Utilize sound
Quick agent molecule can be enriched with tumour cell, and the light for replacing photodynamic therapy using ultrasonic excitation is excited, and producing has cell
The effects such as the singlet oxygen and formation ultrasonic cavitation of toxicity, cause apoptosis of tumor cells or death.Compared with photodynamic therapy,
Also have penetration power strong, the advantages of noninvasive.Many Photosensitive compounds also have the quick effect of sound, and sensitising agent can be used as sound sensitiser
And use.Current light, sound sensitiser also exist not high to tumor cells selectivity, and required dosage is larger, dissolubility under physiological condition
It is poor and the shortcomings of clearance rate is slower in vivo.Accordingly, it would be desirable to develop new light, sound sensitiser to promote photodynamic therapy
With the development of Sonodynamic therapy.
The content of the invention
The present invention have found active more preferable, dark toxicity lower by synthesizing a class dihydro porphin light, the quick type compound of sound
Can be used for light, the antitumoral compounds of Sonodynamic therapy.
Dihydro porphin light of the present invention, sound sensitiser, with below formula I, II, III or IV：
Wherein：R1For methoxyl group；
R2It is selected from：
R3It is selected from：Methoxyl group,
M is selected from Cu2+, Fe2+, Zn2+, Mg2+, Ni2+, Co2+, Sn4+, Pt2+, Ti4+, Rh2+, Ru4+, Ir3+。
Described dihydro porphin light, the preparation method of sound sensitiser, comprise the following steps：
1. it is raw material with compound 1, it is 4~5 to be dissolved in volume ratio:1 DCM and DMF mixed solution, obtain 0.1M chemical combination
The mixed solution of thing 1；Sequentially add HOBt, TBTU, DIEA and N- (2- aminoethyls) maleimide, compound 1：HOBt：
TBTU：DIEA：The mol ratio of N- (2- aminoethyls) maleimide is 1：1~2：1~2：0.1~0.5：1~2, reaction 0.5~
Compound a is obtained through amidation process within 4 hours；It is 4 that compound a is dissolved in into volume ratio again:1 THF and the mixed solution of water, are obtained
To the mixed solution of 0.1M compound as, cysteine or glutathione are added, compound a and cysteine or glutathione
Mol ratio is 1：1~3, react 1~6 hour, obtain compound b or compound c；Reaction equation is as follows：
2. it is raw material with compound 2, compound 2 is dissolved in DMF, obtains the DMF solution of 0.1M compounds 2；Add
EDCI, N- (2- aminoethyls) maleimide and triethylamine, react 1~4 hour, add iodomethane and Carbon Dioxide nak response
1~4 hour, obtain compound d；Wherein, compound 2：EDCI：N- (2- aminoethyls) maleimide：Triethylamine：Iodomethane：
The mol ratio of Anhydrous potassium carbonate is 1：1~5：1~2：0.1~0.5：2~10：2~10；Compound d is dissolved in into volume ratio again is
4:1 THF and the mixed solution of water, obtain 0.1M compounds d mixed solution, add cysteine or glutathione, reaction 1
~6 hours, obtain compound e or compound f；The mol ratio of compound d and cysteine or glutathione is 1：1~3；Reaction
Formula is as follows：
3. it is raw material with compound 2, is dissolved in 5% methanolic solution, 5% methanolic for obtaining 0.1M compounds 2 is molten
Liquid, reaction obtains compound 3；It is 4~5 that compound 3 is dissolved in into volume ratio again:1 DCM and DMF mixed solution, obtain 0.1M
The mixed solution of compound 3, sequentially adds HOBt, TBTU, DIEA and N- (2- aminoethyls) maleimide, and reaction 1~4 is small
When, iodomethane and Anhydrous potassium carbonate are added, reacts 1~6 hour, obtains compound g；Wherein, compound 3：HOBt：TBTU：
DIEA：N- (2- aminoethyls) maleimide：Iodomethane：The mol ratio of Anhydrous potassium carbonate is 1：1~2：1~2：0.1~0.5：1
~2：2~10：2~10；It is 4 that compound g is dissolved in into volume ratio again:In the mixed solution of 1THF and water, 0.1M compounds g is obtained
Mixed solution, add cysteine or glutathione, react 1~6 hour, obtain compound h or compound i；Wherein, chemical combination
The mol ratio of thing g and cysteine or glutathione is 1：1~3；5% methanolic solution is the quality percentage that sulfuric acid accounts for methanol
Than for 5%；Reaction equation is as follows：
4. it is raw material with compound 2, is dissolved in DMF, obtains the DMF solution of 0.1M compounds 2；Add EDCI, 2- ammonia
Base aspartic acid dimethyl ester or 6- amino -2- tertbutyloxycarbonyls-lysine methyl ester and triethylamine, react 1~4 hour, add
Iodomethane and Anhydrous potassium carbonate, react 1~6 hour, obtain compound j or compound k；Wherein, compound 2：EDCI：2- amino
Aspartic acid dimethyl ester or 6- amino -2- tertbutyloxycarbonyls-lysine methyl ester：Triethylamine：Iodomethane：Mole of Anhydrous potassium carbonate
Than for 1：1~5：1~3：0.1~0.5：2~10：2~10；Reaction equation is as follows：
5. using above-mentioned obtained compound a~k as raw material, metal chloride or acetate complex compound, wherein compound a are added
The mol ratio of~k and metal chloride or acetate complex compound is 1：1~6, it is heated to reflux, reacts 2~8 hours, obtain successively
The corresponding metal complex a (M) of compound a~k~k (M).
Dihydro porphin light, the sound sensitiser of above-mentioned preparation are used to prepare antineoplastic or prepare as active part to target
Property antineoplastic.
Dihydro porphin light of the present invention, sound sensitiser are in vitro in antitumor activity evaluation to human liver cancer cell Hep
G2 has different degrees of inhibitory action.The ratio and sound of photolytic activity and secretly activity are active to be above making with dark active ratio
For the hematoporphyrin monomethyl ether of positive control.It is photosensitive in photodynamic therapy, Sonodynamic therapy method available for oncotherapy
Agent and the preparation of sound sensitiser.
Embodiment
Following non-limiting examples can make one of ordinary skill in the art be more fully understood the present invention, but not with
Any mode limits the present invention.
Embodiment 1
The synthesis of compound a
By 100mg commercial compound 1, be dissolved in 10mL dichloromethane and 2mL DMF, sequentially add 25.1mg HOBt,
59.6mg TBTU, 500 μ L DIEA, are stirred at a temperature of 0~50 DEG C, nitrogen ball protection, TLC (stops after monitoring, reaction 30min.
Add 49.2mg N- (2- aminoethyls) maleimide, DIEA500 μ L, 1mL DMF is stirred at a temperature of 0~50 DEG C, nitrogen
Ball is protected, TLC monitorings, is stopped after reaction 6h.Reaction solution 50mL dchloromethanes, are placed in 250mL separatory funnels, spend
Ionized water (50mL × 3) is washed, and dichloromethane layer anhydrous sodium sulfate drying is concentrated to give crude product, and crude product passes through silica gel
Column chromatography (solvent：Petroleum ether：Ethyl acetate=1:4) purify, obtain 57.7mg dark green solids, i.e. compound a.ESI-MS
m/z:715.3[M+H]+.1H NMR(400MHz,CDCl3)δ9.32(1H,s),9.29(1H,s),8.54(1H,s),7.97(1H,
Dd, J=17.2,10.5Hz), 6.58 (2H, s), 6.27 (1H, dd, J=17.2,1.2Hz), 6.16 (2H, dd, J=10.5,
1.2Hz), 5.85 (1H, s), 4.48 (1H, q, J=6.8Hz), 4.15 (1H, d, J=8.2Hz), 3.82 (3H, s), 3.77 (2H,
Q, J=7.7Hz), 3.61 (2H, m), 3.45 (3H, s), 3.38 (3H, s), 3.19 (3H, s), 2.86 (2H, m), 2.65 (1H,
M), 2.36 (1H, m), 2.28 (1H, m), 2.07 (1H, m), 1.81 (3H, d, J=7.3Hz), 1.63 (3H, t, J=7.7Hz) ,-
1.47(1H,s),-1.64(1H,s).
Compound b synthesis
18.2mg compound as are dissolved in 5mL tetrahydrofurans：Water=4:1 solution, adds 5.2mg cysteines thereto
Addition, which adds to react after stirring at a temperature of 200 μ L glacial acetic acids, 0~50 DEG C, the protection of nitrogen ball, TLC monitorings, 1h, to be stopped.Reaction
Liquid is concentrated to give crude product, and crude product passes through silica gel column chromatography (solvent：Dichloromethane：Methanol=7:3) purify, obtain
11.2mg dark green solids, i.e. compound b, yield 55.2%.UV-vis(CH3OH):λmax(ε/M-1cm-1)668nm,
413nm.ESI-MS m/z:836.4[M+H]+.1HNMR(400MHz,DMSO)δ9.66(1H,s),9.30(1H,s),8.90(1H,
S), 8.11 (2H, dd, J=17.3,11.5Hz), 6.44 (1H, dd, J=17.3,1.2Hz), 6.33 (1H, d, J=11.5,
1.2Hz), 6.26 (1H, s), 4.54 (1H, q, J=7.2Hz), 4.29 (1H, d, J=9.9Hz), 4.01 (2H, m), 3.83 (3H,
s),3.76(2H,m),3.61(3H,s),3.59(3H,s),3.10(3H,s),2.82(1H,m),2.21(1H,m),2.15(1H,
M), 1.92 (1H, m), 1.77 (3H, d, J=6.9Hz), 1.57 (3H, t, J=7.0Hz), 1.36 (2H, m), 1.22 (2H, m) ,-
1.71(1H,s),-1.92(1H,s).
Compound c synthesis
16.5mg compound as are dissolved in 5mL tetrahydrofurans：Water=4:1 solution, adds 4.1mg glutathione and puts, then add
Stop after entering stirring at a temperature of 200 μ L glacial acetic acids, 0~50 DEG C, the protection of nitrogen ball, TLC monitorings, reaction 1h.Reaction solution is concentrated to give
To crude product, crude product passes through silica gel column chromatography (solvent：Dichloromethane：Methanol=6:4) purify, obtain 12.1mg blackish green
Solid, i.e. compound c, yield 52%.ESI-MSm/z:1020.3[M-H]-.1H NMR(400MHz,DMSO)δ9.69(1H,s),
9.34 (1H, s), 8.87 (1H, s), 7.88 (1H, dd, J=17.5,11.0Hz), 6.29 (1H, dd, J=17.5,1.2Hz),
6.14 (1H, dd, J=11.0,1.2Hz), 5.55 (1H, s), 5.01 (1H, q, J=7.4Hz), 4.50 (1H, d, J=8.9Hz),
4.33 (1H, m), 3.99 (2H, m), 3.86 (3H, s), 3.80 (2H, q, J=7.6Hz), 3.73 (3H, s), 3.59 (3H, s),
3.13(3H,s),2.76(1H,m),2.40(1H,m),2.32(1H,m),2.14(1H,m),1.88(2H,m),1.72(3H,d,J
=7.2Hz), 1.56 (3H, t, J=8.0Hz), 1.19 (2H, m), 0.82 (2H, m), -1.80 (1H, s), -1.92 (1H, s)
Embodiment 2
Compound d synthesis
40.1mg commercial compound 2 is dissolved in 10mL DMF, 23.3mg N- (2- aminoethyls) maleimide, 1mL is added
Triethylamine, is stirred at a temperature of 0~50 DEG C, the protection of nitrogen ball, TLC monitorings, and reaction stop after 2h.Add into reaction solution
30.2mg Anhydrous potassium carbonates, 230 μ L iodomethane, are stirred at a temperature of continuing 0~50 DEG C, the protection of nitrogen ball, TLC (solvents：Oil
Ether：Ethyl acetate=1:2) detection reaction, reaction stop after 2h.Reaction solution 40mL dchloromethanes, are transferred to
In 250mL separatory funnels, deionized water washing (50mL × 3), saturated aqueous common salt washing (50mL × 2), anhydrous sodium sulfate drying,
Suction filtration, concentration of organic layers obtains crude product, and crude product passes through silica gel column chromatography (solvent petroleum ether:Ethyl acetate=1:2) it is pure
Change, obtain 36.4mg dark green solids, i.e. compound d, yield 62%.ESI-MS m/z:747.4[M+H]+.1H NMR
(400MHz,CDCl3) δ 9.69 (1H, s), 9.58 (1H, s), 8.78 (1H, s), 8.04 (1H, dd, J=17.8,11.5Hz),
6.35 (1H, dd, J=17.8,1.2Hz), 6.15 (1H, dd, J=11.5,1.2Hz), 5.91 (2H, s), 5.16 (1H, d, J=
18.6Hz), 5.05 (1H, d, J=18.6Hz), 4.48 (2H, q, J=9.2Hz), 4.23 (1H, d, J=6.5Hz), 4.20 (3H,
S), 3.78 (2H, q, J=7.5Hz), 3.56 (3H, s), 3.53 (3H, s), 3.47 (3H, s), 3.45 (3H, s), 3.32 (2H,
M), 3.23 (2H, m), 2.61 (1H, m), 2.40 (1H, m), 2.38 (1H, m), 2.10 (1H, m), 1.84 (3H, d, J=
9.0Hz), 1.75 (3H, t, J=7.6Hz), -1.35 (1H, s), -1.49 (1H, s)
Compound e synthesis
16.8mg compounds d, 4.7mg cysteine is placed in 25mL reaction three-necked bottles, 5mL tetrahydrochysene furans are added thereto
Mutter：Water=4:1 solution, adds stirring at a temperature of 50 μ L glacial acetic acids, 0~50 DEG C, the protection of nitrogen ball, TLC monitorings, reaction
Stop after 1.5h, reaction solution is concentrated to give crude product with Rotary Evaporators, and crude product passes through silica gel column chromatography (solvent：Dichloro
Methane：Methanol=7:3) purify, obtain 12.7mg dark green solids, i.e. compound e, yield 64%.UV-vis(CH3OH):λmax
(ε/M-1cm-1)663nm,403nm.ESI-MS m/z:868.4[M+H]+.1H NMR(400MHz,DMSO)δ9.76(1H,s),
9.69 (1H, s), 9.07 (1H, s), 8.30 (1H, dd, J=17.8,11.7Hz), 6.46 (1H, dd, J=17.8,1.2Hz),
6.19 (1H, dd, J=11.7,1.2Hz), 5.02 (1H, d, J=18.5Hz), 4.98 (1H, d, J=18.5Hz), 4.58 (1H,
Q, J=7.3Hz), 4.39 (1H, d, J=9.3Hz), 4.15 (3H, s), 3.81 (2H, q, J=7.5Hz), 3.53 (3H, s),
3.51(3H,s),3.46(3H,s),3.42(2H,m),3.44(3H,s),3.39(2H,m),3.26(1H,m)2.96(1H,m),
2.64 (1H, m), 2.31 (1H, m), 2.14 (1H, m), 1.72 (2H, m), 1.68 (3H, d, J=7.6Hz), 1.60 (3H, t, J=
7.0Hz),1.52(2H,m),1.47(2H,m),1.40(2H,m),1.32(2H,m),-1.54(1H,s),-1.79(1H,s).
Compound f synthesis
15.6mg compounds d, 5.1mg glutathione is placed in 25mL three-necked bottles, 5mL tetrahydrofurans are added thereto：
Water=4:1 solution, adds stirring at a temperature of 50 μ L glacial acetic acids, 0~50 DEG C, the protection of nitrogen ball, TLC (solvent dichloromethanes
Alkane：Methanol=6:4:1) monitor, stop after reaction 1h, reaction solution is concentrated to give crude product with Rotary Evaporators, and crude product passes through
Silica gel column chromatography (dichloromethane：Methanol=6:4) purify, obtain 13.1mg dark green solids, i.e. compound f.ESI-MS m/z:
1054.3[M+H]+.1H NMR(400MHz,DMSO)δ9.72(1H,s),9.64(1H,s),9.05(1H,s),8.24(1H,dd,J
=17.8,11.6Hz), 6.41 (1H, dd, J=17.8,1.2Hz), 6.14 (1H, dd, J=11.6,1.2Hz), 5.06 (1H, d,
), J=18.2Hz 4.93 (1H, d, J=18.2Hz), 4.96 (1H, q, J=6.4Hz), 4.56 (1H, d, J=10.2Hz), 4.32
(1H, m), 4.17 (3H, s), 3.89 (1H, m), 3.75 (3H, q, J=6.6Hz), 3.50 (3H, s), 3.46 (3H, s), 3.45
(3H,s),3.36(2H,m),3.29(2H,m),3.26(3H,s),2.64(1H,m),2.42(1H,m),2.36(1H,m),2.11
(1H, m), 1.65 (3H, d, J=7.6Hz), 1.57 (3H, t, J=7.0Hz), 1.21 (1H, m), -1.56 (1H, s), -1.80
(1H,s).
Embodiment 3
Compound g synthesis
1. 53.2mg commercial compound 2 is dissolved in 10mL methanol, stirring at a temperature of the 200 μ L concentrated sulfuric acids, 0~50 DEG C is added dropwise,
Nitrogen ball is protected, TLC monitorings, is stopped after reaction 4h, 20mL deionized waters is added into reaction solution, and be transferred to 125mL points of liquid
Funnel, is extracted (30ml × 3) with dichloromethane, combined dichloromethane layer, adds anhydrous sodium sulfate drying, suction filtration is concentrated to give
Crude product.Crude product is passed through into silica gel column chromatography (petroleum ether：Ethyl acetate=1:4) purify, obtain 44.2mg dark green solids,
That is compound 3, yield 77%.ESI-MS m/z:625.4[M+H]+.1H NMR(400MHz,CDCl3)δ9.64(1H,s),9.50
(1H, s), 8.72 (1H, s), 8.01 (1H, dd, J=17.8,11.5Hz), 6.32 (1H, dd, J=17.8,1.2Hz), 6.12
(1H, dd, J=11.5,1.2Hz), 5.51 (1H, d, J=18.7Hz), 5.26 (1H, d, J=18.7Hz), 4.46 (1H, q, J=
7.56Hz), 4.12 (1H, d, J=7.1Hz), 3.82 (3H, s), 3.74 (2H, m), 3.72 (3H, s), 3.70 (3H, s), 3.62
(3H, s), 3.25 (3H, s), 2.55 (1H, m), 2.19 (1H, m), 2.16 (1H, m), 1.87 (1H, m), 1.79 (3H, d, J=
7.1Hz), 1.68 (3H, t, J=7.6Hz), -1.29 (1H, s)
2. 40.6mg compounds 3 are dissolved in 10mL dichloromethane and 1mL DMF, sequentially add 9.5mg HOBt, 22.1mg
TBTU, 300 μ L DIPEAs, are stirred at a temperature of 0~50 DEG C, the protection of nitrogen ball, TLC monitorings, are stopped after reaction 1h
Only, 18.2mg N- (2- aminoethyls) maleimide is added, 300 μ L DIEA are stirred at a temperature of 0~50 DEG C, nitrogen protection,
TLC (solvents：Petroleum ether：Ethyl acetate=1:4) monitor, react and stop after 6h.20mL dichloromethane is added into reaction solution,
And 100mL separatory funnels are transferred to, dichloromethane layer (30mL × 3) is extracted to remove DMF with deionized water, and dichloromethane layer is again
Anhydrous sodium sulfate drying is added, suction filtration, Rotary Evaporators are concentrated to give crude product.Crude product is subjected to silica gel column chromatography (expansion
System：Petroleum ether：Ethyl acetate=1:2) purify, obtain 28.7mg dark green solids, i.e. compound g, yield 60%.ESI-MS
m/z:747.4[M+H]+.1H NMR(400MHz,CDCl3)δ9.68(1H,s),9.62(1H,s),8.79(1H,s),8.07(1H,
Dd, J=17.8,11.5Hz), 6.68 (2H, s), 6.34 (1H, dd, J=17.8,1.2Hz), 6.13 (1H, dd, J=11.5,
1.2Hz), 5.45 (1H, d, J=18.9Hz), 5.18 (1H, d, J=18.9Hz), 4.45 (1H, q, J=7.1Hz), 4.34 (1H,
D, J=10.9Hz), 3.99 (2H, m), 3.91 (2H), 3.88 (2H, q, J=5.2Hz), 3.78 (3H, s), 3.59 (3H, s),
3.53(3H,s),3.45(3H,s),3.30(3H,s),2.53(1H,m),2.16(1H,m),2.13(1H,m),1.78(1H,m),
1.74 (3H, d, J=7.1Hz), 1.71 (3H, t, J=7.5Hz), -1.61 (1H, s), -1.80 (1H, s)
Compound h synthesis
15.2mg compounds g, 4.9mg cysteine is placed in 25mL reaction three-necked bottles, 5mL tetrahydrochysene furans are added thereto
Mutter：Water=4:1 solution, then stirring at a temperature of 50 μ L glacial acetic acids, 0~50 DEG C is added thereto, nitrogen ball protection, TLC is monitored,
React and stop after 1.5h, reaction solution is concentrated to give crude product, and crude product passes through silica gel column chromatography (solvent：Dichloromethane：Methanol
=7:3) purify, obtain 13.1mg dark green solids, i.e. compound h, UV-vis (CH3OH):λmax(ε/M-1cm-1)661nm,
402nm.ESI-MS m/z:868.3[M+H]+.1H NMR(400MHz,DMSO)δ9.77(1H,s),9.72(1H,s),9.10
(1H, s), 8.29 (1H, dd, J=17.8,11.7Hz), 6.43 (1H, dd, J=17.8,1.2Hz), 6.16 (1H, dd, J=
), 11.7,1.2Hz 5.48 (1H, d, J=14.2Hz), 5.27 (1H, d, J=14.2Hz), 4.61 (1H, q, J=7.0Hz),
4.40 (1H, d, J=10.0Hz), 3.88 (3H, s), 3.79 (2H, m), 3.68 (3H, s), 3.60 (3H, s), 3.56 (3H, s),
3.51(3H,s),2.94(1H,m),2.43(1H,m),2.19(1H,m),2.17(1H,m),1.90(2H,m),1.67(3H,d,J
=7.4Hz), 1.65 (3H, t, J=7.6Hz), -1.81 (1H, s), -2.10 (1H, s)
Compound i synthesis
11.3mg compounds g, 6.2mg glutathione is placed in 25mL reaction three-necked bottles, 5mL tetrahydrochysene furans are added thereto
Mutter：Water=4:1 solution, then stirring at a temperature of 50 μ L glacial acetic acids, 0~50 DEG C is added thereto, nitrogen ball protection, TLC is monitored,
React and stop after 1h, reaction solution is concentrated to give crude product, and crude product passes through silica gel column chromatography (dichloromethane：Methanol=6:4) it is pure
Change, obtain 9.6mg dark green solids, i.e. compound i, ESI-MS m/z:1054.3[M+H]+.1H NMR(400MHz,DMSO)δ
9.74 (1H, s), 9.70 (1H, s), 9.09 (1H, s), 8.27 (1H, dd, J=17.8,11.7Hz), 6.41 (1H, dd, J=
), 17.8,1.2Hz 6.14 (1H, dd, J=11.7,1.2Hz), 5.47 (1H, d, J=15.2Hz), 5.29 (1H, d, J=
15.2Hz), 4.60 (1H, q, J=7.0Hz), 4.39 (1H, d, J=10.0Hz), 3.77 (2H, q, J=7,7Hz), 3.68 (3H,
s),3.51(1H,m),3.55(3H,s),3.49(3H,s),3.48(3H,s),3.42(2H,m),3.30(2H,m),3.25(3H,
S), 2.76 (1H, m), 2.38 (1H, m), 2.19 (1H, m), 1.74 (1H, m), 1.63 (3H, d, J=7.4Hz), 1.61 (3H, t,
J=7.6Hz), 1.58 (2H, m), 1.47, (2H, m), 1.32 (2H, m), -1.82 (1H, s), -2.11 (1H, s)
Embodiment 4
Compound j synthesis
99.2mg commercial compound 2 is placed in 100mL there-necked flasks, 38.2mg 1- (3- dimethylaminos third are added thereto
Base) -3- ethyl carbodiimides, 10mL DMF are lower at a temperature of 0~50 DEG C to stir, the protection of nitrogen ball, TLC (dichloromethane：Methanol
=7:1) monitor, reaction stop after 1.5h.40mL dichloromethane is added into reaction solution, and is transferred to 250mL points of liquid leakages
In bucket, organic layer is washed with deionized water (50mL × 3), to remove DMF and excess EDC, then with saturated aqueous common salt (50mL × 2)
Organic layer is washed, organic layer adds anhydrous sodium sulfate drying, and suction filtration is concentrated under reduced pressure, and 90.1mg atropurpureus solids is obtained, thereto
Adding 10mLDMF dissolves it, adds 16.5mg 2- amino aspartic acid dimethyl esters, 500uL triethylamines, 0~50 DEG C of temperature
Lower stirring, nitrogen ball protection, TLC monitorings, reaction stop after 2h.Add 21.2mg Anhydrous potassium carbonates, 150 μ L into reaction solution
Iodomethane, is stirred at a temperature of continuing 0~50 DEG C, the protection of nitrogen ball, TLC monitorings, and reaction stop after 2h.Add into reaction solution
Enter 20mL dichloromethane, and be transferred to 150mL separatory funnels, organic layer is extracted with deionized water (30mL × 3), to remove DMF,
Organic layer is extracted with saturated aqueous common salt (30mL × 2) again, organic layer adds anhydrous sodium sulfate drying, and suction filtration uses Rotary Evaporators
Concentration of organic layers, obtains crude product, passes through silica gel column chromatography (solvent：Petroleum ether:Ethyl acetate=1:2) purifying is obtained
19.2mg dark green solids, i.e. compound j, yield 66%.UV-vis(CH3OH):λmax(ε/M-1cm-1)664nm,403nm,
ESI-MS m/z:868.3[M+H]+.1H NMR(400MHz,CDCl3)δ9.69(1H,s),9.57(1H,s),8.75(1H,s),
8.05 (1H, dd, J=17.8,11.5Hz), 6.35 (1H, dd, J=17.8,1.2Hz), 6.15 (1H, d, J=11.5,
1.2Hz), 5.29 (1H, d, J=8.4Hz), 5.22 (1H, d, J=8.9Hz), 4.47 (1H, m), 4.22 (3H, s), 3.77 (3H,
Q, J=8.2Hz), 3.56 (3H, s), 3.55 (3H, s), 3.47 (3H, s), 3.38 (3H, s), 3.30 (3H, s), 3.29 (3H,
S), 2.56 (1H, m), 2.31 (1H, m), 2.26 (1H, m), 1.82 (1H, m), 1.70 (3H, d, J=8.1Hz), 1.68 (3H, t,
J=7.6Hz), 1.42 (2H, m), -1.29 (1H, s), -1.43 (1H, s)
Compound k synthesis
99.1mg commercial compound 2 is placed in 100mL three-necked bottles, plus 10mL DMF dissolve it, to reaction under stirring
36.2mg EDCI, 102.6mg N are added in liquidα- tertbutyloxycarbonyl-lysine methyl ester and 1mL triethylamines, at a temperature of 0~50 DEG C
Reaction, nitrogen ball protection, TLC detections, reaction stop after 20min.Add 70.2mg Anhydrous potassium carbonates, 230 μ into reaction solution
L iodomethane, stirring reaction at a temperature of 0~50 DEG C, nitrogen ball protection, TLC monitorings, reaction stop after 2h.Reaction solution is used
40mL dchloromethanes, and 250mL separatory funnels are transferred to, organic layer is extracted with deionized water (50mL × 3), to remove
DMF, then organic layer is extracted with saturated aqueous common salt (50mL × 2), organic layer adds anhydrous sodium sulfate drying, and suction filtration is steamed with rotation
Instrument concentration of organic layers is sent out, crude product is concentrated to give and is purified by silica gel column chromatography, obtain 89.2mg dark green solids, i.e. compound
K, yield 60%.UV-vis(CH3OH):λmax(ε/M-1cm-1)663(126800),607(9000),ESI-MS m/z:867.6[M
+H]+.1H NMR(400MHz,CDCl3) δ 9.72 (1H, s), 9.60 (1H, s), 8.78 (1H, s), 8.05 (1H, dd, J=
11.4Hz, 17.8Hz), 6.36 (1H, dd, J=17.8,1.2Hz), 6.15 (1H, dd, J=11.4,1.2Hz), 5.18 (1H, d,
), J=18.5Hz 5.04 (1H, d, J=18.5Hz), 4.94 (1H, q, J=7.7Hz), 4.43 (1H, d, J=7.2Hz), 4.26
(3H, s), 4.07 (1H, m) 3.79 (1H, q, J=6.8Hz), 3.58 (3H, s), 3.54 (3H, s), 3.48 (3H, s), 3.45
(3H,s),3.30(3H,s),3.12(2H,m),2.59,2.50(1H,m),2.21(1H,m),2.15(1H,m),1.78(1H,
M), 2.19,1.77 (3H, d, J=7.2), 1.66 (3H, t, J=7.5), 1.88 (2H, m), 1.45 (2H, m), 1.34 (9H, s),
1.25(2H,m),-1.41(1H,s),-1.56(1H,s).
Embodiment 5
Compound k metal tin complex k (Sn4+) synthesis
89.2mg compounds k is placed in 100mL three-necked bottles, 10mL methanol, 47.4mg M, oil bath heating are added thereto
To 65 DEG C of stirring reactions, the protection of nitrogen ball, TLC monitorings are reacted and stopped after 3h.Reaction solution is concentrated with Rotary Evaporators, obtained
Crude product with 50mL dichloromethane dissolve, and shift put 250mL separatory funnels, with deionized water (50mL × 3) extract it is organic
Layer, then organic layer is washed with saturated aqueous common salt (50mL × 2), organic layer adds anhydrous sodium sulfate drying, and suction filtration is concentrated to give thick production
Thing.Crude product is recrystallized to give 74.3mg dark green solids, i.e. compound k (Sn again4+), yield 68%.1H NMR
(400MHz,CDCl3) δ 9.95 (1H, s), 9.86 (1H, s), 8.88 (1H, s), 7.98 (1H, dd, J=17.7,11.6Hz),
6.32 (1H, dd, J=17.7,1.2Hz), 6.23 (1H, dd, J=11.6,1.2Hz), 5.23 (2H, m), 4.76 (3H, q, J=
8.9Hz), 4.62 (1H, d, J=8.4Hz), 4.29 (3H, s), 3.90 (2H, q, J=7.6Hz), 3.67 (3H, s), 3.53
(3H,s),3.48(3H,s),3.43(3H,s),3.43(3H,s),2.88(1H,m),2.75(1H,m),2.62(1H,m),2.44
(1H, m), 1.81 (2H, q, J=6.4Hz), 1.75 (3H, d, J=7.2Hz), 1.42 (2H, m), 1.34 (9H, s), 1.26 (2H,
M), 1.14 (2H, m), 0.88 (2H, t, J=6.8Hz)
Application examples 1
Anticancer Activity in vitro is evaluated：
Photodynamic activity：
Compound a~k, positive control drug hematoporphyrin monomethyl ether DMSO are dissolved, -4 DEG C of preservations；In use, using cell
Nutrient solution is diluted to DMSO ultimate density ＜ 0.1%.
By the HepG2 liver cancer cells in exponential phase, with 5 × 103Individual/sky is inoculated in 96 orifice plates, is added per hole
After the μ L of cell suspension 100, culture 24h, 100 μ L decoctions are added, final concentration is respectively 100 μm of ol/L, 30 μm of ol/L, 10 μm of ol/
L, 1 μm of ol/L, 0.1 μm of ol/L, 0.01 μm of ol/L testing compound, set blank group (containing nutrient solution, acellular), control group
(the not dosing of culture cell), cell is in 37 DEG C of incubator (5%CO2) in be incubated 24h after, carry out phototoxicity experiments.Culture plate away from
Highly it is 20cm, light intensity 1.7J/cm from light source2, wavelength 660nmLED, time 2min place into 37 DEG C of incubator (5%CO2) in
It is incubated after 24h, the μ L of MTT solution 20 that concentration is 5mg/mL is added per hole, continues to cultivate 4h, siphon away supernatant, add 100 μ
LDMSO.ELIASA determines the absorbance (OD values) in each hole under 570nm wavelength, calculates IC50.It the results are shown in Table 1
Sound photodynamic activity：
The difference of activity rating of sharing the same light operation is：On the device that 96 orifice plates for adding decoction are placed in bottom hair ultrasound,
De aerated water is added, makes to be suspended on the water surface, away from ultrasonic vocalization probe 2cm, ultrasonic excitation (2MHz, 2W) 2min, 37 DEG C are placed into
Incubator (5%CO2) in be incubated 24h after, per hole add concentration be 5mg/mL the μ L of MTT solution 20, continue cultivate 4h, siphon away
Clear liquid, adds 100 μ LDMSO.ELIASA determines the absorbance (OD values) in each hole under 570nm wavelength, calculates IC50.It the results are shown in Table 2.
Dark toxicity activity：
The difference of activity rating of sharing the same light operation is：96 orifice plates for adding decoction are placed in 2min in darkroom, 37 are placed into
DEG C incubator (5%CO2) in be incubated 24h after, per hole add concentration be 5mg/mL the μ L of MTT solution 20, continue cultivate 4h, siphon away
Supernatant, adds 100 μ LDMSO.ELIASA determines the absorbance (OD values) in each hole under 570nm wavelength, calculates IC50。
External photolytic activity and dark toxicity of the target compound of table 1 to HepG2 liver cancer cells
| Chemical combination name | Dark toxicity IC50/μM | Photolytic activity IC50/μM | Dark toxicity IC50/ |
| Photolytic activity IC50 | |||
| Hematoporphyrin monomethyl ether | >100 | >100 | -- |
| Compound 2 | 52.9±5.0 | 41.2±3.3 | 1.3 |
| Compound a | >100 | 3.3±0.3 | >30.3 |
| Compound b | >100 | 9.1±0.7 | >11.0 |
| Compound c | >100 | 19.5±0.5 | >5.1 |
| Compound d | >100 | 8.3±1.2 | >12.0 |
| Compound e | >100 | 4.8±0.4 | >20.8 |
| Compound f | >100 | 10.4±0.3 | >9.6 |
| Compound g | >100 | 31.2±2.6 | >3.2 |
| Compound h | >100 | 29.5±2.9 | >3.4 |
| Compound i | >100 | 50.3±6.2 | >2.0 |
| Compound j | >100 | 0.3±0.0 | >333.3 |
| Compound k | >100 | 0.8±0.1 | >125.0 |
External sound photodynamic activity and dark toxicity of the target compound of table 2 to HepG2 liver cancer cells
Claims (4)
1. a kind of dihydro porphin light, sound sensitiser, it is characterised in that described dihydro porphin light, sound sensitiser are
2. dihydro porphin light, the preparation method of sound sensitiser described in claim 1, it is characterised in that comprise the following steps：
1. it is raw material with compound 1, it is 4~5 to be dissolved in volume ratio:1 DCM and DMF mixed solution, obtain 0.1M compounds 1
Mixed solution；Sequentially add HOBt, TBTU, DIEA and N- (2- aminoethyls) maleimide, compound 1：HOBt：
TBTU：DIEA：The mol ratio of N- (2- aminoethyls) maleimide is 1：1~2：1~2：0.1~0.5：1~2, reaction 0.5~
Compound a is obtained through amidation process within 4 hours；It is 4 that compound a is dissolved in into volume ratio again:1 THF and the mixed solution of water, are obtained
To the mixed solution of 0.1M compound as, cysteine or glutathione are added, compound a and cysteine or glutathione
Mol ratio is 1：1~3, react 1~6 hour, obtain compound b or compound c；Reaction equation is as follows：
2. it is raw material with compound 2, compound 2 is dissolved in DMF, obtains the DMF solution of 0.1M compounds 2；Add EDCI,
N- (2- aminoethyls) maleimides and triethylamine, react 1~4 hour, add iodomethane and Carbon Dioxide nak response 1~4
Hour, obtain compound d；Wherein, compound 2：EDCI：N- (2- aminoethyls) maleimide：Triethylamine：Iodomethane：It is anhydrous
The mol ratio of potassium carbonate is 1：1~5：1~2：0.1~0.5：2~10：2~10；It is 4 that compound d is dissolved in into volume ratio again:1
THF and water mixed solution, obtain 0.1M compounds d mixed solution, add cysteine or glutathione, and reaction 1~6 is small
When, obtain compound e or compound f；The mol ratio of compound d and cysteine or glutathione is 1：1~3；Reaction equation is such as
Under：
3. it is raw material with compound 2, is dissolved in 5% methanolic solution, obtains 5% methanolic solution of 0.1M compounds 2, instead
Compound 3 should be obtained；It is 4~5 that compound 3 is dissolved in into volume ratio again:1 DCM and DMF mixed solution, obtain 0.1M chemical combination
The mixed solution of thing 3, sequentially adds HOBt, TBTU, DIEA and N- (2- aminoethyls) maleimide, reacts 1~4 hour,
Iodomethane and Anhydrous potassium carbonate are added, reacts 1~6 hour, obtains compound g；Wherein, compound 3：HOBt：TBTU：
DIEA：N- (2- aminoethyls) maleimide：Iodomethane：The mol ratio of Anhydrous potassium carbonate is 1：1~2：1~2：0.1~0.5：1
~2：2~10：2~10；It is 4 that compound g is dissolved in into volume ratio again:In the mixed solution of 1THF and water, 0.1M compounds g is obtained
Mixed solution, add cysteine or glutathione, react 1~6 hour, obtain compound h or compound i；Wherein, chemical combination
The mol ratio of thing g and cysteine or glutathione is 1：1~3；5% methanolic solution is the quality percentage that sulfuric acid accounts for methanol
Than for 5%；Reaction equation is as follows：
4. it is raw material with compound 2, is dissolved in DMF, obtains the DMF solution of 0.1M compounds 2；Add EDCI, 2- amino day
Winter propylhomoserin dimethyl ester or 6- amino -2- tertbutyloxycarbonyls-lysine methyl ester and triethylamine, react 1~4 hour, add iodine first
Alkane and Anhydrous potassium carbonate, react 1~6 hour, obtain compound j or compound k；Wherein, compound 2：EDCI：2- amino asparagus ferns
Propylhomoserin dimethyl ester or 6- amino -2- tertbutyloxycarbonyls-lysine methyl ester：Triethylamine：Iodomethane：The mol ratio of Anhydrous potassium carbonate is
1：1~5：1~3：0.1~0.5：2~10：2~10；
3. dihydro porphin light, the application of sound sensitiser described in claim 1, it is characterised in that described dihydro porphin light,
Sound sensitiser is used to prepare antineoplastic.
4. dihydro porphin light, the application of sound sensitiser described in claim 3, it is characterised in that described dihydro porphin light,
Sound sensitiser is used to as active part prepare targeting antineoplastic medicine thing.
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