CN103936788B - Schuttgelb quaternary alkylphosphonium salt with anti-tumor activity and preparation method thereof - Google Patents
Schuttgelb quaternary alkylphosphonium salt with anti-tumor activity and preparation method thereof Download PDFInfo
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Abstract
One class Schuttgelb quaternary alkylphosphonium salt, described Schuttgelb quaternary alkylphosphonium salt is such as formula shown in (I) or formula (II):
,
; N=3,4,5 in its Chinese style (I); N=3 or 5 in formula (II); C in formula (II)
8h
17for straight-chain alkyl.Its preparation method is Schuttgelb and Br (CH
2)
nbr is at K
2cO
3there is lower generation Williamsom etherification reaction, products therefrom bromine alkyl emodin derivates generates such as formula the quaternary alkylphosphonium salt shown in (I) or formula (II) with triphenylphosphine or tri octyl phosphine generation nucleophilic substitution reaction again.Schuttgelb quaternary alkylphosphonium salt synthetic method of the present invention is simple, and have comparatively high inhibition effect to leukemia, lymphatic cancer cancer cells, its antitumour activity is higher than Schuttgelb 40 times, has the application prospect preparing cancer therapy drug.
Description
Technical field
The present invention relates to the synthesis that a class has the Schuttgelb quaternary alkylphosphonium salt of anti-cancer function, relate to 5 kinds of Schuttgelb quaternary alkylphosphonium salts with antitumour activity and preparation method thereof more specifically.
Background technology
Schuttgelb is the effective active composition of Chinese herb rhubarb, giant knotweed etc., because having two dimensional structure and quinoid structure and having broad spectrum anticancer activity.But the inhibit activities of Schuttgelb to most cancer cells is not enough to direct patent medicine (IC
50about 30-80 μM), therefore chemically modified is carried out to Schuttgelb inevitable.Earlier innovation people once carried out chemically modified at 6 of Schuttgelb, found to introduce the antitumour activity that long carbon chain quaternary ammonium salt can improve Schuttgelb greatly.But the antitumour activity whether quaternary alkylphosphonium salt, particularly lipotropy quaternary alkylphosphonium salt also can improve Schuttgelb is the research field being not yet indicated in report.
Summary of the invention
One class Schuttgelb quaternary alkylphosphonium salt, is characterized in that: described Schuttgelb quaternary alkylphosphonium salt is such as formula shown in (I) or formula (II):
；
N=3,4,5 in its Chinese style (I); N=3 or 5 in formula (II); C in formula (II)
8h
17for straight-chain alkyl.
Its preparation method, comprises the following steps:
A) Schuttgelb and Br (CH
2)
nbr is at K
2cO
3there is lower generation Williamsom etherification reaction, generate such as formula the bromine alkyl emodin derivates shown in (III); Wherein n is depending on final product;
（III）；
B) bromine alkyl emodin derivates and triphenylphosphine generation nucleophilic substitution reaction generate quaternary alkylphosphonium salt as shown in the formula (I), then become quaternary alkylphosphonium salt as shown in the formula (II) with tri octyl phosphine generation nucleophilic substitution.
Synthetic route is shown below:
Concrete step is as follows:
(1) getting Schuttgelb is dissolved in acetone, adds Anhydrous potassium carbonate, is heated to backflow, under the state of backflow, slowly drip Br (CH
2)
nbr; Wherein Schuttgelb: Anhydrous potassium carbonate: Br (CH
2)
nthe ratio of the amount of substance of Br is 1:1:1.Backflow 2-3h, is cooled to room temperature, revolves and steams except after desolventizing, and add water and stir 30min, suction filtration, obtains the thick product of yellow powder, is separated obtains bright yellow solid through silica gel column chromatography, and it is for such as formula the bromine alkyl emodin derivates shown in (III);
(2) the bromine alkyl emodin derivates getting step (1) gained is dissolved in ethylene glycol monomethyl ether, temperature control 100 DEG C, adds triphenylphosphine or the tri octyl phosphine of the amount of commaterial after all dissolving, reaction 2h; Be chilled to room temperature, solvent ethylene glycol monomethyl ether is spin-dried for, be separated by silica gel column chromatography and obtain yellow solid through gradient elution; For such as formula (I) or quaternary alkylphosphonium salt as shown in the formula (II); Described gradient elution order: methylene dichloride; Methylene dichloride: ethanol (v/v)=100:1; Methylene dichloride: ethanol (v/v)=50:1; Methylene dichloride: ethanol (v/v)=20:1.
Above-described Schuttgelb quaternary alkylphosphonium salt is in the application preparing Therapeutic cancer disease medicament.
Several lipotropy Schuttgelb quaternary alkylphosphonium salt synthetic methods that the present invention relates to are simple, and test their restraining effect to leukemia, lymphatic cancer cancer cells, result shows that these Schuttgelb quaternary alkylphosphonium salts can suppress the activity of these 2 kinds of cancer cells really well.Therefore lipotropy Schuttgelb quaternary alkylphosphonium salt has the application prospect becoming cancer therapy drug.
Embodiment
More being convenient to make content of the present invention understand, below in conjunction with embodiment, technical solutions according to the invention are described further, but the present invention being not limited only to this.
Embodiment 1
The synthesis of { 3-[(4,5-dihydroxyl-7-methyl-9,10-anthraquinone-2-base) oxygen base] propyl group } three phenyl phosphonium bromides (3a)
Get 1.6g (5.8mmol) Schuttgelb to be dissolved in 120ml acetone, add 800mg (5.8mmol) Anhydrous potassium carbonate, under the state of backflow, slowly drip 0.59ml (5.8mmol) 1,3-dibromopropane, backflow 2h.After being chilled to room temperature, revolve to steam and stir 30min except adding 100ml water after desolventizing, suction filtration, obtains the thick product of yellow powder.Be separated through silica gel column chromatography and obtain bright yellow solid 3-bromopropyl Schuttgelb (2a) 813mg, productive rate 34.8%.The characterization data of 3-bromopropyl Schuttgelb (2a) is as follows:
1HNMR(400MHz,CDCl
3)12.34(s,1H,-OH),12.14(s,1H,-OH),7.66(s,1H,Ar-H),7.40(d,J=2.4Hz,1H,Ar-H),7.12(s,1H,Ar-H),6.73(d,J=2.4Hz,1H,Ar-H),4.28(t,J=5.6Hz,2H,ArOC
H 2CH
2CH
2Br),3.64(t,J=5.6Hz,2H,ArOCH
2CH
2C
H 2Br),2.48(s,3H,ArC
H 3);2.41(t,J=5.6Hz,2H,ArOCH
2C
H 2CH
2Br);ESI-MSm/z389.09[M-H]
-.
3-bromopropyl Schuttgelb (2a) 100mg (0.26mmol) and 15ml ethylene glycol monomethyl ether solvent is added, temperature control 100 ° of C in there-necked flask.Treat that raw material adds the triphenylphosphine of about 67mg (0.26mmol) after all dissolving, reaction 2h, is cooled to room temperature.Solvent ethylene glycol monomethyl ether is spin-dried for, obtains yellow solid 54mg (3a, 0.083mmol) by silica gel column chromatography through gradient elution, productive rate 31.9%.Elution order: first use methylene dichloride, then methylene dichloride: ethanol (v/v)=100:1 → 50:1 → 20:1.Characterization of The Products data are as follows:
M.p.98-99 ° of C;
1hNMR (400MHz, CDCl
3): 12.27 (s, 1H, Ar-OH), 12.13 (s, 1H, Ar-OH), 7.95-7.90 (m, 6H, P (C
6 h 5)
3), 7.84-7.82 (m, 3H, P (C
6 h 5)
3), 7.76-7.72 (m, 6H, P (C
6 h 5)
3), 7.62 (d, J=0.4Hz, 1H, Ar-H), 7.21 (d, J=2.0Hz, 1H, Ar-H), 7.09 (s, 1H, Ar-H), 6.68 (d, J=2.0Hz, 1H, Ar-H), 4.52 (t, J=6.0Hz, 2H, ArOC
h 2(CH
2)
2p), 4.23 ((m, 2H, ArO (CH
2)
2c
h 2p), 2.46 (s, 3H, Ar-C
h 3); 2.32 (m, 2H, ArOCH
2 cH 2cH
2p), ESI-MS573.26 (M-Br)
+; Ultimate analysis C
36h
30brO
5p ﹒ 2H
2o calculated value: C62.71, H4.97; Experimental value: C62.33, H5.08.
Embodiment 2
The synthesis of { 4-[(4,5-dihydroxyl-7-methyl-9,10-anthraquinone-2-base) oxygen base] butyl } three phenyl phosphonium bromides (3b)
Get 1.6g (5.8mmol) Schuttgelb to be dissolved in 120ml acetone, add 800mg (5.8mmol) Anhydrous potassium carbonate, under the state of backflow, slowly drip the Isosorbide-5-Nitrae-dibromobutane of 0.72ml (5.8mmol), backflow 3h.Be chilled to room temperature, revolve and steam except after desolventizing, add 100ml water and stir 30min, suction filtration, obtains the thick product of yellow powder, and silica gel column chromatography is separated and obtains bright yellow solid 4-brombutyl Schuttgelb (2b) 801mg, productive rate 33.1%.The characterization data of 4-brombutyl Schuttgelb (2b) is as follows:
1HNMR(400MHz,CDCl
3),δ:12.34(s,1H,Ar-OH),12.15(s,1H,Ar-OH),7.66(s,1H,Ar-H),7.38(d,J=2.4Hz,1H,Ar-H),7.12(s,1H,Ar-H),6.70(d,J=2.4Hz,1H,Ar-H),4.17(t,J=4.8Hz,2H,ArOC
H 2CH
2CH
2CH
2Br),3.66(t,J=6.4Hz,2H,ArOCH
2CH
2CH
2 CH 2Br),2.42(s,3H,Ar-C
H 3),1.97(m,2H,CH
2C
H 2 CH
2CH
2Br),1.87(m,2H,CH
2CH
2C
H 2 CH
2Br).
In there-necked flask, add 4-brombutyl Schuttgelb (2b) 100mg (0.25mmol), be dissolved in 15ml ethylene glycol monomethyl ether, temperature control 100 ° of C.64mg (0.25mmol) triphenylphosphine is added, reaction 3h after raw material all dissolves.Be chilled to room temperature, ethylene glycol monomethyl ether is spin-dried for, obtain yellow solid 57mg by silica gel column chromatography through gradient elution, productive rate 34.2%.Elution order: first use methylene dichloride, then methylene dichloride: ethanol (v/v)=100:1 → 50:1 → 20:1.Characterization of The Products data are as follows:
M.p.214-217 ° of C;
1hNMR (400MHz, CDCl
3): 12.30 (s, 1H, Ar-OH), 12.13 (s, 1H, Ar-OH), 7.90-7.81 (m, 9H, P (C
6 h 5)
3), 7.76-7.71 (m, 6H, P (C
6 h 5)
3), 7.63 (d, J=0.8Hz, 1H, Ar-H), 7.21 (d, J=2.4Hz, 1H, Ar-H), 7.09 (d, J=0.8Hz, 1H, Ar-H), 6.64 (d, J=2.4Hz, 1H, Ar-H), 4.22 (t, J=6.4Hz, 2H, ArOC
h 2(CH
2)
3p), 3.94 ((m, 2H, ArO (CH
2)
3c
h 2p), 2.47 (s, 3H, Ar-C
h 3), 2.35 (m, 2H, ArOCH
2c
h 2c
2h
4p), 1.93 (m, 2H, ArOC
2h
4c
h 2cH
2p); ESI-MS587.50 (M-Br)
+; Ultimate analysis C
37h
32brO
5p2.5H
2o calculated value: C62.37, H5.23; Experimental value: C62.63, H5.69.
Embodiment 3
The synthesis of { 5-[(4,5-dihydroxyl-7-methyl-9,10-anthraquinone-2-base) oxygen base] amyl group } three phenyl phosphonium bromides (3c)
Getting 1.6g (5.8mmol) Schuttgelb is dissolved in 120ml acetone, add 800mg (5.8mmol) Anhydrous potassium carbonate, the pentamethylene bromide of 0.80ml (5.8mmol) is slowly dripped, backflow 3h under the state of backflow, be chilled to room temperature, revolve to steam and stir 30min except adding 100ml water after desolventizing, suction filtration, obtains the thick product of yellow powder, silica gel column chromatography is separated and obtains bright yellow solid 5-bromine amyl group Schuttgelb (2c) 807mg, productive rate 32.6%.Product structure warp
1hNMR, mass spectrum, fusing point are determined.The characterization data of intermediate product 5-bromine amyl group Schuttgelb (2c) is as follows:
1HNMR(400MHz,CDCl
3)12.31(s,1H,Ar-H),12.13(s,1H,Ar-H),7.63(s,1H,Ar-H),7.36(d,J=2.4Hz,1H,Ar-OH),7.09(s,1H,Ar-H),6.67(d,J=2.4Hz,1H,Ar-H),4.13(t,J=6.4Hz,2H,ArOC
H 2(CH
2)
4Br),3.43(t,J=6.4Hz,2H,ArO(CH
2)
4C
H 2Br),2.47(s,3H,Ar-C
H 3);1.91(m,4H,ArOCH
2(C
H 2)
2(CH
2)
2Br),1.60(m,2H,ArO(CH
2)
3C
H 2 CH
2Br);ESI-MSm/z417.36[M-H]
-
In there-necked flask, add 5-bromine amyl group Schuttgelb (2c) 100mg (0.24mmol) that case study on implementation 3 synthesizes, be dissolved in 15ml ethylene glycol monomethyl ether.Temperature control 100 ° of C, add 62mg (0.24mmol) triphenylphosphine after material dissolution, and reaction 3h, is spin-dried for ethylene glycol monomethyl ether after being chilled to room temperature, obtains yellow solid 55mg, productive rate 33.7% by silica gel column chromatography through gradient elution separation.Elution order: first use methylene dichloride, then methylene dichloride: ethanol (v/v)=100:1 → 50:1 → 20:1.Characterization of The Products data are as follows:
M.p.119-121 ° of C;
1hNMR (400MHz, CDCl
3): 12.30 (s, 1H, Ar-OH), 12.15 (s, 1H, Ar-OH), 7.94-7.88 (m, 6H, P (C
6h
5)
3), 7.83-7.80 (m, 3H, P (C
6 h 5)
3), 7.74-7.71 (m, 6H, P (C
6 h 5)
3), 7.63 (s, 1H, Ar-H), 7.23 (d, J=2.0Hz, 1H, Ar-H), 7.09 (s, 1H, Ar-H), 6.59 (d, J=2.0Hz, 1H, Ar-H), 4.08 (t, J=4.0Hz, 2.0H, ArOCH
2(CH
2)
4pPh
3), 3.97 (m, 2.0H, ArO (CH
2)
4c
h 2 p), 2.47 (s, 3H, Ar-CH
3), 1.92 (m, 4H, ArOCH
2c
h 2cH
2c
h 2cH
2p), 1.76 (m, 2H, ArOCH
2cH
2c
h 2cH
2cH
2p); ESI-MS601.57 (M-Br)
+; Ultimate analysis C
38h
34brO
5p3H
2o, calculated value: C62.05, H5.48 experimental value: C61.98, H5.75.
Embodiment 4
{ 3-[(4,5-dihydroxyl-7-methyl-9,10-anthraquinone-2-base) oxygen base] propyl group } trioctylphosphine phosphonium bromide (3d)
In there-necked flask, add 3-bromopropyl Schuttgelb (2a) 100mg (0.26mmol) prepared by case study on implementation 1, be dissolved in 15ml ethylene glycol monomethyl ether solvent.Controlling temperature 100 ° of C, add 0.11ml (0.26mmol) tri octyl phosphine after treating material dissolution.Reaction 2h, is spin-dried for solvent ethylene glycol monomethyl ether after being chilled to room temperature, is about 29mg, productive rate 15% by silica gel column chromatography through the gradient elution separation yellow gummy solid that obtains.Elution order: first use methylene dichloride, then methylene dichloride: ethanol (v/v)=100:1 → 50:1 → 20:1.Characterization of The Products data are as follows:
1hNMR (400MHz), CDCl
3) 12.34 (s, 1H, Ar-OH), 12.15 (s, 1H, Ar-OH), 7.64 (s, 1H, Ar-H), 7.34 (s, 1H, Ar-H), 7.11 (s, 1H, Ar-H), 6.68 (s, 1H, Ar-H), 4.19-4.07 (m, 10H, ArOC
h 2cH
2c
h 2p (C
h 2c
7h
15)
3, 2.47-2.42 (m, 8H, ArOCH
2c
h 2cH
2p (CH
2c
h 2c
6h
13)
3), 2.20 (s, 3H, Ar-CH
3), 1.72-1.28 (m, 30H, P (CH
2cH
2c
5 h 10cH
3)
3, 0.89 (t, J=6.8Hz, 9H, P (C
7h
14c
h 3)
3); ESI-MS681.58 (M-Br
-)
+; Ultimate analysis C
42h
66brO
5p3.5H
2o calculated value: C61.15, H8.92, experimental value: C61.21, H9.07.
Embodiment 5
{ 5-[(4,5-dihydroxyl-7-methyl-9,10-anthraquinone-2-base) oxygen base] amyl group } trioctylphosphine phosphonium bromide (3e)
In there-necked flask, add 5-bromine amyl group Schuttgelb (2c) 100mg (0.26mmol) prepared by case study on implementation 3, be dissolved in 15ml ethylene glycol monomethyl ether solvent.Controlling temperature 100 ° of C, add 0.11ml (0.26mmol) trioctylphosphine phosphorus after treating material dissolution.Reaction 2h, is spin-dried for solvent ethylene glycol monomethyl ether after being chilled to room temperature, is obtained yellow yellow gummy solid by silica gel column chromatography and is about 33mg, productive rate 16.1% through gradient elution separation.Elution order: first use methylene dichloride, then methylene dichloride: ethanol (v/v)=100:1 → 50:1 → 20:1.。Characterization of The Products data are as follows:
1hNMR (400MHz), CDCl
3) 12.33 (s, 1H, Ar-OH), 12.11 (s, 1H, Ar-OH), 7.64 (s, 1H, Ar-H), 7.32 (s, 1H, Ar-H), 7.11 (s, 1H, Ar-H), 6.70 (s, 1H, Ar-H), 4.34-4.24 (m, 6H, P ((C
h 2c
7h
15)
3), 4.11 (m, 4H, ArOC
h 2c
3h
6c
h 2p), 2.48-2.44 (m, 10H, ArOCH
2c
h 2cH
2c
h 2cH
2p (CH
2c
h 2c
6h
13)
3), 2.20 (s, 3H, Ar-CH
3), 1.71-1.29 (m, 32H, ArOC
2h
4c
h 2c
2h
4p (CH
2cH
2c
5 h 10cH
3)
3, 0.89 (t, J=6.8Hz, 9H, P (C
7h
14c
h 3)
3); ESI-MS709.50 (M-Br
-)
+; Ultimate analysis C
44h
70brO
5p3.5H
2o calculated value: C61.96, H9.10, experimental value: C62.21, H9.52.
Case study on implementation 6: Schuttgelb quaternary alkylphosphonium salt antitumour activity is tested
The cell density of leukemia HL60 and lymphoma Molt-4 cancer cells is adjusted to 1.5 × 10
5/ ml, is inoculated in 96 well culture plates, and every hole 100 μ l, puts 37 ° of C, 5%CO
224h is cultivated in incubator; Remove old substratum, add tested derivative, every hole 100 μ L, separately establishes blank group, and often group establishes 6 multiple holes.After drug effect 72h, inhale and abandon pastille substratum, in every hole, add serum-free, without phenol red 1640 substratum 100 μ L, then add MTT solution 10 μ L, continue to hatch 4h, stop cultivating; Supernatant liquor in 96 orifice bores is abandoned in careful suction, and every hole adds 150 μ LDMSO, and vibration 10min, is in microplate reader in 490nm wavelength and measures each hole absorbance value (OD value), calculation of half inhibitory concentration IC
50value.Result is as shown in table 1.
From table 1, no matter Schuttgelb parent nucleus is introduced triphen fundamental mode quaternary alkylphosphonium salt (3a-3c) or introduces trioctylphosphine type quaternary alkylphosphonium salt (3d-3e), the antitumour activity of the Schuttgelb quaternary alkylphosphonium salt obtained is all apparently higher than primer Schuttgelb.The best 3b of antitumour activity is about higher than the activity of Schuttgelb parent 40 times, has the potentiality becoming cancer therapy drug.The structure of these Schuttgelb quaternary alkylphosphonium salts has following common ground: (1) has not by the positive charge that pH controls; (2) there is the lipophilic groups such as many Long carbon chain or multiple phenyl ring.This structure makes Schuttgelb quaternary alkylphosphonium salt easily utilize the higher membrane potential of cancer cells to cross over fat-soluble cytolemma and enters plastosome.Schuttgelb has quinoid structure, easily from trapped electron mitochondrial respiratory chain, is transferred to O
2after namely produce active oxygen (ROS), thus cancer cell specific induction of apoptosis.
Claims (4)
1. a class Schuttgelb quaternary alkylphosphonium salt, is characterized in that: described Schuttgelb quaternary alkylphosphonium salt is such as formula shown in (I) or formula (II):
；
N=3,4,5 in its Chinese style (I); N=3 or 5 in formula (II); C in formula (II)
8h
17for straight-chain alkyl.
2. a preparation method for Schuttgelb quaternary alkylphosphonium salt as claimed in claim 1, comprises the following steps:
Schuttgelb and Br (CH
2)
nbr is at K
2cO
3there is lower generation Williamsom etherification reaction, generate such as formula the bromine alkyl emodin derivates shown in (III)
（III）；
Bromine alkyl emodin derivates and triphenylphosphine generation nucleophilic substitution reaction generate quaternary alkylphosphonium salt as shown in the formula (I), then generate quaternary alkylphosphonium salt as shown in the formula (II) respectively with tri octyl phosphine generation nucleophilic substitution.
3. the preparation method of Schuttgelb quaternary alkylphosphonium salt as claimed in claim 2, is characterized in that concrete step is as follows:
(1) getting Schuttgelb is dissolved in acetone, adds Anhydrous potassium carbonate, is heated to backflow, under the state of backflow, slowly drip Br (CH
2)
nbr; Wherein Schuttgelb: Anhydrous potassium carbonate: Br (CH
2)
nthe ratio of the amount of substance of Br is 1:1:1;
Backflow 2-3h, is cooled to room temperature, revolves and steams except after desolventizing, and add water and stir 30min, suction filtration, obtains the thick product of yellow powder, is separated obtains bright yellow solid through silica gel column chromatography, and it is for such as formula the bromine alkyl emodin derivates shown in (III);
(2) the bromine alkyl emodin derivates getting step (1) gained is dissolved in ethylene glycol monomethyl ether, temperature control 100 DEG C, adds triphenyl phosphorus or the tri octyl phosphine of the amount of commaterial after all dissolving, reaction 2h; Be chilled to room temperature, solvent ethylene glycol monomethyl ether is spin-dried for, be separated by silica gel column chromatography and obtain yellow solid through gradient elution; For such as formula (I) or quaternary alkylphosphonium salt as shown in the formula (II); Described gradient elution order: methylene dichloride; Methylene dichloride: ethanol (v/v)=100:1; Methylene dichloride: ethanol (v/v)=50:1; Methylene dichloride: ethanol (v/v)=20:1.
4. Schuttgelb quaternary alkylphosphonium salt as claimed in claim 1 treats the application of leukemia or lymphoid tumor medicament in preparation.
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| CN112156098B (en) * | 2015-09-23 | 2023-06-13 | 福建医科大学 | Application of emodin quaternary phosphonium salt in preparation of pancreatic cancer treatment drugs |
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