CN114751863B - Terpastacin derivative, preparation method thereof and application thereof in preparation of hypoxia factor inhibitor - Google Patents

Terpastacin derivative, preparation method thereof and application thereof in preparation of hypoxia factor inhibitor Download PDF

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CN114751863B
CN114751863B CN202210427448.6A CN202210427448A CN114751863B CN 114751863 B CN114751863 B CN 114751863B CN 202210427448 A CN202210427448 A CN 202210427448A CN 114751863 B CN114751863 B CN 114751863B
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terpastacin
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CN114751863A (en
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廖升荣
刘永宏
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South China Sea Institute of Oceanology of CAS
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Abstract

The invention discloses a Terpastacin derivative, a preparation method thereof and application thereof in preparing a hypoxia factor inhibitor. Terpastacin O 17 ‑CH 2 CO‑NHCHRCO 2 Me derivative, its characteristic structural formula is shown as formula (I): wherein R is H, CH 3 ,CH(CH 3 ) 2 ,CH 3 CHCH 2 CH 3 ,CH 2 CH(CH 3 ) 2 ,CH 2 CH 2 SCH 3 ,CH 2 OH,CHCH 2 OH,CH 2 Ph,CH 2 ‑3‑indolyl,CH 2 Ph‑4‑OH,CH 2 ‑4‑imidazolyl,CH 2 CH 2 CO 2 Me,CH 2 CH 2 CONH 2 ,CH 2 CO 2 Me,CH 2 CONH 2 ,CH 2 CH 2 CH 2 . The invention discloses a Terpastacin O with the function of inhibiting the expression level of hypoxia factor in cancer cells 17 ‑CH 2 CO‑NHCHRCO 2 Me derivative, and its preparation process is simple and stable. Terpastacin O of the invention 17 ‑CH 2 CO‑NHCHRCO 2 The Me derivative has better activity of inhibiting hypoxia factors, is expected to be used for researching and preparing candidate medicaments with potential anticancer activity, and has great development potential.

Description

Terpastacin derivative, preparation method thereof and application thereof in preparation of hypoxia factor inhibitor
Technical field:
the invention belongs to the field of chemical medicine preparation, and in particular relates to a TerpasticinO 17 -CH 2 CO-NHCHRCO 2 Me derivatives, methods for their preparation, and their use as hypoxia factor (HIF-1 alpha) inhibitors in inhibiting cancer cell growth.
The background technology is as follows:
the rapid growth and proliferation of tumor easily causes hypoxia in tumor tissue microenvironment, and hypoxia inducible factor (HIF-1) is activated and continuously expressed in high level, so as to regulate the rapid adaptation of tumor cells to hypoxia environment and promote the continuous high-speed proliferation of tumor cells. HIF-1 is a type of heterologous protein dimer, consisting essentially of two subunits, HIF-1α and HIF-1β, where HIF-1α is the active subunit under hypoxic conditions. Under normoxic conditions, HIF-1. Alpha. Can be degraded by ubiquitin-proteasome pathway, but under anoxic conditions, the pathway is blocked, HIF-l. Alpha. Is stably expressed, and the stability of HIF-1. Alpha. Is regulated by the level of signal molecule active oxygen ROS (react ive oxygen species). Studies have shown that downregulation of ROS levels will interfere with HIF-1α aggregation, thereby inhibiting its downstream signaling pathway. HIF-l alpha can regulate more than 70 downstream genes and is closely related to the occurrence and development of tumors, wherein a main and extremely important path is the regulation of expression of VEGF by HIF-1 alpha, which can promote VEGF transcription, increase VEGF mRNA stability and up-regulate VEGF expression, so that the inhibition of tumor growth is possible by regulating the expression of HIF-1 alpha. Precisely because of the important regulation of oxygen in cellular function, the nobel physiological or medical prize in 2019 awarded three scientists, william g.kaelin Jr, sir Peter j.rattliffe and Gregg l.semenza, from meiying, "they found how cells perceived and adapted the availability of oxygen". They disclose the mechanism of HIF-1. Alpha. Operation under normoxic and hypoxic conditions, and the important regulatory functions in the development of cancer, which provide a reliable basis for our treatment of cancer by modulating the HIF-1. Alpha. Pathway. Compared with VEGF or VEGFR which directly acts on the protein, the mediated HIF-1 alpha protein expression is beneficial to simultaneously regulating and controlling a plurality of cancer signal channels and is also beneficial to avoiding the generation of tumor drug resistance, so that the regulation and control of the HI F-1 alpha signal channel can inhibit tumor growth and has great advantages. The intervention of specific targets, complexes or genotypes of HIF signaling pathways is a common anti-tumor strategy, and the development of HIF-1 a inhibitors has attracted considerable attention today, with few molecules being studied either preclinically or in clinical trials (I, II). Therefore, the development and preparation of the protein inhibitor have important significance and development prospect.
The invention comprises the following steps:
the first object of the present invention is to provide a class of Terpastacin O having inhibitory activity against hypoxia factor proteins 17 -CH 2 CO-NHCHRCO 2 Me derivatives.
Terpastacin O of the invention 17 -CH 2 CO-NHCHRCO 2 Me derivative or pharmaceutically acceptable salt thereof, and the structural formula is shown in formula (I):
wherein R is a substituent on a side chain of common L-amino acid and is H and CH respectively 3 ,CH(CH 3 ) 2 ,CH 3 CHCH 2 CH 3 ,CH 2 CH(CH 3 ) 2 ,CH 2 CH 2 SCH 3 ,CH 2 OH,CHCH 2 OH,CH 2 Ph,CH 2 -3-indolyl,CH 2 Ph-4-OH,CH 2 -4-imidazolyl,CH 2 CH 2 CO 2 Me,CH 2 CH 2 CONH 2 ,CH 2 CO 2 Me,CH 2 CONH 2 Or CH (CH) 2 CH 2 CH 2 。O 17 Refers to the hydroxyl group at the C atom at position 17 on Terpastacin.
Preferably, the Terpastacin O 17 -CH 2 CO-NHCHRCO 2 The Me derivative or the pharmaceutically acceptable salt thereof is shown in any one of the following:
a second object of the present invention is to provide a terpasticinO as described above 17 -CH 2 CO-NHCHRCO 2 The preparation method of the Me derivative is characterized by comprising the following steps of:
et is added to 3 N and L-amino acid methyl esters orDissolving salt in dichloromethane, slowly dripping dichloromethane solution of chloroacetyl chloride into the solution, adding water and dichloromethane after the reaction is completed, washing, extracting and separating, and purifying the extract to obtain intermediate productThe intermediate was dissolved with terplacin in DMF and a catalytic amount of KI was added followed by Cs 2 CO 3 Stirring, adding water after the reaction is completed, extracting with ethyl acetate, and separating and purifying the product to obtain the target substance +.>Wherein R is a substituent on a side chain of common L-amino acid and is H and CH respectively 3 ,CH(CH 3 ) 2 ,CH 3 CHCH 2 CH 3 ,CH 2 CH(CH 3 ) 2 ,CH 2 CH 2 SCH 3 ,CH 2 OH,CHCH 2 OH,CH 2 Ph,CH 2 -3-indolyl,CH 2 Ph-4-OH,CH 2 -4-imidazolyl,CH 2 CH 2 CO 2 Me,CH 2 CH 2 CONH 2 ,CH 2 CO 2 Me,CH 2 CONH 2 ,CH 2 CH 2 CH 2 。O 17 Refers to the hydroxyl group at the C atom at position 17 on Terpastacin.
Preferably Et 3 N, L-amino acid methyl ester and chloroacetyl chloride in the molar ratio of 3:1:1.5-3:1:3, preferably at 0deg.C for 1-3 hr, and dichloromethane as the reaction solvent.
Preferably, the method comprises the steps of,Cs 2 CO 3 the mass ratio of the Terpastacin to the Terpastacin is 5:3:1-3:3:1, the reaction condition is preferably that the reaction is carried out for 1-3 hours at room temperature, and the reaction solvent is N, N-dimethylformamide.
A third object of the present invention is to provide the above Terpastacin O 17 -CH 2 CO-NHCHRCO 2 Me derivativeThe application of the medicinal salt thereof in preparing cancer cell hypoxia factor (HIF-1 alpha) inhibitor.
A fourth object of the present invention is to provide a cancer cell hypoxia factor (HIF-1. Alpha.) inhibitor comprising termestaci nO 17 -CH 2 CO-NHCHRCO 2 Me derivatives or pharmaceutically acceptable salts thereof as active ingredients.
The invention discloses a Terpastacin O 17 -CH 2 CO-NHCHRCO 2 Me derivative, and a process for its preparation are also disclosed. The marine natural product Terpastacin is obtained by fermentation, the preparation method of the derivative has simple process, is suitable for large-scale production, and has reliable and stable source. Terpastacin O of the invention 17 -CH 2 CO-NHCHRCO 2 The Me derivative is a novel hypoxia factor inhibitor, can be used for inhibiting cancer cells, is used for anticancer drugs, and has huge future development and research prospects.
The specific embodiment is as follows:
the following examples are further illustrative of the invention and are not intended to be limiting thereof.
Example 1: synthesis of Compound 1
Methyl-amino-carboxylate hydrochloride (1 mmol,231 mg) was combined with Et at 0deg.C 3 N (3 mmol,303 mg) was mixed and dissolved in methylene chloride (10 ml), then a chloroacetyl chloride (2mmo l,226mg,0.16ml) mixed solution dissolved in methylene chloride (5 ml) was slowly dropped into the above solution, and stirring was continued for 3 hours after the completion of the dropping. 50ml of methylene chloride and water (20 ml. Times.3) were added thereto, the methylene chloride layer was dried over anhydrous sodium sulfate, and after removal of methylene chloride, the residue was subjected to silica gel column chromatography to give 217mg of the intermediateYield: 80%.
The intermediate (0.037 mmol,10mg,3 eq.) and Terpastacin (0.01242 mmol,5mg,1 eq.) were dissolved in DMF (0.2 ml) and catalysis was addedThe amount KI (0.2 mg) was then added Cs 2 CO 3 (0.037 mmol,12mg,3 eq.) at room temperature until the reaction is complete. After completion of the reaction, 10ml of water was added, and extraction was performed three times with ethyl acetate (3X 3 ml). The ethyl acetate layer was dried over anhydrous sodium sulfate and the product was purified by HPLC to give the title compound 1 in 52% yield.
The nuclear magnetic data of compound 1 are as follows:
1 H NMR(700MHz,MeOD)δ7.03(d,J＝8.5Hz,2H),6.73(d,J＝8.5Hz,2H),5.41(d,J＝5.4Hz,1H),5.33(dd,J＝10.4,5.1Hz,1H),5.21(s,1H),4.81(d,J＝15.1Hz,1H),4.74(dd,J＝7.4,5.7Hz,1H),4.60(d,J＝15.1Hz,1H),4.01(dd,J＝9.9,4.1Hz,1H),3.83(dd,J＝10.6,8.4Hz,1H),3.74(s,3H),3.69(dd,J＝10.7,6.3Hz,1H),3.10(dd,J＝14.0,5.7Hz,1H),3.02(dd,J＝14.0,7.5Hz,1H),2.81(dd,J＝11.2,2.2Hz,1H),2.78–2.70(m,1H),2.49(d,J＝17.2Hz,1H),2.32(ddd,J＝24.2,11.2,8.3Hz,3H),2.20–1.97(m,4H),1.87–1.75(m,3H),1.67(d,J＝5.6Hz,7H),1.60(s,3H),1.20(d,J＝7.1Hz,3H),1.00(s,3H). 13 C NMR(176MHz,MeOD)δ210.11,173.17,171.24,163.63,157.53,149.91,138.88,137.53,133.80,131.34,130.08,128.23,125.38,122.88,116.36,77.07,68.93,66.12,54.86,52.79,51.12,50.88,41.33,40.31,39.27,37.56,35.91,30.86,29.69,24.80,16.83,15.65,15.50,15.03,10.47.
example 2: synthesis of Compound 2
Substitution of tyrosine methyl ester hydrochloride with histidine methyl ester hydrochloride, the synthesis was the same as in example 1, wherein Et 3 The ratio of the amounts of N, histidine methyl ester hydrochloride and chloroacetyl chloride is 3:1:1.5. The target compound 2 was obtained in the yield: 33%.
The nuclear magnetic data of compound 2 are as follows:
1 H NMR(700MHz,MeOD)δ7.59(s,1H),6.90(s,1H),5.38(d,J＝5.2Hz,1H),5.30(dd,J＝10.4,5.0Hz,1H),5.18(s,1H),4.80(d,J＝15.1Hz,1H),4.76(dd,J＝7.3,5.3Hz,1H),4.61(d,J＝14.2Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.83(dd,J＝10.6,8.3Hz,1H),3.72(s,3H),3.67(dd,J＝10.7,6.4Hz,1H),3.15(dd,J＝14.8,5.3Hz,1H),3.10(dd,J＝14.9,7.4Hz,1H),2.79(dd,J＝11.2,2.1Hz,1H),2.75(dd,J＝14.7,7.0Hz,1H),2.46(d,J＝17.1Hz,1H),2.35–2.24(m,3H),2.17–1.95(m,4H),1.85–1.72(m,3H),1.64(d,J＝6.2Hz,7H),1.57(s,3H),1.21(d,J＝7.1Hz,3H),0.96(s,3H). 13 C NMR(176MHz,MeOD)δ210.12,172.93,171.40,163.49,149.95,138.87,137.52,136.47,133.81,130.07,125.37,122.88,77.06,68.96,66.09,53.61,52.91,51.12,50.79,41.32,40.31,39.26,35.90,30.86,29.72,24.80,16.83,15.65,15.49,14.97,10.46.
example 3: synthesis of Compound 3
Substitution of tyrosine methyl ester hydrochloride with methyl glutamate hydrochloride, the synthesis method was the same as in example 1 to give the target compound 3, yield: 33%.
The nuclear magnetic data of compound 3 are as follows:
1 H NMR(700MHz,MeOD)δ5.42–5.36(m,1H),5.31(dd,J＝10.4,5.1Hz,1H),5.21–5.14(m,1H),4.89(d,J＝15.3Hz,1H),4.62(d,J＝15.2Hz,1H),4.57(dd,J＝9.2,4.9Hz,1H),3.98(dd,J＝9.9,4.2Hz,1H),3.88(dd,J＝10.7,8.4Hz,1H),3.74(s,3H),3.69(dd,J＝10.7,6.4Hz,1H),3.66(s,3H),2.78(ddd,J＝22.2,12.5,4.6Hz,2H),2.45(dd,J＝21.6,13.3Hz,3H),2.35–2.26(m,3H),2.23(dtd,J＝14.1,7.7,5.0Hz,1H),2.13(t,J＝12.8Hz,1H),2.10–1.94(m,4H),1.84–1.72(m,3H),1.68–1.61(m,7H),1.57(s,3H),1.24(d,J＝7.1Hz,3H),0.96(s,3H). 13 C NMR(176MHz,MeOD)δ210.09,174.80,173.24,171.89,162.79,149.97,138.87,137.52,133.80,130.07,125.37,122.95,77.06,68.82,66.07,52.92,52.56,52.20,51.16,50.77,41.34,40.39,39.25,35.90,30.87,30.82,29.77,27.70,24.80,16.82,15.65,15.48,14.93,10.45.
example 4: synthesis of Compound 4
Substitution of tyrosine methyl ester hydrochloride with glutamine methyl ester hydrochloride, the synthesis method was the same as in example 1 to give the target compound 4 in the yield: 63%.
The nuclear magnetic data of compound 4 are as follows:
1 H NMR(700MHz,MeOD)δ5.39(d,J＝5.2Hz,1H),5.30(dd,J＝10.4,5.0Hz,1H),5.24–5.13(m,1H),4.84(d,J＝15.2Hz,1H),4.62(d,J＝15.2Hz,1H),4.53(dd,J＝9.1,4.9Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.86(dd,J＝10.7,8.3Hz,1H),3.74(s,3H),3.70(dd,J＝10.7,6.4Hz,1H),2.88–2.71(m,2H),2.47(d,J＝17.0Hz,1H),2.39–2.25(m,5H),2.21(dtd,J＝12.7,7.8,4.9Hz,1H),2.15–2.11(m,1H),2.10–1.97(m,4H),1.84–1.72(m,3H),1.65(t,J＝7.2Hz,7H),1.57(s,3H),1.25(d,J＝7.1Hz,3H),0.97(s,3H). 13 C NMR(176MHz,MeOD)δ210.27,177.58,173.29,171.89,163.28,150.12,138.90,137.54,133.81,130.05,125.36,122.89,77.06,69.04,66.08,52.96,52.89,51.15,50.71,41.33,40.37,39.24,35.90,32.42,30.86,29.76,28.35,24.80,16.84,15.65,15.50,14.93,10.45.
example 5: synthesis of Compound 5
Substitution of tyrosine methyl ester hydrochloride with aspartic acid methyl ester hydrochloride, the synthesis was the same as in example 1 to give the target compound 5 in the yield: 50%.
The nuclear magnetic data of compound 5 are as follows:
1 H NMR(700MHz,MeOD)δ5.38(d,J＝5.3Hz,1H),5.30(dd,J＝10.4,5.2Hz,1H),5.22–5.14(m,1H),4.81(d,J＝15.3Hz,1H),4.64(d,J＝15.3Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.86(dd,J＝10.7,8.3Hz,1H),3.74(s,3H),3.72–3.67(m,4H),2.93(d,J＝5.7Hz,2H),2.79(dd,J＝11.2,2.2Hz,1H),2.75(dt,J＝13.9,6.9Hz,1H),2.47(d,J＝17.1Hz,1H),2.38–2.24(m,3H),2.13(t,J＝13.1Hz,1H),2.10–1.91(m,3H),1.84–1.72(m,3H),1.69–1.60(m,7H),1.57(s,3H),1.25(d,J＝7.1Hz,3H),0.96(s,3H). 13 C NMR(176MHz,MeOD)δ209.97,172.66,172.27,171.42,163.21,149.90,138.87,137.53,133.80,130.08,125.37,122.91,77.06,68.96,66.10,53.18,52.52,51.12,50.83,49.75,49.52,49.51,41.33,40.34,39.29,36.62,35.90,30.87,29.72,24.80,16.83,15.65,15.48,14.96,10.45.
example 6: synthesis of Compound 6
Substitution of tyrosine methyl ester hydrochloride with asparagine methyl ester hydrochloride, the synthesis was the same as in example 1 to give the target compound 6 in the yield: 63%.
The nuclear magnetic data of compound 6 are as follows:
1 H NMR(700MHz,MeOD)δ5.39(d,J＝3.9Hz,1H),5.30(dd,J＝10.3,5.1Hz,1H),5.18(s,1H),4.83(t,J＝5.2Hz,1H),4.76(d,J＝15.2Hz,1H),4.67(d,J＝15.3Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.85(dd,J＝10.6,8.1Hz,1H),3.74(s,3H),3.70(dd,J＝10.7,6.7Hz,1H),2.91(dd,J＝16.2,5.3Hz,1H),2.78(dtd,J＝14.7,10.1,4.7Hz,3H),2.46(d,J＝17.1Hz,1H),2.37–2.23(m,3H),2.13(t,J＝12.7Hz,1H),2.10–1.96(m,3H),1.84–1.73(m,3H),1.67–1.61(m,7H),1.57(s,3H),1.25(d,J＝7.1Hz,3H),0.96(s,3H). 13 C NMR(176MHz,MeOD)δ209.99,174.87,172.71,171.24,163.52,149.84,138.88,137.53,133.81,130.07,125.38,122.89,77.06,69.08,66.08,53.08,51.11,50.76,49.85,41.34,40.31,39.30,37.28,35.91,30.85,29.70,24.80,16.84,15.64,15.49,14.93,10.46.
example 7: synthesis of Compound 7
Substitution of tyrosine methyl ester hydrochloride with proline methyl ester hydrochloride, the synthesis was the same as in example 1 to give the target compound 7 in the yield: 46%.
The nuclear magnetic data for compound 7 are as follows:
1 H NMR(700MHz,MeOD)δ5.38(d,J＝5.4Hz,1H),5.35(d,J＝15.4Hz,1H),5.29(dd,J＝10.2,4.9Hz,1H),5.17(d,J＝5.2Hz,1H),4.77(d,J＝15.4Hz,1H),4.44(dd,J＝8.7,4.1Hz,1H),4.00–3.92(m,2H),3.71(s,3H),3.66–3.61(m,1H),3.61–3.51(m,2H),2.80–2.66(m,2H),2.45(d,J＝17.1Hz,1H),2.36–2.19(m,4H),2.13(t,J＝13.1Hz,1H),2.10–2.01(m,4H),1.96(tdd,J＝12.8,10.6,2.9Hz,2H),1.83–1.71(m,3H),1.67–1.60(m,7H),1.56(s,3H),1.20(d,J＝7.1Hz,3H),0.94(s,3H). 13 C NMR(176MHz,MeOD)δ210.32,174.15,170.13,161.21,149.48,138.73,137.44,133.79,130.19,125.36,123.03,77.07,67.09,65.75,60.40,52.81,51.40,51.04,47.01,41.32,40.47,39.56,35.90,30.83,29.81,29.75,25.79,24.80,16.86,15.65,15.47,14.78,10.44.
example 8: synthesis of Compound 8
The synthesis method of the tyrosine methyl ester hydrochloride is replaced by glycine methyl ester hydrochloride, and the synthesis method is the same as that of example 1, intermediate and Cs 2 CO 3 The ratio of the amounts of the Terpastacin substances was 5:3:1. The target compound 8 was obtained in the yield: 38%.
The nuclear magnetic data for compound 8 are as follows:
1 H NMR(700MHz,MeOD)δ5.39(d,J＝5.0Hz,1H),5.30(dd,J＝10.4,5.0Hz,1H),5.20–5.15(m,1H),4.81(d,J＝15.2Hz,1H),4.66(d,J＝15.2Hz,1H),4.02(s,2H),3.98(dd,J＝9.9,4.1Hz,1H),3.85(dd,J＝10.6,8.3Hz,1H),3.74(s,3H),3.70(dd,J＝10.6,6.4Hz,1H),2.84–2.75(m,2H),2.47(d,J＝17.0Hz,1H),2.35–2.24(m,3H),2.13(t,J＝12.9Hz,1H),2.10–1.96(m,3H),1.84–1.72(m,3H),1.68–1.61(m,7H),1.57(s,3H),1.25(d,J＝7.1Hz,3H),0.97(s,3H). 13 C NMR(176MHz,MeOD)δ210.08,172.18,171.52,163.53,150.07,138.88,137.53,133.81,130.06,125.37,122.88,77.06,69.07,66.13,52.68,51.10,50.67,41.49,41.34,40.32,39.16,35.90,30.87,29.75,24.80,16.83,15.65,15.48,14.95,10.45.
example 9: synthesis of Compound 9
Substitution of tyrosine methyl ester hydrochloride with alanine methyl ester hydrochloride, the synthesis was the same as in example 1 to give the target compound 9 in the yield: 69%.
The nuclear magnetic data of compound 9 are as follows:
1 H NMR(700MHz,MeOD)δ5.39(d,J＝5.2Hz,1H),5.30(dd,J＝10.4,5.0Hz,1H),5.17(d,J＝9.1Hz,1H),4.85(d,J＝15.2Hz,1H),4.62(d,J＝15.1Hz,1H),4.50(q,J＝7.3Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.86(dd,J＝10.7,8.3Hz,1H),3.73(s,3H),3.70(dt,J＝10.7,5.2Hz,1H),2.78(ddd,J＝21.9,12.7,4.6Hz,2H),2.47(d,J＝17.2Hz,1H),2.37–2.25(m,3H),2.13(t,J＝13.3Hz,1H),2.10–1.95(m,3H),1.86–1.72(m,3H),1.69–1.59(m,7H),1.57(s,3H),1.42(d,J＝7.3Hz,3H),1.24(d,J＝7.1Hz,3H),0.97(s,3H). 13 C NMR(176MHz,MeOD)δ210.17,174.32,171.39,163.14,150.09,138.86,137.52,133.80,130.07,125.36,122.90,77.06,68.93,66.08,52.86,51.13,50.75,41.33,40.35,39.23,35.90,30.87,29.76,24.80,17.59,16.83,15.65,15.48,14.95,10.45.
example 10: synthesis of Compound 10
Substitution of tyrosine methyl ester hydrochloride with valine methyl ester hydrochloride, the synthesis was the same as in example 1 to give the title compound 10 in the yield: 71%.
The nuclear magnetic data of compound 10 are as follows:
1 H NMR(700MHz,MeOD)δ5.45–5.35(m,1H),5.30(dd,J＝10.5,5.0Hz,1H),5.21–5.13(m,1H),4.92(d,J＝15.1Hz,1H),4.67(d,J＝15.1Hz,1H),4.43(d,J＝5.7Hz,1H),3.98(dd,J＝9.9,4.2Hz,1H),3.88(dd,J＝10.7,8.4Hz,1H),3.74(s,3H),3.69(dd,J＝10.7,6.4Hz,1H),2.78(ddd,J＝21.9,13.1,4.6Hz,2H),2.47(d,J＝17.2Hz,1H),2.38–2.23(m,3H),2.20(tt,J＝13.7,6.8Hz,1H),2.16–1.93(m,4H),1.86–1.71(m,3H),1.70–1.59(m,7H),1.57(s,3H),1.24(d,J＝7.1Hz,3H),1.03–0.82(m,9H). 13 C NMR(176MHz,MeOD)δ210.15,173.27,171.69,162.84,150.00,138.82,137.52,133.80,130.09,125.36,122.92,77.07,68.83,66.06,58.66,52.62,51.16,50.87,41.33,40.41,39.31,35.90,32.10,30.86,29.76,24.80,19.49,18.37,16.81,15.65,15.47,14.96,10.45.
example 11: synthesis of Compound 11
Substitution of tyrosine methyl ester hydrochloride with isoleucine methyl ester hydrochloride, the synthesis method was the same as in example 1 to give the target compound 11 in the yield: 58%.
The nuclear magnetic data of compound 11 are as follows:
1 H NMR(700MHz,MeOD)δ5.38(d,J＝5.3Hz,1H),5.30(dd,J＝10.5,5.0Hz,1H),5.17(d,J＝8.9Hz,1H),4.92(d,J＝15.1Hz,1H),4.66(d,J＝15.1Hz,1H),4.47(d,J＝5.8Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.88(dd,J＝10.7,8.5Hz,1H),3.73(s,3H),3.69(dd,J＝10.7,6.4Hz,1H),2.83–2.70(m,2H),2.47(d,J＝17.0Hz,1H),2.36–2.22(m,3H),2.19–1.89(m,5H),1.78(ddd,J＝18.5,14.5,10.9Hz,3H),1.71–1.60(m,7H),1.57(s,3H),1.53–1.43(m,1H),1.24(d,J＝7.1Hz,3H),0.98–0.86(m,9H). 13 C NMR(176MHz,MeOD)δ210.12,173.27,171.57,162.73,149.96,138.83,137.53,133.80,130.09,125.36,122.92,77.07,68.80,66.06,57.74,52.57,51.17,50.87,41.33,40.42,39.31,38.66,35.90,30.86,29.77,26.27,24.80,16.80,15.97,15.65,15.47,14.95,11.72,10.45.
example 12: synthesis of Compound 12
Substitution of tyrosine methyl ester hydrochloride with leucine methyl ester hydrochloride, the synthesis was the same as in example 1 to give the title compound 12 in yield: 74%.
The nuclear magnetic data of compound 12 are as follows:
1 H NMR(700MHz,MeOD)δ5.38(d,J＝5.2Hz,1H),5.30(dd,J＝10.3,4.9Hz,1H),5.17(d,J＝8.8Hz,1H),4.95(d,J＝15.2Hz,1H),4.63(d,J＝15.2Hz,1H),4.55(dd,J＝9.8,4.9Hz,1H),3.98(dd,J＝9.9,4.0Hz,1H),3.88(dd,J＝10.6,8.6Hz,1H),3.72(s,3H),3.69(dd,J＝10.7,6.3Hz,1H),2.78(t,J＝11.1Hz,2H),2.47(d,J＝16.6Hz,1H),2.37–2.23(m,3H),2.13(t,J＝12.8Hz,1H),2.10–1.94(m,3H),1.87–1.73(m,3H),1.72–1.59(m,11H),1.56(s,3H),1.23(d,J＝7.1Hz,3H),0.96(t,J＝3.1Hz,6H),0.92(d,J＝6.4Hz,3H). 13 C NMR(176MHz,MeOD)δ210.09,174.32,171.76,162.53,149.94,138.83,137.51,133.80,130.09,125.35,122.93,77.06,68.65,66.07,52.77,51.71,51.17,50.75,41.56,41.33,40.46,39.21,35.90,30.86,29.79,25.86,24.80,23.38,21.81,16.80,15.66,15.47,14.91,10.46.
example 13: synthesis of Compound 13
Substitution of tyrosine methyl ester hydrochloride with methionine methyl ester hydrochloride, the synthesis was the same as in example 1 to give the title compound 13 in yield: 55%.
The nuclear magnetic data of compound 13 are as follows:
1 H NMR(700MHz,MeOD)δ5.38(d,J＝5.4Hz,1H),5.30(dd,J＝10.4,5.2Hz,1H),5.18(s,1H),4.92(d,J＝15.2Hz,2H),4.67(dd,J＝9.1,4.6Hz,1H),4.62(d,J＝15.2Hz,2H),3.98(dd,J＝9.9,4.1Hz,1H),3.88(dd,J＝10.7,8.5Hz,1H),3.74(s,3H),3.69(dd,J＝10.7,6.4Hz,1H),2.78(ddd,J＝17.4,13.2,4.5Hz,2H),2.59(ddd,J＝28.8,17.1,13.0Hz,1H),2.55–2.50(m,1H),2.47(d,J＝17.0Hz,1H),2.35–2.23(m,3H),2.21–2.11(m,2H),1.65(s,6H),1.57(s,3H),1.24(d,J＝7.1Hz,3H),0.96(s,3H). 13 C NMR(176MHz,MeOD)δ210.09,173.51,171.89,162.65,149.98,138.86,137.52,133.79,130.08,125.36,122.94,77.06,68.83,66.07,52.91,52.30,51.17,50.77,41.35,40.44,39.25,35.90,32.00,31.04,30.86,29.79,24.80,16.83,15.65,15.50,15.20,14.94,10.46.
example 14: synthesis of Compound 14
Substitution of tyrosine methyl ester hydrochloride with serine methyl ester hydrochloride, the synthesis was the same as in example 1 to give the title compound 14 in the yield: 26%.
The nuclear magnetic data for compound 14 are as follows:
1 H NMR(700MHz,MeOD)δ5.39(d,J＝5.2Hz,1H),5.31(dd,J＝10.5,5.2Hz,1H),5.23–5.14(m,1H),4.81(d,J＝15.2Hz,1H),4.72(d,J＝15.2Hz,1H),4.66–4.57(m,2H),3.97(ddd,J＝15.5,10.7,4.2Hz,2H),3.91–3.81(m,2H),3.77(d,J＝3.0Hz,3H),3.70(dd,J＝10.7,6.5Hz,1H),2.79(ddd,J＝21.8,13.0,4.6Hz,2H),2.47(d,J＝17.1Hz,1H),2.31(ddd,J＝20.1,11.6,7.1Hz,3H),2.13(t,J＝13.0Hz,1H),2.10–1.97(m,3H),1.85–1.72(m,3H),1.65(s,7H),1.57(s,3H),1.26(d,J＝7.1Hz,3H),0.97(s,3H). 13 C NMR(176MHz,MeOD)δ210.20,171.96,171.51,163.56,149.97,138.88,137.54,133.81,130.06,125.37,122.89,77.06,69.05,66.13,62.75,55.71,52.97,51.15,50.83,41.33,40.33,39.29,35.90,30.86,29.72,24.80,16.82,15.65,15.48,14.97,10.45.
example 15: synthesis of Compound 15
Substitution of tyrosine methyl ester hydrochloride with proline methyl ester hydrochloride, the synthesis was the same as in example 1 to give the title compound 15 in yield: 47%.
The nuclear magnetic data for compound 15 are as follows:
1 H NMR(700MHz,MeOD)δ5.39(d,J＝5.3Hz,1H),5.29(dt,J＝26.8,13.4Hz,1H),5.20–5.13(m,1H),4.86(d,J＝18.1Hz,22H),4.77(d,J＝15.3Hz,1H),4.53(d,J＝2.7Hz,1H),4.34(qd,J＝6.4,2.7Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.88(dt,J＝12.8,6.4Hz,1H),3.76(s,3H),3.73–3.65(m,1H),2.80(dd,J＝11.2,2.1Hz,1H),2.76(dt,J＝14.0,7.0Hz,1H),2.47(d,J＝17.0Hz,1H),2.31(ddd,J＝24.2,11.2,7.9Hz,3H),2.13(t,J＝13.2Hz,1H),2.10–1.95(m,3H),1.85–1.72(m,3H),1.67–1.62(m,7H),1.57(s,3H),1.26(dd,J＝12.6,4.6Hz,3H),1.19(t,J＝7.8Hz,3H),0.98(d,J＝7.3Hz,3H). 13 C NMR(176MHz,MeOD)δ210.03,172.22,171.93,163.30,149.82,138.85,137.54,133.80,130.08,125.36,122.91,77.07,68.93,68.36,66.11,58.67,52.92,51.16,50.91,41.33,40.37,39.35,35.90,30.86,29.73,24.80,20.44,16.82,15.65,15.48,14.99,10.45.
example 16: synthesis of Compound 16
Substitution of tyrosine methyl ester hydrochloride with phenylalanine methyl ester hydrochloride, the synthesis was the same as in example 1 to give the title compound 16 in the yield: 42%.
The nuclear magnetic data of compound 16 are as follows:
1 H NMR(700MHz,MeOD)δ7.28(t,J＝7.4Hz,1H),7.24–7.21(m,1H),7.21–7.18(m,1H),5.38(d,J＝5.4Hz,1H),5.30(dd,J＝10.3,5.0Hz,1H),5.18(s,1H),4.81(d,J＝15.1Hz,1H),4.77(dd,J＝7.9,5.6Hz,1H),4.56(d,J＝15.1Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.81(dd,J＝10.6,8.4Hz,1H),3.71(s,1H),3.66(dd,J＝10.7,6.4Hz,1H),3.22–3.15(m,1H),3.07(dd,J＝13.9,7.9Hz,1H),2.77(dd,J＝11.2,2.2Hz,1H),2.72(dd,J＝14.9,6.9Hz,1H),2.45(d,J＝17.2Hz,1H),2.36–2.20(m,1H),2.13(t,J＝12.9Hz,1H),2.10–1.94(m,1H),1.85–1.72(m,1H),1.64(d,J＝5.7Hz,4H),1.57(s,2H),1.17(d,J＝7.1Hz,1H),0.96(s,1H). 13 C NM R(176MHz,MeOD)δ210.05,173.00,171.31,163.43,149.91,138.86,137.81,137.52,133.80,130.33,130.07,129.59,128.00,125.37,122.90,77.07,68.84,66.10,54.69,52.81,51.11,50.85,41.33,40.33,39.26,38.34,35.91,30.87,29.71,24.80,16.83,15.65,15.49,15.02,10.46.
example 17: synthesis of Compound 17
Substitution of tyrosine methyl ester hydrochloride with tryptophan methyl ester hydrochloride, the synthesis was the same as in example 1 to give the title compound 17 in yield: 58%.
The nuclear magnetic data of compound 17 are as follows:
1 H NMR(700MHz,MeOD)δ7.49(d,J＝7.9Hz,1H),7.33(d,J＝8.1Hz,1H),7.10(s,1H),7.09–7.06(m,1H),7.01–6.98(m,1H),5.37(d,J＝5.2Hz,1H),5.28(dd,J＝10.4,5.0Hz,1H),5.21–5.14(m,1H),4.83(d,J＝5.9Hz,1H),4.75(d,J＝15.1Hz,1H),4.61(d,J＝15.1Hz,1H),3.97(dd,J＝9.9,4.1Hz,1H),3.73(dd,J＝10.7,8.4Hz,1H),3.69(s,3H),3.58(dd,J＝10.7,6.4Hz,1H),2.75(dd,J＝11.2,2.1Hz,1H),2.69–2.58(m,1H),2.42(d,J＝16.9Hz,1H),2.37–2.24(m,3H),2.17–2.06(m,2H),2.03(dd,J＝19.0,6.6Hz,1H),2.00–1.91(m,1H),1.85–1.73(m,3H),1.64(d,J＝14.9Hz,7H),1.57(s,3H),1.04(d,J＝7.1Hz,3H),0.95(s,3H). 13 C NMR(176MHz,MeOD)δ210.04,173.45,171.22,163.53,149.82,138.84,138.04,137.50,133.79,130.08,128.80,125.38,124.61,122.89,122.47,119.93,119.12,112.37,110.06,77.06,68.95,66.08,54.34,52.84,51.08,50.87,41.33,40.30,39.23,35.91,30.87,29.68,28.33,24.80,16.83,15.64,15.49,14.88,10.48.MS-ESI(m/z):415.1(M+H) +
example 18: evaluation of Compound inhibition of hypoxia factor protein Activity
Inoculating the test cells into MEM minimal medium containing 10% fetal bovine serum, culturing for 24 hr, collecting test cells after cancer cells grow normally, culturing in serum-free medium (Dulbecco's modified Eagle's medium/Nutrient Mixture F-12 (Gibco) containing 1X B-27serum-free support) for 16 hr (starvation culture), adding medicine (2.5 μm) or blank for 1 hr, and culturing in 1%O 2 In a low oxygen incubator (containing 5% CO) 2 And N 2 Equilibrium) for 4h, detecting HIF-1 alpha expression level by Western Blot, and analyzing the net optical density value of the target band by a gel image imaging system, wherein each experiment is parallel to 3 groupsThe average inhibition was calculated in duplicate.
The specific results are shown in Table 1:
table 1: compounds inhibit hypoxia factor (HIF-1 alpha) activity
Note that: a represents the expression level of HIF-1 alpha in cancer cells under normoxic and hypoxic conditions, and is used as experimental control
b 4-200 is the compound N- (4-hydroxyphenyl) - [1,1' -biphenyl ]]-4-sulfonamide, having HIF-1 alpha inhibiting activity, is a positive control.

Claims (9)

1.TerpestacinO 17 -CH 2 CO-NHCHRCO 2 Me derivative or pharmaceutically acceptable salt thereof, and the structural formula is shown in formula (I):
formula (I)
Wherein R is H, CH 3 CHCH 2 CH 3 , CH(CH 3 ) 2 ,CH 2 CH 2 SCH 3 , CH 2 OH, CH 3 CHOH, CH 2 -3-indole, CH 2 -4-imidazole, CH 2 CO 2 Me or CH 2 CH 2 CONH 2 。
2.TerpestacinO 17 -CH 2 CO-NHCHRCO 2 Me derivative or pharmaceutically acceptable salt thereof, characterized in that the terpastacin O 17 -CH 2 CO-NHCHRCO 2 The Me derivative or the pharmaceutically acceptable salt thereof is shown in any one of the following:
、/>、
、/>、
、/>、
、/>、
、/>。
3. a Terpastacin O as claimed in claim 1 17 -CH 2 CO-NHCHRCO 2 The preparation method of the Me derivative is characterized by comprising the following steps of:
et is added to 3 Dissolving N and L-amino acid methyl ester or its salt in dichloromethane, slowly dripping dichloromethane solution of chloroacetyl chloride into the solution, adding water and dichloromethane after the reaction, washing, extracting and separating, and purifying the extractIntermediate productsThe method comprises the steps of carrying out a first treatment on the surface of the The intermediate was dissolved with terplacin in DMF and a catalytic amount of KI was added followed by Cs 2 CO 3 Stirring, adding water after the reaction is completed, extracting with ethyl acetate, and separating and purifying the product to obtain the target substance +.>；
Wherein R is H, CH 3 CHCH 2 CH 3 , CH(CH 3 ) 2 ,CH 2 CH 2 SCH 3 , CH 2 OH, CH 3 CHOH, CH 2 -3-indole, CH 2 -4-imidazole, CH 2 CO 2 Me or CH 2 CH 2 CONH 2 。
4. A process according to claim 3, wherein Et 3 N, L-methyl amino acid and chloroacetyl chloride in a mass ratio of 3:1:1.5-3:1:3.
5. The process according to claim 4, wherein Et 3 N, L-amino acid methyl ester and chloroacetyl chloride are reacted for 1-3 hours at the temperature of 0 ℃, and the reaction solvent is methylene dichloride.
6. A process according to claim 3, wherein,、Cs 2 CO 3 the mass ratio of the Terpastacin to the Terpastacin is 5:3:1-3:3:1.
7. The method according to claim 6, wherein,、Cs 2 CO 3 reaction with TerpastacinThe reaction is carried out for 1-3 hours at room temperature, and the reaction solvent is N, N-dimethylformamide.
8. Terpastacin O as claimed in claim 2 17 -CH 2 CO-NHCHRCO 2 Use of Me derivatives or pharmaceutically acceptable salts thereof for the preparation of inhibitors of hypoxia factor of cancer cells, said cancer cells being cancer cells Huh7 or U87MG.
9. A cancer cell hypoxia factor inhibitor comprising the terplacin O according to claim 2 17 -CH 2 CO-NHCHRCO 2 Me derivative or pharmaceutically acceptable salt thereof as active ingredient, wherein the cancer cell is cancer cell Huh7 or U87MG.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20090083619A (en) * 2008-01-30 2009-08-04 연세대학교 산학협력단 Methods for screening anti-angiogenic agents

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20090083619A (en) * 2008-01-30 2009-08-04 연세대학교 산학협력단 Methods for screening anti-angiogenic agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Terpestacin Inhibits Tumor Angiogenesis by Targeting UQCRB of Mitochondrial Complex III and Suppressing Hypoxia-induced Reactive Oxygen Species Production and Cellular Oxygen Sensing;Hye Jin Jung，et al.;《THE JOURNAL OF BIOLOGICAL CHEMISTRY》;第285卷(第15期);11584-11595 *

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