CN105198884B - Pentacyclic indole quinolizine that the G1/G0 phases block, its synthesis, antitumor activity and application - Google Patents
Pentacyclic indole quinolizine that the G1/G0 phases block, its synthesis, antitumor activity and application Download PDFInfo
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- CN105198884B CN105198884B CN201410272991.9A CN201410272991A CN105198884B CN 105198884 B CN105198884 B CN 105198884B CN 201410272991 A CN201410272991 A CN 201410272991A CN 105198884 B CN105198884 B CN 105198884B
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Abstract
The Pentacyclic indole quinolizine blocked the invention discloses the G1/G0 phases; that is (6S) 3 acetyl group 6 (N phenylacetylaminos acyl group) oxidation methyl 4; 6; 7; the Oxoindole of 12 tetrahydrochysene 4 [2,3 a] quinolizine, discloses their synthesis; their antiproliferation is disclosed, antitumor activity and application is further disclosed.
Description
Invention field
The Pentacyclic indole quinolizine blocked the present invention relates to the G1/G0 phases, i.e. (6S) -3- acetyl group -6- (N- phenylacetylamino acyls
Base)-oxidation methyl -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolizines are related to their synthesis, are related to the anti-of them
Cell-proliferation activity, further to their antitumor activities on mice transplanted tumor model.Thus the present invention relates to
(6S) -3- acetyl group -6- (N- phenylacetylaminos acyl group) oxidation methyl -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolines
Piperazine as G1/G0 phase retarding agents potential applicability in clinical practice.The invention belongs to biomedicine field.
Background technology
Cell produces neoblast instead of because aging, the cell that dead and trauma loses, is body growth by breeding
Development and continuity race provide basis.The process of cell propagation is referred to as the cell cycle.Or the cell cycle refers to cell from once dividing
Split end and start growth, undergone process is terminated to division next time.It is divided into a phase and division stage two cell generation cycle
Period.
Phase between entering after cell division, complete the complicated change of structure and biosynthesis.Between the phase be divided into again DNA synthesis before
Phase (G1 phases), DNA synthesis phase (S phases) and DNA post-synthesis phases (G2 phases) three are by stages.G1 phases cell can be divided into rests on G1 forever
Phase is not until dead, temporary transient breed and continue to breed three types.The cell do not bred temporarily is also known as Go phase cells.S is thin initial stage
Intracellular quickly forms archaeal dna polymerase and four kinds of deoxynucleotides.S end of term nucleus DNAs copy as cell division and prepared.The S phases
Last about 7~8 hours greatly.G2 phases cell synthesizes RNA and protein such as histone, tubulin and memebrane protein, is spindle
Body and neoblast film etc. prepare enough raw material, to enter m period.The G2 phases last about 1~1.5 hour greatly.Mitosis is also known as
The M phases.The M phases are the continuous process constituted in early stage, mid-term, later stage and latter stage, complete careful as two by a mother cell division
The task of born of the same parents.Typically need 1~2 hour.
Tumour cell belongs to the G1 phase cells of continuous proliferation, and the cell cycle is the important target spot of antineoplastic.Act on
The chemotherapeutics of tumor cell is also known as CCSA.Although the chemotherapeutics of some clinical practices, for example
5-fluor-uracil, furan fluorouracil, adriamycin, mitomycin C and cytarabine, influence the cell cycle, but lack specificity.
By being, tumour cell cycle inhibitor turns into the key areas that antineoplastic is studied.Especially invention can allow tumour cell
The chemotherapeutics of G1 phases, i.e. G1/G0 phase retarding agents are rested on forever, are the important directions of antineoplastic design.But, so far
There is no the successful case of G1/G0 phase retarding agents.According to these understandings, Pentacyclic indole quinolizine is inventors herein proposed, i.e. (6S) -3- second
Acyl group -6- (N- phenylacetylaminos acyl group)-oxidation methyl -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolizines, as
The invention that the G1/G0 phases block.
The content of the invention
The compound 7a-i that the following formula of the present invention is represented,
AA is L- alanyls in 7a, and AA is that AA is that AA is sweet in L- phenylalanyls, 7d in L- valyl bases, 7c in 7b
AA is L- prolyls in aminoacyl, 7e, and AA is that AA is that AA is L- in L- leucyl-s, 7h in L- isoleucyl-s, 7g in 7f
AA is L- tryptophanyls in methinyl base, 7i.
Second content of the present invention is to prepare (6S) -3- acetyl group -6- (N- phenylacetylamino acyls according to Fig. 1 route
Base) oxidation methyl -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolizines (7a-i), including：
1) 1- (2,2- dimethoxy ethyl) -3- methylols -1,2,3,4- Tetrahydrocarbolines (3) are prepared；
2) (6S) -3- acetyl group -6- methylols -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolizines (6) are prepared；
3) (6S) -3- acetyl group -6- (N- phenylacetylaminos acyl group) oxidation methyl -4,6,7,12- tetrahydrochysene -4- oxidations are prepared
Indoles [2,3-a] quinolizine (7a-i).AA is L- alanyls in 7a, and AA is that AA is L- phenylpropyl alcohol ammonia in L- valyl bases, 7c in 7b
AA is glycyl in acyl group, 7d, and AA is that AA is that AA is the bright ammonia of L- in L- isoleucyl-s, 7g in L- prolyls, 7f in 7e
AA is L- methinyl bases in acyl group, 7h, and AA is L- tryptophanyls in 7i.
The 3rd content of the present invention is to evaluate (6S) -3- acetyl group -6- (N- phenylacetylaminos acyl group) oxidation methyl -4,
The antiproliferation of 6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolizines (7a-i).
The 4th content of the present invention is to evaluate (6S) -3- acetyl group -6- (N- phenylacetylaminos acyl group) oxidation methyl -4,
The antitumor activity of 6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolizines (7a-i).
The 5th content of the present invention is that the influence of cell cycle is investigated using one of compound as representative.
Brief description of the drawings
Fig. 1 (6S) -3- acetyl group -6- (N- phenylacetylaminos acyl group) oxidation methyl -4,6,7,12- tetrahydrochysene -4- oxidations Yin
Synthetic route (i) thionyl chlorides/methanol of diindyl [2,3-a] quinolizine (7a-i)；(ii) 1,1,3,3- tetramethoxy propane, trifluoro
Acetic acid/methanol；(iii)LiAlH4, THF；(iv) ketene dimer, triethylamine/acetone；(v) 2N HCl/ acetone；(vi)K2CO3/ first
Alcohol；(vii) N- phenylacetylaminos acid, DCC/HOBt, NMM, THF.AA is L- alanyls in 7a, and AA is L- valyls in 7b
AA is L- phenylalanyls in base, 7c, and AA is that AA is that AA is the different bright ammonia of L- in L- prolyls, 7f in glycyl, 7e in 7d
AA is L- leucyl-s in acyl group, 7g, and AA is that AA is L- tryptophanyls in L- methinyl bases, 7i in 7h.
Embodiment
In order to which the present invention is expanded on further, a series of embodiments are given below.These embodiments be entirely it is illustrative, it
Only be used for the present invention is specifically described, be not construed as limitation of the present invention.
Embodiment 1 prepares L-Trp methyl ester hydrochloride (1)
50ml absolute methanols are added dropwise in 3.75ml (50mmol) thionyl chloride, 30min after completion of dropping, in batches under ice bath
9.20g (42mmol) L-Trp is added, 24h, TLC (CHCl is stirred at room temperature3: MeOH=2: 3) monitoring disappears to raw material and terminated
Reaction.Water pump takes the complete thionyl chloride SOCl of unreacted away2And HCl, grind to obtain white solid, methanol-diethyl ether repeatedly with ether
Recrystallization, obtains L-Trp methyl ester hydrochloride for colorless solid.Yield is between 85-99%.ESI-MS(m/e)219[M+H]+,
The physical constants such as fusing point, optically-active are consistent with the data reported.
Embodiment 2 prepares 1- (2,2- dimethoxy ethyl) -2,3,4,9- tetrahydro-beta-carboline carboxylate methyl ester (2)
L-Trp methyl ester hydrochloride 20g (78.6mmol) is added in 250ml round-bottomed flask, 100ml methanol is added
Trifluoroacetic acid 20ml, activates half an hour, adds 1,1,3,3- tetramethoxy propane 16ml (97.6mmol), be warming up under stirring
80 DEG C, insulation reaction 10 hours, TLC monitoring raw material spots are disappeared, and reaction solution is cooled into room temperature, saturation NaHCO is added dropwise3It is water-soluble
Liquid adjusts pH to neutrality, and water layer after addition 100ml dichloromethane in methanol, residue, point liquid is recovered under reduced pressure and is extracted with dichloromethane
Take (50ml × 3), merge organic layer, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to dryness, residue silica gel column layer
Analysis (petroleum ether: acetone=2: 1) purifies to obtain 14.2g (57%) compound 2, is yellow oil.ESI-MS(m/e)319[M+H
]+。
Embodiment 3 prepares 1- (2,2- dimethoxy ethyl) -3- methylols -1,2,3,4- Tetrahydrocarbolines (3)
50ml anhydrous tetrahydro furans are added in 250ml round-bottomed flask, LiAlH is added portionwise under stirring40.9g
(23.6mmol), activates half an hour.5g (15.7mmol) compound (2) is dissolved in 50ml anhydrous tetrahydro furans, then delayed
It is slow to instill in reaction bulb, 40 DEG C are warming up to, insulation reaction 3 hours, TLC monitoring raw material spots disappear.Reaction solution is cooled to room
Temperature, adds the 0.5ml15% NaOH aqueous solution, and reaction of finally going out is filtered to remove aluminium salt, filtrate decompression is concentrated into Bush's funnel
It is dry, ethyl acetate is added, ether, which is worn away, obtains mesh 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- Tetrahydrocarbolines (4)
1.0g (3.8mmol) compound (3) is added in 100ml round-bottomed flask, 20ml acetone stirring and dissolvings are added,
Ketene dimer 1ml (11.9mmol), triethylamine 0.4ml are added under ice bath.Reaction solution is stirred at room temperature 24 hours, and TLC monitorings are former
Expect that spot disappears, add 0.2ml water soldier and go out unreacted ketene dimer, solvent is recovered under reduced pressure.50ml dichloros are added in residue
Water layer is extracted (30ml × 3) with dichloromethane after methane and the 50ml saturation NaCl aqueous solution, point liquid, merges organic layer, anhydrous sulphur
Sour sodium is dried, and filtering, filtrate decompression is concentrated to dryness, and residue (petroleum ether: acetone=6: 1) is purified with silica gel column chromatography
1.32g (76%) compound 4, is yellow powder.ESI-MS(m/e)459[M+H]+。
Embodiment 5 prepares 3- acetyl group -6- (1,3- dicarbapentaborane butyl) oxidation methyl -4,6,7,12- tetrahydrochysene -4- oxidations
Indoles [2,3-a] quinolizine (5)
1.98g (4.3mmol) compound (4) is added in 100ml round-bottomed flask, 50ml acetone stirring and dissolvings are added,
3ml aqueous hydrochloric acid solutions (2mol/L) are added under ice bath, are reacted at room temperature 12 hours.TLC monitoring raw material spots disappear, and add saturation
NaHCO3The aqueous solution adjusts pH to neutrality, and water layer after addition 50ml dichloromethane in solvent, residue, point liquid is recovered under reduced pressure and uses two
Chloromethanes extracts (30ml × 3), merges organic layer, and anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to dryness, and residue is used
Silica gel column chromatography (petroleum ether: acetone=6: 1) purifies to obtain 1.26g (75%) compound 5, is yellow powder.ESI-MS(m/e)
393[M+H]+。
Embodiment 6 prepares (6S) -3- acetyl group -6- methylols -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolines
Piperazine (6)
1.06g (2.7mmol) compound (5) is added in 100ml round-bottomed flask, 20ml methanol stirring and dissolvings are added,
745mg (5.4mol/L) potassium carbonate powder is added, reacts at room temperature 8 hours, there is solid generation.TLC monitoring raw material spots disappear,
Filtering, filter cake is washed with methanol, obtains yellow powder 338mg, i.e. target compound (6).Filtrate decompression is concentrated to dryness, and adds acetone
Dissolving, filter desalination, filtrate with silica gel column chromatography (dichloromethane: methanol=40: 1) purify to obtain 709mg (85%) compound 6,
For yellow powder.Mp：210-211℃；[α]D 25=-42.7 (c=0.10, methanol)；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-d6)：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-d6)：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- acetyl group -6- (N- phenylacetyls alanyl) oxidation methyl -4,6,7,12- tetrahydrochysene -4- oxygen
Change indoles [2,3-a] quinolizine (7a)
Under ice bath, 248mg (1.2mmol) N- phenylacetyl alanine is added in 100ml eggplants bottle, it is molten with anhydrous tetrahydro furan
Solution, adds 162mg (1.2mmol) HOBt, adds 247mg (1.2mmol) DCC, activates half an hour.By 308mg (1mmol)
(6S) -3- acetyl group -6- methylols -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolizines (6) are dissolved in anhydrous tetrahydro furan
In, mixed liquor is added in reaction bulb.PH is adjusted to 7-8 with NMM again, ice bath is removed, and lucifuge is reacted at room temperature 48 hours.By reaction solution
It is concentrated under reduced pressure into dry, is dissolved with ethyl acetate, is filtered, filtrate is washed three times with saturated sodium bicarbonate solution, then uses saturated sodium-chloride
Solution is washed three times, ester layer anhydrous sodium sulfate drying, and filtering, filtrate decompression is concentrated to dryness.Residue thin-layer chromatography (dichloromethane
Alkane: methanol=20: 1) purify, then worn away with ether, obtain 157mg (31.6%) compound 7a, be yellow powder.Mp95-96℃；
[α]D 25=-27.3 (c=0.14, methanol)；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-d6)：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-d6)：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- acetyl group -6- (N- phenylacetyl valyls base) oxidation methyl -4,6,7,12- tetrahydrochysene -4- oxygen
Change indoles [2,3-a] quinolizine (7b)
Under ice bath, 423mg (1.8mmol) N- phenylacetyl valines are added in 100ml eggplants bottle, it is molten with anhydrous tetrahydro furan
Solution, adds 243mg (1.8mmol) HOBt, adds 371mg (1.8mmol) DCC, activates half an hour.By 462mg (1.5mmol)
(6S) -3- acetyl group -6- methylols -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolizines (6) are dissolved in anhydrous tetrahydro furan
In, mixed liquor is added in reaction bulb.PH is adjusted to 7-8 with NMM again, ice bath is removed, and lucifuge is reacted at room temperature 48 hours.By reaction solution
It is concentrated under reduced pressure into dry, is dissolved with ethyl acetate, is filtered, filtrate is washed three times with saturated sodium bicarbonate solution, then uses saturated sodium-chloride
Solution is washed three times, ester layer anhydrous sodium sulfate drying, and filtering, filtrate decompression is concentrated to dryness.Residue thin-layer chromatography (dichloromethane
Alkane: methanol=20: 1) purify, then worn away with ether, obtain 226mg (28.7%) compound 7b, be yellow powder.Mp109-110
℃；[α]D 25=-38.0 (c=0.11, methanol)；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-d6)：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-d6)：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- acetyl group -6- (N- phenylacetyls-phenylalanyl) oxidation methyl -4,6,7,12- tetrahydrochysene -4-
Oxoindole [2,3-a] quinolizine (7c)
Under ice bath, 679mg (2.4mmol) N- phenylacetyls-phenylalanine is added in 100ml eggplants bottle, with anhydrous tetrahydrochysene furan
Mutter dissolving, add 324mg (2.4mmol) HOBt, add 494mg (2.4mmol) DCC, activate half an hour.By 616mg
(2.0mmol) (6S) -3- acetyl group -6- methylols -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolizines (6) are dissolved in nothing
In water tetrahydrofuran, mixed liquor is added in reaction bulb.PH is adjusted to 7-8 with NMM again, ice bath is removed, and lucifuge room temperature reaction 48 is small
When.Reaction solution is concentrated under reduced pressure into dry, dissolved with ethyl acetate, filtered, filtrate is washed three times with saturated sodium bicarbonate solution, then is used
Saturated nacl aqueous solution is washed three times, ester layer anhydrous sodium sulfate drying, and filtering, filtrate decompression is concentrated to dryness.Residue thin layer
Chromatography (dichloromethane: methanol=20: 1) is purified, then worn away with ether, obtain 137mg (12.0%) compound 7c, be yellow powder
End.Mp73-74℃；[α]D 25=-57.2 (c=0.10, methanol)；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-
d6)：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-d6)：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- acetyl group -6- (N- phenylacetyls-glycyl) oxidation methyl -4,6,7,12- tetrahydrochysene -4-
Oxoindole [2,3-a] quinolizine (7d)
Under ice bath, 232mg (1.2mmol) N- phenylacetyls-glycine is added in 100ml eggplants bottle, anhydrous tetrahydro furan is used
Dissolving, adds 162mg (1.2mmol) HOBt, adds 247mg (1.2mmol) DCC, activates half an hour.By 308mg (1.0mmol)
(6S) -3- acetyl group -6- methylols -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolizines (6) are dissolved in anhydrous tetrahydro furan
In, mixed liquor is added in reaction bulb.PH is adjusted to 7-8 with NMM again, ice bath is removed, and lucifuge is reacted at room temperature 48 hours.By reaction solution
It is concentrated under reduced pressure into dry, is dissolved with ethyl acetate, is filtered, filtrate is washed three times with saturated sodium bicarbonate solution, then uses saturated sodium-chloride
Solution is washed three times, ester layer anhydrous sodium sulfate drying, and filtering, filtrate decompression is concentrated to dryness.Residue thin-layer chromatography (dichloromethane
Alkane: methanol=20: 1) purify, then worn away with ether, obtain 173mg (35.8%) compound 7d, be yellow powder.Mp84-85℃；
[α]D 25=-29.4 (c=0.11, methanol)；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-d6)：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-d6)：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- acetyl group -6- (N- phenylacetyls-prolyl) oxidation methyl -4,6,7,12- tetrahydrochysene -4-
Oxoindole [2,3-a] quinolizine (7e)
Under ice bath, 559mg (2.4mmol) N- phenylacetyls-proline is added in 100ml eggplants bottle, anhydrous tetrahydro furan is used
Dissolving, adds 324mg (2.4mmol) HOBt, adds 494mg (2.4mmol) DCC, activates half an hour.By 616mg (2.0mmol)
(6S) -3- acetyl group -6- methylols -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolizines (6) are dissolved in anhydrous tetrahydro furan
In, mixed liquor is added in reaction bulb.PH is adjusted to 7-8 with NMM again, ice bath is removed, and lucifuge is reacted at room temperature 48 hours.By reaction solution
It is concentrated under reduced pressure into dry, is dissolved with ethyl acetate, is filtered, filtrate is washed three times with saturated sodium bicarbonate solution, then uses saturated sodium-chloride
Solution is washed three times, ester layer anhydrous sodium sulfate drying, and filtering, filtrate decompression is concentrated to dryness.Residue thin-layer chromatography (dichloromethane
Alkane: methanol=20: 1) purify, then worn away with ether, obtain 450mg (43.0%) compound 7e, be yellow powder.Mp101-102
℃；[α]D 25=-68.0 (c=0.09, methanol)；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-d6)：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-d6)：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.
Preparation 3- acetyl group -6- (N- phenylacetyls-isoleucyl-) oxidation methyl -4,6 of embodiment 12,7,12- tetrahydrochysenes -
4- Oxoindoles [2,3-a] quinolizine (7f)
Under ice bath, 598mg (2.4mmol) N- phenylacetyls-isoleucine is added in 100ml eggplants bottle, with anhydrous tetrahydrochysene furan
Mutter dissolving, add 324mg (2.4mmol) HOBt, add 494mg (2.4mmol) DCC, activate half an hour.By 616mg
(2.0mmol) (6S) -3- acetyl group -6- methylols -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolizines (6) are dissolved in nothing
In water tetrahydrofuran, mixed liquor is added in reaction bulb.PH is adjusted to 7-8 with NMM again, ice bath is removed, and lucifuge room temperature reaction 48 is small
When.Reaction solution is concentrated under reduced pressure into dry, dissolved with ethyl acetate, filtered, filtrate is washed three times with saturated sodium bicarbonate solution, then is used
Saturated nacl aqueous solution is washed three times, ester layer anhydrous sodium sulfate drying, and filtering, filtrate decompression is concentrated to dryness.Residue thin layer
Chromatography (dichloromethane: methanol=20: 1) is purified, then worn away with ether, obtain 202mg (18.7%) compound 7i, be yellow powder
End.Mp148-149℃；[α]D 25=-33.1 (c=0.13, methanol)；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-
d6)：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-
d6)：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- acetyl group -6- (N- phenylacetyls-leucyl-) oxidation methyl -4,6,7,12- tetrahydrochysene -4-
Oxoindole [2,3-a] quinolizine (7g)
Under ice bath, 598mg (2.4mmol) N- phenylacetyls-leucine is added in 100ml eggplants bottle, anhydrous tetrahydro furan is used
Dissolving, adds 324mg (2.4mmol) HOBt, adds 494mg (2.4mmol) DCC, activates half an hour.By 616mg (2.0mmol)
(6S) -3- acetyl group -6- methylols -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolizines (6) are dissolved in anhydrous tetrahydro furan
In, mixed liquor is added in reaction bulb.PH is adjusted to 7-8 with NMM again, ice bath is removed, and lucifuge is reacted at room temperature 48 hours.By reaction solution
It is concentrated under reduced pressure into dry, is dissolved with ethyl acetate, is filtered, filtrate is washed three times with saturated sodium bicarbonate solution, then uses saturated sodium-chloride
Solution is washed three times, ester layer anhydrous sodium sulfate drying, filtering, filtrate decompression concentration as.Residue thin-layer chromatography (dichloromethane
Alkane: methanol=20: 1) purify, then worn away with ether, obtain 350mg (32.5%) compound 71, be yellow powder.Mp82-83℃；
[α]D 25=-133.0 (c=0.09, methanol)；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-d6)：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-d6)：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- acetyl group -6- (N- phenylacetyls-methinyl base) oxidation methyl -4,6,7,12- tetrahydrochysene -4-
Oxoindole [2,3-a] quinolizine (7h)
Under ice bath, 320mg (1.2mmol) N- phenylacetyls-methionine is added in 100ml eggplants bottle, anhydrous tetrahydro furan is used
Dissolving, adds 162mg (1.2mmol) HOBt, adds 247mg (1.2mmol) DCC, activates half an hour.By 308mg (1.0mmol)
(6S) -3- acetyl group -6- methylols -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolizines (6) are dissolved in anhydrous tetrahydro furan
In, mixed liquor is added in reaction bulb.PH is adjusted to 7-8 with NMM again, ice bath is removed, and lucifuge is reacted at room temperature 48 hours.By reaction solution
It is concentrated under reduced pressure into dry, is dissolved with ethyl acetate, is filtered, filtrate is washed three times with saturated sodium bicarbonate solution, then uses saturated sodium-chloride
Solution is washed three times, ester layer anhydrous sodium sulfate drying, and filtering, filtrate decompression is concentrated to dryness.Residue thin-layer chromatography (dichloromethane
Alkane: methanol=20: 1) purify, then worn away with ether, obtain 163mg (30.0%) compound 7m, be yellow powder.Mp84-85℃；
[α]D 25=-29.3 (c=0.12, methanol)；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-d6)：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-d6)：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- acetyl group -6- (N- phenylacetyls-tryptophanyl) oxidation methyl -4,6,7,12- tetrahydrochysene -4-
Oxoindole 12,3-a] quinolizine (7i)
Under ice bath, 773mg (2.4mmol) N- phenylacetyls-tryptophan is added in 100ml eggplants bottle, anhydrous tetrahydro furan is used
Dissolving, adds 324mg (2.4mmol) HOBt, adds 494mg (2.4mmol) DCC, activates half an hour.By 616mg (2.0mmol)
(6S) -3- acetyl group -6- methylols -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolizines (6) are dissolved in anhydrous tetrahydro furan
In, mixed liquor is added in reaction bulb.PH is adjusted to 7-8 with NMM again, ice bath is removed, and lucifuge is reacted at room temperature 48 hours.By reaction solution
It is concentrated under reduced pressure into dry, is dissolved with ethyl acetate, is filtered, filtrate is washed three times with saturated sodium bicarbonate solution, then uses saturated sodium-chloride
Solution is washed three times, ester layer anhydrous sodium sulfate drying, and filtering, filtrate decompression is concentrated to dryness.Residue thin-layer chromatography (dichloromethane
Alkane: methanol=20: 1) purify, then worn away with ether, obtain 300mg (24.6%) compound 7i, be yellow powder.Mp86-87℃；
[α]D 25=-33.4 (c=0.10, methanol)；IR(KBr)：2968,2903,1742,1655,1545,1427,1331,1280,
745cm-1；ESI-MS(m/e)613[M+H]+；1H-NMR (500MHz, DMSO-d6)：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-d6)：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 activities
First screened with S180 (mice sarcoma cell) and HL60 (human leukemia cell).Then selection compound 7b is representative
Them are investigated to tumour cell A549 (human lung carcinoma cell), Bel-7402 (human liver cancer cell), 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) propagation
Influence.
Respectively by growth conditions are good, A549, Bel-7402, HCT-8, L02, HepG2 in exponential phase,
SW480, HL60 and S180 cell are according to 5 × 104Individual/mL density is inoculated in 96 orifice plates, per the μ l of hole 100.In 37 DEG C, 5%CO2
Cultivated 24 hours in incubator, the of the invention of sterilized processing is added by default 100,50,25,10 and 5 μM of concentration gradient
Compound 7a-i, control group adds the solvent of isometric sample dissolution.Continue after cultivating 48 hours, add the 25 μ l concentration to be per hole
5mg/mL MTT solution, is placed in 37 DEG C and is incubated 4 hours, carefully remove supernatant (suspension cell removes supernatant after centrifugation)
100 μ l DMSO (dimethyl sulfoxide (DMSO)) are added per hole afterwards, are vibrated about 15 minutes, dissolving precipitation.Immediately in 570nm ripples on ELIASA
Long lower measure OD values (absorbance).Calculate tumour inhibiting rate and IC50.As a result it is included in Tables 1 and 2.Table 1 illustrates, compound of the invention
Majority of compounds has stronger inhibitory action to S180 and HL60 cells propagation in 7a-i.Then the 7c for selecting activity good enters one
Step is evaluated with tumour cell A549, Bel7402, HepG2 and HCT-8 and non-tumor cell L02.Table 2 illustrates that 7b is to tumour cell
A549, Bel7402, HepG2 and HCT-8 propagation have obvious inhibitory action, and influence very little to non-tumor cell L02.
The 7a-i of table 1 suppresses the activity (IC of tumour cell S180 and HL60 propagation50±SDμM)
The 7c of table 2 suppresses the activity (IC of tumour cell and non-tumor cell propagation50±SDμM)
Embodiment 17 evaluates 7a-i antitumor activity
The compound of the present invention is added into Tween 80 hydrotropy before determining, physiological saline is dissolved in.Taken under aseptic condition and be inoculated in ICR
The mouse S180 sarcomas of 7-10 days, add appropriate normal saline tumor cells suspension, and cell number is 2 × 107/ mL, inoculation
Subcutaneous in healthy male ICR mouse forelimb armpit, every mouse injects 0.2ml.After tumor inoculation 24h, the daily abdomen for the treatment of group mouse
Chamber injects the aqueous solution of 0.2ml the compounds of this invention, successive administration 7 days, and dosage is 0.1 μm of ol/kg.The daily abdomen of naive mice
Chamber injects 0.2ml physiological saline.Positive control is made using adriamycin (dosage is 2 μm of ol/kg).Experiment was carried out to the 8th day, claimed mouse
Body weight, and take the tumour of each group mouse and weigh, finally count the tumour inhibiting rate of each group animal.The curative effect of solid tumor is suppressed with knurl weight
Percentage is represented, is calculated as follows：Tumor-like hyperplasia %=(1- administration groups knurl weight/blank group knurl weight) × 100%.As a result it is included in table
3.Dosage is under 0.1 μm of ol/kg, and compound 7a-i (except 7g) internal antitumor activity has compared with physiological saline
Difference.(antitumor activity is suitable with adriamycin (p ＞ 0.05) by wherein compound 7b, 7c, 7d, 7.Compound 7c activity is most
By force, tumour inhibiting rate is 51.77%.
The influence result of the compound 6 of table 3 and 7a-i to S180 tumor weights
N=12.a) with physiological saline and compound 6 than p ＜ 0.01, with adriamycin than p ＞ 0.05；B) with physiological saline ratio
P ＜ 0.01, with compound 6 than p ＞ 0.05；C) with physiological saline than p ＜ 0.05.
Embodiment 18 evaluates influence of the 7c dosage to antitumor activity
According to the method for embodiment 16,0.01 μm of ol/kg, 0.1 μm of ol/kg, 1 μm of tetra- kinds of ol/kg and 10 μm of ol/kg are determined
7c antitumor activity, the results are shown in Table 4 under dosage.The as shown by data of table 4, in 0.1 μm of ol/kg, 1 μm of ol/kg and 10 μm of ol/kg
7c has obvious antitumor activity under dosage.7c no longer shows antitumor activity under 0.01 μm of ol/kg dosage.Four kinds
7c activity shows obvious dependence under dosage.
The various dose 7c of table 4 rings to the scape of S180 tumor weights
N=12.a) the 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 ratio p ＜ 0.01.
Embodiment 19 evaluates influences of the 7c to tumour cell cycle
Single cell suspension is made in human lung cancer cell A549's digestion, is equably inoculated into 6 orifice plates, is moved into incubator and train
Support overnight it is adherent after, if negative control physiological saline group, positive control adriamycin group (0.51 μM of final concentration) and 7c group (final concentrations
25μM).After being incubated 24 hours, collected by trypsinisation cell is used, supernatant is removed in centrifugation, and cell is resuspended into cell with the ice-cold PBS of 1ml
Single cell suspension, and be transferred in 1.5ml centrifuge tubes, centrifugation is careful to absorb supernatant.Cell is fast with ethanol (70%) ice-cold 1ml
Speed is blown even, it is to avoid form cell mass.Cell is collected by centrifugation in 4 DEG C of fixed 2h in cell, carefully absorbs supernatant, adds 1ml ice-cold
PBS be resuspended cell, cell is collected by centrifugation again, supernatant is carefully absorbed.0.5ml propidium iodides (PI) are added toward the cell retained
Dyeing liquor, makes cell be resuspended and precipitate, 37 DEG C of lucifuge warm bath 30 minutes.Flow cytometer (EPICS XL, Beckman Ku Er
It is special) in 488nm wavelength detectings, as a result use Wincycle software analysis.10,000 cells of every part of sample detection.It the results are shown in Table 4.Knot
Fruit shows that the G1/G0 phases cells ratio that 25 μM of 7c act on 24 hours A549 cells is 87.64%, hence it is evident that made higher than physiological saline
With the 66.64% of 24 hours A549 cells, and S phases and G2/M phases cells ratio are all acted on 24 hours significantly lower than physiological saline
The ratio of A549 cells.The G2/M phases cells ratio that positive control adriamycin acts on 24 hours A549 cells is 29.73%, hence it is evident that
The 6.70% of 24 hours A549 cells is acted on higher than physiological saline, the G2/M phase cells ratios of 24 hours A549 cells are acted on 7c
Only 3.98% compares, then higher.It can be seen that, influences of the 7c to the A549 cell cycles is to block G1 phases cell to G0 phase cell mistakes
Cross, and influence of the adriamycin to the A549 cell cycles is to block G2 phases cell to M phase cell transition.Make G1 phase cells as 7c
Can not enter the G0 phases medicine there is presently no precedent.
The 7c of table 4 acts on the cycle ratio of the A549 cells of 24 hours
Claims (4)
1. the compound 7a-i that following formula is represented,
AA is L- alanyls in 7a, and AA is that AA is that AA is glycyl in L- phenylalanyls, 7d in L- valyl bases, 7c in 7b
AA is L- prolyls in base, 7e, and AA is that AA is that AA is L- egg ammonia in L- leucyl-s, 7h in L- isoleucyl-s, 7g in 7f
AA is L- tryptophanyls in acyl group, 7i.
2. preparing the compound 7a-i of claim 1 method, this method includes being prepared in four keys with five committed steps
Mesosome：
1) 1- (2,2- dimethoxy ethyl) -3- methylols -1,2,3,4- Tetrahydrocarbolines (3) are prepared；
2) 1- (2,2- dimethoxy ethyl) -2- (1,3- dicarbapentaborane butyl) -3- (1,3- dicarbapentaborane butyl) oxidation methyl -1 is prepared,
2,3,4- Tetrahydrocarbolines (4)；
3) 3- acetyl group -6- (1,3- dicarbapentaborane butyl) oxidation methyl -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] are prepared
Quinolizine (5)；
4) 3- acetyl group -6- methylols -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolizines (6) are prepared；
5) toward 3- acetyl group -6- methylols -4,6,7,12- tetrahydrochysene -4- Oxoindoles [2,3-a] quinolizines (6) introduce phenylacetyl ammonia
Base acid.
3. the compound 7a-i of claim 1 is preparing the application of G1/G0 cell block agent.
4. the compound 7a-i of claim 1 is preparing the application of anti-tumor disease medicine.
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