CN104017047A - Peptidyl-substituted double-chain benzofuran quinoline derivative as well as preparation method and application thereof - Google Patents
Peptidyl-substituted double-chain benzofuran quinoline derivative as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN104017047A CN104017047A CN201410259439.6A CN201410259439A CN104017047A CN 104017047 A CN104017047 A CN 104017047A CN 201410259439 A CN201410259439 A CN 201410259439A CN 104017047 A CN104017047 A CN 104017047A
- Authority
- CN
- China
- Prior art keywords
- peptidyl
- compound
- double
- quinoline
- cumarone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- QUFYMFLGYQTUBW-UHFFFAOYSA-N 1-benzofuran;quinoline Chemical class C1=CC=C2OC=CC2=C1.N1=CC=CC2=CC=CC=C21 QUFYMFLGYQTUBW-UHFFFAOYSA-N 0.000 title abstract 4
- -1 benzofuran quinoline compound Chemical class 0.000 claims abstract description 33
- 239000003814 drug Substances 0.000 claims abstract description 23
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 17
- 108010016626 Dipeptides Proteins 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 71
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 67
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 32
- 125000001151 peptidyl group Chemical group 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 27
- 239000011347 resin Substances 0.000 claims description 25
- 229920005989 resin Polymers 0.000 claims description 25
- 150000001408 amides Chemical class 0.000 claims description 21
- 229940079593 drug Drugs 0.000 claims description 17
- 238000011275 oncology therapy Methods 0.000 claims description 17
- 150000001413 amino acids Chemical class 0.000 claims description 14
- 238000006482 condensation reaction Methods 0.000 claims description 12
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 6
- 238000005660 chlorination reaction Methods 0.000 claims description 6
- 239000004471 Glycine Substances 0.000 claims description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 4
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 229920001184 polypeptide Polymers 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 238000006751 Mitsunobu reaction Methods 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
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- HNICLNKVURBTKV-NDEPHWFRSA-N (2s)-5-[[amino-[(2,2,4,6,7-pentamethyl-3h-1-benzofuran-5-yl)sulfonylamino]methylidene]amino]-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)N[C@H](C(O)=O)CCCN=C(N)NS(=O)(=O)C1=C(C)C(C)=C2OC(C)(C)CC2=C1C HNICLNKVURBTKV-NDEPHWFRSA-N 0.000 description 17
- 108010017842 Telomerase Proteins 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 7
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 7
- 230000000087 stabilizing effect Effects 0.000 description 7
- KURWKDDWCJELSV-UHFFFAOYSA-N cryptolepine Chemical compound N1=C2C=CC=C[C]2C(N2C)=C1C=C1[C]2C=CC=C1 KURWKDDWCJELSV-UHFFFAOYSA-N 0.000 description 6
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- 0 CN1CCC(COC2=CC3c4nc(cccc5)c5c(NCC(NCC(N)=O)O)c4O*3C*2)CC1 Chemical compound CN1CCC(COC2=CC3c4nc(cccc5)c5c(NCC(NCC(N)=O)O)c4O*3C*2)CC1 0.000 description 3
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229960005503 cryptolepine Drugs 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- QOAKRWLMTKEDDL-UHFFFAOYSA-N 10h-indolo[3,2-b]quinoline Chemical compound C1=CC=C2N=C3C4=CC=CC=C4NC3=CC2=C1 QOAKRWLMTKEDDL-UHFFFAOYSA-N 0.000 description 2
- NDKDFTQNXLHCGO-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)acetic acid Chemical compound C1=CC=C2C(COC(=O)NCC(=O)O)C3=CC=CC=C3C2=C1 NDKDFTQNXLHCGO-UHFFFAOYSA-N 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
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- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 2
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- 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
- 229960004799 tryptophan Drugs 0.000 description 2
- REITVGIIZHFVGU-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](COC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 REITVGIIZHFVGU-IBGZPJMESA-N 0.000 description 1
- ADOHASQZJSJZBT-SANMLTNESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]propanoic acid Chemical compound C12=CC=CC=C2N(C(=O)OC(C)(C)C)C=C1C[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ADOHASQZJSJZBT-SANMLTNESA-N 0.000 description 1
- JAUKCFULLJFBFN-VWLOTQADSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]propanoic acid Chemical compound C1=CC(OC(C)(C)C)=CC=C1C[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 JAUKCFULLJFBFN-VWLOTQADSA-N 0.000 description 1
- SJVFAHZPLIXNDH-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-phenylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=CC=C1 SJVFAHZPLIXNDH-QFIPXVFZSA-N 0.000 description 1
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- CACULOZOWQKVIW-UHFFFAOYSA-N quindoline Natural products c1ccc2c(c1)nc1cc3ccccc3[nH]c21 CACULOZOWQKVIW-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention provides a peptidyl-substituted double-chain benzofuran quinoline derivative. The structural formula of the peptidyl-substituted double-chain benzofuran quinoline derivative is shown in formula (I). In the formula (I), R1 is dipeptide, tripeptide, tetrapeptide and pentapeptide. Experiments prove that the peptidyl-substituted double-chain benzofuran quinoline derivative provided by the invention has very strong inhibition effects on expression of proto-oncogene DNA (deoxyribonucleic acid) such as telomere DNA, c-myc and the like, has significant inhibition effects on various cancer cell lines, has low toxicity to normal cells, is a peptide chain substituted benzofuran quinoline compound with low toxicity and good anti-cancer effects, and has wide application spaces in preparation of anti-cancer medicaments.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, more specifically, relate to a kind of peptidyl and replace double-stranded cumarone quinoline and its preparation method and application.
Background technology
Cancer is one of principal disease threatening human health and life security.According to statistics, the whole world every year newly-increased cancer patients reach 4,000,000 people left and right.The research and development of cancer therapy drug are the focuses that chemist and medicine scholar pay close attention to always.Find efficient, highly selective, cancer therapy drug that toxic side effect is little is one of important directions of drug development research.The synthetic cancer therapy drug taking DNA as shot design, particularly designs synthesized micromolecule inhibitor for the special higher structure of the proto-oncogene such as telomeric dna and the c-myc DNA with important physiological significance, is the important method of Development of Novel cancer therapy drug.There are some common constitutional featuress with the interactional micromolecular compound of telomeric dna: the plane aromatic ring structure that has three or more; An or positively charged side chain under several physiological conditions.Its mechanism of anticancer action be mainly by with the interaction of telomeric dna, the telomerase activation of anticancer, thereby the copying of anticancer.
G-tetra-serobilas, are a kind of four chain DNA spirane structures, are connected to a quadrangle and form, owing to being rich in the guanine base (G) of series connection repetition, so this structure is also referred to as " G4-DNA " by four.Research in the past only thinks that this structure can only synthetic, but the current research of 2013 finds, " four spirals " DNA of " G-tetra-serobilas " is also present in human genome.This four chain DNA spirane structures are found in human cancer cell, because the division of cancer cells is very fast, and conventionally have defect on telomere, and therefore four chain spirane structures are a kind of exclusive features of cancer cells.If really so talked about, any cancer treatment method for this structure all will can not hurt normal healthy cell.The formation of telomeric dna G-tetra-chain body structures can suppress the activity of Telomerase effectively, thereby target telomeric dna G-tetra-serobilas make its stable part become the new direction of cancer therapy drug research.
Indoles quinolines is the more rare a kind of alkaloid of occurring in nature, there is the structure of four plane aromatic rings, quindoline and cryptolepine are the Typical Representatives of this compounds, and these two kinds of compounds were separated first with nineteen twenty-nine respectively at 1977 from the plant Cryptolepis sanguinolenta of West Africa.This research group has successively reported indoles quinoline derivatives (J.Med.Chem.2005,48, the 7315-7321 of a series of 11 bit amino side substitution; J.Med.Chem.2008,51,6381-6392) by interacting and suppress telomerase activation with telomere G-tetra-serobila DNA, multiple JEG-3 is had to significant restraining effect.Although the anticancer effect of indoles quinolines is confirmed, but because current existing multiple indoles quinolines still has much room for improvement to the selective power of G-tetra-serobila DNA, while is due to the resource-constrained of occurring in nature indoles quinolines, at present, still there is larger restriction in the application of anticancer aspect in indoles quinolines.Cumarone quinoline is a kind of isostere of indoles quinoline, therefore has similar function to indoles quinolines.
Kenji Usui seminar of Japan has reported the short peptide sequence that screens specific binding G-tetra-serobila DNA by the method in structure combined peptide storehouse recently, and then screening antineoplastic drugs.KWK (Lai-Se-Methionin) be reported can fine combination DNA tripeptides, research is taking it as core, connect the various tripeptide sequence of variation at P for N-terminal (proline(Pro)) or G (glycine), obtained the little peptide storehouses of 32 different seven peptides compositions of charging property and hydrophobicity.Further biological means screening find this seven peptide sequence of KFEGKWK can be selectively in conjunction with and stablize positive parallel type c-myc G-tetra-serobila DNA, and to the G-tetra-serobila structure functions of other conformation a little less than.Therefore transforming as basis taking the feature of cumarone quinolines and peptide class sequence, is a feasible way finding to have better antitumour activity lead compound.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, provide the peptide chain that a kind of toxicity is little, anticancer effect is good to replace benzo furoquinoline compounds.
The present invention is according to the constitutional features of some and the interactional micromolecular compound of telomeric dna (cryptolepine derivative), introduce peptide (amino acid) chain, obtain replacing double-stranded cumarone quinoline with the interactional peptidyl of telomeric dna for 11 that the cumarone quinoline replacing at 7-position fat amido is precursor skeleton.
Above-mentioned technical purpose of the present invention is to be achieved through the following technical solutions above-mentioned purpose:
A kind of peptidyl replaces double-stranded cumarone quinoline, and structural formula is suc as formula shown in I,
Described R
1for dipeptides, tripeptides, tetrapeptide, pentapeptide.
Described R
1aminoacid sequence be GG, GR, GH, GK, KR, HR, GRH, GRK, GRR, GRF, GRY, GRW, GRE, GRD, GRQ, GRS, GRA, GRRG or GRHG.Wherein G represents glycine, and R represents arginine, and K represents Methionin, and H represents Histidine, and F represents phenylalanine, and Y represents tyrosine, and E represents L-glutamic acid, and D represents aspartic acid, W representative color propylhomoserin, and Q represents glutamine, and S represents Serine, and A represents L-Ala.
Further provide above-mentioned peptidyl to replace the preparation method of double-stranded cumarone quinoline, comprise the following steps:
S1. will
in alkaline environment, carry out hydrocarbyl reaction with Mono Chloro Acetic Acid, then carry out chlorination with sulfur oxychloride again, obtain compound
S2. S1 gained and anthranilic acid are carried out to condensation reaction, obtain compound
S3. S2 gained and polyphosphoric acid are carried out to ring-closure reaction, obtain compound
S4. S3 gained is carried out to chlorination, obtain compound
S5. utilize boron tribromide to slough the methyl of methoxyl group in the structure of S4 gained, obtain compound
S6. the compound of S5 gained is first carried out to mitsunobu reaction, then react with hydramine, obtain compound
S7. S6 gained and glycine are carried out to substitution reaction, obtain compound
S8. finally by S7 gained and R
1carry out condensation reaction, obtain peptidyl and replace double-stranded cumarone quinoline.
The solvent that reaction described in S7 is used is phenol.
Condensation reaction described in S8 is to obtain by the amino acid of Fmoc radical protection being connected on Rink Amide AM resin.
Condensation reaction described in S8 is to be undertaken after condensation reaction by polypeptide solid-state reaction method, sloughs resin with trifluoroacetic acid, and the described peptidyl of final acquisition replaces double-stranded cumarone quinoline.
Further provide above-mentioned peptidyl to replace double-stranded cumarone quinoline in the application of preparing in cancer therapy drug.
The formulation of described cancer therapy drug is tablet, pill, capsule, injection, suspension agent or emulsion.
Described cancer therapy drug is preferably anti-lung-cancer medicament.
The present invention is according to the constitutional features of some and the interactional micromolecular compound of telomeric dna (cryptolepine derivative), introduce peptide (amino acid) chain, obtain replacing double-stranded cumarone quinoline with the interactional peptidyl of telomeric dna for 11 that the cumarone quinoline replacing at 7-position fat amido is precursor skeleton.
It is the novel G-tetra-serobila small molecules parts that replace according to a series of peptide chains of small molecules part and the interactional constructional feature appropriate design of G-tetra-serobila that 11-position peptidyl involved in the present invention replaces double-stranded cumarone quinoline.Mechanism of action is mainly by tetrad plane generation pi-pi accumulation effect and the electrostatic interaction to a certain degree of the secondary structure of small molecules part and the formation of rich guanine sequence.And the 11-position peptide chain of part can increase sterically hindered in the time that double-stranded DNA is combined of small molecules part, also increase the groove contact ability to G-tetra-serobilas, thereby finally reached the selective power that improves G-tetra-serobilas and the object of affinity simultaneously.
Related peptidyl of the present invention replaces double-stranded cumarone quinoline and has very strong interaction with the telomeric dna that is rich in guanine, shows the Telomerase in cancer cells is had to good inhibition activity.Further experiment proves, it is inhibited to multiple JEG-3 that peptidyl involved in the present invention replaces double-stranded cumarone quinoline, and toxicity is less, therefore can be used for preparing cancer therapy drug.Especially applicable, prepare anti-lung-cancer medicament but be not limited to.
Compared with prior art, the present invention has following beneficial effect:
1. novel peptidyl of the present invention replaces double-stranded cumarone quinoline and has very strong interaction with the telomeric dna that is rich in guanine, shows the inhibition activity good to the Telomerase in cancer cells, thereby multiple JEG-3 is had to significant restraining effect;
2. to replace double-stranded cumarone quinoline little to normal cytotoxicity for novel peptidyl of the present invention, safe in the application of preparing cancer therapy drug;
3. novel peptidyl of the present invention replaces double-stranded cumarone quinoline and can be made into the cancer therapy drug of various formulations, has very high medical value and wide market outlook.
Embodiment
Further describe the present invention below in conjunction with specific embodiment.Unless stated otherwise, reagent, equipment and the method that the present invention adopts is the conventional commercial reagent of the art, equipment and the conventional method using.
Embodiment mono-: Compound D synthetic
0.3mol Mono Chloro Acetic Acid is dissolved in 60ml water, with sodium hydroxide tune pH to 9, add again 0.2mol MEHQ, 100 DEG C of backflows, obtain T1, then add again sulfur oxychloride to carry out chlorination, obtain T2, boil off sulfur oxychloride solvent and obtain brown liquid, carry out condensation reaction with anthranilic acid again, obtain T3, then PPA being preheated to 130 DEG C adds T3 to carry out combination reaction, obtain compound T4, T4 and sulfur oxychloride are carried out to chlorination 80 DEG C of backflows, obtain compound T5, in methylene dichloride, utilize afterwards boron tribromide to slough 7 methyl, obtain compound T6.Then do under the condition of solvent at chloroform (300mL), add 6.0g triphenylphosphine, 2.0g T6,6mL N-methyl-4-piperidine carbinols, 6mL diisopropyl azodiformate, N
2under protection, drip diisopropyl azodiformate, drip rear normal-temperature reaction and spend the night.Filter, revolve and steamed the laggard row chromatographic column separation of solvent, obtain compound T7, last T7 does at phenol under the condition of solvent, and with glycine reactant 12h, chromatographic column separates and obtains sterling D.
Productive rate: 89%;
1h NMR (400MHz, DMSO) δ 8.33 (d, J=8.0Hz, 1H), 8.05 – 7.97 (m, 1H), 7.66 (s, 2H), 7.55 (d, J=8.3Hz, 1H), 7.53 – 7.43 (m, 1H), 7.17 (d, J=8.0Hz, 1H), 4.50 (s, 2H), 4.01 – 3.87 (m, 2H), 3.19 (d, J=21.2Hz, 2H), 2.73 – 2.61 (m, 1H), 2.55 (s, 3H), 1.91 (d, J=11.7Hz, 3H), 1.62 – 1.45 (m, 2H);
C
24H
25N
3O
4,LC-MS m/z：420[M+H]
+.
Embodiment bis-: Compound D GG's is synthetic
Fmoc-Gly-OH amino acid is dissolved in DMF (dimethyl formamide) solvent, add HOBT (I-hydroxybenzotriazole), DIC (N, N-DIC) two kinds of condensation reagents (1:1), in solid phase reactor with the Rink Amide AM resin reaction 3h of deprotection, use again 5% piperidines, 2%DBU (1, 8-diazabicylo [5.4.0] 11 carbon-7-alkene) and the mixed solution of 93%DMF slough Fmoc group, obtain amino acid side chain, and then again Fmoc-Gly-OH amino acid is connected on the amino acid that accesses resin with aforesaid method.
Finally itself and D are carried out to condensation reaction in the DMF of HOBT, DIC solution, 72h, sloughs resin with trifluoroacetic acid, collects, and purifies with preparative high-performance liquid chromatographic, finally obtains white solid DGG.
Faint yellow solid; Productive rate: 43%.Fusing point: 171-173 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 9.48 (s, 1H), 8.64 (t, J=5.3Hz, 1H), 8.59 (d, J=8.4Hz, 1H), 8.12 (dd, J=11.5, 7.0Hz, 2H), 8.01 (t, J=7.4Hz, 1H), 7.91 (s, 1H), 7.79 (d, J=9.2Hz, 1H), 7.77-7.72 (m, 1H), 7.45 (d, J=8.8Hz, 1H), 7.23 (s, 1H), 7.02 (s, 1H), 4.73 (d, J=5.9Hz, 2H), 4.00 (d, J=5.6Hz, 2H), 3.82 (d, J=5.3Hz, 2H), 3.61 (d, J=5.4Hz, 2H), 3.01 (d, J=11.4Hz, 4H), 2.79 (s, 3H), 2.05 (d, J=14.4Hz, 2H), 1.90 (s, 1H), 1.64-1.48 (m, 2H), HRMS (ESI): m/z calcd for C
28h
32n
6o
5([M+H]
+) 533.2507, found533.2518.
Embodiment tri-: Compound D GR's is synthetic
Method is with embodiment bis-, and different is that Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH amino acid are connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DGR.
Faint yellow solid; Productive rate: 31%.Fusing point: 182-183 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 9.63 (s, 1H), 8.60 (s, 2H), 8.16 (d, J=8.0Hz, 1H), 8.07 (d, J=5.5Hz, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.81-7.65 (m, 3H), 7.69 (s, 1H), 7.44 (d, J=8.8Hz, 1H), 7.37 (s, 1H), 7.08 (s, 1H), 4.73 (d, J=3.4Hz, 2H), 4.19 (s, 1H), 3.99 (d, J=3.9Hz, 2H), 3.84 (s, 2H), 3.05 (s, 6H), 2.79 (s, 3H), 2.05 (d, J=14.1Hz, 3H), 1.67 (s, 2H), 1.57 (d, J=12.2Hz, 2H), 1.45 (d, J=4.4Hz, 4H)., HRMS (ESI): m/z calcd for C
32h
41n
9o
5([M+2H]
2+), 316.6688found316.6175.
Embodiment tetra-: Compound D GH's is synthetic
Method is with embodiment bis-, and different is that Fmoc-His (Trt)-OH, Fmoc-Gly-OH amino acid are connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DGH.
Faint yellow solid; Productive rate: 34%.Fusing point: 161-163 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 8.88 (s, 1H), 8.64-8.51 (m, 2H), 8.27 (d, J=8.0Hz, 1H), 8.12 (d, J=8.5Hz, 1H), 8.00-7.93 (m, 1H), 7.89 (s, 1H), 7.72 (d, J=9.2Hz, 2H), 7.40 (s, 2H), 7.25 (d, J=13.9Hz, 2H), 4.70 (s, 2H), 4.49 (d, J=4.9Hz, 1H), 4.00 (d, J=4.8Hz, 2H), 3.84-3.78 (m, 2H), 3.10 (dd, J=15.4, 4.9Hz, 2H), 3.03-2.94 (m, 2H), 2.88 (dd, J=15.4, 8.8Hz, 2H), 2.79 (s, 3H), 2.05 (d, J=13.8Hz, 3H), 1.69-1.47 (m, 2H), HRMS (ESI): m/z calcd for C
32h
36n
8o
5([M+2H]
2+) 307.1477, found307.1507.
Embodiment five: Compound D GK's is synthetic
Method is with embodiment bis-, and different is that Fmoc-Lys-OH, Fmoc-Gly-OH amino acid are connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DGK.
Faint yellow solid; Productive rate: 33%.Fusing point: 179-180 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 9.56 (s, 1H), 8.65-8.57 (m, 2H), 8.15 (d, J=8.4Hz, 1H), 8.08-7.98 (m, 2H), 7.93 (s, 1H), 7.78 (d, J=9.5Hz, 1H), 7.73 (d, J=6.9Hz, 3H), 7.44 (d, J=10.0Hz, 1H), 7.34 (s, 1H), 7.04 (s, 1H), 4.73 (d, J=6.0Hz, 2H), 4.16 (d, J=8.4Hz, 1H), 4.00 (d, J=5.6Hz, 2H), 3.87-3.79 (m, 2H), 3.50 (d, J=14.6Hz, 2H), 3.01 (dd, J=22.6, 11.1Hz, 2H), 2.72 (d, J=5.7Hz, 3H), 2.07 (t, J=14.8Hz, 2H), 1.74-1.60 (m, 1H), 1.55 (s, 1H), 1.48 (d, J=8.5Hz, 4H), 1.26 (d, J=7.0Hz, 2H) .HRMS (ESI): m/z calcd for C
32h
41n
7o
5([M+2H]
2+), 302.6657found302.6683.
Embodiment six: Compound D KR's is synthetic
Method is with embodiment bis-, and different is that Fmoc-Arg (Pbf)-OH, Fmoc-Lys-OH amino acid are connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DKR.
Faint yellow solid; Productive rate: 33%.Fusing point: 184-186 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 9.70 (s, 1H), 9.55 (s, 1H), 8.58 (dd, J=14.0, 8.5Hz, 2H), 8.18 (d, J=8.4Hz, 1H), 8.08 (s, 1H), 8.04-7.99 (m, 1H), 7.97 (d, J=2.5Hz, 1H), 7.77 (d, J=7.8Hz, 2H), 7.73 (d, J=9.1Hz, 2H), 7.46 (dd, J=9.2, 2.6Hz, 1H), 7.38 (s, 1H), 7.07 (s, 1H), 4.76-4.70 (m, 2H), 4.34 (d, J=5.1Hz, 1H), 4.19-4.12 (m, 1H), 3.97 (d, J=5.9Hz, 2H), 3.51 (d, J=10.9Hz, 2H), 3.00 (dd, J=20.7, 7.5Hz, 4H), 2.79 (s, 3H), 2.65 (s, 2H), 2.16-1.99 (m, 3H), 1.70-1.24 (m, 14H), HRMS (ESI): m/z calcd for C
36h
50n
10o
5([M+2H]
2+) 352.2056, found352.2078.
Embodiment seven: Compound D HR's is synthetic
Method is with embodiment bis-, and different is that Fmoc-Arg (Pbf)-OH, Fmoc-His (Trt)-OH amino acid is connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DHR.
Faint yellow solid; Productive rate: 30%.Fusing point: 179-181 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 9.63 (s, 1H), 9.51 (s, 1H), 8.90 (s, 1H), 8.80 (d, J=7.3Hz, 1H), 8.59 (d, J=8.0Hz, 1H), 8.20 (dd, J=13.1, 8.1Hz, 2H), 8.07-7.99 (m, 1H), 7.95 (s, 1H), 7.74 (dd, J=16.8, 7.1Hz, 2H), 7.65 (d, J=8.8Hz, 1H), 7.53 (s, 1H), 7.44 (d, J=8.9Hz, 1H), 7.32 (s, 1H), 7.20 (s, 1H), 4.72 (s, 2H), 4.16 (s, 1H), 3.98 (d, J=2.5Hz, 1H), 3.51 (d, J=11.2Hz, 2H), 3.11 (d, J=12.9Hz, 2H), 3.00 (s, 6H), 2.79 (s, 3H), 2.03 (s, 3H), 1.79-1.23 (m, 8H), HRMS (ESI): m/z calcd for C
36h
45n
11o
5([M+2H]
2+) 356.6875, found356.6893.
Embodiment eight: Compound D GRH's is synthetic
Method is with embodiment bis-, and different is that Fmoc-His (Trt)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH amino acid are connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DGRH.
Faint yellow solid; Productive rate: 25%.Fusing point: 172-173 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 9.52 (d, J=68.1Hz, 1H), 8.91 (s, 1H), 8.64 (s, 1H), 8.58 (d, J=8.4Hz, 1H), 8.21 (d, J=7.6Hz, 2H), 8.15 (d, J=8.4Hz, 1H), 8.03-7.96 (m, 1H), 7.93 (s, 1H), 7.73 (dd, J=16.4, 8.4Hz, 2H), 7.65 (s, 1H), 7.43 (d, J=7.6Hz, 1H), 7.32 (s, 1H), 7.27 (s, 1H), 7.21 (s, 1H), 4.75 (s, 2H), 4.46 (d, J=5.7Hz, 1H), 4.23 (d, J=5.8Hz, 1H), 3.98 (d, J=4.9Hz, 2H), 3.83 (d, J=4.7Hz, 2H), 3.10-2.98 (m, 6H), 2.93-2.86 (m, 2H), 2.79 (s, 3H), 2.13-1.98 (m, 3H), 1.73-1.53 (m, 4H), 1.51-1.33 (m, 4H), HRMS (ESI): m/z calcd for C
38h
48n
12o
6([M+2H]
2+), 385.1983found385.2002.
Embodiment nine: Compound D GRK's is synthetic
Method is with embodiment bis-, and different is that Fmoc-Lys-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH amino acid are connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DGRK.
Faint yellow solid; Productive rate: 27%.Fusing point: 181-182 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 8.57 (d, J=10.1Hz, 2H), 8.12 (dd, J=15.4, 8.0Hz, 2H), 8.02-7.90 (m, 3H), 7.73 (dd, J=21.0, 8.6Hz, 4H), 7.62 (d, J=5.3Hz, 1H), 7.43 (d, J=9.6Hz, 1H), 7.29 (s, 2H), 7.16 (s, 2H), 7.03 (s, 2H), 4.73 (d, J=3.8Hz, 2H), 4.29 (d, J=5.0Hz, 1H), 4.20-4.10 (m, 1H), 4.00 (s, 2H), 3.82 (d, J=1.6Hz, 2H), 3.04 (dd, J=12.0, 6.3Hz, 6H), 2.79 (s, 3H), 2.72 (d, J=3.5Hz, 2H), 2.17-2.00 (m, 3H), 1.65 (dd, J=14.1, 6.8Hz, 2H), 1.50 (dd, J=19.1, 11.1Hz, 8H), 1.25 (dd, J=12.4, 9.6Hz, 4H), HRMS (ESI): m/z calcd for C
38h
53n
11o
6([M+2H]
2+) 380.7163, found380.7193.
Embodiment ten: Compound D GRR's is synthetic
Method is with embodiment bis-, and different is that Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH amino acid are connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DGRR.
Faint yellow solid; Productive rate: 30%.Fusing point: 185-186 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 9.49 (s, 1H), 8.58 (d, J=2.1Hz, 2H), 8.12 (t, J=8.7Hz, 2H), 7.98 (d, J=7.4Hz, 2H), 7.92 (s, 1H), 7.80-7.70 (m, 2H), 7.60 (s, 1H), 7.56 (s, 1H), 7.43 (d, J=9.2Hz, 1H), 7.32 (s, 1H), 7.24 (s, 1H), 7.11 (s, 1H), 7.04 (s, 1H), 6.98 (s, 1H), 4.73 (d, J=4.3Hz, 2H), 4.31 (d, J=13.5Hz, 1H), 4.17 (d, J=6.0Hz, 1H), 4.00 (d, J=5.3Hz, 2H), 3.83 (s, 2H), 3.50 (d, J=11.8Hz, 2H), 3.06 (d, J=6.1Hz, 6H), 2.80 (s, 3H), 2.07 (t, J=13.9Hz, 3H), 1.74-1.39 (m, 10H), HRMS (ESI): m/z calcd for C
38h
53n
13o
6([M+2H]
2+) 394.7194, found394.7224.
Embodiment 11: Compound D GRF's is synthetic
Method is with embodiment bis-, and different is that Fmoc-Phe-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH amino acid are connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DGRF.
Faint yellow solid; Productive rate: 29%.Fusing point: 179-180 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 9.47 (s, 1H), 8.58 (d, J=7.1Hz, 2H), 8.14-8.06 (m, 2H), 8.01-7.96 (m, 1H), 7.88 (s, 2H), 7.78-7.69 (m, 2H), 7.51-7.40 (m, 2H), 7.28 (s, 1H), 7.16 (dd, J=17.4, 7.1Hz, 6H), 7.01 (s, 1H), 4.73 (s, 2H), 4.43-4.34 (m, 1H), 4.19 (t, J=12.1Hz, 1H), 3.99 (d, J=7.7Hz, 2H), 3.79 (d, J=14.6Hz, 2H), 3.50 (d, J=14.0Hz, 2H), 3.05-2.92 (m, 6H), 2.79 (s, 3H), 2.18-1.95 (m, 3H), 1.61-1.52 (m, 2H), 1.36 (d, J=16.6Hz, 5H), 1.23 (s, 1H), HRMS (ESI): m/z calcd for C
41h
50n
10o
6([M+2H]
2+) 390.2030, found390.2049.
Embodiment 12: Compound D GRY's is synthetic
Method is with embodiment bis-, and different is that Fmoc-Tyr (tBu)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH amino acid are connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DGRY.
Faint yellow solid; Productive rate: 25%.Fusing point: 174-175 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 9.38 (s, 1H), 9.12 (s, 1H), 8.55 (s, 2H), 8.09 (d, J=4.3Hz, 2H), 7.85 (s, 2H), 7.71 (d, J=16.4Hz, 2H), 7.43 (d, J=12.5Hz, 2H), 7.27 (s, 1H), 7.09 (s, 1H), 6.96 (s, 4H), 6.60 (d, J=6.5Hz, 2H), 4.71 (s, 2H), 4.30 (s, 1H), 4.24 (s, 1H), 4.01 (s, 2H), 3.81 (s, 2H), 3.47 (d, J=9.9Hz, 2H), 3.02 (s, 6H), 2.79 (s, 3H), 2.05 (d, J=13.7Hz, 3H), 1.66-1.51 (m, 3H), 1.40 (s, 3H), 1.24 (s, 2H) .HRMS (ESI): m/z calcd for C
41h
50n
10o
7([M+2H]
2+) 398.2005, found398.2017.
Embodiment 13: Compound D GRW's is synthetic
Method is with embodiment bis-, and different is that Fmoc-Trp (Boc)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH amino acid are connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DGRW.
Faint yellow solid; Productive rate: 24%.Fusing point: 164-165 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 10.73 (s, 1H), 9.29 (s, 1H), 8.53 (s, 2H), 8.06 (s, 2H), 7.93 (s, 2H), 7.82 (s, 1H), 7.72 (s, 1H), 7.53 (s, 1H), 7.39 (s, 1H), 7.32 (s, 2H), 7.21 (s, 1H), 7.11-6.93 (m, 5H), 4.70 (s, 2H), 4.44 (s, 1H), 4.28 (s, 1H), 4.00 (s, 2H), 3.81 (s, 2H), 3.48 (s, 2H), 3.07-2.99 (m, 6H), 2.79 (s, 3H), 2.65 (d, J=14.5Hz, 2H), 2.06 (s, 3H), 1.63 (s, 2H), 1.42 (s, 4H), 1.24 (s, 2H), HRMS (ESI): m/z calcd for C
43h
51n
11o
6([M+2H]
2+) 409.7085, found409.7118.
Embodiment 14: Compound D GRE's is synthetic
Method is with embodiment bis-, and different is that Fmoc-Glu (tBu)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH amino acid are connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DGRE.
Faint yellow solid; Productive rate: 31%.Fusing point: 178-179 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 9.44 (s, 1H), 8.59 (s, 2H), 8.12 (d, J=7.8Hz, 2H), 8.03-7.94 (m, 2H), 7.90 (s, 1H), 7.81-7.68 (m, 2H), 7.47 (d, J=19.4Hz, 2H), 7.28 (s, 1H), 7.04 (s, 1H), 4.74 (s, 2H), 4.29 (d, J=3.6Hz, 1H), 4.17 (s, 1H), 4.01 (s, 2H), 3.84 (s, 2H), 3.05 (s, 4H), 2.87 (s, 2H), 2.79 (s, 3H), 2.21 (s, 2H), 2.06 (d, J=13.4Hz, 2H), 1.90 (s, 1H), 1.74 (s, 2H), 1.50 (dd, J=46.4, 18.2Hz, 6H), 1.14 (s, 2H), HRMS (ESI): m/z calcd for C
37h
48n
10o
8([M+2H]
2+) 381.1901, found381.1933.
Embodiment 15: Compound D GRD's is synthetic
Method is with embodiment bis-, and different is that Fmoc-Asp (OtBu)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH amino acid are connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DGRD.
Faint yellow solid; Productive rate: 29%.Fusing point: 182-184 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 9.37 (d, J=5.9Hz, 1H), 8.57 (s, 2H), 8.20-8.06 (m, 3H), 8.01-7.95 (m, 1H), 7.87 (d, J=2.1Hz, 1H), 7.79-7.67 (m, 2H), 7.52-7.40 (m, 2H), 7.22 (s, 1H), 7.07 (d, J=15.3Hz, 3H), 6.97 (s, 1H), 4.72 (s, 2H), 4.51-4.40 (m, 1H), 4.30-4.19 (m, 1H), 4.00 (s, 2H), 3.82 (s, 2H), 3.03 (s, 6H), 2.78 (s, 3H), 2.68-2.58 (m, 2H), 2.04 (d, J=13.6Hz, 3H), 1.72-1.61 (m, 2H), 1.57-1.38 (m, 6H), HRMS (ESI): m/z calcd for C
36h
46n
10o
8([M+2H]
2+) 374.1823, found374.1847.
Embodiment 16: Compound D GRQ's is synthetic
Method is with embodiment bis-, and different is that Fmoc-Gln-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH amino acid are connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DGRQ.
Faint yellow solid; Productive rate: 26%.Fusing point: 176-177 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 9.49 (s, 1H), 8.59 (s, 2H), 8.12 (s, 2H), 7.99 (s, 2H), 7.92 (s, 1H), 7.82-7.70 (m, 2H), 7.53 (s, 1H), 7.44 (d, J=8.3Hz, 1H), 7.26 (s, 2H), 7.12 (s, 1H), 7.01 (s, 1H), 6.73 (s, 1H), 4.74 (s, 2H), 4.28 (s, 1H), 4.13 (d, J=4.7Hz, 1H), 4.00 (s, 2H), 3.84 (s, 2H), 3.02 (d, J=19.4Hz, 6H), 2.79 (s, 3H), 2.07 (m, 4H), 1.87 (d, J=5.8Hz, 2H), 1.77-1.63 (m, 2H), 1.58-1.40 (m, 5H), 1.24 (s, 1H), HRMS (ESI): m/z calcd for C
37h
49n
11o
7([M+2H]
2+) 380.6981, found380.7002.
Embodiment 17: Compound D GRS's is synthetic
Method is with embodiment bis-, and different is that Fmoc-Ser (tBu)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH amino acid are connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DGRS.
Faint yellow solid; Productive rate: 27%.Fusing point: 174-176 DEG C;
1h NMR (400MHz, DMSO-d
6) δ 9.30 (s, 1H), 8.54 (s, 2H), (8.09 d, J=19.0Hz, 2H), 7.86 (d, J=21.0Hz, 2H), 7.73 (s, 2H), 7.42 (s, 2H), 7.22 (s, 2H), (7.00 d, J=38.6Hz, 2H), 4.88 (s, 1H), 4.69 (s, 2H), 4.34 (s, 1H), 4.18 (s, 1H), 4.01 (s, 2H), 3.82 (s, 2H), 3.50 (s, 2H), 3.05 (m, 6H), 2.78 (s, 3H), 2.05 (d, J=11.0Hz, 3H), 1.46 (dd, J=99.5,76.7Hz, 8H); HRMS (ESI): m/z calcd for C
36h
48n
10o
7([M+2H]
2+) 367.1926; Found367.1960.
Embodiment 18: Compound D GRA's is synthetic
Method is with embodiment bis-, and different is that Fmoc-Ala-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH amino acid are connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DGRA.
Faint yellow solid; Productive rate: 21%.Fusing point: 177-179 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 9.49 (d, J=17.1Hz, 1H), 8.60 (s, 2H), 8.14 (d, J=7.8Hz, 2H), 8.02 (s, 1H), 7.93 (s, 2H), 7.83-7.70 (m, 2H), 7.54 (s, 1H), 7.45 (d, J=8.1Hz, 1H), 7.24 (s, 1H), 7.12 (s, 1H), 6.99 (s, 1H), 6.94 (s, 1H), 4.75 (s, 2H), 4.29 (s, 1H), 4.17 (d, J=6.4Hz, 1H), 4.01 (s, 2H), 3.84 (s, 2H), 3.05 (s, 6H), 2.80 (s, 3H), 2.06 (d, J=13.4Hz, 3H), 1.67 (s, 1H), 1.62-1.42 (m, 5H), 1.23 (s, 2H), 1.18 (s, 3H), HRMS (ESI): m/z calcd for C
35h
46n
11o
6([M+2H]
2+) 352.1874, found352.1904.
Embodiment 19: Compound D GRRG's is synthetic
Method is with embodiment bis-, and different is that Fmoc-Gly-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH amino acid are connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DGRRG.
Faint yellow solid; Productive rate: 25%.Fusing point: 159-161 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 9.58 (s, 1H), 8.56 (s, 2H), 8.13 (s, 2H), 8.06 (s, 1H), 7.95 (d, J=18.1Hz, 2H), 7.78-7.70 (m, 2H), 7.59 (s, 2H), 7.43 (d, J=7.5Hz, 1H), 7.26 (s, 1H), 7.13 (s, 1H), 7.08 (s, 1H), 7.01 (s, 1H), 4.73 (s, 2H), 4.31 (s, 1H), 4.22 (s, 1H), 4.00 (s, 2H), 3.83 (s, 2H), 3.65 (d, J=16.9Hz, 2H), 3.17 (s, 2H), 3.05 (s, 6H), 2.79 (s, 3H), 2.05 (d, J=13.7Hz, 3H), 1.67 (s, 5H), 1.51 (d, J=28.8Hz, 8H), 1.24 (s, 1H), HRMS (ESI): m/z calcd for C
40h
56n
14o
7([M+2H]
2+) 423.2301, found423.2328.
Embodiment 20: Compound D GRHG's is synthetic
Method is with embodiment bis-, different is by Fmoc-Gly-OH, Fmoc-His (Trt)-OH, Fmoc-Arg (Pb f)-OH, Fmoc-Gly-OH amino acid be connected on Rink Amide AM resin successively.Final through preparing high efficiency chromatography purifying, finally obtain faint yellow solid DGRHG.
Faint yellow solid; Productive rate: 19%.Fusing point: 160-161 DEG C,
1h NMR (400MHz, DMSO-d
6) δ 8.90 (s, 1H), 8.57 (s, 2H), 8.24 (s, 1H), 8.19-8.10 (m, 2H), 7.97 (s, 1H), 7.90 (s, 1H), 7.73 (s, 2H), 7.56 (s, 1H), 7.45 (s, 2H), 7.32 (s, 1H), 7.24 (s, 1H), 7.20 (s, 1H), 7.11 (s, 1H), 6.98 (s, 1H), 4.74 (s, 2H), 4.55 (s, 1H), 4.27 (s, 1H), 4.00 (s, 2H), 3.83 (s, 2H), 3.69 (s, 2H), 3.04 (t, J=23.5Hz, 6H), 2.79 (s, 3H), 2.65 (d, J=4.4Hz, 2H), 2.05 (d, J=13.7Hz, 3H), 1.68-1.53 (m, 4H), 1.43 (s, 3H), 1.24 (s, 1H), HRMS (ESI): m/z calcd for C
40h
51n
13o
7([M+2H]
2+) 413.7090, found413.7108.
Embodiment 21: peptidyl of the present invention replaces the stabilization of double-stranded cumarone quinoline to G-tetra-serobila DNA.
Select the compound of embodiment bis-～20 preparation, adopt this series compound of FRET (fluorescence resonance energy transfer) (FRET) fusing point the effects can form the rich G sequence F21T (FAM-d[G of G-tetra-serobila DNA to telomere end
3(T
2aG
3)
3]-TAMRA), oncogene c-myc promoter region can form the rich G sequence Pu18 (FAM-d[AG3TG3TAG3TG3TA]-TAMRA) of G-tetra-serobilas, ckit-1 and can form the stabilizing power of the rich G sequence bcl-2 of G-tetra-serobilas.The sequence F10T (FAM-d[TATAGCTATA-HEG-TATAGC-TATA]-TAMRA) that has simultaneously also chosen double-stranded DNA hairpin structure is as with reference to DNA sequence dna, for studying the selectivity of compound between G-tetra-serobilas and double-stranded DNA.Test the change Delta T that has obtained the melting temperature(Tm) of a series of compound to different G-tetra-serobila DNA by FRET
mvalue (melting temperature, in table 1).
Utilize the method to calculate the Δ T of stability of compounds G-tetra-serobila DNA
m(as table 4-1), by table, 4-1 can find out, 11-peptidyl replaces the Δ T of double-stranded cumarone quinoline compound to G-tetra-serobila DNA
mvalue all more than 10 DEG C, have at 20 DEG C even up to 30 DEG C.And the ability of such stability of compounds G-tetra-serobila DNA is more much higher than the compound 2c having reported, as the Δ T of compound f3 to telomere G-tetra-serobilas
mhigher 10.7 DEG C than 2c, higher 10.9 DEG C than 2c to c-myc G-tetra-serobilas, higher 10 DEG C than 2c to c-kit1G-tetra-serobilas.Two three or four amino acids formed polypeptide are introduced in compound 11-position, as seen from table, introduce two amino acid whose activity better, when introducing after the 3rd amino acid, the ability of stability of compounds G-tetra-serobila DNA slightly declines, and its stabilizing power is stronger than other amino acid in the time that the 3rd amino acid of compound peptide chain is basic aminoacids or aromatic amino acid.But in the time that the 3rd amino acid is tryptophane, the ability of its stable G-tetra-serobilas obviously weakens, may be because the aromatic group in tryptophane is too large, hinder compound peptide chain and be combined with groove or the loop of G-tetra-serobilas, thereby reduced interaction.The stabilizing power difference of this compounds to different G-tetra-serobila DNA simultaneously, wherein compound is generally strong than the stabilizing power of other two kinds of G-tetra-serobila DNA to the stabilizing power of c-kit1G-tetra-serobilas, as the Δ T of f19 to c-kit1G-tetra-serobilas
mbe 35.6 DEG C, 15.3 DEG C of comparison c-myc G-tetra-chain heights, 18 DEG C of comparison telomere G-tetra-chain heights.In addition, this compounds is very low to the stabilizing power of double-stranded DNA, the even Δ T having
mvalue, less than 1 DEG C, also can say that this compounds does not almost have stabilization to double-stranded DNA, and the selectivity of this compound is fine.
Embodiment 22: peptidyl of the present invention replaces the restraining effect of double-stranded cumarone quinoline to Telomerase.
Select the compound of embodiment bis-～20 preparation, adopt TRAP method to carry out cell-free system telomerase activity.From Human Lung Cancer cell line A549, extract total protein (including Telomerase), a certain amount of total protein extracting solution and medicament mixed to be measured are added in TRAP reaction mixture, after PCR reaction, utilize fluorescence gel imager or fluorescence microplate reader to detect.Compound described in this patent, in the time that concentration is 10 μ M/L, has obvious restraining effect (in table 2) to Telomerase in vitro.And experimental result is consistent with other experiment in vitro results before, can be good at illustrating effect feature and the structure activity relationship of this compounds.Therefore peptidyl of the present invention replaces double-stranded cumarone quinoline and can be used for the cancer therapy drug of preparation taking Telomerase as target spot.
Table 1: the stabilizing power Δ T of series compound of the present invention to G-tetra-serobila DNA stabilization G-tetra-serobila DNA
mvalue
Table 2: series compound of the present invention is the inhibition activity to Telomerase in the time of 10 μ M/L:
Claims (9)
1. peptidyl replaces a double-stranded cumarone quinoline, it is characterized in that, structural formula is suc as formula shown in I,
formula I,
Described R
1for dipeptides, tripeptides, tetrapeptide, pentapeptide.
2. peptidyl according to claim 1 replaces double-stranded cumarone quinoline, it is characterized in that described R
1aminoacid sequence be GG, GR, GH, GK, KR, HR, GRH, GRK, GRR, GRF, GRY, GRW, GRE, GRD, GRQ, GRS, GRA, GRRG or GRHG.
3. peptidyl according to claim 1 replaces the preparation method of double-stranded cumarone quinoline, it is characterized in that, comprises the following steps:
S1. will
in alkaline environment, carry out hydrocarbyl reaction with Mono Chloro Acetic Acid, then carry out chlorination with sulfur oxychloride again, obtain compound
；
S2. the compound of S1 gained and anthranilic acid are carried out to condensation reaction, obtain compound
；
S3. the compound of S2 gained and polyphosphoric acid are carried out to ring-closure reaction, obtain compound
；
S4. the compound of S3 gained is carried out to chlorination, obtain compound
;
S5. utilize boron tribromide to slough the methyl of methoxyl group in S4 gained compound structure, obtain compound
;
S6. the compound of S5 gained is first carried out to mitsunobu reaction, then react with hydramine, obtain compound
;
S7. the compound of S6 gained and glycine are carried out to substitution reaction, obtain compound
；
S8. finally by S7 gained and R
1carry out condensation reaction, obtain peptidyl and replace double-stranded cumarone quinoline.
4. peptidyl according to claim 3 replaces the preparation method of double-stranded cumarone quinoline, it is characterized in that, the solvent that the reaction described in S7 is used is phenol.
5. peptidyl according to claim 3 replaces the preparation method of double-stranded cumarone quinoline, it is characterized in that, the condensation reaction described in S8 is to obtain by the amino acid of Fmoc radical protection being connected on Rink Amide AM resin.
6. peptidyl according to claim 3 replaces the preparation method of double-stranded cumarone quinoline, it is characterized in that, condensation reaction described in S8 is to be undertaken after condensation reaction by polypeptide solid-state reaction method, slough resin with trifluoroacetic acid, the described peptidyl of final acquisition replaces double-stranded cumarone quinoline.
7. peptidyl according to claim 1 replaces double-stranded cumarone quinoline in the application of preparing in cancer therapy drug.
8. peptidyl according to claim 7 replaces double-stranded cumarone quinoline in the application of preparing in cancer therapy drug, it is characterized in that, the formulation of described cancer therapy drug is tablet, pill, capsule, injection, suspension agent or emulsion.
9. peptidyl according to claim 7 replaces double-stranded cumarone quinoline in the application of preparing in cancer therapy drug, it is characterized in that, described cancer therapy drug is anti-lung-cancer medicament.
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| CN105418735A (en) * | 2015-12-05 | 2016-03-23 | 李斯文 | Angiogenesis inhibitor polypeptide HS-1 and application thereof |
| CN105622721A (en) * | 2015-12-16 | 2016-06-01 | 李斯文 | Polyethylene glycol modified angiogenesis inhibitor HS-1 and application thereof |
| CN108530453A (en) * | 2018-03-29 | 2018-09-14 | 中山大学 | One kind 2（3）To methylthio phenyl vinyl-benzofuran quinoline and its preparation method and application |
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| CN102516355A (en) * | 2011-12-05 | 2012-06-27 | 中山大学 | Peptide derivative of benzfuran quinoline and preparation method thereof and application thereof as antitumor medicament |
| CN103382207A (en) * | 2013-06-25 | 2013-11-06 | 中山大学 | Methylbenzofuran quinoline derivative, preparation method thereof, and application of derivative as antitumor drug |
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| CN102516355A (en) * | 2011-12-05 | 2012-06-27 | 中山大学 | Peptide derivative of benzfuran quinoline and preparation method thereof and application thereof as antitumor medicament |
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| CN105418735A (en) * | 2015-12-05 | 2016-03-23 | 李斯文 | Angiogenesis inhibitor polypeptide HS-1 and application thereof |
| CN105622721A (en) * | 2015-12-16 | 2016-06-01 | 李斯文 | Polyethylene glycol modified angiogenesis inhibitor HS-1 and application thereof |
| CN108530453A (en) * | 2018-03-29 | 2018-09-14 | 中山大学 | One kind 2（3）To methylthio phenyl vinyl-benzofuran quinoline and its preparation method and application |
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