CN102268003A - Unsymmetrical poly-substituted porphyrin gold (III) type anticancer compound and preparation method thereof - Google Patents
Unsymmetrical poly-substituted porphyrin gold (III) type anticancer compound and preparation method thereof Download PDFInfo
- Publication number
- CN102268003A CN102268003A CN2011101626589A CN201110162658A CN102268003A CN 102268003 A CN102268003 A CN 102268003A CN 2011101626589 A CN2011101626589 A CN 2011101626589A CN 201110162658 A CN201110162658 A CN 201110162658A CN 102268003 A CN102268003 A CN 102268003A
- Authority
- CN
- China
- Prior art keywords
- porphyrin
- iii
- compound
- preparation
- anticancer compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 CCC**(C(C=C1)=C)C1=C(C(C=C1)=*C1=C)c1ccc(*)cc1 Chemical compound CCC**(C(C=C1)=C)C1=C(C(C=C1)=*C1=C)c1ccc(*)cc1 0.000 description 4
- URLKBWYHVLBVBO-UHFFFAOYSA-N Cc1ccc(C)cc1 Chemical compound Cc1ccc(C)cc1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses an unsymmetrical poly-substituted porphyrin gold (III) type anticancer compound and a preparation method thereof, belonging to the technical field of preparation of medicaments. The preparation method comprises the following steps of: making unsymmetrical poly-substituted porphyrin serving as a ligand react with potassium chloroaurate in an acetic acid system; and performing ion exchange through lithium chloride to obtain the anticancer compound. In the preparation method, different high-polarity radicals are introduced into a porphyrin ring, so that the symmetrical characteristic of molecules is improved, the targeting effect of a poly-substituted tetraphenyl chloride porphyrin gold compound on cancer cells is enhanced, and the dissolving capacity of the compound in water can be facilitated. The compound synthesized with the method has a remarkable inhibiting effect on SGC-7901 and SMMC-7721 tumor cells in vitro and is superior to cis-platinum serving as a positive control medicament, the highest inhibiting rates of 4c and 4a are higher than a pilot compound G0, the IC50 of 4a is less than G0, and higher targeting selectivity is shown. The unsymmetrical poly-substituted porphyrin gold (III) type anticancer compound prepared with the method has high anti-cancer activity, small toxic or side effect and simple, convenient and practicable preparation process, and is suitable for industrial production.
Description
Technical field
The invention discloses asymmetric polysubstituted porphyrin gold (III) class anticancer compound and preparation method thereof, belong to field of medicine preparing technology.
Background technology
Cancer is the high common disease of present lethality rate, and its clinical treatment means are mainly operation, radiotherapy and chemotherapy.In antineoplastic chemotherapy medicine, some widespread use clinically of precious metal coordination compound, for example cis-platinums.But the same with most of chemotherapeutics, the target selectivity of cis-platinum is relatively poor, also injures the normal cell of body in anticancer, shows bigger toxicity.
Document announcement was once arranged, Zhi Zhiming etc. discover that tetraphenylarsonium chloride base porphyrin gold (III)-[AuIII (TPP)] Cl is not only simple in structure, and it is highly stable under physiological condition, to multiple human body cancerous cell line (as cancer cell of oral cavity KB-3-1, cervical cancer cell HeLa, leukemia HL-60, nasopharyngeal carcinoma cell SUNE1, liver cancer cell HepG2 etc.) have the antitumour activity also stronger, probably become anticancer drug candidate [Che, C.M. than cis-platinum; Sun, R.W.Y.; Yu, W.Y.et al.Chem.Commun.2003,1718-1719].Yet, have to studies show that [AuIII (TPP)] Cl is also relatively poor to the target selectivity of cancer cells, thereby also have bigger distance between its experimental study and the clinical application.Therefore, carry out chemically modified, make this metalloid coordination compound have ideal antitumour activity and lower toxic side effect, then become the technological difficulties that the synthetic field of medicine is captured.
Structural analysis shows that [AuIII (TPP)] Cl is similar to cis-platinum, it also is the symmetric metal complex of molecule, symmetry based on drug molecule can influence its biological activity and toxicity, therefore, synthetic tetraphenylarsonium chloride base porphyrin gold (III) derivative with unsymmetrical structure, and carry out antitumour activity and target Journal of Sex Research, significant for the anti-cancer agent of seeking high-efficiency low-toxicity.
Summary of the invention
The objective of the invention is at the deficiencies in the prior art, asymmetric polysubstituted porphyrin gold (III) class anticancer compound and preparation method thereof is provided.
First purpose of the present invention, asymmetric polysubstituted porphyrin gold (III) class anticancer compound, its general formula is:
In the formula, R
1Be bromine or methyl or methoxy, R
2Be methoxyl group or methoxycarbonyl or hydroxyl or ethoxycarbonyl butoxy.
Described R
1Be methyl, R
2Be methoxyl group.
Described R
1Be bromine, R
2Be methoxyl group.
Described R
1Be methoxyl group, R
2Be methoxycarbonyl.
Described R
1Be methyl, R
2Be hydroxyl.
Described R
1Be methyl, R
2Be the ethoxycarbonyl butoxy.
Second purpose of the present invention, the preparation method of asymmetric polysubstituted porphyrin gold (III) class anticancer compound is characterized in that, described compound with asymmetric polysubstituted porphyrin as part, in the acetic acid solution system,, carry out ion-exchange by lithium chloride then and obtain with the potassium chloraurate reaction; The general formula of described asymmetric polysubstituted porphyrin is:
In the formula, R
1Be bromine or methyl or methoxy, R
2Be methoxyl group or methoxycarbonyl or hydroxyl or ethoxycarbonyl butoxy.
Described R
1Be methyl, R
2Be methoxyl group.
Described R
1Be bromine, R
2Be methoxyl group.
Described R
1Be methoxyl group, R
2Be methoxycarbonyl.
Described R
1Be methyl, R
2Be hydroxyl.
Described R
1Be methyl, R
2Be the ethoxycarbonyl butoxy.
Described preparation method may further comprise the steps:
(1) be 1 with mol ratio: the glacial acetic acid of the asymmetric polysubstituted porphyrin of 2.4-3.2: 8-12, potassium chloraurate, sodium acetate and the asymmetric polysubstituted porphyrin 300-600ml of corresponding every mmole adds in the reaction vessel successively, at reaction vessel internal reflux 9-13h, TLC monitors to reacting completely;
(2) steam the acetate that removes in step (1) reaction solution through rotatory evaporator and obtain the purple solid, the purple solid is dissolved in the methylene dichloride of the asymmetric polysubstituted porphyrin 150-300ml of corresponding every mmole, and with the distilled water wash of the asymmetric polysubstituted porphyrin 600-1200ml of corresponding every mmole 3-5 time;
(3) methylene dichloride in the solution behind distilled water wash in the step (2) is used mutually the anhydrous sodium sulfate drying of the asymmetric polysubstituted porphyrin 32-40g of corresponding every mmole, filtered, remove methylene dichloride through the rotatory evaporator vacuum rotary steam;
(4) with the methylene chloride eluent with the solution of removing methylene dichloride through the rotatory evaporator vacuum rotary steam in the step (3), neutral alumina or silica gel column chromatography, the second colour band product that forms is removed eluent methylene dichloride, methyl alcohol fully, use acetone until dissolved product afterwards, remove by filter insolubles;
(5) filtrate in the step (4) being added concentration is the lithium chloride solution of 0.1-0.3g/mL, the asymmetric polysubstituted porphyrin 100-200ml of corresponding every mmole, slowly revolve steaming, treat that the purple solid occurs, filter polysubstituted porphyrin gold (III) the class anticancer compound that the back acquisition has the asymmetric characteristics of molecule.
The present invention by suitable asymmetric polysubstituted porphyrin and potassium chloraurate reaction, carries out ion-exchange with lithium chloride then and obtains the asymmetric polysubstituted porphyrin gold of chlorination in acetic acid solution, under the sodium acetate catalyst action.The present invention is a lead compound with tetraphenylporphyrin gold (III), on porphyrin ring, introduce the symmetry that different strong polar groups improve molecule, and the introducing by strong polar group promotes this compounds dissolving power in water, and strengthens the targeting of polysubstituted tetraphenylarsonium chloride base porphyrin gold compound to cancer cells.In the group of introducing, mainly select halogen, alkoxyl group and the hydroxyl etc. of strong electronegativity for use, effect by strong electrostatic attraction and hydrogen bond increases the solvability of compound molecule in water, strengthens avidity and then the selectivity attack cancer cells of compound molecule to cancer cells simultaneously.Synthetic compound of the present invention is external all to have the obvious suppression effect and is better than the positive control drug cis-platinum SGC-7901 and SMMC-7721 tumour cell, chlorination 5-(4-methoxycarbonyl phenyl)-10 wherein, 15,20-three (4-p-methoxy-phenyl) porphyrin gold (4c) and chlorination 5-(4-p-methoxy-phenyl)-10,15, the highest inhibiting rate of 20-three (4-aminomethyl phenyl) porphyrin gold (4a) all is higher than lead compound G0, the IC of 4a
50All less than G0,, and, shown stronger target selectivity again to normal cell inhibiting effect minimum so the anti-tumor activity of 4a is the strongest.The present invention is scientific and reasonable, and asymmetric polysubstituted porphyrin gold (III) the compounds antitumour activity of preparation is good, and toxic side effect is little, and the target selectivity is strong, and preparation technology is simple and feasible, is fit to industrialized production.
Description of drawings
Fig. 1 is the influence figure of the anticancer compound for preparing respectively of embodiment 1,2,3,4,5 to normal mouse spleen lymphocyte.
Embodiment
Following examples are used to illustrate the present invention.Plant and instrument used in the following example before use should be dry, and reaction will be carried out under anhydrous condition, the logical atmosphere of reflux condensing tube upper end dress drying tube.
Embodiment 1 chlorination 5-(4-p-methoxy-phenyl)-10,15,20-three (4-aminomethyl phenyl) porphyrin gold (4a) compound and preparation method.
In the round-bottomed flask of 250mL, add 200mL propionic acid, p-tolyl aldehyde (7.2g, 60mmol) and aubepine (2.7g 20mmol), is heated to backflow.(5.53mL 80mmol) and after the 10mL propionic acid mixes, slowly is added drop-wise in the propionic acid solution in 30min will newly to steam the pyrroles.Continue reaction 1h then, be cooled to room temperature, separate out solid, filter, solid is used methyl alcohol, hot wash, drying respectively.Obtain yield and be 9.5% 5-(4-p-methoxy-phenyl)-10,15,20-three (4-aminomethyl phenyl) porphyrin (1a) (1.47g):
1H NMR (CDCl
3, 600MHz), δ (ppm): 8.85 (s, 8H, Por-CH), 8.13-8.12 (m, 8H, Ar-CH), 7.55 (d, J=7.2Hz, 6H, Ar-CH), 7.28 (d, J=7.2Hz, 2H, Ar-CH), 4.10 (s, 3H, O-CH
3), 2.70 (s, 9H ,-CH
3) ,-2.77 (s, 2H, inner-NH); IR (KBr): 3021,2914,2857,1605,1505,1467,1346,1244,1175,1030,965,797,736cm
-1More than Fan Ying equation is:
R wherein
1Be methyl, R
2Be methoxyl group.
Add 5-(4-p-methoxy-phenyl)-10 in the 50ml flask, 15,20-three (4-aminomethyl phenyl) porphyrin (1a) (17.15mg, 0.025mmol), potassium chloraurate (22.5-29.9mg, 0.06-0.08mmol), sodium acetate (16.4-24.6mg, 0.2-0.3mmol) and the 7.5-15mL glacial acetic acid, backflow 9h.The TLC monitoring is to reacting completely.Steaming removes acetate and obtains the purple solid.The purple solid is dissolved in the 3.75-7.5ml methylene dichloride, and with 15-30mL distilled water wash 3-5 time.Methylene dichloride 800-1000mg anhydrous sodium sulfate drying filters.Revolve to steam and remove methylene dichloride.With the methylene chloride is eluent, the further refined product of neutral alumina or silica gel column chromatography.First colour band is unreacted raw material, and saffron second colour band is the product of wanting.Remove fully behind eluent methylene dichloride, the methyl alcohol with minimum acetone solution product, remove by filter insolubles, filtrate adds the aqueous solution (concentration is 1-3g LiCl/10mL distilled water) of 2.5-5ml lithium chloride.Slowly revolve steaming, promptly have the purple solid to occur, filter product.The acquisition yield is 65.3% chlorination 5-(4-p-methoxy-phenyl)-10,15, and 20-three (4-aminomethyl phenyl) porphyrin gold (4a) (14.9mg).
1HNMR(CDCl
3，600MHz)，δ(ppm)：9.31-9.29(m，8H，Por-CH)，8.16-8.14(m，8H，Ar-CH)，7.67(d，J＝7.2Hz，6H，Ar-CH)，7.40(d，J＝7.8Hz，2H，Ar-CH)，4.13(s，3H，O-CH
3)，2.74(s，9H，CH
3)；LC-MS(M+Na-Cl)：903.30(100％).IR(KBr)：3023，2920，2852，1604，1502，1452，1357，1239，1179，1031，803，707，609cm
-1。More than Fan Ying equation is:
R wherein
1Be methyl; R
2Be methoxyl group.
Chlorination 5-(4-p-methoxy-phenyl)-10,15, the structural formula of 20-three (4-aminomethyl phenyl) porphyrin gold (4a) is:
Embodiment 2 chlorination 5-(4-p-methoxy-phenyl)-10,15,20-three (4-bromophenyl) porphyrin gold (4b) compound and preparation method thereof.
In the round-bottomed flask of 250mL, add the 200mL propionic acid, to the bromo phenyl aldehyde (11.1g, 60mmol) and aubepine (2.7g 20mmol), is heated to backflow.(5.53mL 80mmol) and after the 10mL propionic acid mixes, slowly is added drop-wise in the propionic acid solution in 30min will newly to steam the pyrroles.Continue reaction 1.5h then, be cooled to room temperature, separate out solid, filter, solid is used methyl alcohol, hot wash, drying respectively.Obtain yield and be 8.6% 5-(4-p-methoxy-phenyl)-10,15,20-three (4-bromophenyl) porphyrin (1b) (1.64g): 2922,2853,1603,1506,1469,1345,1244,1172,1010,963,798,732,591cm
-1 1H NMR (CDCl
3, 600MHz): δ (ppm): 8.83 (s, 2H, Por-CH), 8.76 (s, 6H, Por-CH), 8.04 (d, J=7.8Hz, 2H, Ar-CH), 8.0 (d, J=7.2Hz, 6H, Ar-CH), 7.83 (d, J=7.2Hz, 6H, Ar-CH), 7.23 (d, J=7.8Hz, 2H, Ar-CH), 4.03 (s, 3H, O-CH
3) ,-2.91 (s, 2H, inner-NH).More than Fan Ying equation is:
R wherein
1Be bromine, R
2Be methoxyl group.
Use the method for embodiment 1, with 5-(4-p-methoxy-phenyl)-10,15,20-three (4-bromophenyl) porphyrin (1b) replaces 5-(4-p-methoxy-phenyl)-10,15,20-three (4-aminomethyl phenyl) porphyrin (1a), the reflux time is 13h, the acquisition productive rate is 78.5% chlorination 5-(4-p-methoxy-phenyl)-10,15,20-three (4-bromophenyl) porphyrin gold (4b):
1H NMR (CDCl
3, 600MHz) δ (ppm): 9.16 (s, 2H, Por-CH), 9.08 (s, 6H, Por-CH), 8.08 (m, 8H), 7.89 (d, J=7.8Hz, 2H, Ar-CH), 7.46 (d, J=7.8Hz, 2H, Ar-CH), 4.04 (s, 3H, O-CH
3); LC-MS (M+Na-Cl): 1100.71 (100%); IR (KBr): 2924,2854,1580,1458,1375,1261,909,708cm
-1More than Fan Ying equation is:
R wherein
1Be bromine, R
2Be methoxyl group.
Chlorination 5-(4-p-methoxy-phenyl)-10,15, the structural formula of 20-three (4-bromophenyl) porphyrin gold (4b) is:
Embodiment 3 chlorination 5-(4-methoxycarbonyl phenyl)-10,15,20-three (4-p-methoxy-phenyl) porphyrin gold (4c) compound and preparation method.
In the round-bottomed flask of 250mL, add 200mL propionic acid, p formylbenzoic acid methyl esters (3.2g, 20mmol) and aubepine (8.1g 60mmol), is heated to backflow.(5.53mL 80mmol) and after the 10mL propionic acid mixes, slowly is added drop-wise in the propionic acid solution in 30min will newly to steam the pyrroles.Continue reaction 2h then, be cooled to room temperature, separate out solid, filter, solid is used methyl alcohol, hot wash, drying respectively.Obtain yield and be 9.5% 5-(4-methoxycarbonyl phenyl)-10,15,20-three (4-p-methoxy-phenyl) porphyrin (1c) (1.58g):
1H NMR (CDCl
3, 600MHz) δ (ppm): 8.88 (s, 8H, Por-CH), 8.14 (d, J=7.2Hz, 2H, Ar-CH), 8.05 (d, J=6.6Hz, 6H, Ar-CH), 7.22 (d, J=6.0Hz, 2H, Ar-CH), 4.05 (s, 9H, CH
3), 2.42 (s, 3H, O-CH
3) ,-2.84 (s, 2H, inner-NH); IR (KBr): 2955,2925,2855,1752,1603,1503,1463,1349,1246,1169,1033,962,803,735cm
-1More than Fan Ying equation is:
R wherein
1Be methoxyl group, R
2Be methoxycarbonyl.
Use the method for embodiment 1, with 5-(4-methoxycarbonyl phenyl)-10,15,20-three (4-p-methoxy-phenyl) porphyrin (1c) replaces 5-(4-p-methoxy-phenyl)-10,15,20-three (4-aminomethyl phenyl) porphyrin (1a) participates in reaction, and the acquisition yield is 68.8% chlorination 5-(4-methoxycarbonyl phenyl)-10,15,20-three (4-p-methoxy-phenyl) porphyrin gold (4c):
1H NMR (CDCl
3, 600MHz) δ (ppm): 9.22 (s, 6H, Por-CH), 9.19 (s, 2H, Por-CH), 8.19 (d, J=7.8Hz, 2H, Ar-CH), 8.09-8.08 (m, 6H, Ar-CH), 7.31 (d, J=7.8Hz, 8H, Ar-CH), 4.05 (s, 9H, CH
3), 2.45 (s, 3H, O-CH
3); LC-MS (M+Na-Cl): 980.19 (100%); IR (KBr): 2916,2835,1752,1606,1511,1464,1359,1260,1184,1021,801,756cm
-1More than Fan Ying equation is:
R wherein
1Be methoxyl group, R
2Be methoxycarbonyl.
Chlorination 5-(4-methoxycarbonyl phenyl)-10,15, the structural formula of 20-three (4-p-methoxy-phenyl) porphyrin gold (4c) is:
Embodiment 4 chlorination 5-(4-hydroxy phenyl)-10,15,20-three (4-aminomethyl phenyl) porphyrin gold (5a) compound and preparation method.
The compound 5-(4-p-methoxy-phenyl)-10 that in the 50mL round-bottomed flask, adds embodiment 1 preparation, 15,20-three (4-aminomethyl phenyl) porphyrin (1a) (0.4mmol, 0.27g), the frozen water cooling adds 30ml down and newly steams methylene dichloride, and boron tribromide (0.2mmol, 50mg), stirring at room 2h, TLC follows the tracks of reaction.After adding less water cancellation reaction, produce black solid, filter, use methylene dichloride respectively, water, saturated aqueous common salt organic layer, anhydrous Na
2SO
4Dry.With methylene dichloride/sherwood oil=1: 1 was eluent, and silica gel column chromatography is collected second colour band and got product, obtained yield and be 90.5% 5-(4-hydroxy phenyl)-10,15, and 20-three (4-aminomethyl phenyl) porphyrin (2a) (0.24g);
1H NMR (600MHz, CDCl
3), δ (ppm): 8.84 (s, 8H, Por-CH), 8.04 (m, 8H, Ar-CH), 7.55 (d, J=7.2Hz, 6H, Ar-CH), 7.19 (d, J=7.8Hz, 2H, Ar-CH), 2.70 (s, 9H, CH
3) ,-2.71 (s, 2H, inner-NH); IR (KBr): υ 3207,2923,2852,1606,1506,1466,1350,1247,1174,1033,965,802,737cm
-1More than Fan Ying equation is:
Add 5-(4-hydroxy phenyl)-10 in the 50ml flask, 15,20-three (4-aminomethyl phenyl) porphyrin (2a) (16.8mg, 0.025mmol), potassium chloraurate (22.5-29.9mg, 0.06-0.08mmol), sodium acetate (16.4-24.6mg, 0.2-0.3mmol) and the 7.5-15mL glacial acetic acid, backflow 12h.The TLC monitoring is to reacting completely.Steaming removes acetate and obtains the purple solid.The purple solid is dissolved in the 3.75-7.5ml methylene dichloride, and with 15-30mL distilled water wash 3-5 time.Methylene dichloride 800-1000mg anhydrous sodium sulfate drying filters.Revolve to steam and remove methylene dichloride.With the methylene chloride is eluent, the further refined product of neutral alumina or silica gel column chromatography.First colour band is unreacted raw material, and saffron second colour band is the product of wanting.Remove fully behind eluent methylene dichloride, the methyl alcohol with minimum acetone solution product, remove by filter insolubles, filtrate adds the aqueous solution (concentration is 1-3g LiCl/10mL distilled water) of 2.5-5ml lithium chloride.Slowly revolve steaming, promptly have the purple solid to occur, filter product.Obtain yield and be 78.0% chlorination 5-(4-hydroxy phenyl)-10,15,20-three (4-aminomethyl phenyl) porphyrin gold (5a) (17.6mg),
1H NMR (CDCl
3, 600MHz) δ (ppm): 9.23 (m, 8H, Por-CH), 8.05 (m, 8H, Ar-CH), 7.60 (s, 6H, Ar-CH), 7.40 (d, J=7.8Hz, 2H, Ar-CH), 2.67 (s, 9H, Ar-CH); LC-MS (M+Na-Cl) 890.82 (100%); IR (KBr): 3632,1601,1446,1356,1261,1095,1025,801,703cm
-1More than Fan Ying equation is:
Chlorination 5-(4-hydroxy phenyl)-10,15, the structural formula of 20-three (4-aminomethyl phenyl) porphyrin gold (5a) is:
Embodiment 5 chlorination 5-(4-ethoxycarbonyl butoxy phenyl)-10,15,20-three (4-aminomethyl phenyl) porphyrin gold (6a) compound and preparation method.
Under nitrogen protection; compound 5-(4-hydroxy phenyl)-10 with embodiment 4 preparations; 15; 20-three (4-aminomethyl phenyl) porphyrin (2a) (168mg; 0.25mmol) be dissolved in the dry DMF of 15ml, add sodium hydrate solid (300mg, 7.5mmol); adding 5-bromine Valeric acid ethylester behind the stirring at normal temperature 0.5h (62mg, 0.30mmol).Reaction mixture at room temperature continues to stir, and TLC tracks to reaction raw materials and disappears.After adding 20mL water dilute reaction solution, suction filtration is dissolved in the purple solid methylene dichloride and uses 30mL distilled water wash 3 times.Methylene dichloride liquid layer anhydrous sodium sulfate drying filters.Revolve to steam and remove methylene dichloride.With methylene dichloride/sherwood oil=1: 1 was eluent, silica gel column chromatography, and collecting first colour band is product, obtains yield and be 80% 5-(4-ethoxycarbonyl butoxy phenyl)-10,15,20-three (4-aminomethyl phenyl) porphyrin (3a) is (160.8mg);
1H NMR (CDCl
3, 600MHz) δ (ppm): 8.85 (s, 8H, Por-CH), 8.11 (m, 8H, Ar-CH), 7.55-7.54 (d, J=7.2Hz, 6H, Ar-CH), 7.26 (s, 2H, Ar-CH), 4.27-4.26 (m, 2H, O-CH
2), 4.22-4.18 (m, 2H ,-OCH
2), 2.70 (s, 9H, CH
3), 2.53-2.52 (m, 2H, CH
2), 2.04-2.02 (m, 4H, CH
2CH
2), 1.33 (t, J=7.2Hz, 3H, CH
3) ,-2.77 (s, 2H, inner-NH); IR:(KBr): 3331,3022,2917,2848,1731,1603,1558,1505,1468,1371,1346,1241,1173,1025,985,963,841,799,734cm
-1More than Fan Ying equation is:
Add in the 50ml flask 5-(4-ethoxycarbonyl butoxy phenyl)-, 10,15,20-three (4-aminomethyl phenyl) porphyrin (3a) (20mg, 0.025mmol), potassium chloraurate (22.5-29.9mg, 0.06-0.08mmol), sodium acetate (16.4-24.6mg, 0.2-0.3mmol) and the 7.5-15mL glacial acetic acid, backflow 12h.The TLC monitoring is to reacting completely.Steaming removes acetate and obtains the purple solid.The purple solid is dissolved in the 3.75-7.5ml methylene dichloride, and with 15-30mL distilled water wash 3-5 time.Methylene dichloride is used the 800-1000mg anhydrous sodium sulfate drying mutually, filters.Revolve to steam and remove methylene dichloride.With the methylene chloride is eluent, the further refined product of neutral alumina or silica gel column chromatography.First colour band is unreacted raw material, and saffron second colour band is the product of wanting.Remove fully behind eluent methylene dichloride, the methyl alcohol with minimum acetone solution product, remove by filter insolubles, filtrate adds the aqueous solution (concentration is 1-3g LiCl/10mL distilled water) of 2.5-5ml lithium chloride.Slowly revolve steaming, promptly have the purple solid to occur, filter product.Obtain yield and be 72.9% chlorination 5-(4-ethoxycarbonyl butoxy phenyl)-, 10,15,20-three (4-aminomethyl phenyl) porphyrin gold (6a) (18.8mg);
1H NMR (CDCl
3, 600MHz) δ (ppm): 9.25 (m, 8H, Por-CH), 8.07 (m, 8H, Ar-CH), 7.60-7.59 (d, J=7.8Hz, 6H, Ar-CH), 7.30-7.29 (d, J=8.4Hz, 2H, Ar-CH), 4.24-4.23 (m, 2H, O-CH
2), 4.15-4.13 (m, 2H, O-CH
2), 2.67 (s, 9H, CH
3), 2.47-2.44 (m, 2H, CH
2), 1.99-1.93 (m, 4H, CH
2CH
2), 1.32-1.30 (t, J=7.2Hz, 3H, CH
3); LC-MS:(M+1): 996.19 (100%); IR:(KBr) 2918,2849,1729,1602,1500,1466,1358,1243,1176,1031,802,722cm
-1More than Fan Ying equation is:
Chlorination 5-(4-ethoxycarbonyl butoxy phenyl)-10,15, the structural formula of 20-three (4-aminomethyl phenyl) porphyrin gold (6a) is:
Its high-efficiency low-toxicity characteristic sees following explanation for details:
1. to the inhibiting rate height of tumour cell, half-inhibition concentration is little
After SGC-7901 (people's cancer of the stomach 7901 cell strains) or the digestion of SMMC-7721 (people's liver cancer 7721 cell strains) cell routine, be 2 * 10 with cell count
5ML
-1Density be inoculated in 96 orifice plates, treat that 24h is adherent after, the every hole of dosing group adds the testing sample 100 μ L of different concns, control group adds RPMI RPMI-1640 100 μ L, each concentration is established 3 multiple holes.It is fixing to cultivate 50%TCA (Tricholroacetic Acid) the liquid 50 μ L (final concentration is 10%) that every hole behind the 48h adds precooling, leaves standstill flat board to be moved to 4 ℃ behind the 5min and place 1h.Outwell stationary liquid, aperture dries dry air with distillation washing 5 times.Every hole adds 1% acetic acid that 100 μ L contain 0.4%SRB (sulfo group rhodamine B), at room temperature places 10min; Wash 5 times dry air with 1% acetate solution; It is 10mmolL that every hole adds concentration
-1Non-buffering Tris (Tutofusin tris) alkali lye 150 μ L after the 5min that on micro oscillator, vibrates; Measure the OD value of each aperture at 570nm wavelength place with the enzyme linked immunological monitor, the height of dosing group OD value is directly proportional with cell count, is inversely proportional to inhibiting rate.It is external to SGC-7901 or SMMC-7721 tumor cell proliferation inhibition rate that by formula " inhibiting rate=(1-medicine hole OD value/control wells OD value) * 100% " calculates test-compound, and calculation of half inhibitory concentration IC
50The results are shown in Table 1 and table 2.
Table 1 is external to the effect of SGC-7901 tumor cell proliferation inhibition
Table 2 is external to the effect of SMMC-7721 tumor cell proliferation inhibition
Table 1, table 2 result show, asymmetric polysubstituted porphyrin gold (III) class anticancer compound and lead compound G0 are external all to have the obvious suppression effect and is better than positive control drug cis-platinum (Cis) SGC-7901 and SMMC-7721 tumour cell, wherein the highest inhibiting rate of 4c and 4a all is higher than lead compound G0,6a only is higher than G0 to the highest inhibiting rate of SMMC-7721 tumour cell, again the IC of 4a
50All less than G0, so the anti-tumor activity of 4a is the strongest.
2. the toxicity to normal mouse spleen lymphocyte is little
Prepare ICR mouse spleen lymphocyte suspension according to a conventional method, regulating cell concn is 3 * 10
6ML
-1Get this cell suspension 100 μ L, add 96 well culture plates, the every hole of dosing group adds the testing sample 100 μ L of different concns, and control group adds RPMI RPMI-1640 100 μ L, and each concentration is established 3 multiple holes, and culture plate is placed 5%CO
2, 37 ℃ of saturated humidities incubator in cultivate 24h.4h sucking-off 100 μ L supernatants from each hole discard before cultivating end, add MTT (tetramethyl-azo azoles indigo plant) 10 μ L (final concentration 5mgmL
-1), continue to cultivate 4h after, add 100 μ L acidifying Virahol termination reactions, vibration 10min, with the OD value of microplate reader in each hole of mensuration, 570nm place, the height of dosing group OD value becomes positive correlation with the quantity of viable cell, and Normocellular toxicity is become negative correlation.The results are shown in Figure 1.
Fig. 1 result shows: test-compound all has certain toxicity to normal mouse spleen lymphocyte, wherein lead compound G0, positive control drug cis-platinum (Cis) and 4b, 4c toxicity are all bigger, compound 4a is chlorination 5-(4-p-methoxy-phenyl)-10,15,20-three (4-aminomethyl phenyl) porphyrin gold toxicity is less, is 5a and 6a secondly, measures in conjunction with antitumour activity, the target selectivity that shows 4a is good, toxicity is low, probably becomes anticancer drug candidate.
Claims (8)
1. asymmetric polysubstituted porphyrin gold (III) class anticancer compound, its general formula is:
In the formula, R
1Be bromine or methyl or methoxy, R
2Be methoxyl group or methoxycarbonyl or hydroxyl or ethoxycarbonyl butoxy.
2. asymmetric polysubstituted porphyrin gold according to claim 1 (III) class anticancer compound is characterized in that described R
1Be methyl, R
2Be methoxyl group.
3. asymmetric polysubstituted porphyrin gold according to claim 1 (III) class anticancer compound is characterized in that described R
1Be bromine, R
2Be methoxyl group.
4. asymmetric polysubstituted porphyrin gold according to claim 1 (III) class anticancer compound is characterized in that described R
1Be methoxyl group, R
2Be methoxycarbonyl.
5. asymmetric polysubstituted porphyrin gold according to claim 1 (III) class anticancer compound is characterized in that described R
1Be methyl, R
2Be hydroxyl.
6. asymmetric polysubstituted porphyrin gold according to claim 1 (III) class anticancer compound is characterized in that described R
1Be methyl, R
2Be the ethoxycarbonyl butoxy.
7. the preparation method of asymmetric polysubstituted porphyrin gold (III) class anticancer compound, it is characterized in that, described compound, with the potassium chloraurate reaction, carries out ion-exchange by lithium chloride then and obtains in the acetic acid solution system as part with asymmetric polysubstituted porphyrin.
8. the preparation method of asymmetric polysubstituted porphyrin gold according to claim 7 (III) class anticancer compound is characterized in that described preparation method may further comprise the steps:
(1) be 1 with mol ratio: the glacial acetic acid of the asymmetric polysubstituted porphyrin of 2.4-3.2: 8-12, potassium chloraurate, sodium acetate and the asymmetric polysubstituted porphyrin 300-600ml of corresponding every mmole adds in the reaction vessel successively, at reaction vessel internal reflux 9-13h, TLC monitors to reacting completely;
(2) steam the acetate that removes in step (1) reaction solution through rotatory evaporator and obtain the purple solid, the purple solid is dissolved in the methylene dichloride of the asymmetric polysubstituted porphyrin 150-300ml of corresponding every mmole, and with the distilled water wash of the asymmetric polysubstituted porphyrin 600-1200ml of corresponding every mmole 3-5 time;
(3) with the anhydrous sodium sulfate drying of the methylene dichloride in the solution behind distilled water wash in the step (2) with the asymmetric polysubstituted porphyrin 32-40g of corresponding every mmole, filter, remove methylene dichloride through the rotatory evaporator vacuum rotary steam;
(4) with the methylene chloride eluent with the solution of removing methylene dichloride through the rotatory evaporator vacuum rotary steam in the step (3), neutral alumina or silica gel column chromatography, the second colour band product that forms is removed eluent methylene dichloride, methyl alcohol fully, use acetone until dissolved product afterwards, remove by filter insolubles;
(5) filtrate in the step (4) being added concentration is the lithium chloride solution of 0.1-0.3g/mL, the asymmetric polysubstituted porphyrin 100-200ml of corresponding every mmole, slowly revolve steaming, treat that the purple solid occurs, filter the back and obtain asymmetric polysubstituted porphyrin gold (III) class anticancer compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110162658 CN102268003B (en) | 2011-06-16 | 2011-06-16 | Unsymmetrical poly-substituted porphyrin gold (III) type anticancer compound and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110162658 CN102268003B (en) | 2011-06-16 | 2011-06-16 | Unsymmetrical poly-substituted porphyrin gold (III) type anticancer compound and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102268003A true CN102268003A (en) | 2011-12-07 |
| CN102268003B CN102268003B (en) | 2013-10-30 |
Family
ID=45050480
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110162658 Expired - Fee Related CN102268003B (en) | 2011-06-16 | 2011-06-16 | Unsymmetrical poly-substituted porphyrin gold (III) type anticancer compound and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102268003B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017097226A1 (en) * | 2015-12-08 | 2017-06-15 | The University Of Hong Kong | Gold porphyrin-peg conjugates and methods of use |
| WO2019008013A1 (en) | 2017-07-04 | 2019-01-10 | Szczepaniak Stanislaw | Water-soluble gold (iii) complexes, methods of producing water-soluble gold (iii) complexes and their use |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004024146A1 (en) * | 2002-09-16 | 2004-03-25 | The University Of Hong Kong | Methods for using gold (iii) complexes as anti-tumor and anti-hiv agents |
| CN1968705A (en) * | 2004-05-20 | 2007-05-23 | 布鲁克哈文科学协会 | Carboranylporphyrins and uses thereof |
| CN101665496A (en) * | 2009-09-18 | 2010-03-10 | 华东师范大学 | Method for synthesizing ionic type metal porphyrin |
-
2011
- 2011-06-16 CN CN 201110162658 patent/CN102268003B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004024146A1 (en) * | 2002-09-16 | 2004-03-25 | The University Of Hong Kong | Methods for using gold (iii) complexes as anti-tumor and anti-hiv agents |
| CN1968705A (en) * | 2004-05-20 | 2007-05-23 | 布鲁克哈文科学协会 | Carboranylporphyrins and uses thereof |
| CN101665496A (en) * | 2009-09-18 | 2010-03-10 | 华东师范大学 | Method for synthesizing ionic type metal porphyrin |
Non-Patent Citations (4)
| Title |
|---|
| 《Chem. Eur. J.》 20100216 Raymond Wai-Yin Sun，等 Stable Anticancer Gold(III)-Porphyrin Complexes: Effects of Porphyrin Structure 第3099页，3101页，第3102页图2和图3 1-6 第16卷, 第10期 * |
| 《Chem. Eur. J.》 20100216 Raymond Wai-Yin Sun，等 Stable Anticancer GoldACHTUNGTRENUNG(III)-Porphyrin Complexes:Effects of Porphyrin Structure 第3099页，3101页，3102页图2和图3 7-8 第16卷, 第10期 * |
| RAYMOND WAI-YIN SUN，等: "Stable Anticancer Gold(III)–Porphyrin Complexes: Effects of Porphyrin Structure", 《CHEM. EUR. J.》 * |
| RAYMOND WAI-YIN SUN，等: "Stable Anticancer GoldACHTUNGTRENUNG(III)–Porphyrin Complexes:Effects of Porphyrin Structure", 《CHEM. EUR. J.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017097226A1 (en) * | 2015-12-08 | 2017-06-15 | The University Of Hong Kong | Gold porphyrin-peg conjugates and methods of use |
| WO2019008013A1 (en) | 2017-07-04 | 2019-01-10 | Szczepaniak Stanislaw | Water-soluble gold (iii) complexes, methods of producing water-soluble gold (iii) complexes and their use |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102268003B (en) | 2013-10-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101633640B (en) | Naphthalimide derivative | |
| CN105175410A (en) | Triazine compound and preparing method and antineoplastic application thereof | |
| CN109438365B (en) | N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide derivative | |
| CN105669565A (en) | Isolongifolanone pyrimidine compound, and preparation method and application thereof | |
| CN108610348A (en) | A kind of simultaneously [2,3-b] pyridine -3- carbonitrile derivatives and its preparation and application of the 5H- chromenes containing imidazole substituent | |
| CN109134384A (en) | A kind of preparation method of aggregation-induced emission hydrogen-bonded polymer network | |
| CN102268003B (en) | Unsymmetrical poly-substituted porphyrin gold (III) type anticancer compound and preparation method thereof | |
| JP7101781B2 (en) | Salt morphology as an Akt inhibitor and its crystalline morphology | |
| CN103922992A (en) | Anti-cancer active indolone derivate as well as synthesis method and application thereof | |
| CN108997319B (en) | Thioimidazolidone derivative and synthesis method and application thereof | |
| CN110922415A (en) | Synthesis and application of novel anti-tumor active compound | |
| CN102558042A (en) | 4-bromine-6-methylnicotinicacid and preparation method thereof | |
| CN106554362B (en) | It is a kind of using 1- pyridines-B-carboline as copper chloride (II) chelate and its synthetic method of ligand and application | |
| CN103601730A (en) | Crown ether ring-shaped quinazoline nitrogen mustard compound, and preparation method and application thereof in tumor treatment | |
| CN104098524B (en) | 1-meta-methoxy benzoyl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine and Synthesis and applications | |
| CN102180883B (en) | Substituted porphyrin gold (III) compounds with anticancer activity and preparation method thereof | |
| CN108484623B (en) | Camptothecin derivative and preparation method and application thereof | |
| CN103254143B (en) | 4-[4-(2-diethylin kharophen) anilino]-6-substituted quinazoline compounds and Synthesis and applications | |
| CN102516313B (en) | Quasi-cis-platinum complex with anticancer activity and two-photon biological development function and preparation method thereof | |
| CN103130803B (en) | Oxidized iso-aporphine alkaloid derivative, synthetic method and application | |
| CN103044326A (en) | 5-bromo oxoisoaporphine, and synthesis method and application thereof | |
| CN104098523B (en) | 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine and preparation and application | |
| CN106632490A (en) | Cyclometalated beta-carboline ruthenium complex and preparation method and application thereof | |
| CN103145768A (en) | Method for preparing ferrocenecarboxaldehyde | |
| CN110105260B (en) | Aromatic ring ureido indole derivative and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20131030 Termination date: 20160616 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |