CN107698658B - Bis [3- (acetyl-Lys-AA-OBzl) -indol-2-yl ] ethane, preparation, activity and application thereof - Google Patents
Bis [3- (acetyl-Lys-AA-OBzl) -indol-2-yl ] ethane, preparation, activity and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 47
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 title abstract description 112
- 230000000694 effects Effects 0.000 title abstract description 7
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 22
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- SEOVTRFCIGRIMH-UHFFFAOYSA-N indole-3-acetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 5
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
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- 150000001875 compounds Chemical class 0.000 description 48
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
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- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开了通式I所代表的双[3‑(乙酰‑Lys‑AA‑OBzl)‑吲哚‑2‑基]乙烷(式中AA＝Gly,Ala,Leu,Ile,Val,Trp,Phe,Lys,Tyr,Pro,Met,Ser,Thr,Asn,Asp(OBzl),Glu(OBzl),NG‑NO2‑Arg和The残基),公开了它们的制备方法,公开了它们抑制S180小鼠肿瘤生长的活性,阐明了它们在制备抗肿瘤药物中的应用。
The present invention discloses bis[3-(acetyl-Lys-AA-OBzl)-indol-2-yl]ethane represented by general formula I (where AA=Gly, Ala, Leu, Ile, Val, Trp, Phe, Lys, Tyr, Pro, Met, Ser, Thr, Asn, Asp(OBzl), Glu(OBzl), NG-NO 2 -Arg and The residues), their preparation methods are disclosed, their inhibition The activity of tumor growth in S180 mice clarified their application in the preparation of antitumor drugs.
Description
Technical Field
The invention relates to bis [3- (acetyl-Lys-AA-OBzl) -indol-2-yl]Ethane, Glu (OBzl), NG-NO2-Arg and The residue), to a process for their preparation, to their activity in inhibiting The growth of S180 mouse tumors, and to their use in The preparation of anti-tumor medicaments. The invention belongs to the field of biological medicine.
Technical Field
Indomethacin (Indomethacin), a derivative of indoleacetic acid, has anti-inflammatory, antipyretic and analgesic effects, and can inhibit platelet aggregation by inhibiting the synthesis of thromboxane TXA 2. Our previous invention discloses that bisindole derivatives of general formula II (wherein AA is an amino acid residue) have antithrombotic activity at an oral dose of 1 nmol/kg.
In acute toxicity studies, the inventors found that the bis-indole derivatives of formula II were insoluble at the dose. In the metabolic studies of the bis-indole derivatives of formula II, the inventors found that rat feces contained higher amounts of the bis-indole derivatives of formula II. These findings have stimulated interest by the inventors in improving the bioavailability and altering the mode of action of bis-indole derivatives. After 3 years of investigation, the change of 3-acetyl-AA in the general formula II into 3-acetyl-Lys-AA-OBzl not only can improve the bioavailability, but also can change the antithrombotic effect into the antitumor effect. Thus, the inventors have proposed the present invention.
Disclosure of Invention
The first aspect of the present invention is to provide bis [3- (acetyl-Lys-AA-OBzl) -indol-2-yl group represented by the general formula I]Ethane (in the formula AA ═ Gly, Ala, Leu, Ile, Val, Trp, Phe, Lys, Tyr, Pro, Met, Ser, Thr, Asn, Asp (OBzl), Glu (OBzl), NG-NO2-Arg and The residue).
The second aspect of the present invention is to provide bis [3- (acetyl-Lys-AA-OBzl) -indol-2-yl group represented by the general formula I]Ethane (in the formula AA ═ Gly, Ala, Leu, Ile, Val, Trp, Phe, Lys, Tyr, Pro, Met, Ser, Thr, Asn, Asp (OBzl), Glu (OBzl), NG-NO2-Arg and The residue) comprising:
(1) adding concentrated sulfuric acid and 40% acetaldehyde solution into methanol solution of indoleacetic acid under ice bath to prepare bis [3- (methyl acetate) -indol-2-yl ] ethane;
(2) hydrolyzing bis [3- (methyl acetate) -indol-2-yl ] ethane in 6N NaOH solution to prepare bis [3- (acetic acid) -indol-2-yl ] ethane;
(3) bis [3- (acetic acid) -indol-2-yl ] ethane HCl lys (boc) -OBzl coupling to produce bis [3- (acetyl-lys (boc) -OBzl) -indol-2-yl ] ethane;
(4) carrying out catalytic hydrogenolysis on bis [3- (acetyl-Lys (Boc) -OBzl) -indol-2-yl ] ethane in methanol by Pb/C to obtain bis [3- (acetyl-Lys (Boc) -indol-2-yl ] ethane;
(5) bis [3- (acetyl-Lys (Boc)) -indol-2-yl]Coupling of ethane with HCl. AA-OBzl to give bis [3- (acetyl-Lys (Boc) -AA-OBzl) -indol-2-yl]Ethane (in the formula AA ═ Gly, Ala, Leu, Ile, Val, Trp, Phe, Lys, Tyr, Pro, Met, Ser, Thr, Asn, Asp (OBzl), Glu (OBzl), NG-NO2-Arg and The residue);
(6) bis [3- (acetyl-Lys (Boc) -AA-OBzl) -indol-2-yl]The ethane is deprived of Boc in anhydrous dichloromethane/trifluoroacetic acid to obtain bis [3- (acetyl-Lys-AA-OBzl) -indol-2-yl]Ethane (in the formula AA ═ Gly, Ala, Leu, Ile, Val, Trp, Phe, Lys, Tyr, Pro, Met, Ser, Thr, Asn, Asp (OBzl), Glu (OBzl), NG-NO2-Arg and The residue).
The third aspect of the present invention is to evaluate the tumor growth inhibition effect of bis [3- (acetyl-Lys-AA-OBzl) -indol-2-yl ] ethane represented by the general formula I on S180 tumor mice.
Drawings
FIG. 1 is a synthetic scheme for compounds a-r. i) CH (CH)3OH,CH3CHO, concentrated H2SO4；ii)CH3OH,2N NaOH; iii) DCC, HOBt, NMM, THF; iv) tfa.a AA ═ Gly, b AA ═ Ala, c AA ═ Lys, d AA ═ Thr, e AA ═ Tyr, f AA ═ Ser, g AA ═ Pro, h AA ═ Phe, i AA ═ Val, j AA ═ Ile, k AA ═ Leu, l AA ═ Trp, m AA ═ Glu, n AA ═ Asp, o AA ═ Met, p AA ═ then, q AA ═ Asn, r AA ═ Arg residue.
Detailed Description
In order to further illustrate the invention, some examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
EXAMPLE 1 preparation of bis [3- (methyl acetate) -indol-2-yl ] ethane
Indoleacetic acid (40 g, 0.228mol) was dissolved in 250mL of methanol, 5mL of concentrated sulfuric acid was added under ice-cooling, and after 20min of reaction, 5mL of 40% acetaldehyde solution was added. After 72h the reaction was complete, the reaction was concentrated under reduced pressure and the residue was purified on a silica gel column (gradient elution, petroleum ether: acetone ═ 10:1-3:1) to give 10g (22%) of the title compound as a colourless powder.
ESI-MS(m/e):427[M+Na]+。
EXAMPLE 2 preparation of bis [3- (acetic acid) -indol-2-yl ] ethane
To 4g (1mmol) of bis [3- (methyl acetate) -indol-2-yl]After hydrolysis for 24h by addition of 4mL of aqueous NaOH (2N) to dissolve ethane and 20mL of acetone, the pH was adjusted to 7, the acetone was removed by concentration under reduced pressure, the residue was diluted with 25mL of distilled water, the pH was adjusted to 2 with dilute hydrochloric acid, and the precipitate which had precipitated was filtered to give 3.5g (95%) of the title compound as a yellow powder. ESI-MS (M/e):377[ M + H]+。
EXAMPLE 3 preparation of bis [3- (acetyl-Lys (Boc) -OBzl) -indol-2-yl ] ethane
3.8g (10.2mmol) of bis [3- (acetic acid) -indol-2-yl are placed under ice]Ethane was dissolved in 25mL of tetrahydrofuran, and 3.5g (25.9mmol) of 1-hydroxybenzotriazole (HOBt) and 5g (24.3mmol) of Dicyclohexylcarbodiimide (DCC) were added thereto, and after activation for half an hour, a solution of 10g (26.7mmol) of L-Lys-OBzl hydrochloride and 25mL of tetrahydrofuran was added. Adjusting pH of the reaction solution to 8 with N-methylmorpholine (NMM), reacting completely after 12 hr, filtering to remove DCU, concentrating the filtrate under reduced pressure to dryness, dissolving the residue with 150mL ethyl acetate, filtering to remove insoluble NaHCO, sequentially dissolving the filtrate with 5% NaHCO3Washing with 5% KHSO 3 times and 3 times with saturated NaCl aqueous solution43 washes with aqueous solution and 3 washes with saturated aqueous NaCl solution. The combined ethyl acetate layers were washed with anhydrous Na2SO4Dried for 12h, filtered, the filtrate concentrated to dryness under reduced pressure and the resulting yellow oily liquid purified by silica gel column chromatography (gradient elution, dichloromethane: methanol 250:1-100:1) to give 8g (78%) of the title compound as a yellow oil. ESI-MS (M/e):1013[ M + H]+；1H NMR:(300M,DMSO-d6):11.00(m,2H),8.50(t,J＝7.5Hz,2H),7.30(m,14H),6.95(m,4H),6.75(s,2H),5.10(m,4H),4.90(m,1H),4.25(m,2H),3.65(m,3H),2.85(m,4H),2.05(s,4H),1.65(m,6H),1.35(m,29H)。
EXAMPLE 4 preparation of bis [3- (acetyl-Lys (Boc) -indol-2-yl ] ethane
8g (7.9mmol) of bis [3- (acetyl-Lys (Boc) -OBzl) -indol-2-yl]The reaction was completed after ethane was dissolved in 20mL of methanol, 1g of Pd/C was added, hydrogen was introduced, and the reaction was carried out at room temperature for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 6.5g (99%) of the title compound as a pale yellow powder. ESI-MS (M/e):833[ M + H]+。
EXAMPLE 5 preparation of bis [3- (acetyl-Lys (Boc) -Gly-OBzl) -indol-2-yl ] ethane
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 1.4g (4.1mmol) Gly-OBzl hydrochloride to give 500mg (25%) of the title compound as a yellow oil;1H NMR:(300M,DMSO-d6)9.80(m,2H),7.55(m,2H),7.35(m,14H),7.10(m,4H),6.90(m,4H),6.60(m,2H),5.10(m,4H),4.85(m,1H),4.65(m,2H),4.45(m,2H),3.95(m,3H),2.95(s,4H),1.85(d,J＝7.2Hz,3H),1.65(m,4H),1.45(m,19H),1.25(m,12H)。
EXAMPLE 6 preparation of bis [3- (acetyl-Lys-Gly-OBzl) -indol-2-yl ] ethane (a)
500mg (0.44mmol) of bis [3- (acetyl-Lys (Boc) -Gly-OBzl) -indol-2-yl group are placed under ice-bath]The ethane was dissolved in 20mL of anhydrous dichloromethane, 2mL of TFA was added and the reaction was complete after 2 h. The reaction solution was concentrated under reduced pressure, and the residue was added with ether to precipitate a solid, yielding 350mg (85%) of the title compound as a pale yellow powder. ESI-MS (M/e):928[ M + H]+；Mp 115-116℃；
1H NMR(300M,DMSO-d6):11.00(m,2H),8.45(m,1H),8.35(m,1H),8.26(m,1H),7.95(m,1H),7.55(m,1H),7.35(m,12H),7.24(m,2H),6.90(m,4H),5.10(m,4H),4.90(m,1H),4.33(m,2H),3.90(m,4H),3.75(m,4H),2.64(m,4H),1.95(m,2H),1.75(m,2H),1.65(m,2H),1.50(m,7H),1.20(m,4H)。
EXAMPLE 7 preparation of bis [3- (acetyl-Lys (Boc) -Ala-OBzl) -indol-2-yl ] ethane
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 0.5g of (2.3mmol) Ala-OBzl hydrochloride 600mg (29%) of the title compound are obtained as a yellow oil.1H NMR(300M,DMSO-d6)10.90(m,2H),8.45(d,J＝9.0Hz,1H),8.37(d,J＝6.0Hz,1H),8.30(d,J＝9.0Hz,1H),8.20(d,J＝9.0Hz,1H),7.80(d,J＝9.0Hz,1H),7.55(m,2H),7.35(m,10H),7.20(m,2H),6.90(m,4H),6.70(s,2H),5.10(m,4H),4.90(m,1H),4.30(m,4H),3.70(m,4H),2.80(m,4H),1.60(m,4H),1.30(m,35H)。
EXAMPLE 8 preparation of bis [3- (acetyl-Lys-Ala-OBzl) -indol-2-yl ] ethane (b)
From 600mg (0.34mmol) of bis [3- (acetyl-Lys (Boc) -Ala-OBzl) -indol-2-yl group according to the method of example 6]Ethane gave 400mg (80%) of the title compound as a pale yellow powder. ESI-MS (M/e):955[ M + H ]]+；Mp:124-125℃；
IR(KBr):3273.20,3062.96,2943.37,1737.86,1674.21,1525.69,1456.26,1199.72,1139.93,738.74；1H NMR:(300M,DMSO-d6):11.00(m,2H),8.46(m,1H),8.38(m,1H),8.30(m,1H),8.20(m,1H),7.82(m,1H),7.55(m,1H),7.35(m,12H),7.24(m,2H),6.95(m,4H),5.13(m,4H),4.90(m,1H),4.33(m,4H),3.75(m,4H),3.43(m,2H),2.74(m,4H),1.95(m,2H),1.75(m,2H),1.65(m,2H),1.50(m,7H),1.20(m,4H)。
EXAMPLE 9 preparation of bis [3- (acetyl-Lys (Boc) -OBzl) -indol-2-yl ] ethane
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 1.5g (4mmol) Lys (Boc) -OBzl hydrochloride gave 400mg (17%) of the title compound as a yellow oil.1H NMR:(300MH,DMSO-d6):11.00(m,2H),8.30(m,2H),7.55(m,2H),7.35(m,10H),7.20(m,2H),6.95(m,3H),6.65(m,3H),5.10(m,4H),4.90(m,1H),4.25(m,2H),3.75(m,2H),2.85(m,7H),1.80(m,3H),1.55(m,5H),1.40(m,46H)。
EXAMPLE 10 preparation of bis [3- (acetyl-Lys-Lys-OBzl) -indol-2-yl ] ethane (c)
From 400mg (0.32mmol) of bis [3- (acetyl-Lys (Boc) -Ala-OBzl) -indol-2-yl group according to the method of example 6]Ethane was used to give 200mg (59%) of the title compound as a pale yellow powder. ESI-MS (M/e) 1069[ M + H ]]+；Mp:116-117℃；
1H NMR(300MHz,DMSO-d6):11.00(m,2H),8.43(m,2H),8.35(m,1H),8.24(m,1H),7.88(m,1H),7.55(m,1H),7.35(m,12H),7.20(m,2H),6.90(m,4H),5.10(m,4H),4.90(m,1H),4.23(m,4H),3.72(m,4H),3.40(m,4H),2.64(m,8H),1.76(m,2H),1.68(m,2H),1.59(m,4H),1.45(m,11H),1.25(m,8H)。
EXAMPLE 11 preparation of bis [3- (acetyl-Lys (Boc) -Thr-OBzl) -indol-2-yl ] ethane
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 0.5g (2.3mmol) Thr-OBzl hydrochloride gave 650mg (33%) of the title compound as a yellow oil.1H NMR(300MHz,DMSO-d6):10.90(m,2H),8.25(m,4H),7.80(m,1H),7.55(m,2H),7.35(m,10H),7.20(m,2H),6.90(m,4H),5.10(m,4H),4.85(m,1H),4.35(m,4H),4.15(m,2H),3.70(m,3H),2.80(m,4H),1.60(m,2H),1.50(m,2H),1.35(s,18H),1.25(m,9H),1.10(m,6H)。
EXAMPLE 12 preparation of bis [3- (acetyl-Lys-Thr-OBzl) -indol-2-yl ] ethane (d)
From 650mg (0.54mmol) of bis [3- (acetyl-Lys (Boc) -Thr-OBzl) -indol-2-yl group according to the method of example 6]Ethane gave 500mg (93%) of the title compound as a pale yellow powder. ESI-MS (M/e):1016[ M + H]+；Mp124-125℃；
1H NMR:(300MHz,DMSO-d6):11.00(m,2H),8.45(m,1H),8.37(m,1H),8.21(m,1H),7.85(m,1H),7.56(m,2H),7.30(m,10H),7.20(m,2H),6.90(m,4H),5.00(m,4H),4.90(m,1H),4.39(m,4H),4.16(m,2H),3.73(m,6H),2.75(m,4H),1.76(m,2H),1.56(m,2H),1.50(m,4H),1.45(m,3H),1.20(m,9H)。
EXAMPLE 13 preparation of bis [3- (acetyl-Lys (Boc) -Tyr-OBzl) -indol-2-yl ] ethane
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 1.5g (4.9mmol) Tyr-OBzl hydrochloride gave 300mg (15%) of the title compound as a yellow oil.1H NMR:(300MHz,DMSO-d6):10.90(m,2H),8.45(d,J＝6.0Hz,2H),8.30(d,J＝9.0Hz,1H),8.20(d,J＝9.0Hz,1H),7.55(m,2H),7.35(m,6H),7.20(m,6H),6.90(m,8H),6.65(m,6H),5.10(m,4H),4.85(m,1H),4.35(m,4H),3.70(m,4H),2.80(m,8H),1.80(m,3H),1.45(m,23H),1.25(m,9H)。
EXAMPLE 14 preparation of bis [3- (acetyl-Lys-Tyr-OBzl) -indol-2-yl ] ethane (e)
From 300mg (0.22mmol) of bis [3- (acetyl-Lys (Boc) -Tyr-OBzl) -indol-2-yl group according to the method of example 6]Ethane gave 200mg (78%) of the title compound as a pale yellow powder. ESI-MS (M/e):1139[ M + H]+；Mp125-126℃；
1H NMR:(300MHz,DMSO-d6):11.00(m,2H),9.23(m,2H),8.44(m,1H),8.34(m,1H),8.16(m,1H),7.54(m,1H),7.25(m,12H),6.95(m,8H),6.63(m,4H),5.00(m,4H),4.90(m,1H),4.42(m,4H),3.70(m,4H),2.87(m,4H),2.68(m,4H),1.78(m,3H),1.50(m,8H),1.24(m,10H)。
EXAMPLE 15 preparation of bis [3- (acetyl-Lys (Boc) -Ser-OBzl) -indol-2-yl ] ethane
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 0.8g (3.7mmol) Ser-OBzl hydrochloride gave 300mg (15%) of the title compound as a yellow oil.1H NMR:(300MHz,DMSO-d6):10.90(m,2H),8.35(m,2H),8.20(d,J＝6.0Hz,1H),7.75(d,J＝9.0Hz,1H),7.55(m,2H),7.35(m,10H),7.20(m,2H),6.90(m,4H),6.70(s,2H),5.10(m,4H),5.05(m,2H),4.90(m,1H),4.35(m,4H),3.70(m,6H),2.80(m,4H),1.55(m,4H),1.30(m,20H),1.20(m,9H)。
EXAMPLE 16 preparation of bis [3- (acetyl-Lys-Ser-OBzl) -indol-2-yl ] ethane (f)
From 300mg (0.25mmol) of bis [3- (acetyl-Lys (Boc) -Ser-OBzl) -indol-2-yl group according to the method of example 6]Ethane gave 200mg (78%) of the title compound as a pale yellow powder. ESI-MS (M/e):987[ M + H]+；Mp124-125℃；
1H NMR:(300MHz,DMSO-d6):11.00(m,2H),8.45(m,1H),8.37(m,1H),8.21(m,1H),7.85(m,1H),7.56(m,1H),7.41(m,1H),7.30(m,10H),7.24(m,2H),6.90(m,4H),5.00(m,4H),4.90(m,1H),4.39(m,4H),3.70(m,6H),3.40(m,2H),2.63(s,4H),1.91(m,2H),1.77(m,2H),1.50(m,4H),1.45(m,3H),1.20(m,4H)。
EXAMPLE 17 preparation of bis [3- (acetyl-Lys (Boc) -Pro-OBzl) -indol-2-yl ] ethane
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 1.6g (6.6mmol) Pro-OBzl hydrochloride gave 500mg (36%) of the title compound as a yellow oil.1H NMR:(300MHz,DMSO-d6):10.90(m,2H),8.45(m,2H),7.55(m,2H),7.35(m,10H),7.20(m,2H),6.90(m,4H),6.70(s,2H),5.10(m,4H),4.90(m,1H),4.45(m,2H),4.35(m,2H),3.70(m,5H),3.55(m,3H),2.80(m,4H),2.10(m,2H),1.85(m,6H),1.75(m,3H),1.35(m,18H),1.25(m,9H)。
EXAMPLE 18 preparation of bis [3- (acetyl-Lys-Pro-OBzl) -indol-2-yl ] ethane (g)
From 500mg (0.41mmol) of bis [3- (acetyl-Lys (Boc) -Pro-OBzl) -indol-2-yl group according to the method of example 6]Ethane gave 300mg (73%) of the title compound as a pale yellow powder. ESI-MS (M/e):1008[ M + H [)]+；Mp128-129.0℃；
1H NMR:(300MHz,DMSO-d6):11.00(m,2H),8.45(m,2H),8.08(m,1H),7.55(m,2H),7.34(m,10H),7.22(m,2H),6.90(m,4H),5.00(m,4H),4.90(m,1H),4.45(m,4H),3.54(m,14H),2.64(m,4H),2.13(m,2H),1.84(m,10H),1.50(m,7H),1.27(m,4H)。
EXAMPLE 19 preparation of bis [3- (acetyl-Lys (Boc) -Phe-OBzl) -indol-2-yl ] ethane
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 1.8g (4.2mmol) Phe-OBzl hydrochloride gave 600mg (38%) of the title compound as a yellow oil.1H NMR:(300MHz,DMSO-d6):10.90(m,2H),8.45(m,2H),8.30(m,1H),8.15(m,1H),7.80(m,1H),7.55(m,1H),7.25(m,24H),6.90(m,4H),6.70(m,2H),5.10(m,4H),4.90(m,1H),4.50(m,2H),4.30(m,2H),3.70(m,4H),3.00(m,4H),2.30(m,5H),1.55(m,4H),1.35(s,18H),1.20(m,11H),0.95(m,3H)。
EXAMPLE 20 preparation of bis [3- (acetyl-Lys-Phe-OBzl) -indol-2-yl ] ethane (h)
From 600mg (0.50mmol) of bis [3- (acetyl-Lys (Boc) -Phe-OBzl) -indol-2-yl group according to the method of example 6]Ethane gave 500mg (98%) of the title compound as a pale yellow powder. ESI-MS (M/e):1108[ M + H]+；Mp:121-123℃；
1H NMR:(300MHz,DMSO-d6):11.00(m,2H),8.50(m,2H),8.21(m,2H),7.55(m,1H),7.25(m,24H),6.90(m,4H),5.10(m,4H),4.90(m,1H),4.55(m,2H),4.32(m,2H),3.67(m,4H),3.00(m,6H),2.58(m,4H),1.76(m,3H),1.30(m,11H),0.95(m,2H)。
EXAMPLE 21 preparation of bis [3- (acetyl-Lys (Boc) -Val-OBzl) -indol-2-yl ] ethane
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 1.5g (3.8mmol) Val-OBzl hydrochloride gave 300mg (21%) of the title compound as a yellow oil.1H NMR:(300MHz,DMSO-d6):10.90(m,2H),8.30(m,1H),8.20(m,1H),8.13(m,1H),7.80(m,1H),7.50(m,2H),7.35(m,10H),7.15(m,2H),6.90(m,4H),6.65(s,2H),5.10(m,4H),4.85(m,1H),4.35(m,2H),4.15(m,2H),3.70(m,3H),3.45(m,2H),2.80(m,4H),2.00(m,2H),1.50(m,4H),1.35(s,18H),1.25(m,9H),0.80(m,12H)。
EXAMPLE 22 preparation of bis [3- (acetyl-Lys-Val-OBzl) -indol-2-yl ] ethane (8i)
From 300mg (0.25mmol) of bis [3- (acetyl-Lys (Boc) -Val-OBzl) -indol-2-yl]Ethane was used to give 100mg (40%) of the title compound as a pale yellow powder. ESI-MS (M/e) 1012[ M + H]+；Mp 119-120℃；
1H NMR:(300MHz,DMSO-d6):11.00(m,2H),8.24(m,3H),7.85(m,1H),7.55(t,J＝9.0Hz,1H),7.40(m,12H),7.21(m,2H),6.98(m,4H),5.10(m,4H),4.90(m,1H),4.40(m,2H),4.20(m,2H),3.73(m,2H),3.37(m,4H),2.64(m,4H),2.04(m,2H),1.90(s,2H),1.77(d,J＝6.0Hz,2H),1.50(m,7H),1.30(m,4H),0.83(m,12H)。
EXAMPLE 23 preparation of bis [3- (acetyl-Lys (Boc) -Ile-OBzl) -indol-2-yl ] ethane
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 1g (2.5mmol) Ile-OBzl hydrochloride gave 400mg (27%) of the title compound as a yellow oil.1H NMR:(300MHz,DMSO-d6):10.90(m,2H),8.20(m,3H),7.85(m,1H),7.50(m,1H),7.35(m,11H),7.20(m,2H),6.90(m,4H),6.65(s,2H),5.10(m,4H),4.85(m,1H),4.35(m,2H),4.20(m,2H),3.70(m,3H),2.80(m,4H),1.75(m,4H),1.50(m,4H),1.30(s,18H),1.25(m,7H),1.10(m,5H),0.75(m,12H)。
EXAMPLE 24 preparation of bis [3- (acetyl-Lys-Ile-OBzl) -indol-2-yl ] ethane (8j)
From 400mg (0.32mmol) of bis [3- (acetyl-Lys (Boc) -Ile-OBzl) -indol-2-yl group according to the method of example 6]Ethane gave 250mg (76%) of the title compound as a pale yellow powder. ESI-MS (M/e):1040[ M + H]+；Mp124-126℃；
1H NMR:(300MHz,DMSO-d6):11.00(m,2H),8.26(m,3H),7.94(m,1H),7.55(t,J＝9.0Hz,2H),7.40(m,10H),7.20(m,2H),7.00(m,4H),5.10(m,4H),4.90(m,2H),4.38(m,4H),4.24(m,4H),3.73(m,4H),2.65(m,4H),1.91(s,2H),1.78(d,J＝6.0Hz,2H),1.48(m,7H),1.19(m,8H),0.77(m,12H)。
EXAMPLE 25 preparation of bis [3- (acetyl-Lys (Boc) -Leu-OBzl) -indol-2-yl ] ethane
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 1g (2.5mmol) Leu-OBzl hydrochloride gave 500mg (33.7%) of the title compound as a yellow oil.1H NMR:(300MHz,DMSO-d6):10.90(m,2H),8.30(m,4H),7.80(d,J＝12.0Hz,1H),7.50(m,2H),7.35(m,10H),7.15(m,2H),6.90(m,4H),6.65(s,2H),5.10(m,4H),4.85(m,1H),4.25(m,4H),3.70(m,3H),2.80(m,4H),1.50(m,10H),1.35(s,18H),1.25(m,9H),0.75(m,12H)。
EXAMPLE 26 preparation of bis [3- (acetyl-Lys-Leu-OBzl) -indol-2-yl ] ethane (k)
From 500mg (0.40mmol) of bis [3- (acetyl-Lys (Boc) -Leu-OB ] according to the method of example 6zl) -indol-2-yl]Ethane gave 360mg (86%) of the title compound as a pale yellow powder. ESI-MS (M/e):1039[ M + H]+；Mp124-125℃；
1H NMR:(300MHz,DMSO-d6):11.00(m,2H),8.36(m,3H),7.94(m,1H),7.55(m,2H),7.38(m,10H),7.22(m,2H),6.93(m,4H),5.11(m,4H),4.90(m,1H),4.32(m,4H),3.73(m,8H),2.62(m,4H),1.91(m,2H),1.78(m,2H),1.52(m,15H),1.25(m,4H),0.80(m,12H)。
EXAMPLE 27 preparation of bis [3- (acetyl-Lys (Boc) -Trp-OBzl) -indol-2-yl ] ethane
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 1g (3mmol) Trp-OBzl hydrochloride gave 700mg (35%) of the title compound as a yellow oil.1H NMR:(300MHz,DMSO-d6):10.90(m,4H),8.45(d,J＝6.0Hz,2H),8.30(m,1H),8.15(m,1H),7.80(d,J＝9.0Hz,1H),6.90(m,4H),6.80-7.60(m,26H),6.70(s,2H),5.00(m,4H),4.50(m,2H),4.30(m,2H),3.70(m,2H),3.10(m,4H),2.80(m,4H),1.55(m,3H),1.35(s,18H),1.20(m,9H)。
EXAMPLE 28 preparation of bis [3- (acetyl-Lys-Trp-OBzl) -indol-2-yl ] ethane (l)
From 700mg (0.51mmol) of bis [3- (acetyl-Lys (Boc) -Trp-OBzl) -indol-2-yl group according to the method of example 6]Ethane gave 500mg (83%) of the title compound as a pale yellow powder. ESI-MS (M/e):1187[ M +2H]+；Mp131-133℃；
1H NMR:(300MHz,DMSO-d6):11.00(m,4H),8.45(m,2H),8.14(m,1H),7.76(m,1H),6.80-7.80(m,30H),5.00(m,4H),4.60(m,2H),4.30(m,2H),3.69(m,8H),3.38(m,4H),3.17(m,4H),2.61(m,4H),1.90(s,2H),1.75(m,2H),1.50(m,7H),1.24(m,8H)。
EXAMPLE 29 preparation of bis [3- (acetyl-Lys (Boc) -Glu (OBzl) -indol-2-yl ] ethane
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 1.6g (4.4mmol) Glu (OBzl) -OBzl hydrochloride to yield 600mg (23%) of the title compoundAs a yellow oil.1H NMR:(300MHz,DMSO-d6):10.90(m,2H),8.45(m,2H),8.30(m,1H),7.90(m,1H),7.55(t,J＝6.0Hz,1H),7.35(m,20H),7.20(m,2H),6.90(m,4H),6.70(s,2H),5.10(m,8H),4.90(m,1H),4.30(m,4H),3.70(m,2H),2.80(s,4H),2.50(m,4H),2.00(m,2H),1.90(m,4H),1.55(m,4H),1.35(s,18H),1.20(m,10H)。
EXAMPLE 30 preparation of bis [3- (acetyl-Lys (Boc) -Glu (OBzl) -indol-2-yl ] ethane (m)
From 600mg (0.41mmol) of bis [3- (acetyl-Lys (Boc) -Glu (OBzl) -indol-2-yl group according to the method of example 6]Ethane gave 400mg (77%) of the title compound as a pale yellow powder. ESI-MS (M/e):1252[ M + H]+；Mp 108-109℃；
1H NMR:(300MHz,DMSO-d6):11.00(m,2H),8.39(m,3H),7.89(m,1H),7.54(m,2H),7.30(m,22H),6.90(m,4H),5.10(m,8H),4.90(m,1H),4.32(m,4H),3.67(m,4H),2.62(m,4H),2.05(m,2H),1.89(m,4H),1.74(m,2H),1.50(m,7H),1.20(m,8H)。
EXAMPLE 31 preparation of bis [3- (acetyl-Lys (Boc) -Asp (OBzl) -indol-2-yl ] ethane
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 1.5g (3.1mmol) Asp (OBzl) -OBzl hydrochloride gave 650mg (38%) of the title compound as a yellow oil.1H NMR:(300M,DMSO-d6):10.90(m,2H),8.55(m,2H),8.30(m,1H),7.90(d,J＝9.0Hz,1H),7.35(m,24H),7.20(m,2H),6.90(m,4H),6.70(s,2H),5.10(m,8H),4.90(m,1H),4.75(m,2H),4.30(m,2H),3.70(m,5H),2.80(m,8H),1.75(m,2H),1.55(m,2H),1.35(m,20H),1.20(m,10H)。
EXAMPLE 32 preparation of bis [3- (acetyl-Lys-Asp (OBzl) -indol-2-yl ] ethane (n)
From 650mg (0.46mmol) of bis [3- (acetyl-Lys (Boc) -Asp (OBzl) -indol-2-yl group according to the method of example 6]Ethane gave 500mg (89.3%) of the title compound as a pale yellow powder. ESI-MS (M/e):1223[ M + H]+；Mp 108-109℃；
1H NMR:(300MHz,DMSO-d6):11.00(m,2H),8.54(m,2H),8.30(m,1H),7.90(m,1H),7.54(m,2H),7.30(m,22H),7.21(m,4H),6.69(m,2H),5.05(m,8H),4.86(m,1H),4.75(m,2H),4.30(m,2H),3.74(m,4H),3.38(m,4H),2.86(m,8H),1.90(m,4H),1.74(m,4H),1.45(m,7H),1.20(m,8H)。
EXAMPLE 33 preparation of bis [3- (acetyl-Lys (Boc) -Met-OBzl) -indol-2-yl ] ethane
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 1.1g (4mmol) Met-OBzl hydrochloride gave 800mg (35%) of the title compound as a yellow oil.1H NMR:(300MHz,DMSO-d6):11.00(m,2H),8.40(m,3H),8.30(d,J＝9.0Hz,1H),8.20(d,J＝9.0Hz,1H),7.90(d,J＝9.0Hz,1H),7.50(m,12H),7.20(m,2H),6.90(m,4H),6.70(s,2H),5.10(m,4H),4.90(m,1H),4.50(m,2H),4.30(m,2H),3.70(m,4H),2.80(m,4H),1.90(m,11H),1.50(m,24H),1.30(m,9H)。
EXAMPLE 34 preparation of bis [3- (acetyl-Lys-Met-OBzl) -indol-2-yl ] ethane (o)
From 800mg (0.63mmol) of bis [3- (acetyl-Lys (Boc) -Met-OBzl) -indol-2-yl]Ethane gave 500mg (75%) of the title compound as a pale yellow powder. ESI-MS (M/e):1075[ M + H]+；Mp134-136℃；
1H NMR:(300MHz,DMSO-d6):11.00(m,2H),8.37(m,3H),8.23(m,1H),7.88(m,1H),7.60(m,2H),7.45(m,10H),7.22(m,2H),6.97(m,4H),5.11(m,4H),4.90(m,1H),4.40(m,4H),3.72(m,4H),3.41(m,2H),2.81(m,4H),2.00(m,10H),1.70(m,3H),1.50(m,9H),1.20(m,5H)。
EXAMPLE 35 preparation of bis [3- (acetyl-Lys (Boc) -The-OBzl) -indol-2-yl ] ethane
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 1.1g (3.7mmol) of The hydrochloride salt of The OBzl yield 550mg (25%) of The title compound as a yellow oil.1H NMR:(300MHz,DMSO-d6):10.90(m,2H),8.25(m,4H),7.65(m,2H),7.55(m,2H),7.35(m,10H),7.20(m,2H),6.90(m,4H),6.65(m,2H),5.10(m,4H),4.85(m,1H),4.35(m,4H),4.15(m,2H),3.70(m,4H),3.00(m,4H),2.80(m,4H),1.90(m,11H),1.50(m,32H),0.90(m,6H)。
EXAMPLE 36 preparation of bis [3- (acetyl-Lys-The-OBzl) -indol-2-yl ] ethane (p)
From 550mg (0.42mmol) bis [3- (acetyl-Lys (Boc) -The-OBzl) -indol-2-yl group according to The method of example 6]Ethane gave 400mg (85%) of the title compound as a pale yellow powder. ESI-MS (M/e):1126[ M + H]+；Mp117-118℃；
1H NMR:(300MHz,DMSO-d6):11.00(m,2H),8.47(m,4H),7.60(m,4H),7.40(m,10H),7.20(m,2H),7.00(m,4H),5.00(m,4H),4.90(m,1H),4.40(m,4H),3.70(m,4H),3.00(m,4H),2.60(m,4H),2.10(m,4H),1.80(m,8H),1.60(m,2H),1.50(m,7H),1.20(m,4H),0.90(m,6H)。
EXAMPLE 37 preparation of bis [3- (acetyl-Lys (Boc) -Asn-OBzl) -indol-2-yl ] ethane
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 1g (3.8mmol) Asn-OBzl hydrochloride gave 300mg (14%) of the title compound as a yellow oil.1H NMR:(300MHz,DMSO-d6)10.90(m,2H),8.35(m,3H),8.15(m,2H),7.40(m,17H),6.90(m,6H),6.65(m,2H),5.10(m,4H),4.85(m,1H),4.65(m,2H),4.35(m,2H),3.70(m,4H),3.00(m,4H),2.80(m,4H),1.40(m,2H),1.35(m,22H),1.25(m,10H)。
EXAMPLE 38 preparation of bis [3- (acetyl-Lys-Asn-OBzl) -indol-2-yl ] ethane (8q)
From 300mg (0.24mmol) of bis [3- (acetyl-Lys (Boc) -Asn-OBzl) -indol-2-yl group according to the method of example 6]Ethane gave 130mg (52%) of the title compound as a pale yellow powder. ESI-MS (M/e):1042[ M + H]+；Mp126-128℃；
1H NMR:(300MHz,DMSO-d6):11.00(m,2H),8.41(m,2H),8.20(m,1H),7.55(m,1H),7.45(m,2H),7.30(m,10H),7.21(m,2H),6.95(m,4H),5.00(m,4H),4.90(m,1H),4.70(m,2H),4.35(m,4H),3.71(m,4H),2.59(m,8H),1.80(m,4H),1.50(m,7H),1.20(m,4H)。
Example 39Preparation of bis [3- (acetyl-Lys (Boc) -Arg (NO)2) -OBzl) -indol-2-yl]Ethane (III)
From 1.5g (1.8mmol) of bis [3- (acetyl-Lys (Boc)) indol-2-yl]Ethane and 1g (3.2mmol) of Arg (NO)2) OBzl hydrochloride gives 400mg (20%) of the title compound as a yellow oil.1H NMR:(300MHz,DMSO-d6)10.90(m,2H),8.30(m,5H),7.80(d,J＝9.0Hz,1H),7.55(m,2H),7.35(m,10H),7.20(m,2H),6.90(m,4H),6.65(s,2H),5.10(m,4H),4.90(m,1H),4.30(m,4H),3.70(m,3H),3.10(m,5H),2.80(s,4H),1.75(d,J＝6.0Hz,4H),1.50(m,10H),1.40(m,19H),1.20(m,11H)。
EXAMPLE 40 preparation of bis [3- (acetyl-Lys-Arg (NO)2) -OBzl) -indol-2-yl]Ethane (r)
From 400mg (0.28mmol) of bis [3- (acetyl-Lys (Boc) -Arg (NO) according to the method of example 62) -OBzl) -indol-2-yl]Ethane gave 270mg (79%) of the title compound as a pale yellow powder. ESI-MS (M/e):1215[ M + H]+；Mp 127-128℃；
1H NMR:(300MHz,DMSO-d6):11.00(m,2H)，8.19(m,4H),7.60(m,2H),7.34(m,10H),7.20(m,2H),6.95(m,4H),5.00(m,4H),4.90(m,1H),4.40(m,4H),3.72(m,4H),3.12(m,4H),2.60(m,4H),2.00(s,2H),1.70(m,4H),1.50(m,15H),1.20(m,4H)。
Experimental example 1 evaluation of tumor growth inhibitory Activity of Compounds a-r
Compound a-r is solubilized in normal saline with tween 80; doxorubicin was dissolved with physiological saline. Taking S180 sarcoma inoculated in ICR mouse for 7 days under aseptic condition, adding appropriate amount of normal saline to prepare into tumor cell suspension with cell number of 1 × 107one/mL, inoculated subcutaneously in the hind axilla of healthy male ICR mice, 0.2mL per mouse. 24h after tumor inoculation, the treated mice were orally administered with 0.2mL of compound a-r in physiological saline daily at a dose of 0.1. mu. mol/kg 1 time per day for 10 consecutive days. The blank mice were orally administered with 0.2mL of physiological saline. Positive control mice were given a 10-day continuous intraperitoneal injection of doxorubicin (at a dose of 2. mu. mol/kg) 1 time per day. The experiment was carried out until day 11, the mice were weighed and anesthetized with ether before being administeredAnd (4) killing the broken neck, dissecting and weighing tumors of each group of mice, and finally counting the tumor inhibition rate of each group of animals. The therapeutic effect of solid tumors was expressed as percent tumor weight inhibition,% tumor weight inhibition ═ 1- (compound group tumor weight/blank group tumor weight)]X 100%. The results are shown in Table 1. The tumor weights of the mice treated with 0.1. mu. mol/kg of compounds a-q were significantly smaller than those of the mice treated with physiological saline, indicating that the compounds had good anti-tumor activity. Wherein the tumor weight of the mice treated with 0.1. mu. mol/kg of the compound b, k, q is equivalent to that of the mice treated with 2. mu. mol/kg of doxorubicin, indicating that they have an antitumor activity 20-fold stronger than that of doxorubicin. Therefore, the invention has unexpected technical effects.
TABLE 1 Effect of Compounds a-r on tumor weight in S180 tumor-bearing mice
n is 10; a) p <0.01 to saline; b) p <0.01 to saline and p >0.05 to doxorubicin.
Claims (3)
1. bis-3-acetyl-Lys-AA-OBzl-indol-2-yl-ethanes of the general formula I, wherein AA ═ Gly, Ala, Leu, Ile, Val, Trp, Phe, Lys, Tyr, Pro, Met, Ser, Thr, Asn, Asp (OBzl), Glu (OBzl), Arg (NO)2) Or a residue of The at least one amino acid,
2. a process for preparing bis-3-acetyl-Lys-AA-OBzl-indol-2-yl-ethane according to claim 1, comprising:
(1) adding concentrated sulfuric acid and 40% acetaldehyde solution into methanol solution of indoleacetic acid under ice bath to prepare bis-3-methyl acetate-indol-2-yl-ethane;
(2) hydrolyzing bis-3-methyl acetate-indol-2-yl-ethane in a 6N NaOH solution to prepare bis-3-acetic acid-indol-2-yl-ethane;
(3) bis-3-acetic acid-indol-2-yl-ethaneWith HCl & NωPreparation of bis-3-acetyl-N by coupling of-Boc-Lys-OBzlω-Boc-Lys-OBzl-indol-2-yl-ethane;
(4) bis-3-acetyl-Nω-Boc-Lys-OBzl-indol-2-yl-ethane in methanol with Pb/C catalytic hydrogenolysis to obtain bis-3-acetyl-Nω-Boc-Lys-indol-2-yl-ethane;
(5) bis-3-acetyl-NωCoupling of-Boc-Lys-indol-2-yl-ethane with HCl. AA-OBzl to give bis-3-acetyl-Nω-Boc-Lys-AA-OBzl-indol-2-yl-ethane, wherein AA ═ Gly, Ala, Leu, Ile, Val, Trp, Phe, Lys, Tyr, Pro, Met, Ser, Thr, Asn, Asp (NO)2),Glu(NO2),Arg(NO2) Or The residue;
(6) reacting bis-3-acetyl-Nω-Boc-Lys-AA-OBzl-indol-2-yl-ethane removal of Boc in anhydrous dichloromethane/trifluoroacetic acid to give bis-3-acetyl-Lys-AA-OBzl-indol-2-yl-ethane, wherein AA ═ Gly, Ala, Leu, Ile, Val, Trp, Phe, Lys, Tyr, Pro, Met, Ser, Thr, Asn, asp (OBzl), glu (OBzl), Arg (NO)2) Or The residue.
3. Use of bis-3-acetyl-Lys-AA-OBzl-indol-2-yl-ethane according to claim 1 for the preparation of a medicament against S180 sarcoma.
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