CN105198884A - G1/G0-phase blocked pentacyclic indol-quinolizidine and compound, antineoplastic activity and application thereof - Google Patents

G1/G0-phase blocked pentacyclic indol-quinolizidine and compound, antineoplastic activity and application thereof Download PDF

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CN105198884A
CN105198884A CN201410272991.9A CN201410272991A CN105198884A CN 105198884 A CN105198884 A CN 105198884A CN 201410272991 A CN201410272991 A CN 201410272991A CN 105198884 A CN105198884 A CN 105198884A
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compound
cell
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quinolizine
oxoindole
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CN105198884B (en
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彭师奇
赵明
李春钰
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Capital Medical University
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Capital Medical University
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Abstract

The invention discloses G1/G0-phase blocked pentacyclic indol-quinolizidine which is (6S)-3-acetyl-6-(N-phenylacetyl amino acyl)-oxidative methyl-4,6,7,12-tetrahydro-4-oxoindole-[2,3-1] quinolizidine, and discloses a compound, cell proliferation resistance activity, antineoplastic activity and application thereof.

Description

The G1/G0 phase block Pentacyclic indole quinolizine, its synthesis, anti-tumor activity and application
Invention field
The present invention relates to the Pentacyclic indole quinolizine that the G1/G0 phase blocks; i.e. (6S)-3-ethanoyl-6-(N-phenylacetylamino acyl group)-oxidation methyl-4; 6; 7; 12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine, relates to their synthesis; relate to their antiproliferation, relate to their anti-tumor activities on mice transplanted tumor model further.Thus the present invention relates to the potential applicability in clinical practice of (6S)-3-ethanoyl-6-(N-phenylacetylamino acyl group) oxidation methyl-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine as G1/G0 phase retarding agent.The invention belongs to biomedicine field.
Background technology
Cell replaces because of old and feeble by the new cell of propagation generation, the cell that dead and trauma loses, and growing for body growth and continue race provides basis.The process of cell proliferation is called the cell cycle.Or the cell cycle is that phalangeal cell grows from once dividing end, terminate the process experienced to division next time.Be divided into interval and two periods of division stage cell generation cycle.
Enter interval after cell fission, complete structure and biosynthetic complexity change.The pre-synthesis phase that interval being divided into again DNA (G1 phase), DNA synthesis phase (S phase) and DNA post-synthesis phase (G2 phase) three are by stages.G1 phase cell can be divided into and forever rests on the G1 phase until death, temporarily do not breed and continues propagation three types.The cell of temporarily not breeding is also known as Go phase cell.Archaeal dna polymerase and four kinds of deoxynucleotides are formed rapidly in S incipient cell.S end of term nucleus DNA copies as cell fission and prepares.The S phase approximately continues 7 ~ 8 hours.G2 phase cell synthesis RNA and protein such as histone, tubulin and membranin etc., for spindle body and new cytolemma etc. prepare enough raw material, to enter m period.The G2 phase approximately continues 1 ~ 1.5 hour.Mitotic division is also known as the M phase.The M phase is the successive processes formed in early stage, mid-term, later stage and latter stage, completes and divides the task of becoming two daughter cells by a parent cell.General need 1 ~ 2 hour.
Tumour cell belongs to the G1 phase cell of continuous proliferation, and the cell cycle is the important target spot of antitumor drug.Act on the chemotherapeutics of tumor cell also known as cell cycle specific agents.Although such as, the chemotherapeutics of some clinical application, 5-fluor-uracil, Tegafur, Zorubicin, zilimeisu and cytosine arabinoside, affect the cell cycle, lacks specificity.By being, tumour cell cycle inhibitor becomes the key areas of antitumor drug research.Especially invention can allow tumour cell forever rest on the chemotherapeutics of G1 phase, i.e. G1/G0 phase retarding agent, is the important directions of antitumor drug design.But, the successful case of G1/G0 phase retarding agent is not had so far.Understand according to these, inventors herein propose Pentacyclic indole quinolizine, i.e. (6S)-3-ethanoyl-6-(N-phenylacetylamino acyl group)-oxidation methyl-4; 6,7,12-tetrahydrochysene-4-Oxoindole [2; 3-a] quinolizine, as the invention that the G1/G0 phase blocks.
Summary of the invention
The compound 7a-i of represented by formula of the present invention,
In 7a, AA is L-alanyl, and in 7b, AA is that L-is valyl, and in 7c, AA is L-phenylalanyl; in 7d, AA is glycyl, and in 7e, AA is L-prolyl, and in 7f, AA is L-isoleucyl; in 7g, AA is L-leucyl, and in 7h, AA is L-methionyl, and in 7i, AA is L-tryptophyl.
Second content of the present invention prepares (6S)-3-ethanoyl-6-(N-phenylacetylamino acyl group) oxidation methyl-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (7a-i) according to the route of Fig. 1, comprising:
1) 1-(2,2-dimethoxy ethyl)-3-methylol-1,2,3,4-Tetrahydrocarboline (3) is prepared;
2) (6S)-3-ethanoyl-6-methylol-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (6) is prepared;
3) (6S)-3-ethanoyl-6-(N-phenylacetylamino acyl group) oxidation methyl-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (7a-i) is prepared.In 7a, AA is L-alanyl, and in 7b, AA is that L-is valyl, and in 7c, AA is L-phenylalanyl; in 7d, AA is glycyl, and in 7e, AA is L-prolyl, and in 7f, AA is L-isoleucyl; in 7g, AA is L-leucyl, and in 7h, AA is L-methionyl, and in 7i, AA is L-tryptophyl.
3rd content of the present invention evaluates the antiproliferation of (6S)-3-ethanoyl-6-(N-phenylacetylamino acyl group) oxidation methyl-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (7a-i).
4th content of the present invention evaluates the anti-tumor activity of (6S)-3-ethanoyl-6-(N-phenylacetylamino acyl group) oxidation methyl-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (7a-i).
5th content of the present invention is with one of them compound for representative, investigates the impact of cell cycle.
Accompanying drawing explanation
Fig. 1. the synthetic route of (6S)-3-ethanoyl-6-(N-phenylacetylamino acyl group) oxidation methyl-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (7a-i). (i) thionyl chloride/methyl alcohol; (ii) 1,1,3,3-tetramethoxy propane, trifluoroacetic acid/methyl alcohol; (iii) LiAlH 4, THF; (iv) ketene dimer, triethylamine/acetone; (v) 2NHCl/ acetone; (vi) K 2cO 3/ methyl alcohol; (vii) N-phenylacetylamino acid, DCC/HOBt, NMM, THF.In 7a, AA is L-alanyl, and in 7b, AA is that L-is valyl, and in 7c, AA is L-phenylalanyl; in 7d, AA is glycyl, and in 7e, AA is L-prolyl, and in 7f, AA is L-isoleucyl; in 7g, AA is L-leucyl, and in 7h, AA is L-methionyl, and in 7i, AA is L-tryptophyl.
Embodiment
In order to set forth the present invention further, provide a series of embodiment below.These embodiments are illustrative completely, and they are only used for being specifically described the present invention, not should be understood to limitation of the present invention.
Embodiment 1 prepares L-Trp methyl ester hydrochloride (1)
50ml anhydrous methanol drips 3.75ml (50mmol) sulfur oxychloride under ice bath, after dropwising, adds 9.20g (42mmol) L-Trp, stirring at room temperature 24h, TLC (CHCl in 30min in batches 3: MeOH=2: 3) monitoring is to raw material disappearance termination reaction.The complete sulfur oxychloride SOCl of unreacted taken away by water pump 2and HCl, repeatedly grind to obtain white solid with ether, methanol-diethyl ether recrystallization, obtaining L-Trp methyl ester hydrochloride is colorless solid.Yield is between 85-99%.ESI-MS (m/e) 219 [M+H] +, the physical constant such as fusing point, optically-active and the data consistent reported.
Embodiment 2 prepares 1-(2,2-dimethoxy ethyl)-2,3,4,9-tetrahydro-beta-carboline carboxylate methyl ester (2)
In the round-bottomed flask of 250ml, add L-Trp methyl ester hydrochloride 20g (78.6mmol), 100ml methyl alcohol, add trifluoroacetic acid 20ml, activate half an hour, add 1 again, 1,3,3-tetramethoxy propane 16ml (97.6mmol), be warmed up to 80 DEG C under stirring, insulation reaction 10 hours, TLC monitors raw material spot and disappears, reaction solution is cooled to room temperature, drips saturated NaHCO 3the aqueous solution regulates pH to neutral, reclaim under reduced pressure methyl alcohol, 100ml methylene dichloride is added in resistates, after separatory, water layer is with dichloromethane extraction (50ml × 3), merges organic layer, anhydrous sodium sulfate drying, filter, filtrate reduced in volume is to dry, and (sherwood oil: acetone=2: 1) purifying obtains 14.2g (57%) compound 2 is yellow oil to residue over silica gel column chromatography.ESI-MS(m/e)319[M+H] +。
Embodiment 3 prepares 1-(2,2-dimethoxy ethyl)-3-methylol-1,2,3,4-Tetrahydrocarboline (3)
In the round-bottomed flask of 250ml, add 50ml anhydrous tetrahydro furan, under stirring, add LiAlH in batches 40.9g (23.6mmol), activates half an hour.Be dissolved in 50ml anhydrous tetrahydro furan by 5g (15.7mmol) compound (2), then by its slowly instillation reaction flask, be warmed up to 40 DEG C, insulation reaction 3 hours, TLC monitors raw material spot and disappears.Reaction solution is cooled to room temperature, adds the NaOH aqueous solution of 0.5ml15%, reaction of finally going out, crosses with Bush's funnel and filters aluminium salt, and filtrate reduced in volume is to dry, and add ethyl acetate, ether is worn away and obtained order 2.52g (54%) compound 3, is colourless powder.ESI-MS(m/e)291[M+H] +。
Embodiment 4 prepares 1-(2,2-dimethoxy ethyl)-2-(1,3-dicarbapentaborane butyl)-3-(1,3-dicarbapentaborane butyl) oxidation methyl-1,2,3,4-Tetrahydrocarboline (4)
In the round-bottomed flask of 100ml, add 1.0g (3.8mmol) compound (3), then add 20ml acetone stirring and dissolving, under ice bath, add ketene dimer 1ml (11.9mmol), triethylamine 0.4ml.Reaction solution stirring at room temperature 24 hours, TLC monitors raw material spot and disappears, and adds 0.2ml water soldier and to go out unreacted ketene dimer, decompression and solvent recovery.50ml methylene dichloride and the saturated NaCl aqueous solution of 50ml is added in resistates, after separatory, water layer is with dichloromethane extraction (30ml × 3), merge organic layer, anhydrous sodium sulfate drying, filter, filtrate reduced in volume is to dry, and (sherwood oil: acetone=6: 1) purifying obtains 1.32g (76%) compound 4 is yellow powder to residue over silica gel column chromatography.ESI-MS(m/e)459[M+H] +。
Embodiment 5 prepares 3-ethanoyl-6-(1,3-dicarbapentaborane butyl) oxidation methyl-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (5)
In the round-bottomed flask of 100ml, add 1.98g (4.3mmol) compound (4), add 50ml acetone stirring and dissolving, under ice bath, add 3ml aqueous hydrochloric acid (2mol/L), room temperature reaction 12 hours.TLC monitors raw material spot and disappears, and adds saturated NaHCO 3the aqueous solution regulates pH to neutral, decompression and solvent recovery, 50ml methylene dichloride is added in resistates, after separatory, water layer is with dichloromethane extraction (30ml × 3), merges organic layer, anhydrous sodium sulfate drying, filter, filtrate reduced in volume is to dry, and (sherwood oil: acetone=6: 1) purifying obtains 1.26g (75%) compound 5 is yellow powder to residue over silica gel column chromatography.ESI-MS(m/e)393[M+H] +。
Embodiment 6 prepares (6S)-3-ethanoyl-6-methylol-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (6)
In the round-bottomed flask of 100ml, add 1.06g (2.7mmol) compound (5), add 20ml methyl alcohol stirring and dissolving, then add 745mg (5.4mol/L) potassium carbonate powder, room temperature reaction 8 hours, has solid to generate.TLC monitors raw material spot and disappears, and filter, filter cake methanol wash column, obtains yellow powder 338mg, i.e. target compound (6).Filtrate reduced in volume, to dry, adds acetone solution, and filter desalination, with silica gel column chromatography, (methylene dichloride: methyl alcohol=40: 1) purifying obtains 709mg (85%) compound 6 is yellow powder to filtrate.Mp:210-211 DEG C; [α] d 25=-42.7 (c=0.10, methyl alcohol); IR (KBr): 3321,2974,2922,1655,1551,1429,1364,1327,974,831,743cm -1; ESI-MS (m/e) 307 [M-H] -; 1h-NMR (300MHz, DMSO-d 6): δ/ppm=11.83 (s, 1H), 8.10 (d, J=7.8Hz, 1H), 7.65 (d, J=7.8Hz, 1H), 7.45 (d, J=8.1Hz, 1H), 7.28 (t, J=7.8Hz, 1H), 7.11 (t, J=7.8Hz, 1H), 6.82 (d, J=7.8Hz, 1H), 5.40-5.46 (m, 1H), 5.18 (t, J=6.0Hz, 1H), 3.54-3.60 (m, 1H), 3.28-3.41 (m, 2H), 3.11 (dd, J=6.9Hz, J=17.1Hz, 1H), 2.59 (s, 1H); 13c-NMR (75MHz, DMSO-d 6): δ/ppm=196.62,160.68,142.75,142.51,139.64,126.79,126.21,125.43,123.90,120.53,120.41,114.07,112.60,100.36,59.24,51.43,31.18,19.70.
Embodiment 7 prepares 3-ethanoyl-6-(N-phenylacetyl alanyl) oxidation methyl-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (7a)
Under ice bath, in 100ml eggplant bottle, add 248mg (1.2mmol) N-phenylacetyl L-Ala, dissolve with anhydrous tetrahydro furan, add 162mg (1.2mmol) HOBt, add 247mg (1.2mmol) DCC, activate half an hour.308mg (1mmol) (6S)-3-ethanoyl-6-methylol-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (6) are dissolved in anhydrous tetrahydro furan, mixed solution is added in reaction flask.Adjust PH to 7-8 with NMM again, remove ice bath, lucifuge room temperature reaction 48 hours.Be evaporated to by reaction solution dry, with acetic acid ethyl dissolution, filter, filtrate washes three times with saturated sodium bicarbonate solution, then washes three times with saturated nacl aqueous solution, ester layer anhydrous sodium sulfate drying, filters, and filtrate reduced in volume is to dry.With thin-layer chromatography, (methylene dichloride: methyl alcohol=20: 1) purifying, then wear away with ether, obtain 157mg (31.6%) compound 7a, be yellow powder to resistates.Mp95-96 DEG C, [α] d 25=-27.3 (c=0.14, methyl alcohol), IR (KBr): 2978,2930,1753,1668,1643,1545,1427,1329,1153,1107,745cm -1, ESI-MS (m/e) 498 [M+H] +, 1h-NMR (300MHz, DMSO-d 6): δ/ppm=11.90 (s, 1H), 8.40-8.48 (m, 1H), 8.13 (d, J=7.8Hz, 1H), 7.59 (d, J=7.8Hz, 1H), 7.45 (d, J=8.1Hz, 1H), 7.17-7.31 (m, 6H), 7.10 (t, J=7.2Hz, 1H), 6.85 (d, J=7.5Hz, 1H), 5.68-5.70 (m, 1H), 4.11-4.27 (m, 2H), 3.98 (dd, J=6.0Hz, J=10.8Hz, 1H), 3.43 (d, J=5.1Hz, 2H), 3.09-3.27 (m, 2H), 2.59 (s, 3H), 1.17 (d, J=7.2Hz, 3H), 13c-NMR (75MHz, DMSO-d 6): δ/ppm=196.47,172.54,172.48,170.42,160.79,142.90,142.63,139.62,136.53,129.45 (2C), 128.60 (2C), 126.78,126.56,125.95,123.95,120.53,113.86,112.63,100.72,62.93,48.29,42.20,31.21,20.87,17.04.
Embodiment 8 prepares 3-ethanoyl-6-(N-phenylacetyl is valyl) oxidation methyl-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (7b)
Under ice bath, in 100ml eggplant bottle, add 423mg (1.8mmol) N-phenylacetyl α-amino-isovaleric acid, dissolve with anhydrous tetrahydro furan, add 243mg (1.8mmol) HOBt, add 371mg (1.8mmol) DCC, activate half an hour.462mg (1.5mmol) (6S)-3-ethanoyl-6-methylol-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (6) are dissolved in anhydrous tetrahydro furan, mixed solution is added in reaction flask.Adjust PH to 7-8 with NMM again, remove ice bath, lucifuge room temperature reaction 48 hours.Be evaporated to by reaction solution dry, with acetic acid ethyl dissolution, filter, filtrate washes three times with saturated sodium bicarbonate solution, then washes three times with saturated nacl aqueous solution, ester layer anhydrous sodium sulfate drying, filters, and filtrate reduced in volume is to dry.With thin-layer chromatography, (methylene dichloride: methyl alcohol=20: 1) purifying, then wear away with ether, obtain 226mg (28.7%) compound 7b, be yellow powder to resistates.Mp109-110 DEG C, [α] d 25=-38.0 (c=0.11, methyl alcohol), IR (KBr): 2963,2926,1744,1651,1545,1499,1360,1321,1261,1194,1146,824,745cm -1, ESI-MS (m/e) 526 [M+H] +, 1h-NMR (300MHz, DMSO-d 6): δ/ppm=11.92 (s, 1H), 8.31 (d, J=8.1Hz, 1H), 8.13 (d, J=7.8Hz, 1H), 7.56 (d, J=7.8Hz, 1H), 7.45 (d, J=8.4Hz, 1H), 7.19-7.31 (m, 6H), 7.09 (t, J=7.5Hz, 1H), 6.85 (d, J=7.5Hz, 1H), 5.67-5.71 (m, 1H), 4.08-4.19 (m, 2H), 3.98 (dd, J=5.4Hz, J=10.5Hz, 1H), 3.50 (d, J=6.2Hz, 2H), 3.12-3.29 (m, 2H), 2.59 (s, 3H), 1.91-1.97 (m, 1H), 0.75-0.83 (m, 6H), 13c-NMR (75MHz, DMSO-d 6): δ/ppm=196.45,171.92,169.29,160.75,142.94,142.74,139.61,135.55,129.86 (2C), 128.63 (2C), 126.80,126.56,125.92,123.84,120.54,114.06,112.57,100.70,63.04,58.89,48.40,47.16,31.22,28.81,24.80 (2C), 20.95.
Embodiment 9 prepares 3-ethanoyl-6-(N-phenylacetyl-phenylalanyl) oxidation methyl-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (7c)
Under ice bath, in 100ml eggplant bottle, add 679mg (2.4mmol) N-phenylacetyl-phenylalanine, dissolve with anhydrous tetrahydro furan, add 324mg (2.4mmol) HOBt, add 494mg (2.4mmol) DCC, activate half an hour.616mg (2.0mmol) (6S)-3-ethanoyl-6-methylol-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (6) are dissolved in anhydrous tetrahydro furan, mixed solution is added in reaction flask.Adjust PH to 7-8 with NMM again, remove ice bath, lucifuge room temperature reaction 48 hours.Be evaporated to by reaction solution dry, with acetic acid ethyl dissolution, filter, filtrate washes three times with saturated sodium bicarbonate solution, then washes three times with saturated nacl aqueous solution, ester layer anhydrous sodium sulfate drying, filters, and filtrate reduced in volume is to dry.With thin-layer chromatography, (methylene dichloride: methyl alcohol=20: 1) purifying, then wear away with ether, obtain 137mg (12.0%) compound 7c, be yellow powder to resistates.Mp73-74 DEG C, [α] d 25=-57.2 (c=0.10, methyl alcohol), IR (KBr): 3059,2965,2932,1746,1659,1547,1501,1362,1333,1261,818,746cm -1, ESI-MS (m/e) 574 [M+H] +, 1h-NMR (500MHz, DMSO-d 6): δ/ppm=11.91 (s, 1H), 8.38-8.43 (m, 1H), 8.14 (d, J=7.5Hz, 1H), 7.60 (t, J=8Hz, 1H), 7.44 (d, J=8Hz, 1H), 7.27-7.30 (m, 1H), 7.17-7.23 (m, 6H), 7.09-7.13 (m, 3H), 7.00-7.04 (m, 2H), 6.86 (d, J=7.5Hz, 1H), 5.69-5.74 (m, 1H), 4.25-4.36 (m, 2H), 4.16 (t, J=6.5Hz, 1H), 4.03-4.06 (m, 1H), 3.36-3.40 (m, 2H), 3.17-3.22 (m, 1H), 2.75-2.86 (m, 2H), 2.59 (s, 3H), 13c-NMR (75MHz, DMSO-d 6): δ/ppm=196.44,171.41,170.53,160.83,160.79,142.95,142.69,142.62,139.63,137.56,136.40,129.41 (2C), 128.58 (2C), 128.46,126.91,126.71,126.66,126.58,125.88,123.97,120.54,113.88,112.65,100.73,63.70,53.91,48.21,42.28,36.58,31.21,21.02.
Embodiment 10 prepares 3-ethanoyl-6-(N-phenylacetyl-glycyl) oxidation methyl-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (7d)
Under ice bath, in 100ml eggplant bottle, add 232mg (1.2mmol) N-phenylacetyl-glycine, dissolve with anhydrous tetrahydro furan, add 162mg (1.2mmol) HOBt, add 247mg (1.2mmol) DCC, activate half an hour.308mg (1.0mmol) (6S)-3-ethanoyl-6-methylol-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (6) are dissolved in anhydrous tetrahydro furan, mixed solution is added in reaction flask.Adjust PH to 7-8 with NMM again, remove ice bath, lucifuge room temperature reaction 48 hours.Be evaporated to by reaction solution dry, with acetic acid ethyl dissolution, filter, filtrate washes three times with saturated sodium bicarbonate solution, then washes three times with saturated nacl aqueous solution, ester layer anhydrous sodium sulfate drying, filters, and filtrate reduced in volume is to dry.With thin-layer chromatography, (methylene dichloride: methyl alcohol=20: 1) purifying, then wear away with ether, obtain 173mg (35.8%) compound 7d, be yellow powder to resistates.Mp84-85 DEG C, [α] d 25=-29.4 (c=0.11, methyl alcohol), IR (KBr): 3327,3064,2922,2858,1753,1657,1541,1433,1331,1180,976,743cm -1, ESI-MS (m/e) 484 [M+H] +, 1h-NMR (300MHz, DMSO-d 6): δ/ppm=11.93 (s, 1H), 8.48 (t, J=5.7Hz, 1H), 8.13 (d, J=7.8Hz, 1H), 7.61 (d, J=8.1Hz, 1H), 7.45 (d, J=8.4Hz, 1H), 7.20-7.31 (m, 6H), 7.10 (t, J=7.5Hz, 1H), 6.85 (d, J=7.8Hz, 1H), 5.67-5.73 (m, 1H), 4.21-4.27 (m, 1H), 4.00 (dd, J=6.6Hz, J=10.8Hz, 1H), 3.75 (d, J=5.7Hz, 2H), 3.47 (s, 2H), 3.13-3.32 (m, 2H), 2.59 (s, 3H), 13c-NMR (75MHz, DMSO-d 6): δ/ppm=196.49,171.09,169.96,160.85,142.95,142.42,139.61,136.46,129.48 (2C), 128.63 (2C), 126.82,126.54,125.92,125.56,123.89,120.52,113.69,112.64,100.80,62.60,48.12,42.28,31.32.20.73.
Embodiment 11 prepares 3-ethanoyl-6-(N-phenylacetyl-prolyl) oxidation methyl-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (7e)
Under ice bath, in 100ml eggplant bottle, add 559mg (2.4mmol) N-phenylacetyl-proline(Pro), dissolve with anhydrous tetrahydro furan, add 324mg (2.4mmol) HOBt, add 494mg (2.4mmol) DCC, activate half an hour.616mg (2.0mmol) (6S)-3-ethanoyl-6-methylol-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (6) are dissolved in anhydrous tetrahydro furan, mixed solution is added in reaction flask.Adjust PH to 7-8 with NMM again, remove ice bath, lucifuge room temperature reaction 48 hours.Be evaporated to by reaction solution dry, with acetic acid ethyl dissolution, filter, filtrate washes three times with saturated sodium bicarbonate solution, then washes three times with saturated nacl aqueous solution, ester layer anhydrous sodium sulfate drying, filters, and filtrate reduced in volume is to dry.With thin-layer chromatography, (methylene dichloride: methyl alcohol=20: 1) purifying, then wear away with ether, obtain 450mg (43.0%) compound 7e, be yellow powder to resistates.Mp101-102 DEG C, [α] d 25=-68.0 (c=0.09, methyl alcohol), IR (KBr): 2974,2880,2845,1748,1659,1545,1425,1331,1277,1167,1109,966,745cm -1, ESI-MS (m/e) 524 [M+H] +, 1h-NMR (300MHz, DMSO-d 6): δ/ppm=11.91 (s, 1H), 8.13 (d, J=7.8Hz, 1H), 7.56 (d, J=7.8Hz, 1H), 7.45 (d, J=8.1Hz, 1H), 7.17-7.31 (m, 6H), 7.08 (q, J=7.2Hz, 1H), 6.85 (d, J=7.5Hz, 1H), 5.68-5.71 (m, 1H), 4.21-4.26 (m, 2H), 4.09 (dd, J=5.7Hz, J=10.8Hz, 1H), 3.53 (s, 2H), 3.17-3.45 (m, 6H), 2.59 (s, 3H), 1.92-2.01 (m, 1H), 1.53-1.77 (m, 3H), 13c-NMR (75MHz, DMSO-d 6): δ/ppm=196.45,171.92,169.29,160.75,142.94,142.74,139.61,135.55,129.64 (2C), 128.63 (2C), 126.80,126.56,125.92,125.56,123.84,120.54,114.06,112.57,100.70,65.37,63.04,58.89,48.40,47.16,31.22,28.81,24.80,20.95.
Embodiment 12 prepares 3-ethanoyl-6-(N-phenylacetyl-isoleucyl) oxidation methyl-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (7f)
Under ice bath, in 100ml eggplant bottle, add 598mg (2.4mmol) N-phenylacetyl-Isoleucine, dissolve with anhydrous tetrahydro furan, add 324mg (2.4mmol) HOBt, add 494mg (2.4mmol) DCC, activate half an hour.616mg (2.0mmol) (6S)-3-ethanoyl-6-methylol-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (6) are dissolved in anhydrous tetrahydro furan, mixed solution is added in reaction flask.Adjust PH to 7-8 with NMM again, remove ice bath, lucifuge room temperature reaction 48 hours.Be evaporated to by reaction solution dry, with acetic acid ethyl dissolution, filter, filtrate washes three times with saturated sodium bicarbonate solution, then washes three times with saturated nacl aqueous solution, ester layer anhydrous sodium sulfate drying, filters, and filtrate reduced in volume is to dry.With thin-layer chromatography, (methylene dichloride: methyl alcohol=20: 1) purifying, then wear away with ether, obtain 202mg (18.7%) compound 7i, be yellow powder to resistates.Mp148-149 DEG C, [α] d 25=-33.1 (c=0.13, methyl alcohol), IR (KBr): 2967,2930,2716,1742,1657,1547,1337,1265,1192,1153,976,745cm -1, ESI-MS (m/e) 540 [M+H] +, 1h-NMR (300MHz, DMSO-d 6): δ/ppm=11.91 (s, 1H), 8.16-8.29 (m, 1H), 8.13 (d, J=7.8Hz, 1H), 7.58 (d, J=7.8Hz, 1H), 7.45 (d, J=8.1Hz, 1H), 7.16-7.31 (m, 6H), 7.10 (t, J=7.5Hz, 1H), 6.86 (d, J=7.8Hz, 1H), 5.67-5.71 (m, 1H), 4.25-4.31 (m, 2H), 3.97-4.02 (m, 1H), 3.57 (t, J=5.4Hz, 1H), 3.49 (d, J=5.7Hz, 2H), 3.36-3.44 (m, 1H), 3.17-3.26 (m, 1H), 2.59 (s, 3H), 1.56-1.62 (m, 1H), 1.00-1.20 (m, 2H), 0.75 (d, J=6.9Hz, 3H), 0.67 (t, J=7.2Hz, 3H), 13c-NMR (75MHz, DMSO-d 6): δ/ppm=196.43,171.92,171.02,170.88,160.73,142.86,142.65,139.61,136.82,136.76,129.39 (2C), 128.59 (2C), 126.72,125.95,125.52,123.94,120.51,113.76,112.62,100.69,63.41,55.31,48.21,42.17,36.54,31.18,26.04,21.01,15.34,11.74.
Embodiment 13 prepares 3-ethanoyl-6-(N-phenylacetyl-leucyl) oxidation methyl-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (7g)
Under ice bath, in 100ml eggplant bottle, add 598mg (2.4mmol) N-phenylacetyl-leucine, dissolve with anhydrous tetrahydro furan, add 324mg (2.4mmol) HOBt, add 494mg (2.4mmol) DCC, activate half an hour.616mg (2.0mmol) (6S)-3-ethanoyl-6-methylol-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (6) are dissolved in anhydrous tetrahydro furan, mixed solution is added in reaction flask.Adjust PH to 7-8 with NMM again, remove ice bath, lucifuge room temperature reaction 48 hours.Reaction solution is evaporated to dry, with acetic acid ethyl dissolution, filter, filtrate washes three times with saturated sodium bicarbonate solution, then washes three times with saturated nacl aqueous solution, ester layer anhydrous sodium sulfate drying, filter, filtrate reduced in volume as.With thin-layer chromatography, (methylene dichloride: methyl alcohol=20: 1) purifying, then wear away with ether, obtain 350mg (32.5%) compound 71, be yellow powder to resistates.Mp82-83 DEG C, [α] d 25=-133.0 (c=0.09, methyl alcohol), IR (KBr): 2957,2930,2870,1748,1653,1545,1499,1360,1331,1261,1148,968,744cm -1, ESI-MS (m/e) 540 [M+H] +, 1h-NMR (300MHz, DMSO-d 6): δ/ppm=11.90 (s, 1H), 8.39 (d, J=7.5Hz, 1H), 8.13 (d, J=7.8Hz, 1H), 7.58 (d, J=7.8Hz, 1H), 7.44 (d, J=8.1Hz, 1H), 7.16-7.31 (m, 6H), 7.10 (t, J=7.5Hz, 1H), 6.86 (d, J=7.8Hz, 1H), 5.69-5.76 (m, 1H), 4.28 (dd, J=6.6Hz, J=11.1Hz, 1H), 4.07-4.19 (m, 1H), 4.00 (dd, J=6.0Hz, J=11.1Hz, 1H), 3.43 (s, 2H), 3.14-3.26 (m, 2H), 2.59 (s, 3H), 1.39-1.52 (m, 2H), 1.15-1.22 (m, 1H), 0.81 (d, J=6.3Hz, 3H), 0.64 (d, J=6.3Hz, 3H), 13c-NMR (75MHz, DMSO-d 6): δ/ppm=196.42,172.65,172.51,170.72,160.80,142.91,142.78,142.62,139.58,136.61,129.38 (2C), 128.58 (2C), 126.76,126.62,125.83,123.89,120.51,113.96,112.69,100.70,63.51,50.70,48.17,42.26,31.36,24.54,23.21 (2C), 21.33.
Embodiment 14 prepares 3-ethanoyl-6-(N-phenylacetyl-methionyl) oxidation methyl-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (7h)
Under ice bath, in 100ml eggplant bottle, add 320mg (1.2mmol) N-phenylacetyl-methionine(Met), dissolve with anhydrous tetrahydro furan, add 162mg (1.2mmol) HOBt, add 247mg (1.2mmol) DCC, activate half an hour.308mg (1.0mmol) (6S)-3-ethanoyl-6-methylol-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (6) are dissolved in anhydrous tetrahydro furan, mixed solution is added in reaction flask.Adjust PH to 7-8 with NMM again, remove ice bath, lucifuge room temperature reaction 48 hours.Be evaporated to by reaction solution dry, with acetic acid ethyl dissolution, filter, filtrate washes three times with saturated sodium bicarbonate solution, then washes three times with saturated nacl aqueous solution, ester layer anhydrous sodium sulfate drying, filters, and filtrate reduced in volume is to dry.With thin-layer chromatography, (methylene dichloride: methyl alcohol=20: 1) purifying, then wear away with ether, obtain 163mg (30.0%) compound 7m, be yellow powder to resistates.Mp84-85 DEG C, [α] d 25=-29.3 (c=0.12, methyl alcohol), IR (KBr): 2957,2920,2855,1744,1668,1585,1541,1362,1335,1109,970,745cm -1, ESI-MS (m/e) 596 [M+K] +, 1h-NMR (300MHz, DMSO-d 6): δ/ppm=11.90 (s, 1H), 8.59 (d, J=7.5Hz, 1H), 8.14 (d, J=7.5Hz, 1H), 7.58 (d, J=8.1Hz, 1H), 7.45 (d, J=8.1Hz, 1H), 7.31-7.18 (m, 6H), 7.10 (t, J=7.5Hz, 1H), 6.85 (d, J=7.8Hz, 1H), 5.68-5.72 (m, 1H), 4.23-4.30 (m, 2H), 3.97-4.17 (m, 1H), 3.45 (s, 2H), 3.11-3.27 (m, 2H), 2.59 (s, 3H), 2.29-2.46 (m, 2H), 1.91 (s, 3H), 1.78 (q, J=7.2Hz, 2H), 13c-NMR (75MHz, DMSO-d 6): δ/ppm=196.44,171.27,170.85,170.82,160.80,142.94,142.57,139.63,136.48,136.44,129.47 (2C), 128.65 (2C), 126.85,126.59,125.93,123.93,120.53,113.71,112.67,100.83,63.16,51.72,49.91,48.22,42.33,38.50,31.28,20.81,15.62.
Embodiment 15 prepares 3-ethanoyl-6-(N-phenylacetyl-tryptophyl) oxidation methyl-4,6,7,12-tetrahydrochysene-4-Oxoindole 12,3-a] quinolizine (7i)
Under ice bath, in 100ml eggplant bottle, add 773mg (2.4mmol) N-phenylacetyl-tryptophane, dissolve with anhydrous tetrahydro furan, add 324mg (2.4mmol) HOBt, add 494mg (2.4mmol) DCC, activate half an hour.616mg (2.0mmol) (6S)-3-ethanoyl-6-methylol-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (6) are dissolved in anhydrous tetrahydro furan, mixed solution is added in reaction flask.Adjust PH to 7-8 with NMM again, remove ice bath, lucifuge room temperature reaction 48 hours.Be evaporated to by reaction solution dry, with acetic acid ethyl dissolution, filter, filtrate washes three times with saturated sodium bicarbonate solution, then washes three times with saturated nacl aqueous solution, ester layer anhydrous sodium sulfate drying, filters, and filtrate reduced in volume is to dry.With thin-layer chromatography, (methylene dichloride: methyl alcohol=20: 1) purifying, then wear away with ether, obtain 300mg (24.6%) compound 7i, be yellow powder to resistates.Mp86-87 DEG C; [α] d 25=-33.4 (c=0.10, methyl alcohol); IR (KBr): 2968,2903,1742,1655,1545,1427,1331,1280,745cm -1; ESI-MS (m/e) 613 [M+H] +; 1h-NMR (500MHz, DMSO-d 6): δ/ppm=11.93 (s, 1H), 10.87 (d, J=8.7Hz, 1H), 8.43 (d, J=7.3Hz, 1H), 8.15 (d, J=7.6Hz, 1H), 7.44-7.59 (m, 2H), 7.11-7.42 (m, 13H), 5.68-5.74 (m, 1H), 4.42-4.45 (m, 1H), 4.02-4.13 (m, 2H), 3.41-3.45 (m, 2H), 3.12-3.31 (m, 2H), 2.87-3.11 (m, 2H), 2.59 (s, 3H); 13c-NMR (75MHz, DMSO-d 6): δ/ppm=171.28,171.10,171.00,170.87,161.26,143.16,142.17,139.62,136.08,134.41,129.30 (2C), 128.81 (2C), 127.43,126.05,125.73,122.78,122.09,121.04,120.05,119.98,118.27,112.51,111.41,109.28,65.88,53.44,53.09,27.04,21.57,15.29.
Embodiment 16 evaluates 7a-i anti-tumour cell proliferative activity
First use S180 (mice sarcoma cell) and HL60 (human leukemia cell) screening.Then compound 7b is selected to be that representative investigates them to tumour cell A549 (human lung carcinoma cell), Bel-7402 (human liver cancer cell), the impact that HepG2 (human liver cancer cell), SW480 (human colon cancer cell) and HCT-8 (people's ileocecum adenocarcinoma cell) and non-tumor cell L02 (Human normal hepatocyte) breed.
Respectively by A549 that is good for growth conditions, that be in logarithmic phase, Bel-7402, HCT-8, L02, HepG2, SW480, HL60 and S180 cell is according to 5 × 10 4the density of individual/mL is inoculated in 96 orifice plates, every hole 100 μ l.At 37 DEG C, 5%CO 2cultivate 24 hours in incubator, add the compound 7a-i of the present invention through sterilising treatment by the concentration gradient 100,50,25,10 and 5 μMs preset, control group adds the solvent of equal-volume sample dissolution.Continue cultivation after 48 hours, every hole adds the MTT solution that 25 μ l concentration are 5mg/mL, be placed in 37 DEG C and hatch 4 hours, careful removing supernatant liquor (suspension cell removes supernatant liquor after centrifugal) afterwards every hole adds 100 μ lDMSO (dimethyl sulfoxide (DMSO)), vibrate about 15 minutes, dissolution precipitation.OD value (absorbancy) is measured under 570nm wavelength immediately in microplate reader.Calculate tumour inhibiting rate and IC 50.Result lists table 1 and table 2 in.Table 1 illustrates, in compound 7a-i of the present invention, majority of compounds has stronger restraining effect to S180 and HL60 cell proliferation.So select active good 7c to evaluate with tumour cell A549, Bel7402, HepG2 and HCT-8 and non-tumor cell L02 further.Table 2 illustrates, 7b has obvious restraining effect to tumour cell A549, Bel7402, HepG2 and HCT-8 propagation, and affects very little on non-tumor cell L02.
Activity (the IC of table 17a-i inhibition tumor cell S180 and HL60 propagation 50± SD μM)
Activity (the IC of table 27c inhibition tumor cell and non-tumor cell propagation 50± SD μM)
Embodiment 17 evaluates the anti-tumor activity of 7a-i
Before measuring, compound of the present invention is added tween 80 hydrotropy, be dissolved in physiological saline.Get under aseptic condition and be inoculated in the ICR mouse S180 sarcoma of 7-10 days, add appropriate normal saline tumor cells suspension, cell count is 2 × 10 7/ mL, is inoculated in healthy male ICR mouse forelimb armpit subcutaneous, every injected in mice 0.2ml.After tumor inoculation 24h, the aqueous solution for the treatment of group mouse abdominal injection every day 0.2ml the compounds of this invention, successive administration 7 days, dosage is 0.1 μm of ol/kg.Naive mice abdominal injection every day 0.2ml physiological saline.Positive control is made with Zorubicin (dosage is 2 μm of ol/kg).Experiment proceeds to the 8th day, claim Mouse Weight, and the tumour taking each group of mouse is weighed, and finally adds up the tumour inhibiting rate of each treated animal.The curative effect of solid tumor represents with the heavy inhibition percentage of knurl, is calculated as follows: tumor-like hyperplasia %=(1-administration group knurl heavy/blank group knurl weight) × 100%.Result lists table 3 in.Dosage is under 0.1 μm of ol/kg, and the anti-tumor in vivo of compound 7a-i (except 7g) is active all variant compared with physiological saline.Wherein compound 7b, 7c, 7d, 7 (anti-tumor activity and Zorubicins suitable (p > 0.05).The activity of compound 7c is the strongest, and tumour inhibiting rate is 51.77%.
Table 3 compound 6 and 7a-i affect result to S180 tumor weight
N=12.a) with physiological saline and compound 6 than p < 0.01, with Zorubicin than p > 0.05; B) with physiological saline than p < 0.01, with compound 6 than p > 0.05; C) with physiological saline than p < 0.05.
Embodiment 18 evaluates the impact of dosage on anti-tumor activity of 7c
According to the method for embodiment 16, measure 0.01 μm of ol/kg, 0.1 μm of ol/kg, under 1 μm of ol/kg and 10 μm ol/kg, tetra-kinds of dosage, the anti-tumor activity of 7c, the results are shown in Table 4.The data of table 4 show, at 0.1 μm of ol/kg, under 1 μm of ol/kg and 10 μm of ol/kg dosage, 7c has obvious anti-tumor activity.Under the dosage of 0.01 μm of ol/kg, 7c no longer shows anti-tumor activity.Under four kinds of dosage, the activity of 7c shows obvious dependence.
Table 4 various dose 7c rings the scape of S180 tumor weight
N=12.a) p < 0.01 compared with physiological saline group; B) with 0.1 μm of ol/kg7c than p < 0.05; C) with 0.1pmol/kg and l μm of ol/kg7c than p < 0.01.
Embodiment 19 evaluates the impact of 7c on tumour cell cycle
Single cell suspension is made in human lung cancer cell A549's digestion, be inoculated in 6 orifice plates equably, move into overnight incubation in incubator adherent after, if negative control physiological saline group, positive control Zorubicin group (final concentration 0.51 μM) and 7c group (final concentration 25 μMs).After hatching 24 hours, use collected by trypsinisation cell, centrifugally remove supernatant, the ice-cold PBS of cell 1ml resuspended for cell one-tenth single cell suspension, and is transferred in 1.5ml centrifuge tube, centrifugal careful absorption supernatant.The ethanol (70%) that cell 1ml is ice-cold blows even fast, avoids the formation of cell mass.Cell is in 4 DEG C of fixing 2h, and centrifugal collecting cell, carefully absorbs supernatant, and add the PBS re-suspended cell that 1ml is ice-cold, recentrifuge collecting cell, carefully absorbs supernatant.Add 0.5ml propidium iodide (PI) staining fluid toward the cell retained, make cell resuspended and precipitate, 37 DEG C of lucifuge temperature are bathed 30 minutes.Flow cytometer (EPICSXL, Beckman Ku Erte) at 488nm wavelength detecting, result Wincycle software analysis.Every part of sample detection 10,000 cells.The results are shown in Table 4.Result shows, the G1/G0 phase cells ratio that 25 μMs of 7c act on 24 hours A549 cells is 87.64%, apparently higher than 66.64% of physiological saline effect 24 hours A549 cells, and S phase and G2/M phase cells ratio are all starkly lower than the ratio of physiological saline effect 24 hours A549 cells.The G2/M phase cells ratio of positive control Zorubicin effect 24 hours A549 cells is 29.73%, apparently higher than 6.70% of physiological saline effect 24 hours A549 cells, the G2/M phase cells ratio acting on 24 hours A549 cells with 7c only has compared with in the of 3.98%, then higher.Visible, the impact of 7c on the A549 cell cycle blocks G1 phase cell to the transition of G0 phase cell, and the impact of Zorubicin on the A549 cell cycle blocks G2 phase cell to the transition of M phase cell.Resembling 7c makes G1 phase cell can not enter the medicine of G0 phase at present also beyond example like this.
Table 47c acts on the period ratio of the A549 cell of 24 hours

Claims (4)

1. the compound 7a-i of represented by formula,
In 7a, AA is L-alanyl, and in 7b, AA is that L-is valyl, and in 7c, AA is L-phenylalanyl; in 7d, AA is glycyl, and in 7e, AA is L-prolyl, and in 7f, AA is L-isoleucyl; in 7g, AA is L-leucyl, and in 7h, AA is L-methionyl, and in 7i, AA is L-tryptophyl.
2. prepare the method for the compound 7a-i of claim 1, the method comprises prepares four key intermediates by five committed steps:
1) 1-(2,2-dimethoxy ethyl)-3-methylol-1,2,3,4-Tetrahydrocarboline (3) is prepared;
2) 1-(2,2-dimethoxy ethyl)-2-(1,3-dicarbapentaborane butyl)-3-(1,3-dicarbapentaborane butyl) oxidation methyl-1,2,3,4-Tetrahydrocarboline (4) is prepared;
3) 3-ethanoyl-6-(1,3-dicarbapentaborane butyl) oxidation methyl-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (5) is prepared;
4) 3-ethanoyl-6-methylol-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (6) is prepared;
5) phenylacetylamino acid is introduced toward 3-ethanoyl-6-methylol-4,6,7,12-tetrahydrochysene-4-Oxoindole [2,3-a] quinolizine (6).
3. the compound 7a-i of claim 1 is in the application preparing the agent of G1/G0 cell block.
4. the compound 7a-i of claim 1 is in the application preparing anti-tumor disease medicine.
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