CN114656519A - 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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CN114656519A
CN114656519A CN202210251829.3A CN202210251829A CN114656519A CN 114656519 A CN114656519 A CN 114656519A CN 202210251829 A CN202210251829 A CN 202210251829A CN 114656519 A CN114656519 A CN 114656519A
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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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Abstract

The compounds of the invention are rhodium-catalyzed, maleimide-modified with site-selective C7 and are obtainable under mild conditions and without polymerization. Compared with the reaction catalyzed by copper (II) trifluoromethanesulfonate reported in the literature, the reaction can effectively carry out modification, connection and drug modification on the peptide by using C7. The compound has the advantages of simple operation process, no guide group, high site selectivity and high reaction efficiency, can be prepared by only one step, has better anti-tumor application prospect, and provides a new scheme for researching and developing anti-tumor drugs.

Description

Tryptophan No. 7 maleimide cyclized derivative and preparation method and application thereof
(I) technical field
The invention relates to a tryptophan No. 7 site maleimide cyclized derivative, and a preparation method and application thereof.
(II) background of the invention
The polypeptide is an important bioactive molecule and has wide application in the fields of medicinal chemistry, biotechnology, chemical biology and the like. Cyclic peptides have attracted extensive attention in the pharmaceutical industry due to their excellent cell penetration, stability, thermal stability and drug-like properties. The existing simple and efficient methods for creating such peptides are quite limited. Transition metal catalyzed Late Stage Functionalization (LSF) of complex molecules has good site specificity and high functional group tolerance, and provides a simple method for efficient C-H functionalization/macrocyclization. In recent years, several methods based on the late modification of Trp (tryptophan) residues have been successfully developed. Whereas the traditional approach to late modification of Trp residues: usually, a protecting group or a guiding group is introduced to No. 1 of an indole heterocycle of Trp, and after modification of other sites is completed, deprotection or the guiding group is finally carried out to realize modification. The method of catalyzing by copper (II) trifluoromethanesulfonate adopted in the literature has the known reaction yield of only 30 percent, the reaction temperature of 140 ℃ and the reaction time of 48 hours. The method has the defects of multiple steps, low reaction yield and severe reaction conditions, and the existing problems greatly reduce the progress of the later modification research of the polypeptide containing Trp. There are many modification methods, but no literature is available for modifying the C _ C bond at position 7, and thus, the prior art cannot realize cyclization at C-7. Here, we report for the first time a highly selective and direct late peptide maleimide modification/cyclization technique to the C7 site. The developed reaction allows efficient, highly selective modification, ligation and cyclization of polypeptides.
Disclosure of the invention
The invention aims to provide a tryptophan No. 7 site maleimide cyclic derivative, and a preparation method and application thereof.
In order to achieve the purpose, the invention adopts the technical scheme that:
the invention provides a tryptophan 7-position maleimide cyclized derivative shown in a formula I or a formula III,
Figure BDA0003547231610000021
in the formula I, m1＝1～20，n1When n is 0 to 61When not 0, AA1～AAn1Is any amino acid residue; in the formula III, n2When n is 0 to 62When not 0, aa1～aan2Is any amino acid residue. n is1Or n2At 0, the amino group is directly attached to the carbonyl group.
Preferably, the tryptophan maleimide cyclized derivative at position 7 shown in the formula I is one of the following:
Figure BDA0003547231610000022
preferably, the tryptophan maleimide cyclized derivative at position 7 shown in the formula III is one of the following:
Figure BDA0003547231610000031
the invention also provides a preparation method of the Tryptophan No. 7 maleimide cyclized derivative shown in the formula I or the formula III:
Figure BDA0003547231610000032
specifically, the method comprises the following steps: taking the polypeptide containing tryptophan modified by maleimide shown in formula II or formula VI as a substrate, in the presence of a catalyst, an additive and an oxidant, stirring and reacting in a solvent at 60-120 ℃ (preferably 80 ℃) for 6-48 hours (preferably 24 hours), and carrying out aftertreatment on the obtained reaction liquid to obtain the tryptophan No. 7 maleimide cyclized derivative shown in formula I or formula III;
Figure BDA0003547231610000033
Figure BDA0003547231610000041
in the formula I, m1＝1～20，n1When n is 0 to 61When not 0, AA1～AAn1Is any amino acid residue; in the formula III, n2When n is 0 to 62When 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, dichlorobis (4-methylisopropylphenyl) ruthenium (II), palladium acetate;
the additive is one of the following: silver hexafluoroantimonate, silver tetrafluoroborate, bis (trifluoromethanesulfonylimide) silver 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 substrate, the catalyst, the additive and the oxidant is 1: 0.05-0.15: 0.2-1: 0.1 to 2.
Due to the targeting effect of pivaloyl (Piv) at position one, the unique reactivity of C-H activation at position seven of tryptophan indole and tolerance to functional groups of later peptide functionalization can be increased. The maleimide is subjected to a hydrocarbon activation reaction at the seven-position of tryptophan indole.
Preferably, the catalyst is dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer.
Preferably, the additive is a bis (trifluoromethanesulfonyl) imide silver salt.
Preferably, the oxidizing agent is silver oxide.
Preferably, the solvent is dichloromethane.
Further, the volume of the solvent is 20-100 mL/mmol based on the amount of the substrate. Preferably 83.3 mL/mmol.
Preferably, the ratio of the amounts of the substances of the substrate, the catalyst, the additive and the oxidant is 1:0.1:0.4: 1.5.
Further, the post-treatment is as follows: adding a saturated NaCl aqueous solution into the reaction solution, extracting with ethyl acetate, taking an organic layer, drying with anhydrous sodium sulfate, filtering, and rotationally evaporating at normal temperature to remove the solvent to obtain a crude product; the crude product is prepared by mixing the following raw materials in a volume ratio of 10-40: 1, performing silica gel column chromatography by using a mixed solution of dichloromethane and methanol as an eluent, collecting an eluent containing the target compound, removing the solvent under reduced pressure, and drying to obtain the tryptophan No. 7 maleimide cyclized derivative shown in the formula (I) or the formula (III).
The invention also relates to application of the maleimide derivative in preparing antitumor drugs.
Preferably, the tumor is lung cancer.
Compared with the prior art, the invention has the following beneficial effects: the compounds of the invention are rhodium-catalyzed, maleimide-modified with site-selective C7 and are obtainable under mild conditions and without polymerization. This reaction is effective for peptide modification, ligation and drug modification with C7. The compound has the advantages of simple operation process, high site selectivity and high reaction efficiency, can be prepared by only one step, has good anti-tumor application prospect, and provides a new scheme for researching and developing anti-tumor drugs.
(IV) description of the drawings
FIG. 1 shows a cyclic peptide compound (I)a) The research on the anti-tumor activity;
FIG. 2 shows a cyclic peptide compound (I)b) The research on the anti-tumor activity;
FIG. 3 shows a cyclic peptide compound (I)c) The research on the anti-tumor activity;
FIG. 4 shows a cyclic peptide compound (I)d) The research on the anti-tumor activity;
FIG. 5 shows a cyclic peptide compound (I)e) Is/are as followsResearch on anti-tumor activity;
FIG. 6 shows a cyclic peptide compound (III)f) The research on the anti-tumor activity;
FIG. 7 shows a cyclic peptide compound (III)g) The research on the antitumor activity of (1).
(V) detailed description of the preferred embodiments
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
the general synthesis procedure for the cyclic peptide precursors of the present invention is as follows:
Figure BDA0003547231610000061
this method is cited in the literature "Late-stage construction of small peptides through Fujiwara-Moritani interaction beta entertypophan and oleffs". Dichlororesin (300mg, 0.3mmol) was suspended in 5mL of dichloromethane, then Fmoc-Gly-OH (0.9mmol) and N, N-diisopropylethylamine (154.8mg, 1.2mmol) were added, and after 2 hours of reaction in a shaker, 300 microliters of methanol was added to the block for 10 minutes, and then Fmoc-Gly-dichlororesin was washed 3 times with N, N-Dimethylformamide (DMF). Fmoc-Gly-dichloro resin was Fmoc deprotected with 20% piperidine/DMF for 30 min. After completion, the H-Gly-dichloro-resin was washed four times with DMF. Subsequent amino acid couplings were performed using standard solid phase peptide synthesis procedures (SPPS). 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 were combined and concentrated in vacuo to give the polypeptide. Finally, the hydrochloride (66.2mg, 0.2mmol) of the linear peptide (0.2mmol) H-Trp (Piv) -OMe,
1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (58mg, 0.3mmol) and 1-Hydroxybenzotriazole (HOBT) (40mg, 0.3mmol) were dissolved in 3mL DMF, followed by addition of N, N-Diisopropylethylamine (DIEA) (78mg, 0.6mmol) and stirring at room temperature for 12 h. After completion of the reaction, 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, and 20mL of saturated sodium chloride solution, respectively, and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give linear peptide (II).
Example 1: compound (I)a) Preparation of
Figure BDA0003547231610000071
As shown in formula IIaIndicated maleimide-containing tryptophan linear polypeptide (general Synthesis procedure for Cyclic peptide precursor (II)) (67.84mg, 0.12mmol), [ RhCp Cl2]2(7.4mg, 0.012mmol) was suspended in 10mL DCM, then AgNTf was added2(18.6mg, 0.048mmol) and silver oxide (41.7mg, 0.18 mmol). The tube was sealed and the mixture was heated to 80 ℃ for 24 hours. Adding saturated NaCl water solution into the reaction mixture, extracting with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, filtering, and rotary evaporating at normal temperature to remove solvent to obtain crude product; further purification by silica gel column or preparative silica gel plate (dichloromethane to methanol volume ratio 15: 1; Rf ═ 0.4), solvent collection and spin drying to give formula IaThe pure product of the compound is 15.0mg, the yield is 22 percent, and the compound IaThe anti-tumor activity of (2) was measured, and IC was calculated50And IC50The 95% confidence interval was 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) Preparation of
Figure BDA0003547231610000091
As shown in formula IIbIndicated maleimide-containing tryptophan linear polypeptides (general procedure for the synthesis of cyclic peptide precursor (II)) (74.89mg, 0.12mmol), [ RhCp. multidot. Cl2]2(7.4mg, 0.012mmol) was suspended in 10mL DCM, then AgNTf was added2(18.6mg, 0.048mmol) and silver oxide (41.7mg, 0.18 mmol). The tube was sealed and the mixture was heated to 80 ℃ for 24 hours. Adding saturated NaCl water solution into the reaction mixture, extracting with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, filtering, and rotary evaporating at normal temperature to remove solvent to obtain crude product; further purification by silica gel column or preparative silica gel plate (dichloromethane to methanol volume ratio 10: 1; Rf ═ 0.3), collection of solvent and spin drying to give formula IbThe pure compound (11.3 mg) was obtained in 15% yield. Compound IbThe anti-tumor activity of (2) was measured, and IC was calculated50And IC50The 95% confidence interval was 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) Preparation of
Figure BDA0003547231610000101
As shown in formula IIcIndicated maleimide-containing tryptophan linear polypeptides (general procedure for the synthesis of cyclic peptide precursor (II)) (114.66mg 0.12mmol), [ RhCp. multidot. Cl2]2(7.4mg, 0.012mmol) was suspended in 10mL DCM, then AgNTf was added2(18.6mg, 0.048mmol) and silver oxide (41.7mg, 0.18 mmol). The tube was sealed and the mixture was heated to 80 ℃ for 24 hours. Adding saturated NaCl water solution into the reaction mixture, extracting with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, filtering, and rotary evaporating at normal temperature to remove solvent to obtain crude product; further purification by silica gel column or preparative silica gel plate (dichloromethane to methanol volume ratio 20: 1; Rf ═ 0.23), solvent collection and spin drying to give formula IcThe pure compound (11.23 mg) was obtained at a yield of 35%. Compound IcThe anti-tumor activity of (2) was measured, and IC was calculated50And IC50The 95% confidence interval was 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) Preparation of (2)
Figure BDA0003547231610000111
As shown in formula IIdIndicated maleimide-containing tryptophan linear polypeptides (general procedure for the synthesis of cyclic peptide precursor (II)) (102.16mg, 0.12mmol), [ RhCp. multidot. Cl2]2(7.4mg, 0.012mmol) was suspended in 10mL DCM, then AgNTf was added2(18.6mg, 0.048mmol) and silver oxide (41.7mg, 0.18 mmol). The tube was sealed and the mixture was heated to 80 ℃ for 24 hours. Adding saturated NaCl water solution into the reaction mixture, extracting with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, filtering, and rotary evaporating at normal temperature to remove solvent to obtain crude product; further purification by silica gel column or preparative silica gel plate (dichloromethane to methanol volume ratio 40: 1; Rf ═ 0.3), solvent collection and spin drying to give formula IdThe pure compound (43.9 mg) was obtained in 43% yield. Compound IdThe anti-tumor activity of (2) was measured, and IC was calculated50And IC50The 95% confidence interval was 24.162. + -. 0.2335. mu.M, 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) Preparation of
Figure BDA0003547231610000121
As shown in formula IIeIndicated maleimide-containing tryptophan linear polypeptides (general procedure for the synthesis of cyclic peptide precursor (II)) (81.52mg, 0.12mmol), [ RhCp. multidot. Cl2]2(7.4mg, 0.012mmol) was suspended in 10mL DCM, then AgNTf was added2(18.6mg, 0.048mmol) and silver oxide (41.7mg, 0.18 mmol). The tube was sealed and the mixture was heated to 80 ℃ for 24 hours. Adding saturated NaCl water solution into the reaction mixture, extracting with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, filtering, and rotationally evaporating at normal temperature to remove the solvent to obtain a crude product; further purification by silica gel column or preparative silica gel plate (dichloromethane to methanol volume ratio 20: 1; Rf ═ 0.3), solvent collection and spin drying to give formula IeThe pure compound (31.0 mg) was obtained in 38% yield. Compound IhThe anti-tumor activity of (2) was measured, and IC was calculated50And IC50The 95% confidence interval was 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) Preparation of
Figure BDA0003547231610000141
As shown in formula VIfIndicated maleimide-containing tryptophan linear polypeptides (general procedure for the synthesis of cyclic peptide precursor (II)) (119.82mg, 0.12mmol), [ RhCp. multidot. Cl2]2(7.4mg, 0.012mmol) was suspended in 10mL DCM, then AgNTf was added2(18.6mg, 0.048mmol) and silver oxide (41.7mg, 0.18 mmol). The tube was sealed and the mixture was heated to 80 ℃ for 24 hours. Adding saturated NaCl water solution into the reaction mixture, extracting with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, filtering, and rotary evaporating at normal temperature to remove solvent to obtain crude product; further purification by silica gel column or preparative silica gel plate (dichloromethane to methanol volume ratio 20: 1; Rf ═ 0.4), solvent collection and spin drying to afford formula IIIfThe pure compound (41.9 mg) was obtained with a yield of 35%. Compound IiThe anti-tumor activity of (2) was measured, and IC was calculated50And IC50The 95% confidence interval was 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) Preparation of
Figure BDA0003547231610000151
As shown in formula VIgIndicated maleimide-containing tryptophan linear polypeptides (general procedure for the synthesis of cyclic peptide precursor (II)) (109.61mg, 0.12mmol), [ RhCp. multidot. Cl2]2(7.4mg, 0.012mmol) was suspended in 10mL DCM, then AgNTf was added2(18.6mg, 0.048mmol) and silver oxide (41.7mg, 0.18 mmol). The tube was sealed and the mixture was heated to 80 ℃ for 24 hours. Adding saturated NaCl water solution into the reaction mixture, extracting with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, filtering, and rotary evaporating at normal temperature to remove solvent to obtain crude product; further purification by silica gel column or preparative silica gel plate (dichloromethane to methanol volume ratio 25: 1; Rf ═ 0.3), solvent collection and spin drying to afford formula IIIgThe pure compound (42.7 mg) showed 39% yield, Compound IgThe anti-tumor activity of (2) was measured, and IC was calculated50And IC50The 95% confidence interval was 26.177. + -. 0.222. mu.M, and the results are shown in 7.
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
Selecting tumor cell A549 (lung cancer cell), and detecting the proliferation activity of the anti-tumor cell by adopting an MTT method. The cells were seeded at 4000-5000 cells/well in a 96-well plate containing a 1640 culture medium of 10% fetal bovine serum, and the plate cover was annotated with 5% CO2Culturing at 37 ℃ for 12 hours, adding the drug to be detected by using a liquid transfer gun in a sterile operating platform when the cells adhere to the wall on a 96-well plate, enabling the drug concentration of each well to be five concentration gradients of 2 mu M, 5 mu M, 10 mu M, 20 mu M and 40 mu M respectively, arranging three parallel groups for each concentration, and placing the 96-well plate in 5% CO again2And incubated at 37 ℃ for 24 hours. The 96-well plate was removed, and 10. mu.L of MTT kit reagent (purchased from Promega) was added to each well, protected from light at 5% CO2And incubating for 4 hours at 37 ℃, absorbing supernatant, adding 150uL sterile DMSO to dissolve formazan, further dissolving in an incubator at 37 ℃ for 5-10 min, and finally measuring absorbance by using an enzyme-labeling instrument. Thus cell viability and cytotoxicity were calculated, processed with GraphPad Prism software, and IC calculated50And IC5095% confidence interval. The experimental result shows that the compound has certain antitumor activity.
Comparative example 1: selection of the catalyst
The procedure is as in example 1, the catalyst is prepared from [ RhCp Cl ]2]2Substitution with dichloro (pentamethylcyclopentadienyl) iridium (III) dimer (9.552mg, 0.012mmol) gave 7.5mg of product in 11% reaction yield.
Comparative example 2: selection of additives
The process is as in example 1, the additive is prepared from AgNTf2Replacement with silver hexafluoroantimonate (17.13mg, 0.048mmol) gave 5.5mg of product in 8% reaction yield.
Comparative example 3: selection of oxidizing agents
The procedure of example 1 was followed, substituting the oxidant from silver oxide for silver carbonate (4***mg, 0.18mmol) to give 7.5mg of product in 11% yield.
Comparative example 4: selection of solvents
The procedure is as in example 1, replacing the solvent from DCM with DMF10ml to give 4.7mg of product in 7% yield.
Comparative example 5: selection of solvent to reactant ratio
The procedure is as in example 1, replacing the amount of methylene chloride from 10ml to 20ml and giving a reaction yield of 11.2%.
Comparative example 6: selection of the ratio of the amounts of substances of substrate, catalyst, additive, oxidant
The procedure of example 1 was repeated except that the amount of silver oxide added was changed from 41.7mg to 14mg, to give 7.6mg of a product in a reaction yield of 4.3%.
Comparative example 7: selection of the catalyst
The procedure is as in example 1, the catalyst is prepared from [ RhCp Cl ]2]2Replacement with dichlorobis (4-methylisopropylphenyl) ruthenium (II) (7.3mg, 0.012mmol) gave 7.6mg of product in 11.2% reaction yield.
Comparative example 8: selection of the catalyst
The procedure is as in example 1, the catalyst is prepared from [ RhCp Cl ]2]2Replacement with palladium acetate (2.68mg, 0.012mmol) gave 7.8mg of product in 11.6% reaction yield.
Comparative example 9: selection of additives
The process is as in example 1, the additive is prepared from AgNTf2Replacement with silver tetrafluoroborate (9.3mg, 0.048mmol) gave 5.8mg of product in 8.6% reaction yield.
Comparative example 10: selection of oxidising agents
The procedure of example 1 was followed, substituting silver oxide for silver acetate (29.88mg, 0.18mmol) as the oxidizing agent, to give 7.0mg of product in 10% yield.
Comparative example 11: selection of oxidizing agents
The procedure of example 1 was followed, substituting the oxidant from silver oxide for copper acetate (35.82mg, 0.18mmol) to give 5.5mg of product in 8% yield.
Comparative example 12: selection of oxidizing agents
The procedure of example 1 was followed, substituting silver oxide for silver nitrate (30.42mg, 0.18mmol) to give 5.7mg of product in 8.4% yield.
Comparative example 13: selection of solvents
The procedure is as in example 1, replacing the solvent from DCM by 10ml of tetrahydrofuran to give 5.1mg of the product in a reaction yield of 7.8%.
Comparative example 14: selection of solvents
The procedure is as in example 1, replacing the solvent from DCM by 10ml of dichloroethane to yield 3.75mg of product with a reaction yield of 5.5%.

Claims (10)

1. A7-position maleimide cyclized derivative of tryptophan shown in formula I or formula III,
Figure FDA0003547231600000011
in the formula I, m1＝1～20，n1When n is 0 to 61When it is not 0, AA1～AAn1Is any amino acid residue; in the formula III, n2When n is 0 to 62When not 0, aa1～aan2Is any amino acid residue.
2. The tryptophan maleimide cyclized derivative at the 7-position as set forth in claim 1, wherein the tryptophan maleimide cyclized derivative at the 7-position as shown in formula I is one of:
Figure FDA0003547231600000012
3. the tryptophan maleimide cyclized derivative at the 7-position as set forth in claim 1, wherein the tryptophan maleimide cyclized derivative at the 7-position as shown in the formula III is one of:
Figure FDA0003547231600000021
4. a process for the preparation of the tryptophan maleimide cyclized derivative at the 7-position of formula I or formula III as claimed in claim 1, wherein the process comprises: taking the tryptophan-containing polypeptide modified by the maleimide shown in the formula II or the 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 carrying out aftertreatment on the obtained reaction liquid to obtain the tryptophan 7-position maleimide cyclized derivative shown in the formula I or the formula III;
Figure FDA0003547231600000022
Figure FDA0003547231600000031
in the formula I, m1＝1～20，n1When n is 0 to 61When not 0, AA1～AAn1Is any amino acid residue; in the formula III, n2When n is 0 to 62When 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, dichlorobis (4-methylisopropylphenyl) ruthenium (II), palladium acetate;
the additive is one of the following: silver hexafluoroantimonate, silver tetrafluoroborate, bis (trifluoromethanesulfonylimide) silver 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 substrate, the catalyst, the additive and the oxidant is 1: 0.05-0.15: 0.2-1: 0.1 to 2.
5. The process for producing the tryptophan maleimide-cyclized derivative at the 7-position according to claim 4, wherein: the catalyst is dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer.
6. The process for producing the tryptophan maleimide-cyclized derivative at the 7-position according to claim 4, wherein: the additive is bis (trifluoromethane) sulfimide silver salt.
7. The process for producing the tryptophan maleimide-cyclized derivative at the 7-position according to claim 4, wherein: the oxidant is silver oxide.
8. The process for producing the tryptophan maleimide-cyclized derivative at the 7-position according to claim 4, wherein: the volume of the solvent is 20-100 mL/mmol based on the amount of the substrate.
9. The process for the preparation of the tryptophan No. 7 maleimide cyclized derivative according to claim 4, wherein the post-treatment is: adding a saturated NaCl aqueous solution into the reaction solution, extracting with ethyl acetate, taking an organic layer, drying with anhydrous sodium sulfate, filtering, and rotationally evaporating at normal temperature to remove the solvent to obtain a crude product; the crude product is prepared by mixing the following raw materials in a volume ratio of 10-40: 1 as eluent, collecting eluent containing the target compound, removing the solvent under reduced pressure, and drying to obtain the 7-position maleimide cyclized derivative of tryptophan shown in formula (I) or formula (III).
10. Use of the maleimide derivative according to claim 1 for the preparation of an antitumor agent.
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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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