CN114656519B - tryptophan No. 7 maleimide cyclized derivative, and preparation method and application thereof - Google Patents

tryptophan No. 7 maleimide cyclized derivative, and preparation method and application thereof Download PDF

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CN114656519B
CN114656519B CN202210251829.3A CN202210251829A CN114656519B CN 114656519 B CN114656519 B CN 114656519B CN 202210251829 A CN202210251829 A CN 202210251829A CN 114656519 B CN114656519 B CN 114656519B
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maleimide
tryptophan
formula
silver
iii
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CN114656519A (en
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姜吉瞳
朱勍
严佳辉
王鹏
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Zhejiang University of Technology ZJUT
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Zhejiang University of Technology ZJUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Abstract

The compounds of the invention are rhodium catalyzed, site-selective C7 maleimide modified, and can be obtained under mild and non-polymeric conditions. This reaction is effective for modification, ligation and drug modification of peptides with C7, as opposed to the copper (II) triflate catalyzed reaction reported in the literature. The preparation method has the advantages of simple operation process, no guide group, high site selectivity, high reaction efficiency, and capability of being prepared in one step, has good anti-tumor application prospect, and provides a new scheme for developing anti-tumor drugs.

Description

tryptophan No. 7 maleimide cyclized derivative, and preparation method and application thereof
field of the art
The invention relates to a tryptophan number 7 locus maleimido cyclic derivative, and a preparation method and application thereof.
(II) background art
the polypeptide is an important bioactive molecule and has wide application in the fields of pharmaceutical chemistry, biotechnology, chemical biology and the like. Cyclic peptides have attracted considerable attention in the pharmaceutical industry due to their excellent cell penetration, stability, thermal stability and drug-like properties. Existing simple and efficient methods of creating such peptides are quite limited. The transition metal catalyzed complex molecular late functionalization (LSF) has good site specificity and high tolerance of functional groups, and provides a simple method for efficient C-H functionalization/macrocyclization. In recent years, several approaches based on the post-modification of Trp (tryptophan) residues have been successfully developed. Whereas traditional methods for post-modification of Trp residues: it is generally necessary to introduce a protecting group or a guiding group into the number 1 of the indole heterocycle of Trp, and then to deprotect or guide the group after finishing the modification of other sites, so as to realize the modification. The reaction yield of the copper (II) trifluoromethane sulfonate catalysis method adopted in the known literature is only 30%, the reaction temperature is 140 ℃, and the reaction time is 48 hours. The method has the advantages of numerous steps, low reaction yield and severe reaction conditions, and the problems greatly reduce the development of the subsequent modification research of the Trp-containing polypeptide. There are many modification methods at present, but modification of the C-C bond at the 7-position has not been reported in the literature, so that the prior art cannot realize cyclization reaction at the C-7 position. Here, we report for the first time a technique of modification/cyclization of the advanced peptide maleimide with high selectivity and directness to the C7 site. The developed reactions can efficiently, with high selectivity, carry out modification, ligation and cyclization of polypeptides.
(III) summary of the invention
the invention aims to provide a tryptophan number 7 locus maleimido cyclic derivative, and a preparation method and application thereof.
in order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
The invention provides a tryptophan No.7 maleimide cyclized derivative shown in a formula I or a formula III,
In the formula I, m1＝1～20，n1When n is =0 to 61When the AA is not 01～AAn1Is any amino acid residue; in formula III, n2When n is =0 to 62When it is not 0, aa1～aan2Is any amino acid residue. n is n1Or n2When 0, the amino group is directly bonded to the carbonyl group.
Preferably, the tryptophan maleimide at position 7 cyclized derivative represented by formula I is one of the following:
preferably, the tryptophan maleimide 7-cyclized derivative represented by formula III is one of the following:
The invention also provides a preparation method of the tryptophan No. 7 maleimide cyclized derivative shown in the formula I or the formula III, which comprises the following steps:
Specifically, the method comprises the following steps: taking maleimide modified tryptophan-containing polypeptide shown in formula II or formula VI as a substrate, stirring and reacting in a solvent at 60-120 ℃ (preferably 80 ℃) for 6-48 hours (preferably 24 hours) in the presence of a catalyst, an additive and an oxidant, and performing aftertreatment on the obtained reaction liquid to obtain a tryptophan number 7 maleimide cyclized derivative shown in formula I or formula III;
In the formula I, m1＝1～20，n1When n is =0 to 61When the AA is not 01～AAn1Is any amino acid residue; in formula III, n2When n is =0 to 62When it is not 0, aa1～aan2Is any amino acid residue;
The catalyst is one of the following: dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, dichloro (pentamethylcyclopentadienyl) iridium (III) dimer, dichloro bis (4-cymene) ruthenium (II) and palladium acetate;
The additive is one of the following: silver hexafluoroantimonate, silver tetrafluoroborate, silver bistrifluoromethane sulfonimide salt;
The oxidant is one of the following: silver carbonate, silver acetate, silver oxide, copper acetate, silver nitrate;
The solvent is one of the following: tetrahydrofuran, dichloromethane, dichloroethane, N-dimethylformamide;
The ratio of the substances of the substrate, the catalyst, the additive and the oxidant is 1:0.05-0.15:0.2-1: 0.1 to 2.
the unique reactivity of tryptophan indole C-H at position seven and tolerance to functional groups of post peptide functionalization can be increased due to the targeting effect of Piv at position one. The maleimide realizes hydrocarbon activation reaction at the seventh position of tryptophan indole.
Preferably, the catalyst is dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer.
preferably, the additive is silver bis (trifluoromethanesulfonyl) imide salt.
Preferably, the oxidizing agent is silver oxide.
Preferably, the solvent is dichloromethane.
Further, the volume of the solvent is 20 to 100mL/mmol in terms of the amount of the substance of the substrate. Preferably 83.3mL/mmol.
preferably, the substrate, catalyst, additive, oxidant are present in a ratio of amounts of materials of 1:0.1:0.4:1.5.
Further, the post-treatment is as follows: adding saturated NaCl aqueous solution into the reaction solution, extracting with ethyl acetate, drying an organic layer by anhydrous sodium sulfate, filtering, and removing a solvent by rotary evaporation at normal temperature to obtain a crude product; the volume ratio of the crude product is 10-40: 1 as eluent, collecting eluent containing target compound, removing solvent under reduced pressure, and drying to obtain tryptophan No. 7 maleimide cyclized derivative shown in formula (I) or formula (III).
The invention also relates to application of the maleimide derivative in preparation of antitumor drugs.
Preferably, the tumor is lung cancer.
Compared with the prior art, the invention has the beneficial effects that: the compounds of the invention are rhodium catalyzed, site-selective C7 maleimide modified, and can be obtained under mild and non-polymeric conditions. This reaction is effective for modification, ligation and drug modification of peptides with C7. The compound has good anti-tumor application prospect, and provides a new scheme for developing anti-tumor drugs.
(IV) description of the drawings
FIG. 1 shows a cyclic peptide compound (I)a) Is used for researching the anti-tumor activity;
FIG. 2 shows a cyclic peptide compound (I)b) Is used for researching the anti-tumor activity;
FIG. 3 shows a cyclic peptide compound (I)c) Is used for researching the anti-tumor activity;
FIG. 4 shows a cyclic peptide compound (I)d) Is used for researching the anti-tumor activity;
FIG. 5 shows a cyclic peptide compound (I)e) Is used for researching the anti-tumor activity;
FIG. 6 shows a cyclic peptide compound (III)f) Is used for researching the anti-tumor activity;
FIG. 7 shows a cyclic peptide compound (III)g) Is a study of antitumor activity.
(fifth) detailed description of the invention
The invention will be further described with reference to the following specific examples, but the scope of the invention is not limited thereto:
The general synthetic procedure for cyclic peptide precursors of the present invention is as follows:
This method is cited in the document Late-stage construction of stapled peptides through Fujiwara-Moritani reaction betweentryptophan and olefins. Dichloro resin (300 mg,0.3 mmol) was suspended in 5mL of dichloromethane, fmoc-Gly-OH (0.9 mmol) and N, N-diisopropylethylamine (154.8 mg,1.2 mmol) were then added, after 2 hours of reaction in a shaker, 300. Mu.L of methanol was added to cap for 10 minutes, and then Fmoc-Gly-dichloro resin was washed 3 times with N, N-Dimethylformamide (DMF). Fmoc-Gly-dichloro resin was deprotected with 20% piperidine/DMF for 30 min. After completion, the H-Gly-dichloro resin was washed four times with DMF. Subsequent amino acid coupling, standard solid phase peptide synthesis procedure (SPPS) was used. The polypeptide was cleaved from the dichloro resin using 25% hexafluoroisopropanol/dichloromethane for 1 hour, filtered, the resin was washed 3 times with dichloromethane, the filtrates combined and concentrated in vacuo to give the polypeptide. Finally, the hydrochloride (66.2 mg,0.2 mmol) of the linear peptide (0.2 mmol) H-Trp (Piv) -OMe,
1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (58 mg,0.3 mmol) and 1-Hydroxybenzotriazole (HOBT) (40 mg,0.3 mmol) were dissolved in 3mL DMF, then N, N-Diisopropylethylamine (DIEA) (78 mg,0.6 mmol) was added and stirred at room temperature for 12 hours. After the reaction was completed, 20mL of ethyl acetate and 20mL of water were added, and the organic layer was separated, washed with 20mL of 1n hydrochloric acid, 20mL of saturated sodium bicarbonate, 20mL of saturated sodium chloride solution, and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give linear peptide (II), respectively.
Example 1: compound (I)a) Is prepared from
As shown in IIathe indicated maleimide-containing tryptophan linear polypeptide (general synthetic procedure for cyclopeptide precursor (II) (67.84 mg,0.12 mmol), [ RhCp. Times. Cl)2]2(7.4 mg,0.012 mmol) was suspended in 10mL DCM and AgNTf was then added2(18.6 mg,0.048 mmol) and silver oxide (41.7 mg,0.18 mmol). The tube was sealed and the mixture was heated to 80℃for 24 hours. Adding saturated NaCl aqueous solution into the reaction mixture, extracting with ethyl acetate, drying an organic layer by anhydrous sodium sulfate, filtering, and removing a solvent by rotary evaporation at normal temperature to obtain a crude product; further purification by column on silica gel or preparation of silica gel plates (volume ratio of dichloromethane to methanol 15:1; rf=0.4), collecting the solvent and spin-drying to obtain formula IaThe pure product of the compound is 15.0mg, the yield is 22 percent, and the compound IaIs used for detecting the anti-tumor activity of the (C) and calculating IC50IC and method for manufacturing the same50The 95% confidence interval is 20.462.+ -. 0.214. Mu.M, and the results are shown in FIG. 1.
1H NMR(500MHz,DMSO)δ8.15(d,J＝8.7Hz,1H),7.96(s,1H),7.74(dd,J＝7.7,1.3Hz,1H),7.39(t,J＝7.6Hz,1H),7.34(dd,J＝7.4,1.3Hz,1H),6.84(s,1H),4.56(ddd,J＝12.4,8.6,3.3Hz,1H),3.75(s,3H),3.52(ddd,J＝13.9,6.8,3.8Hz,1H),3.43(ddd,J＝14.0,8.2,3.7Hz,1H),3.31(dd,J＝13.9,3.3Hz,1H),2.93(dd,J＝14.1,12.7Hz,1H),2.04–1.90(m,2H),1.47(s,1H),1.41(s,9H),1.33–1.25(m,3H),1.22–1.15(m,3H),1.14–0.78(m,9H).13C NMR(126MHz,DMSO)δ178.26,172.95,172.27,171.48,171.22,147.67,133.89,130.46,127.39,127.07,123.53,122.56,120.79,117.97,115.32,52.60,51.10,41.35,36.18,36.12,30.02,29.99,29.48,28.87,28.63,28.25,27.50,26.69,25.58,24.99.HRMS(ESI)m/z calcd for C32H41N3O6Na(M+Na)+586.2888,found 586.2893.
Example 2: compound (I)b) Is prepared from
As shown in IIbThe indicated maleimide-containing tryptophan linear polypeptide (general synthetic procedure for cyclopeptide precursor (II) (74.89 mg,0.12 mmol), [ RhCp. Times. Cl)2]2(7.4 mg,0.012 mmol) was suspended in 10mL DCM and AgNTf was then added2(18.6 mg,0.048 mmol) and silver oxide (41.7 mg,0.18 mmol). The tube was sealed and the mixture was heated to 80℃for 24 hours. Adding saturated NaCl aqueous solution into the reaction mixture, extracting with ethyl acetate, drying an organic layer by anhydrous sodium sulfate, filtering, and removing a solvent by rotary evaporation at normal temperature to obtain a crude product; further purification by column on silica gel or preparation of silica gel plates (volume ratio of dichloromethane to methanol 10:1; rf=0.3), collecting the solvent and spin-drying to obtain formula IbThe pure product of the compound shown is 11.3mg, and the yield is 15%. Compound IbIs used for detecting the anti-tumor activity of the (C) and calculating IC50IC and method for manufacturing the same50The 95% confidence interval is 22.237.+ -. 0.278. Mu.M, and the results are shown in FIG. 2.
1H NMR(500MHz,Chloroform-d)δ7.63(dd,J＝7.8,1.3Hz,1H),7.59(s,1H),7.33(t,J＝7.7Hz,1H),7.28(d,J＝1.3Hz,1H),7.27(d,J＝1.2Hz,0H),6.91(d,J＝7.1Hz,1H),6.74(d,J＝6.1Hz,1H),6.44(s,1H),6.34(d,J＝8.3Hz,1H),4.89(ddd,J＝8.7,7.1,4.7Hz,1H),4.32(dd,J＝8.1,7.0Hz,1H),3.97(dd,J＝15.6,6.0Hz,1H),3.87(s,3H),3.75–3.62(m,2H),3.56–3.47(m,2H),3.41(dd,J＝14.8,4.7Hz,1H),3.10(dd,J＝14.9,8.6Hz,1H),2.24(ddd,J＝13.5,7.3,5.8Hz,1H),2.17–2.07(m,1H),1.87–1.78(m,1H),1.67(tt,J＝13.5,6.3Hz,2H),1.48(s,9H),1.32(ddd,J＝9.1,6.9,3.0Hz,2H),0.46(d,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ178.63,173.37,172.27,172.11,171.30,171.07,169.31,147.81,133.99,130.82,127.46,125.56,123.47,121.34,120.67,117.88,114.22,52.76,51.47,47.92,43.50,41.34,36.71,29.68,28.58,28.31,27.20,25.18,24.16,18.32.HRMS(ESI)m/z calcd for C32H39N5O8Na(M+Na)+644.2691,found 644.2694.
Example 3: compound (I)c) Is prepared from
As shown in IIcThe indicated maleimide-containing tryptophan linear polypeptides (general synthetic procedure for cyclopeptide precursor (II)) (114.66mg 0.12mmol), [ RhCp. Times. Cl ]2]2(7.4 mg,0.012 mmol) was suspended in 10mL DCM and AgNTf was then added2(18.6 mg,0.048 mmol) and silver oxide (41.7 mg,0.18 mmol). The tube was sealed and the mixture was heated to 80℃for 24 hours. Adding saturated NaCl aqueous solution into the reaction mixture, extracting with ethyl acetate, drying an organic layer by anhydrous sodium sulfate, filtering, and removing a solvent by rotary evaporation at normal temperature to obtain a crude product; further purification by column on silica gel or preparation of silica gel plates (volume ratio of dichloromethane to methanol 20:1; rf=0.23), collecting the solvent and spin-drying to obtain formula Icthe pure product of the compound shown is 11.23mg, and the yield is 35%. Compound IcIs used for detecting the anti-tumor activity of the (C) and calculating IC50IC and method for manufacturing the same50The 95% confidence interval is 24.528.+ -. 0.215. Mu.M, and the results are shown in FIG. 3.
1H NMR(500MHz,DMSO-d6)δ8.53(d,J＝8.4Hz,1H),7.98(s,1H),7.89(s,1H),7.69(t,J＝26.4Hz,2H),7.44–7.22(m,4H),7.09(s,4H),6.81(d,J＝37.3Hz,3H),4.51(d,J＝74.3Hz,2H),4.06(t,J＝7.2Hz,1H),3.74(s,9H),3.29(d,J＝14.0Hz,1H),2.93(t,J＝13.4Hz,1H),2.78(d,J＝15.6Hz,1H),2.36(d,J＝37.1Hz,3H),1.94–1.78(m,2H),1.73–1.60(m,2H),1.47(s,1H),1.38(d,J＝3.0Hz,18H),0.74(d,J＝18.6Hz,6H).13C NMR(126MHz,DMSO)δ171.88,171.39,170.84,170.77,170.74,170.45,170.43,170.30,170.28,170.27,170.11,168.31,168.28,167.40,137.86,137.52,132.74,130.38,128.75,127.70,127.14,125.80,123.01,120.69,117.35,79.56,57.30,53.54,52.25,41.43,40.93,36.44,34.51,30.90,28.98,28.04,27.95,27.72,26.59,26.24,24.17,15.36,11.38,11.26.HRMS(ESI)m/z calcd for C50H63N7O12Na(M+Na)+976.4427,found 976.4429.
Example 4: compound (I)d) Is prepared from
As shown in IIdthe indicated maleimide-containing tryptophan linear polypeptide (general synthetic procedure for cyclopeptide precursor (II) (102.16 mg,0.12 mmol), [ RhCp. Times. Cl)2]2(7.4 mg,0.012 mmol) was suspended in 10mL DCM and AgNTf was then added2(18.6 mg,0.048 mmol) and silver oxide (41.7 mg,0.18 mmol). The tube was sealed and the mixture was heated to 80℃for 24 hours. Adding saturated NaCl aqueous solution into the reaction mixture, extracting with ethyl acetate, drying an organic layer by anhydrous sodium sulfate, filtering, and removing a solvent by rotary evaporation at normal temperature to obtain a crude product; further purification by column on silica gel or preparation of silica gel plates (volume ratio of dichloromethane to methanol 40:1; rf=0.3), collecting the solvent and spin-drying to obtain formula Idthe pure product of the compound shown in 43.9mg was obtained in 43% yield. Compound IdIs used for detecting the anti-tumor activity of the (C) and calculating IC50IC and method for manufacturing the same50the 95% confidence interval is 24.162 + -0.2335 μm, and the results are shown in FIG. 4.
1H NMR(500MHz,Chloroform-d)δ7.68(d,J＝7.8Hz,1H),7.37(t,J＝7.7Hz,1H),7.29(s,1H),7.12(d,J＝7.2Hz,2H),7.03(d,J＝8.5Hz,1H),6.70(d,J＝9.1Hz,1H),6.54(d,J＝6.4Hz,2H),6.31(s,1H),5.22(ddd,J＝12.2,8.5,3.9Hz,1H),4.73(ddd,J＝12.0,9.2,3.3Hz,1H),4.43(dd,J＝17.2,8.3Hz,1H),3.95(dqt,J＝14.7,9.5,5.5Hz,2H),3.82(d,J＝9.2Hz,4H),3.46–3.32(m,2H),3.28(dd,J＝17.2,4.5Hz,1H),2.75(dd,J＝16.9,11.2Hz,1H),2.56(dd,J＝13.6,6.6Hz,1H),2.40(dd,J＝16.9,3.3Hz,1H),2.35–2.28(m,1H),2.14(h,J＝6.8Hz,1H),1.84–1.76(m,1H),1.38(s,9H),1.33(s,9H),0.92(dd,J＝9.4,6.8Hz,6H),0.64(d,J＝7.3Hz,3H).13C NMR(126MHz,CDCl3)δ179.04,173.65,171.70,171.28,170.99,170.45,170.06,147.86,133.35,131.92,126.08,123.95,123.36,122.79,120.91,117.69,116.36,81.68,60.63,52.74,51.59,49.81,48.32,42.72,41.41,38.19,36.61,34.53,29.64,28.64,28.59,27.83,26.11,19.41,19.31,16.05,9.45.HRMS(ESI)m/z calcd for C42H55N7O12Na(M+Na)+872.3801,found 872.3803.
Example 5: compound (I)e) Is prepared from
As shown in IIeThe indicated maleimide-containing tryptophan linear polypeptide (general synthetic procedure for cyclopeptide precursor (II) (81.52 mg,0.12 mmol), [ RhCp. Times. Cl)2]2(7.4 mg,0.012 mmol) was suspended in 10mL DCM and AgNTf was then added2(18.6 mg,0.048 mmol) and silver oxide (41.7 mg,0.18 mmol). The tube was sealed and the mixture was heated to 80℃for 24 hours. Adding saturated NaCl aqueous solution into the reaction mixture, extracting with ethyl acetate, drying an organic layer by anhydrous sodium sulfate, filtering, and removing a solvent by rotary evaporation at normal temperature to obtain a crude product; further purification by column on silica gel or preparation of silica gel plates (volume ratio of dichloromethane to methanol 20:1; rf=0.3), collecting the solvent and spin-drying to obtain formula IeThe pure product of the compound shown is 31.0mg, and the yield is 38%. Compound IhIs used for detecting the anti-tumor activity of the (C) and calculating IC50IC and method for manufacturing the same50The 95% confidence interval is 25.136.+ -. 0.257. Mu.M, and the results are shown in FIG. 5.
1H NMR(500MHz,Chloroform-d)δ7.59(s,1H),7.55(dd,J＝7.8,1.3Hz,1H),7.33(t,J＝7.6Hz,1H),7.26(dd,J＝7.4,1.3Hz,1H),7.08(d,J＝8.3Hz,1H),7.01(t,J＝5.9Hz,1H),6.44(s,1H),6.43(d,J＝5.4Hz,1H),5.04(td,J＝8.0,4.3Hz,1H),3.89(dd,J＝16.3,5.9Hz,1H),3.82–3.77(m,4H),3.54(t,J＝6.8Hz,4H),3.36(dd,J＝15.7,4.0Hz,1H),3.19(dd,J＝15.6,7.8Hz,1H),2.05(t,J＝7.6Hz,2H),1.70–1.60(m,2H),1.53(d,J＝8.0Hz,3H),1.45(s,9H),1.34(t,J＝3.3Hz,5H),1.30–1.27(m,3H).13C NMR(126MHz,CDCl3)δ178.49,174.37,171.83,171.19,169.84,169.06,149.07,133.55,131.49,127.40,125.00,123.62,121.51,120.97,117.81,115.02,52.73,51.36,43.27,42.90,41.22,37.76,35.74,31.42,29.66,28.98,28.50,28.24,27.91,27.71,27.53,26.98,25.42,24.94.HRMS(ESI)m/z calcd for C36H47N5O8Na(M+Na)+700.3317,found 700.3317.
Example 6: compound (III)f) Is prepared from
As shown in VIfthe indicated maleimide-containing tryptophan linear polypeptide (general synthetic procedure for cyclopeptide precursor (II) (119.82 mg,0.12 mmol), [ RhCp. Times. Cl)2]2(7.4 mg,0.012 mmol) was suspended in 10mL DCM and AgNTf was then added2(18.6 mg,0.048 mmol) and silver oxide (41.7 mg,0.18 mmol). The tube was sealed and the mixture was heated to 80℃for 24 hours. Adding saturated NaCl aqueous solution into the reaction mixture, extracting with ethyl acetate, drying an organic layer by anhydrous sodium sulfate, filtering, and removing a solvent by rotary evaporation at normal temperature to obtain a crude product; further purification by column on silica gel or preparation of silica gel plates (volume ratio of dichloromethane to methanol 20:1; rf=0.4), collecting the solvent and spin-drying to obtain formula IIIfthe pure product of the compound shown is 41.9mg, and the yield is 35%. Compound IiIs used for detecting the anti-tumor activity of the (C) and calculating IC50IC and method for manufacturing the same50The 95% confidence interval is 26.579.+ -. 0.246. Mu.M, and the results are shown in FIG. 6.
1H NMR(500MHz,DMSO)δ8.50(d,J＝8.4Hz,1H),8.01(d,J＝8.0Hz,1H),7.90(s,1H),7.80–7.66(m,3H),7.58–7.49(m,1H),7.41–7.35(m,2H),7.21–7.10(m,6H),6.94(d,J＝7.8Hz,1H),6.84(s,1H),4.63(t,J＝10.6Hz,1H),4.43(td,J＝8.4,5.2Hz,1H),4.29(td,J＝9.2,4.6Hz,1H),4.15(t,J＝7.3Hz,1H),3.83–3.58(m,7H),3.35(d,J＝7.3Hz,1H),3.33–3.27(m,1H),3.07(dd,J＝14.2,5.1Hz,1H),2.99(dd,J＝14.9,11.9Hz,1H),2.76(dd,J＝14.3,8.9Hz,1H),1.61–1.44(m,8H),1.37(s,9H),1.36(s,9H),1.11(d,J＝7.0Hz,3H),0.83(d,J＝6.5Hz,6H).13C NMR(126MHz,DMSO)δ178.71,172.63,172.42,172.21,171.94,171.43,170.67,170.56,168.93,155.72,148.77,137.93,133.38,131.04,129.51,128.45,127.81,126.63,126.26,123.68,121.56,121.20,118.06,115.65,78.50,54.98,53.95,52.73,51.80,51.05,48.59,41.90,41.19,37.52,37.06,32.16,28.63,28.52,28.38,26.65,24.46,23.49,22.81,22.10,18.66.HRMS(ESI)m/z calcd for C52H68N8O12Na(M+Na)+1019.4849,found 1019.4853.
Example 7: compound (III)g) Is prepared from
As shown in VIgThe indicated maleimide-containing tryptophan linear polypeptide (general synthetic procedure for cyclopeptide precursor (II) (109.61 mg,0.12 mmol), [ RhCp. Times. Cl)2]2(7.4 mg,0.012 mmol) was suspended in 10mL DCM and AgNTf was then added2(18.6 mg,0.048 mmol) and silver oxide (41.7 mg,0.18 mmol). The tube was sealed and the mixture was heated to 80℃for 24 hours. Adding saturated NaCl aqueous solution into the reaction mixture, extracting with ethyl acetate, drying an organic layer by anhydrous sodium sulfate, filtering, and removing a solvent by rotary evaporation at normal temperature to obtain a crude product; further purification by column on silica gel or preparation of silica gel plates (volume ratio of dichloromethane to methanol 25:1; rf=0.3), collecting the solvent and spin-drying to obtain formula IIIg42.7mg of the pure product of the shown compound, and 39% of the yield of the compound IgIs used for detecting the anti-tumor activity of the (C) and calculating IC50IC and method for manufacturing the same50The 95% confidence interval is 26.177.+ -. 0.222. Mu.M, see 7 for results.
1H NMR(500MHz,CDCl3)δ7.81(s,1H),7.62(d,J＝7.7Hz,1H),7.45(s,1H),7.39(d,J＝6.1Hz,1H),7.29(d,J＝8.2Hz,2H),7.24(d,J＝7.6Hz,1H),7.20–7.08(m,6H),6.49(s,1H),5.87(s,1H),5.32(d,J＝11.3Hz,1H),4.91(s,1H),4.61(s,1H),4.50(dd,J＝17.6,7.4Hz,1H),3.95(d,J＝5.5Hz,1H),3.82(s,3H),3.68(dd,J＝17.6,8.6Hz,1H),3.56(dd,J＝17.4,4.9Hz,1H),3.42(dq,J＝27.8,15.9,15.4Hz,5H),3.05–2.97(m,1H),2.51(s,1H),2.30(t,J＝13.8Hz,1H),2.14–1.98(m,2H),1.79–1.68(m,1H),1.58(s,1H),1.42(s,9H),1.15(s,9H),0.43(d,J＝6.9Hz,3H),0.21(d,J＝6.9Hz,3H).13C NMR(126MHz,CDCl3)δ178.51,172.68,171.87,171.81,171.04,169.88,156.72,137.45,133.96,131.72,129.45,128.27,127.92,127.01,126.35,123.07,121.06,118.98,117.40,115.98,81.31,59.52,56.33,54.93,52.71,49.68,48.00,43.24,41.03,35.24,34.91,29.65,28.94,28.69,28.59,28.44,27.83,26.23,19.52,19.30,16.57.HRMS(ESI)m/z calcd for C48H61N7O11Na(M+Na)+934.4321,found 934.4328.
Example 8: detection of antitumor Activity of Compounds
Tumor cell A549 (lung cancer cell) is selected, and the MTT method is adopted to detect the proliferation activity of the anti-tumor cell. Cells were seeded at 4000-5000 cells/well in 96-well plates containing 1640 medium with 10% fetal bovine serum and annotated on the plate cover at 5% CO2Culturing at 37deg.C for 12 hr, allowing cells to adhere to 96-well plate, adding the drug to be tested in sterile operation table by pipetting gun to give five concentration gradients of 2 μM, 5 μM, 10 μM, 20 μM, and 40 μM for each well, arranging three parallel groups for each concentration, and placing 96-well plate in 5% CO again2Culturing at 37 ℃ for 24 hours. The 96-well plates were removed, 10. Mu.L of MTT kit reagent (from Promega) was added to each well, protected from light at 5% CO2incubating for 4 hours at 37 ℃, absorbing the supernatant, adding 150uL of sterile DMSO to dissolve formazan, further dissolving in an incubator at 37 ℃ for 5-10 min, and finally measuring the absorbance by using an enzyme-labeled instrument. Thus, cell viability and cytotoxicity were calculated, and IC was calculated by treatment with GraphPad Prism software software50IC and method for manufacturing the same5095% confidence interval. Experimental results show that the compound has a certain antitumor activity.
Comparative example 1: catalyst selection
The procedure is as in example 1, the catalyst is prepared from [ RhCp. Times. Cl2]2substitution with dichloro (pentamethylcyclopentadienyl) iridium (III) dimer (9.552 mg,0.012 mmol) gave 7.5mg of product in 11% reaction yield.
Comparative example 2: selection of additives
The procedure is as in example 1, with the additive AgNTf2Replacement with silver hexafluoroantimonate (17.13 mg,0.048 mmol) gave 5.5mg of product with a reaction yield of 8%.
Comparative example 3: selection of oxidizing agent
The procedure is as in example 1 substituting silver oxide for silver carbonate (49.635 mg,0.18 mmol) to give 7.5mg of product in 11% yield.
Comparative example 4: selection of solvent
the procedure is as in example 1, substituting DMF10ml for solvent from DCM to give 4.7mg of the product in 7% yield.
Comparative example 5: selection of solvent to reactant ratio
the procedure was as in example 1, substituting 10ml of methylene chloride into 20ml, and the reaction yield was 11.2%.
Comparative example 6: selection of the ratio of the amounts of substrate, catalyst, additive, oxidant
The procedure was as in example 1 except that the amount of silver oxide added was changed from 41.7mg to 14mg to give 7.6mg of a product with a reaction yield of 4.3%.
Comparative example 7: catalyst selection
The procedure is as in example 1, the catalyst is prepared from [ RhCp. Times. Cl2]2Substitution with bis (4-cymene) ruthenium (II) dichloride (7.3 mg,0.012 mmol) gave 7.6mg of the product in 11.2% reaction yield.
Comparative example 8: catalyst selection
The procedure is as in example 1, the catalyst is prepared from [ RhCp. Times. Cl2]2Substitution with palladium acetate (2.68 mg,0.012 mmol) gave 7.8mg of the product in 11.6% reaction yield.
Comparative example 9: selection of additives
The procedure is as in example 1, with the additive AgNTf2Replacement with silver tetrafluoroborate (9.3 mg,0.048 mmol) gave 5.8mg of product with a reaction yield of 8.6%.
Comparative example 10: selection of oxidizing agent
the procedure is as in example 1 substituting silver oxide for silver acetate (29.88 mg,0.18 mmol) to give 7.0mg of the product in 10% yield.
Comparative example 11: selection of oxidizing agent
The procedure is as in example 1 substituting silver oxide for copper acetate (35.82 mg,0.18 mmol) to give 5.5mg of the product in 8% reaction yield.
Comparative example 12: selection of oxidizing agent
The procedure is as in example 1 substituting silver oxide for silver nitrate (30.42 mg,0.18 mmol) to give 5.7mg of the product in 8.4% yield.
Comparative example 13: selection of solvent
The procedure was as in example 1 substituting tetrahydrofuran for DCM to give 5.1mg of the product in 7.8% yield.
Comparative example 14: selection of solvent
The procedure was as in example 1 substituting DCM for dichloroethane 10ml to give 3.75mg of the product in 5.5% yield.

Claims (8)

1. A tryptophan No.7 maleimide cyclized derivative shown in a formula I or a formula III, In the formula I, m1=1~20，n1=0 to 6, when n1When the AA is not 01～AAn1Is any amino acid residue; in formula III, n2=0 to 6, when n2When it is not 0, aa1～aan2Is any amino acid residue; the method is characterized in that the 7-maleimide cyclized derivative of tryptophan shown in the formula I is one of the following: /(I)the method comprises the steps of carrying out a first treatment on the surface of the The tryptophan maleimide 7-cyclized derivative represented by formula III is one of the following: /(I)。
2. a process for the preparation of a cyclic maleimide derivative of tryptophan number 7 of formula I or formula III according to claim 1, characterized in that it comprises: taking maleimide modified tryptophan-containing polypeptide shown in formula II or formula VI as a substrate, stirring and reacting in a solvent at 60-120 ℃ for 6-48 hours in the presence of a catalyst, an additive and an oxidant, and performing post-treatment on the obtained reaction liquid to obtain a tryptophan number 7 maleimide cyclized derivative shown in formula I or formula III; In the formula I, m1=1~20，n1=0 to 6, when n1When the AA is not 01～AAn1Is any amino acid residue; in formula III, n2=0 to 6, when n2When it is not 0, aa1～aan2Is any amino acid residue;
The catalyst is one of the following: dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, dichloro (pentamethylcyclopentadienyl) iridium (III) dimer, dichloro bis (4-cymene) ruthenium (II) and palladium acetate;
The additive is one of the following: silver hexafluoroantimonate, silver tetrafluoroborate, silver bistrifluoromethane sulfonimide salt;
The oxidant is one of the following: silver carbonate, silver acetate, silver oxide, copper acetate, silver nitrate;
The solvent is one of the following: tetrahydrofuran, dichloromethane, dichloroethane, N-dimethylformamide;
the mass ratio of the substrate, the catalyst, the additive and the oxidant is 1:0.05-0.15:0.2-1: 0.1 to 2.
3. The process for producing a maleimide cyclized derivative at position 7 of tryptophan as claimed in claim 2, wherein: the catalyst is dichloro (pentamethyl cyclopentadienyl) rhodium (III) dimer.
4. The process for producing a maleimide cyclized derivative at position 7 of tryptophan as claimed in claim 2, wherein: the additive is silver bis (trifluoromethanesulfonyl) imide salt.
5. the process for producing a maleimide cyclized derivative at position 7 of tryptophan as claimed in claim 2, wherein: the oxidant is silver oxide.
6. the process for producing a maleimide cyclized derivative at position 7 of tryptophan as claimed in claim 2, wherein: the volume of the solvent is 20-100 mL/mmol based on the amount of the substance of the substrate.
7. The process for the preparation of a maleimide cyclized derivative of tryptophan number 7 according to claim 2, wherein said post-treatment is: adding saturated NaCl aqueous solution into the reaction solution, extracting with ethyl acetate, drying an organic layer by anhydrous sodium sulfate, filtering, and removing a solvent by rotary evaporation at normal temperature to obtain a crude product; the volume ratio of the crude product is 10-40: 1 as eluent, collecting eluent containing target compound, removing solvent under reduced pressure, and drying to obtain tryptophan No. 7 maleimide cyclized derivative shown in formula (I) or formula (III).
8. Use of a maleinized derivative according to claim 1 for the preparation of an anti-lung cancer drug.
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CN112739345A (en) * 2017-11-06 2021-04-30 斯奈普生物公司 PIM kinase inhibitor compositions, methods and uses thereof
CN113480606A (en) * 2021-08-05 2021-10-08 浙江工业大学 Tryptophan-containing polypeptide alkene cyclization derivative and preparation and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112739345A (en) * 2017-11-06 2021-04-30 斯奈普生物公司 PIM kinase inhibitor compositions, methods and uses thereof
CN113480606A (en) * 2021-08-05 2021-10-08 浙江工业大学 Tryptophan-containing polypeptide alkene cyclization derivative and preparation and application thereof

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