CN114315963B - LSH series cyclic pentapeptide ester and synthetic method and application thereof - Google Patents
LSH series cyclic pentapeptide ester and synthetic method and application thereof Download PDFInfo
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- CN114315963B CN114315963B CN202111527415.0A CN202111527415A CN114315963B CN 114315963 B CN114315963 B CN 114315963B CN 202111527415 A CN202111527415 A CN 202111527415A CN 114315963 B CN114315963 B CN 114315963B
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- 150000002148 esters Chemical class 0.000 title claims abstract description 49
- 125000004122 cyclic group Chemical group 0.000 title claims abstract description 47
- 238000010189 synthetic method Methods 0.000 title description 3
- 102000001189 Cyclic Peptides Human genes 0.000 claims abstract description 23
- 108010069514 Cyclic Peptides Proteins 0.000 claims abstract description 23
- -1 2, 4-dimethylheptanoyl side chains Chemical group 0.000 claims abstract description 14
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- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 9
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- 238000006243 chemical reaction Methods 0.000 claims description 37
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- 238000006482 condensation reaction Methods 0.000 claims description 21
- 125000006239 protecting group Chemical group 0.000 claims description 19
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical group CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
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- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 6
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- 238000003786 synthesis reaction Methods 0.000 claims description 6
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- CNBUSIJNWNXLQQ-NSHDSACASA-N (2s)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 CNBUSIJNWNXLQQ-NSHDSACASA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 4
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 3
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 2
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 210000004881 tumor cell Anatomy 0.000 description 13
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- 239000002904 solvent Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
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- 150000001875 compounds Chemical class 0.000 description 7
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 5
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical group CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
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- 150000002993 phenylalanine derivatives Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- QTBSBXVTEAMEQO-MICDWDOJSA-N 2-deuterioacetic acid Chemical compound [2H]CC(O)=O QTBSBXVTEAMEQO-MICDWDOJSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- KJOZJSGOIJQCGA-UHFFFAOYSA-N dichloromethane;2,2,2-trifluoroacetic acid Chemical compound ClCCl.OC(=O)C(F)(F)F KJOZJSGOIJQCGA-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- 150000003587 threonine derivatives Chemical group 0.000 description 2
- 150000003667 tyrosine derivatives Chemical class 0.000 description 2
- 150000003679 valine derivatives Chemical class 0.000 description 2
- CNBUSIJNWNXLQQ-LLVKDONJSA-N (2r)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](C(O)=O)CC1=CC=C(O)C=C1 CNBUSIJNWNXLQQ-LLVKDONJSA-N 0.000 description 1
- VQNDBXJTIJKJPV-UHFFFAOYSA-N 2h-triazolo[4,5-b]pyridine Chemical compound C1=CC=NC2=NNN=C21 VQNDBXJTIJKJPV-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
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- 108010019160 Pancreatin Proteins 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
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- 229960000310 isoleucine Drugs 0.000 description 1
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- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
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- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
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- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention provides LSH series cyclic pentapeptide ester, a synthesis method and application thereof, and belongs to the field of pharmacy, wherein the LSH series cyclic pentapeptide ester is prepared by constructing peptide chains from a plurality of amino acid derivatives by a 3+2 strategy, then cyclization, obtaining cyclic peptide with carbon-carbon unsaturated bonds by elimination reaction under alkaline condition, and then carrying out acylation reaction; the LSH series cyclic pentapeptide ester is used for treating melanoma/lung cancer/colon cancer/stomach cancer/cervical cancer. The LSH series cyclic pentapeptide ester is a LSH series novel cyclic peptide, the structure of the cyclic peptide comprises chiral 2, 4-dimethylheptanoyl side chains and cis-unsaturated amino acids, the LSH series cyclic pentapeptide ester has good anti-tumor activity, and the activity depends on the chirality of the side chains and the configuration of the amino acids in the cyclic peptide ester; the LSH series cyclic pentapeptide ester has higher activity on melanoma cells, lung cancer cells, colon cancer cells, stomach cancer cells and cervical cancer cells.
Description
Technical Field
The invention relates to cyclic pentapeptide esters, in particular to LSH series cyclic pentapeptide esters, and a synthesis method and application thereof.
Background
Cyclic peptide esters and cyclic peptides are a class of peptide compounds with a relatively special structure, and are mostly found in marine organisms, biological fermentation broths, grains and plants, and most of the compounds have strong physiological and pharmacological activities, wherein the antitumor activity is particularly prominent. Since free carboxyl groups and amino groups are not present in the structure, the peptide has better stability than chain peptide, especially in organisms, and therefore has very high medicinal value. In addition, these structural features provide valuable molecular models for drug design, and provide a library of lead compounds for reference in the development of new drugs. In recent years, a number of polypeptide drugs have entered clinical trials or have been approved for sale. Since different amino acids can form different cyclic peptides, and different cyclic peptides have different activities, even no activity, how to obtain a cyclic peptide structure with strong antitumor activity has been a difficult point of study.
Disclosure of Invention
Based on the physicochemical characteristics of the cyclic peptide ester, the invention provides an LSH series cyclic pentapeptide ester and a synthesis method and application thereof.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
an LSH series cyclic pentapeptide ester having the chemical structural formula:
wherein:
R 1 and R is 2 Independently hydrogen or methyl;
R 3 is independently hydrogen, alkyl, halogen, hydroxy, amino/amino, hydrocarbyloxy or siloxy;
R 4 and R is 5 Each independently isopropyl, isobutyl, sec-butyl or benzyl.
Further, the raw materials for preparing the LSH series cyclic pentapeptide ester comprise a plurality of amino acid derivatives;
the configuration of the plurality of amino acid derivatives is respectively independent L-type or D-type.
Further, the plurality of amino acid derivatives are each independently aliphatic amino acid derivatives or aryl propyl amino acid derivatives, and the plurality of amino acid derivatives are not identical.
Further, the aliphatic amino acid derivative is threonine derivative, leucine derivative, isoleucine derivative or valine derivative;
wherein the threonine derivative is threonine with a nitrogen end protected by tert-butoxycarbonyl and a carbon end protected by allyl;
the leucine derivative is leucine with a tert-butoxycarbonyl protecting nitrogen end and an allyl protecting carbon end;
the isoleucine derivative is isoleucine with a tert-butoxycarbonyl protecting nitrogen end and an allyl protecting carbon end;
the valine derivative is valine with a tert-butoxycarbonyl protecting nitrogen end and an allyl protecting carbon end;
the aryl propyl amino acid derivative is phenylalanine derivative, 4-substituted phenylalanine derivative or tyrosine derivative;
wherein the phenylalanine derivative is phenylalanine with a tert-butyloxycarbonyl protecting nitrogen end and an allyl protecting carbon end;
the substituted phenylalanine derivative is 4-substituted phenylalanine with a tert-butyloxycarbonyl protecting nitrogen end and an allyl protecting carbon end;
the tyrosine derivative is tyrosine with a tert-butyloxycarbonyl protecting nitrogen end and an allyl protecting carbon end.
Further, R 1 And R is 2 When both are methyl, R 1 And R is 2 The chiral carbon is in the R-type or S-type configuration independently.
Further, the chemical structural formula of the LSH series cyclic pentapeptide ester is LSH-1 to LSH-16, and the bioisostere cyclic peptide derivative is prepared from a hydroxy-substituted phenylalanine derivative;
wherein, the specific structural formulas of LSH-1 to LSH-16 are as follows:
among them, bioisostere cyclic peptide derivatives include corresponding compounds in which hydroxy groups are substituted by alkyl groups, amino groups (amine groups) are substituted, and halogens are substituted.
The synthesis method of the LSH series cyclic pentapeptide ester comprises the steps of constructing peptide chains from a plurality of amino acid derivatives through a 3+2 strategy, cyclizing, obtaining cyclic peptide with carbon-carbon unsaturated bonds through elimination reaction under alkaline conditions, and obtaining the LSH series cyclic pentapeptide ester through acylation reaction.
Further, the synthesis method comprises the following specific steps performed in sequence:
1) Synthetic intermediate T-1
Taking initial raw materials S-1 and Boc-Thr (T-Bu) -OH, and carrying out condensation reaction under the action of a condensing agent and a catalyst to obtain an intermediate T-1, wherein the specific chemical reaction formula is as follows:
wherein, the structural formula of Boc-Thr (t-Bu) -OH is as follows:
the solvent of the condensation reaction is a polar solvent;
the polar solvent is dichloromethane;
the condensing agent is 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI);
the catalyst is 4-Dimethylaminopyridine (DMAP);
the temperature of the condensation reaction is room temperature;
after the condensation reaction is finished, the obtained reaction solution is washed by potassium carbonate aqueous solution, water, hydrochloric acid and saturated saline water, dried and concentrated to obtain an intermediate T-1;
2) Synthetic intermediate T-2:
removing Boc protecting group from intermediate T-1 with trifluoroacetic acid, and reacting with Boc-Tyr (R 3 ) The intermediate T-2 is obtained by condensation reaction of OH again, and the specific chemical reaction formula is as follows:
wherein Boc-Tyr (R 3 ) -OH has the structural formula:
R 3 is independently hydrogen, alkyl, halogen, hydroxy, amino/amino, hydrocarbyloxy or siloxy;
the reaction solvent for removing the Boc protecting group is methylene dichloride, and the temperature is room temperature;
after the reaction of removing the Boc protecting group is completed and before the condensation reaction, the solvent, trifluoroacetic acid and generated acetic acid in the reaction system are also required to be concentrated and removed;
the peptide coupling reagent is benzotriazol-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU);
the organic base is N, N-Diisopropylethylamine (DIPEA);
the solvent for condensation reaction is dichloromethane, and the temperature is room temperature;
after the condensation reaction is completed, the mixture is concentrated, water is added into the obtained residue, and the mixture is extracted by ethyl acetate, phase separation is carried out, and the ethyl acetate phase is subjected to 5 weight percent of K 2 CO 3 Washing the aqueous solution, water, 2wt% hydrochloric acid aqueous solution and saturated saline water for a plurality of times, and then drying, filtering, concentrating and purifying to obtain an intermediate T-2;
3) Synthetic intermediate T-3:
after removing Boc protecting group from intermediate T-2 by trifluoroacetic acid, carrying out condensation reaction with raw material S-2 again under the action of peptide coupling reagent and organic base to obtain intermediate T-3, wherein the specific chemical reaction formula is as follows:
wherein R is 4 And R is 5 Respectively independent isopropyl, isobutyl, sec-butyl or benzyl;
the reaction solvent for removing the Boc protecting group is methylene dichloride, and the temperature is room temperature;
after the reaction of removing the Boc protecting group is completed and before the condensation reaction, the solvent, trifluoroacetic acid and generated acetic acid in the reaction system are also required to be concentrated and removed;
the peptide coupling reagent is benzotriazol-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU);
the organic base is N, N-Diisopropylethylamine (DIPEA);
the solvent for condensation reaction is dichloromethane, and the temperature is room temperature;
after the condensation reaction is completed, the mixture is concentrated, water is added into the obtained residue, and the mixture is extracted by ethyl acetate, phase separation is carried out, and the ethyl acetate phase is subjected to 5 weight percent of K 2 CO 3 Washing the aqueous solution, water, 2wt% hydrochloric acid aqueous solution and saturated saline water for a plurality of times, and then drying, filtering, concentrating and purifying to obtain an intermediate T-3;
4) Synthetic intermediate T-4:
the intermediate T-3 is subjected to allyl removal under the catalytic action of N-methylmorpholine and tetra (triphenylphosphine) palladium, boc protecting group is removed by trifluoroacetic acid, and condensation reaction is carried out under the action of a peptide coupling reagent and an organic base, so that the intermediate T-4 has the following specific chemical reaction formula:
the reaction solvent for removing allyl is chloroform, and the temperature is room temperature;
after the reaction for removing allyl groups is completed and before the reaction for removing Boc protecting groups is started, concentrating, dissolving ethyl acetate, and passing through 15wt% KHSO 4 Washing the aqueous solution with water for several times, drying, filtering, and concentrating;
the reaction solvent for removing the Boc protecting group is methylene dichloride, and the temperature is room temperature;
after the reaction of removing the Boc protecting group is completed and before the condensation reaction, the solvent, trifluoroacetic acid and produced acetic acid in the reaction system are also required to be concentrated and removed;
the peptide coupling reagent is 2- (7-aza-benzotriazol) -N, N' -tetramethylurea Hexafluorophosphate (HATU);
the organic base is N, N-Diisopropylethylamine (DIPEA);
the solvent for condensation reaction is dichloromethane, and the temperature is room temperature;
after the condensation reaction is completed, the mixture is concentrated, water is added into the obtained residue, and the mixture is extracted by ethyl acetate, phase separation is carried out, and the ethyl acetate phase is subjected to 5 weight percent of K 2 CO 3 Washing the aqueous solution, water, 2wt% hydrochloric acid aqueous solution and saturated saline water for a plurality of times, and then drying, filtering, concentrating and purifying to obtain an intermediate T-4;
5) Synthetic intermediate T-5:
the intermediate T-4 reacts with di-tert-butyl dicarbonate under the catalysis of 4-dimethylaminopyridine, then carries out elimination reaction under the action of nano potassium carbonate, and simultaneously removes Fmoc protecting groups to obtain the intermediate T-5, wherein the specific chemical reaction formula is as follows:
6) Synthesis of LSH series cyclic pentapeptides esters
The raw material S-3 and isobutyl chloroformate are subjected to transesterification reaction at the temperature of minus 15 to minus 8 ℃ under the action of N-methylmorpholine, then an intermediate T-5 is added for acylation reaction, and the LSH series cyclic pentapeptide is obtained, wherein the specific chemical reaction formula is as follows:
wherein R is 1 And R is 2 Independently hydrogen or methyl;
after the acylation reaction is finished, the obtained reaction liquid is diluted by adding water and is extracted by ethyl acetate, and the obtained ethyl acetate phase is dried, filtered, concentrated and purified to obtain the LSH series cyclic pentapeptide ester.
Application of the LSH series cyclic pentapeptide ester in preparing medicines for treating melanoma/lung cancer/colon cancer/stomach cancer/cervical cancer.
Further toThe LSH series cyclic pentapeptide ester has inhibitory activity IC on melanoma cells/lung cancer cells/colon cancer cells/stomach cancer cells/cervical cancer cells 50 ≥0.98μM。
The LSH series cyclic pentapeptide ester and the synthetic method and application thereof have the beneficial effects that:
the LSH series cyclic pentapeptide ester is a LSH series novel cyclic peptide, the structure of the cyclic peptide comprises a chiral dimethylheptanoyl side chain and cis-unsaturated amino acid, the LSH series cyclic pentapeptide ester has good anti-tumor activity, and the activity depends on the chirality of the side chain and the sequence and configuration of the amino acid in the cyclic peptide ester; the LSH series cyclic pentapeptide ester has higher activity on melanoma cells, lung cancer cells, colon cancer cells, stomach cancer cells and cervical cancer cells.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of LSH-2 prepared in example 2 of the present invention;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of LSH-2 prepared in example 2 of the present invention;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of LSH-4 prepared in example 4 of the present invention;
FIG. 4 is a nuclear magnetic resonance carbon spectrum of LSH-4 prepared in example 4 of the present invention;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of LSH-10 prepared in example 10 of the present invention;
FIG. 6 is a nuclear magnetic resonance carbon spectrum of LSH-10 prepared in example 10 of the present invention;
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of LSH-14 prepared in example 14 of the present invention;
FIG. 8 is a nuclear magnetic resonance carbon spectrum of LSH-14 prepared in example 14 of the present invention.
Detailed Description
The following description of the technical solution in the embodiments of the present invention is clear and complete. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present invention is not limited to the specific embodiments disclosed below.
Example 1 Synthesis of LSH-series cyclic pentapeptides esters
The embodiment is a synthesis method of LSH series cyclic pentapeptide ester (LSH-1), and the specific preparation process comprises the following steps in sequence:
1) Synthetic intermediate T-1 (su-su):
10mmol of Fmoc-L-Thr-OAllyl (S-1 in the chemical reaction formula) and 11mmol of Boc-Thr (t-Bu) -OH as starting materials were dissolved in 100mL of methylene chloride, then 12mmol of EDCI and 12mmol of DMAP were added thereto, and the mixture was stirred at room temperature for condensation reaction for 24 hours, and after completion of the reaction, the reaction solutions were each prepared with 5wt% of K 2 CO 3 Washing the aqueous solution, water, 2wt% hydrochloric acid aqueous solution and saturated saline water for several times, drying by anhydrous magnesium sulfate, filtering, concentrating and purifying to obtain an intermediate T-1 (Su-su), wherein the specific chemical reaction formula is as follows:
2) Synthetic intermediate T-2 (Casein-su)
Dissolving 8mmol of intermediate T-1 (Perilla-Perilla) in 100mL of 10wt% trifluoroacetic acid dichloromethane solution, stirring at room temperature for 30 min, removing Boc protecting group, concentrating under reduced pressure to remove solvent, trifluoroacetic acid and produced acetic acid in the reaction system, dissolving the obtained residue in 100mL of dichloromethane, adding 8.8mmol of Boc-D-Tyr-OH, 8.8mmol of HBTU and 16mmol of DIPEA, stirring at room temperature overnight, concentrating the obtained reaction solution, adding water into the concentrated residue, extracting with ethyl acetate, separating phase, and subjecting ethyl acetate phase to 5wt% K 2 CO 3 Washing the aqueous solution, water, 2wt% hydrochloric acid aqueous solution and saturated saline water for several times, and drying, filtering, concentrating and purifying by anhydrous magnesium sulfate to obtain an intermediate T-2 (casein-threo), wherein the specific chemical reaction formula is as follows:
wherein R is 3 Is OTBS.
3) Synthetic intermediate T-3 (light-valyl-tyrosin-threo)
Dissolving 6mmol of intermediate T-2 (Caso-su) in 60mL of 10wt% trifluoroacetic acid in dichloromethane, stirring at room temperature for 30 min, removing Boc protecting group, concentrating under reduced pressure to remove solvent, trifluoroacetic acid and produced acetic acid in the reaction system, dissolving the obtained residue in 50mL of dichloromethane, adding 6.6mmol of Boc-L-Leu-L-Val-OH (raw material S-2), 6.6mmol of HBTU and 12mmol of DIPEA, stirring at room temperature overnight, concentrating the obtained reaction solution, adding water into the concentrated residue, extracting with ethyl acetate, separating phase, and subjecting ethyl acetate phase to 5wt% K 2 CO 3 Washing the aqueous solution, water, 2wt% hydrochloric acid aqueous solution and saturated saline water for several times, drying by anhydrous magnesium sulfate, filtering, concentrating and purifying to obtain an intermediate T-3 (light-valyl-casein-threo), wherein the specific chemical reaction formula is as follows:
wherein R is 4 Is isopropyl, R 5 Is isobutyl.
4) Synthetic intermediate T-4 (cyclopeptide leu-val-tyr-su)
4mmol of intermediate T-3 (light-valyl-tyrosol-threo) was dissolved in 20mL of chloroform, 24mmol of N-methylmorpholine and 1.6mmol of tetrakis (triphenylphosphine) palladium were added, stirred at room temperature overnight, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and taken up in 15wt% KHSO 4 Washing with water for several times, drying with anhydrous magnesium sulfate, filtering, concentrating, dissolving the concentrate in 20mL of 10wt% trifluoroacetic acid dichloromethane solution, stirring at room temperature for 30 min, removing Boc protecting group, concentrating under reduced pressure to remove solvent, trifluoroacetic acid and produced acetic acid, dissolving the chain peptide product in 50mL of dichloromethane, adding 8mmol of HATU and 8mmol of DIPEA, stirring at room temperature overnight, concentrating the reaction solution, concentratingThe residue was taken up in water and extracted with ethyl acetate, the phases separated and the ethyl acetate phase was subjected to 5% by weight of K 2 CO 3 Washing the aqueous solution, water, 2wt% hydrochloric acid aqueous solution and saturated saline water for several times, drying by anhydrous magnesium sulfate, filtering, concentrating and purifying to obtain an intermediate T-4 (cyclopeptide leu-val-tyr-su), wherein the specific chemical reaction formula is as follows:
5) Synthesis of intermediate T-5 (cyclopeptide leu-val-tyr-su-elimination product)
2mmol of intermediate T-4 (cyclopeptide leu-val-tyr-su) was dissolved with 50mL of acetonitrile and 2.2mmol (Boc) was added 2 O and 0.2mmol of DMAP are stirred at room temperature for 2 hours, fmoc protecting groups are removed, and then 6mmol of nano K is directly added into the reaction solution 2 CO 3 Stirring at room temperature for 5 hr, filtering, concentrating under reduced pressure, adding the residue into water, stirring, extracting with ethyl acetate, separating phase, and subjecting the organic phase to 1M KHSO 4 Aqueous solution, 1M NaHCO 3 Washing with water, drying, filtering, concentrating, purifying to obtain intermediate T-5 (cyclopeptide leu-val-tyr-su-elimination product), and the specific chemical reaction formula is as follows:
6) Synthesis of LSH series cyclic pentapeptides esters (LSH-1)
1.1mmol of 2S, 4S-dimethylheptanoic acid (S-3) and 1.1mmol of N-methylmorpholine are dissolved in 10mL of tetrahydrofuran, cooled to-10 ℃,1.1 mmol of isobutyl chloroformate is added, stirred for 30 minutes, then heated to 0 ℃, 1mmol of intermediate T-5 (cyclopeptide leuca-tyr-su) is added, stirred overnight at room temperature, the obtained reaction solution is diluted with water and extracted with ethyl acetate, and the obtained ethyl acetate phase is dried, filtered, concentrated and purified by anhydrous magnesium sulfate to obtain a final product LSH series cyclic pentapeptide ester (LSH-1 for short), the total yield is 44%, and the specific chemical reaction formula is as follows:
wherein R is 1 And R is 2 Methyl groups in the S configuration respectively.
Examples 2 to 16 Synthesis of LSH-series cyclic pentapeptides esters
Examples 2 to 16 are respectively a synthesis method of LSH series cyclic pentapeptide esters, which have the same steps as example 1, but differ only in the raw material amount and the process parameters, and are specifically shown in tables 1 to 2:
table 1 list of process parameters in examples 2 to 8
Table 2 list of process parameters in examples 9 to 16
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Wherein, the steps and process parameters of the other parts of examples 2 to 16 are the same as those of example 1;
the specific structural formulas of LSH-1 to LSH-16 are as follows:
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to save time for examination, only the nuclear magnetic patterns and mass spectra of four compounds are selected for description, and the method is specifically as follows:
LSH-2 nuclear magnetic resonance hydrogen spectrum 1 H NMR (500 MHz, acetone-d 6) delta 8.50-8.46 (1H, m), 8.42 (1H, s), 8.19 (1H, s), 7.91-7.87 (1H, m), 7.38 (1H, t, J=7.0 Hz), 7.22 (2H, t, J=8.5 Hz), 6.76 (2H, d, J=8.0 Hz), 6.61-6.55 (1H, m), 5.22-5.19 (1H, m), 4.95-4.56 (1H, m), 4.43-4.32 (1H, m), 4.22-4.20 (1H, m), 3.81-3.77 (1H, m), 3.35-3.32 (1H, m), 3.30-3.25 (1H, m), 3.03-2.94 (1H, m), 2.82 (3H, s), 2.48-2.43 (1H, m), 1.97-1.77 (1H, m), 1.70 (3H, d, j=7.0 Hz), 1.69-1.64 (2H, m), 1.59-1.54 (2H, m), 1.42-1.39 (2H, m), 1.35 (3H, d, j=6.0 Hz), 1.20-1.14 (2H, m), 1.06 (2H, d, j=7.0 Hz), 1.05-1.01 (1H, m), 0.99-0.94 (9H, m), 0.89-0.86 (2H, m), 0.83-0.78 (6H, m), 0.75 (3H, d, j=7.0 Hz); the carbon spectrogram is 13 C NMR (125 MHz, acetone-d 6) delta 177.25, 175.33, 171.37, 170.42, 170.38, 156.86, 134.61, 134.28, 131.00, 130.82, 128.57, 116.04, 74.91, 71.61, 60.67, 58.36, 57.46, 57.09, 55.56, 54.90, 42.56, 41.13, 39.94, 39.29, 36.92, 31.04, 28.79, 25.33, 23.19, 21.97, 20.61, 20.25, 19.77, 19.15, 16.37; mass spectrum is HRMS (ESI) m/z: [ M+H ]]+found for 700.4277，calcd for C 37 H 58 N 5 O 8 700.4285。
LSH-4 nuclear magnetic resonance hydrogen spectrum 1 H NMR(500MHz，Acetone-d6)δ8.47(1H，d，J＝7.0Hz)，8.42(1H，s)，8.20-8.19(1H，m)，7.91-7.88(1H，m)，7.41-7.38(1H，m)，7.23-7.20(2H，m)，7.08(1H，d，J＝9.0Hz)，6.76(2H，d，J＝8.5Hz)，6.61-6.56(1H，m)，5.23-5.20(1H，m)，4.88(1H，dd，J＝3.0，9.0Hz)，4.43-4.34(1H，m)，4.22-4.18(1H，m)，3.83-3.77(1H，m)，3.34(1H，t，J＝6.5Hz)，3.27(1H，dd，J＝3.5，14.5Hz)，3.03-2.94(1H，m)，2.83(3H，s)，2.67-2.62(1H，m)，2.47-2.43(1H，m)，1.89-1.83(1H，m)，1.71(3H，d，J＝7.0Hz)，1.68-1.64(1H，m)，1.59-1.53(1H，m)，1.42-1.39(1H，m)，1.37(3H，d，J＝6.0Hz)，1.24-1.16(2H，m)，1.07(3H，d，J＝7.0Hz)，O.99-o.94 (10 h, m), 0.89-0.86 (1 h, m), 0.83-0.81 (4 h, m), 0.80 (3 h, d, j=4.0 Hz); the carbon spectrogram is 13 C NMR (125 MHz, acetone-d 6) delta 177.28, 175.36, 171.44, 170.45, 169.72, 165.46, 156.88, 134.44, 130.88, 130.82, 130.42, 128.57, 116.09, 116.00, 74.56, 71.61, 60.65, 57.36, 55.96, 55.00, 42.50, 41.09, 40.28, 39.19, 36.83, 31.19, 28.79, 25.34, 23.17, 22.00, 21.77, 20.57, 19.86, 19.77, 19.27, 16.57, 14.79, 14.51; mass spectrum is HRMS (ESI) m/z: [ M+H ]]+found for 700.4288，calcd for C 37 H 58 N 5 O 8 700.4285。
LSH-10 nuclear magnetic resonance hydrogen spectrum 1 H NMR (500 mhz, acetate-d 6) delta 8.46 (1H, d, j=7.0 Hz), 8.42 (1H, s), 8.20 (1H, br), 7.89 (1H, s), 7.40 (1H, d, j=7.5 Hz), 7.22 (2H, d, j=8.5 Hz), 7.06 (1H, d, j=9.0 Hz), 6.76 (2H, d, j=8.5 Hz), 6.58 (1H, q, j=7.0 Hz), 5.35 (1H, t, j=4.5 Hz), 5.23-5.21 (1H, m), 4.88 (1H, dd, j=3.0, 9.0 Hz), 4.40-4.35 (1H, m), 4.22-4.18 (1H, m), 3.35 (1H, t, j=6.5 Hz), 3.28.28 (j=3.0 Hz), 14.0 Hz), 3.00 (1H, t, J=13.0 Hz), 2.67-2.62 (1H, m), 2.48-2.41 (1H, m), 2.15 (1H, t, J=7.0 Hz), 1.92-1.85 (1H, m), 1.71 (3H, d, J=7.0 Hz), 1.68-1.64 (1H, m), 1.59-1.54 (2H, m), 1.37 (3H, d, J=6.0 Hz), 1.23-1.17 (2H, m), 1.06 (3H, d, J=7.0 Hz), 1.04-1.01 (1H, m), O.98 (6H, t, J=6.5 Hz), O.95 (3H, d, J=6.5 Hz), 0.92-0.87 (4H, m), O.82 (3H, t, j=4.0 Hz), 0.80 (3 h, d, j=4.0 Hz); the carbon spectrogram is 13 C NMR (125 MHz, acetone-d 6) delta 177.29, 175.36, 171.46, 170.47, 169.78, 165.46, 156.90, 134.48, 130.88, 130.59, 128.59, 116.10, 74.56, 60.67, 57.34, 55.97, 55.03, 42.52, 41.12, 40.30, 39.23, 36.84, 31.21, 27.79, 25.35, 23.18, 22.02, 21.77, 20.58, 19.87, 19.77, 19.27, 16.57, 14.77, 14.51; mass spectrum is HRMS (ESI) m/z: [ M+H ]]+found for 700.4280，calcd for C 37 H 58 N 5 O 8 700.4285。
The nuclear magnetic resonance hydrogen spectrum of LSH-14 is 1 H NMR(500mhz, acetate-d 6) delta 8.14 (1 h, d, j=25.0 Hz), 8.07 (1 h, s), 7.79 (1 h, s), 7.48 (1 h, s), 7.20-7.18 (3 h, m), 6.76 (2 h, d, j=8.0 Hz), 6.61 (1 h, q, j=7.0 Hz), 5.23 (1 h, s), 4.77 (1 h, s), 4.48 (1 h, s), 4.05 (1 h, s), 3.86 (1 h, s), 3.33 (1 h, dd, j=3.5, 14.0 Hz), 3.00 (1 h, t, j=13.0 Hz), 2.70 (2 h, q, j=7.0 Hz), 2.03-2.01 (2 h, m), 1.76-1.76 (2 h, m), 1.66 (3 h, d, j=7.0 Hz), 1.61-1.49 (1 h, m), 1.42-1.37 (1 h, m), 1.33 (3 h, d, j=6.0 Hz), 1.25-1.19 (2 h, m), 1.15 (3 h, d, j=6.5 Hz), 1.03 (1 h, s), 0.95 (3 h, d, j=6.5 Hz), 0.92 (3 h, d, j=6.5 Hz), 0.90-0.87 (4 h, m), 0.84 (3 h, t, j=7.0 Hz), 0.72 (3 h, d, j=6.5 Hz), 0.67 (3 h, d, j=6.5 Hz); the carbon spectrogram is 13 C NMR (125 MHz, acetone-d 6) delta 173.96, 171.40, 170.40, 169.25, 165.10, 156.99, 133.93, 130.94, 130.10, 128.26, 116.04, 74.00, 62.02, 56.87, 56.12, 54.36, 42.67, 40.06, 39.49, 36.73, 32.63, 31.12, 25.72, 23.80, 21.31, 20.69, 20.31, 19.35, 19.10, 18.46, 16.72, 14.88, 14.56; mass spectrum is HRMS (ESI) m/z: [ M+H ]]+found for 700.4282，calcd for C 37 H 58 N 5 O 8 700.4285。
EXAMPLE 17 anti-tumor Activity assay
The test was performed based on the Sulfonyl Rhodamine B (SRB) method, and samples to be tested (LSH-series cyclic pentapeptides prepared in examples 1 to 16) were prepared as DMSO solutions of different concentrations of 1000, 500, 250, 100, 50, 25 and 10. Mu.M, respectively.
Suspending selected tumor cells in PRMI culture solution (DMEM culture solution can also be used) containing 10% fresh foetal calf serum, subjecting to pancreatin digestion, counting cells, and fixing cell concentration to 5×10 4 Obtaining tumor cell fluid by cells/mL;
tumor cell liquid (experiments are carried out on tumor cells by using melanoma cell line SK-MEL-1, lung cancer cell line HePG-2 and colon cancer cell line HT-29 respectively) is added into a 96-well plate, 90 mu L of tumor cell liquid is added into each well, about 4500 tumor cells are added into each well, 10 mu L of DMSO solutions with different concentrations are added into each well respectively, and the mixture is moved to 37 ℃ and relatively wetDegree of 100% and CO content 2 Culturing in an incubator under the condition of mixed atmosphere with air in the ratio of 5:95 for 48 hours; taking out the 96-well plate, discarding the solution, adding 100. Mu.L of TCA with concentration of 10wt%, fixing at 4deg.C for 30 min, discarding the solution again, and adding 100. Mu.L of ddH to each well 2 O was washed three times, dried at room temperature for 6 hours, dissolved in 100. Mu.L of Trisbase, shaken for 5 minutes on a plate, measured at 570nm (570 nm is the absorbance of the solution related to the number of living cells) with a microplate reader, and the proliferation of the cells was measured, and the inhibition of tumor cells was calculated. Each set of experiments was repeated three times and the average value calculated; and normal cells 239-T are used to replace tumor cells for the above experiment, and the average value of the cell inhibition rate is calculated; specific results are shown in tables 3 to 4 (the values in tables 3 to 4 are average values, and it should be noted that "-" in the tables means that no specific experimental measurement was performed, since the measurement of the tumor suppression rate was performed with respect to the similar compounds, and no repeated measurement was performed in the subsequent step).
TABLE 3 inhibition of 48h by LSH1-LSH 8 (25. Mu.M)
TABLE 4 inhibition of 48h by LSH9-LSH 16 (25. Mu.M)
From tables 3 to 4, it can be seen that the LSH-series cyclic pentapeptide esters of the present invention have good inhibitory activity on various tumor cells, and are particularly more prominent against melanoma cell line SK-MEL-1, lung cancer cell line HePG-2 and colon cancer cell line HT-29. The LSH-series cyclic pentapeptide esters of the present invention have very low toxicity to normal cells 239-T at 25 μM concentrations.
The quantitative relation research (specific results are shown in table 5) of the selected compound LSH-15 on HT-29 tumor cells according to the experimental method is carried out, and the inhibition rates in tumor cell solutions with different concentrations are measured, so that the two tumor cell solutions have good correlationThe half-inhibitory concentration was calculated using the concentration and inhibition rate data in Table 5 to obtain IC 50 0.98. Mu.M.
TABLE 5 inhibition of HT-29 cells by LSH-15 at various concentrations for 48h (25. Mu.M)
The other compounds obtained also have good tumor cell inhibitory activity, and specific experiments are not listed here.
It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Claims (7)
1. An LSH series cyclic pentapeptide ester, characterized in that the chemical structural formula of the LSH series cyclic pentapeptide ester is as follows:
wherein:
R 1 and R is 2 Independently hydrogen or methyl;
R 3 is an independent hydroxyl, hydrocarbyloxy or siloxy group;
R 4 is isopropyl;
R 5 is isobutyl.
2. The LSH series cyclic pentapeptide esters according to claim 1, wherein R 1 And R is 2 Are all methyl, R 1 And R is 2 The structure of the chiral carbon in which it is locatedThe forms are respectively independent R type or S type.
3. The LSH series cyclic pentapeptide ester according to claim 1 or 2, wherein the chemical structural formula of LSH series cyclic pentapeptide ester is selected from LSH-1 to LSH-16;
wherein, the specific structural formulas of LSH-1 to LSH-16 are as follows:
4. the method for synthesizing LSH series cyclic pentapeptide esters according to any one of claims 1-3, wherein the method is characterized in that a plurality of amino acid derivatives are taken to construct peptide chains through a 3+2 strategy, then cyclized, and then cyclic peptide with carbon-carbon unsaturated bonds is obtained through elimination reaction under alkaline condition, and then the LSH series cyclic pentapeptide esters are obtained through acylation reaction.
5. The method for synthesizing LSH series cyclic pentapeptide esters according to claim 4, wherein the method comprises the following specific steps performed in sequence:
1) Synthetic intermediate T-1:
taking initial raw materials S-1 and Boc-Thr (T-Bu) -OH, and carrying out condensation reaction under the action of a condensing agent and a catalyst to obtain an intermediate T-1, wherein the specific chemical reaction formula is as follows:
wherein, the structural formula of Boc-Thr (t-Bu) -OH is as follows:
2) Synthetic intermediate T-2:
intermediate T-1 is removed by trifluoroacetic acidAfter Boc protecting group, under the action of peptide coupling reagent and organic base, boc-Tyr (R 3 ) The intermediate T-2 is obtained by condensation reaction of OH again, and the specific chemical reaction formula is as follows:
wherein Boc-Tyr (R 3 ) -OH has the structural formula:
R 3 is independently hydrogen, halogen, hydroxy, amino/amino, hydrocarbyloxy or siloxy;
3) Synthetic intermediate T-3:
after removing Boc protecting group from intermediate T-2 by trifluoroacetic acid, carrying out condensation reaction with raw material S-2 again under the action of peptide coupling reagent and organic base to obtain intermediate T-3, wherein the specific chemical reaction formula is as follows:
wherein R is 4 And R is 5 Respectively independent isopropyl, isobutyl, sec-butyl or benzyl;
4) Synthetic intermediate T-4:
the intermediate T-3 is subjected to allyl removal under the catalytic action of N-methylmorpholine and tetra (triphenylphosphine) palladium, boc protecting group is removed by trifluoroacetic acid, and condensation reaction is carried out under the action of a peptide coupling reagent and an organic base, so that the intermediate T-4 has the following specific chemical reaction formula:
5) Synthetic intermediate T-5:
the intermediate T-4 reacts with di-tert-butyl dicarbonate under the catalysis of 4-dimethylaminopyridine, then carries out elimination reaction under the action of nano potassium carbonate, and simultaneously removes Fmoc protecting groups to obtain the intermediate T-5, wherein the specific chemical reaction formula is as follows:
6) Synthesis of LSH series cyclic pentapeptides esters
The raw material S-3 and isobutyl chloroformate are subjected to transesterification reaction under the action of N-methylmorpholine, then an intermediate T-5 is added for acylation reaction, and the LSH series cyclic pentapeptide ester is obtained, wherein the specific chemical reaction formula is as follows:
wherein R is 1 And R is 2 Each independently hydrogen or methyl.
6. Use of the LSH series cyclic pentapeptide esters of any one of claims 1-3 in the manufacture of a medicament for treating melanoma/lung/colon cancer.
7. The use of LSH series cyclic pentapeptide esters according to claim 6, wherein the LSH series cyclic pentapeptide esters have inhibitory activity IC against melanoma/lung/colon cancer cells 50 ≥0.98μM。
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| CN104861046A (en) * | 2015-06-02 | 2015-08-26 | 河北科技大学 | N-methyl cyclic pentapeptide compound as well as synthetizing method and application thereof |
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| CN101659694A (en) * | 2009-05-06 | 2010-03-03 | 河北科技大学 | Anti-tumor cyclic pentapeptide compound and preparation method thereof |
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