CN102268003B - 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
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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 substituted 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, the clinically widespread use of some noble metal coordination compounds, for example cis-platinum.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 larger toxicity.
Document announcement was once arranged, the research such as Zhi Zhiming finds that tetraphenylarsonium chloride base porphyrin gold (III)-[AuIII (TPP)] Cl is not only simple in structure, and highly stable under physiological condition, to multiple human body cancerous cell line (such 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 than cis-platinum strong antitumour activity also, probably become anticancer drug candidate [Che, C.M.; 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 larger distance between its experimental study and the clinical application.Therefore, carry out chemically modified, make this metalloid coordination compound have desirable 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 metal complex of molecule symmetry, symmetry based on drug molecule can affect its biological activity and toxicity, therefore, synthetic tetraphenylarsonium chloride base porphyrin gold (III) derivative with unsymmetrical structure, and carry out antitumour activity and targeting research, significant for the anti-cancer agent of seeking high-efficiency low-toxicity.
Summary of the invention
The objective of the invention is for the deficiencies in the prior art, asymmetric substituted porphyrin gold (III) class anticancer compound and preparation method thereof is provided.
First purpose of the present invention, asymmetric substituted 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 substituted porphyrin gold (III) class anticancer compound, it is characterized in that, described compound with asymmetric substituted porphyrin as part, in the acetic acid solution system, with the potassium chloraurate reaction, then carry out ion-exchange by lithium chloride and obtain; The general formula of described asymmetric substituted 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 substituted porphyrin of 2.4-3.2: 8-12, potassium chloraurate, sodium acetate and the asymmetric substituted 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 acetic acid 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 substituted porphyrin 150-300ml of corresponding every mmole, and with the distilled water wash of the asymmetric substituted 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 substituted porphyrin 32-40g of corresponding every mmole, filtered, remove methylene dichloride through the rotatory evaporator vacuum rotary steam;
(4) will remove the solution of methylene dichloride take methylene chloride/methanol as eluent through the rotatory evaporator vacuum rotary steam in the step (3), neutral alumina or silica gel column chromatography, the the second colour band product that forms is removed eluent methylene dichloride, methyl alcohol fully, use acetone afterwards until dissolved product removes 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 substituted porphyrin 100-200ml of corresponding every mmole, slowly revolve steaming, treat that the purple solid occurs, obtain substituted porphyrin gold (III) the class anticancer compound with the asymmetric characteristics of molecule after filtering.
The present invention by suitable asymmetric substituted porphyrin and potassium chloraurate reaction, then carries out ion-exchange with lithium chloride and obtains the asymmetric substituted porphyrin gold of chlorination in acetic acid solution, under the sodium acetate catalyst effect.The present invention is take tetraphenylporphyrin gold (III) as lead compound, introduce the stronger polar group of difference at porphyrin ring and improve molecular symmetry, and the introducing by stronger polar group promotes this compounds dissolving power in water, and strengthens polysubstituted tetraphenylarsonium chloride base porphyrin gold compound to the targeting of cancer cells.In the group of introducing, mainly select halogen, alkoxyl group and the hydroxyl etc. of strong electronegativity, effect by strong electrostatic attraction and hydrogen bond increases the solvability of compound molecule in water, strengthens simultaneously compound molecule to avidity and then the selectivity attack cancer cells of cancer cells.The compound that the present invention synthesizes is external all to have obvious restraining 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, so the anti-tumor activity of 4a is the strongest, and to Normocellular restraining effect minimum, shown stronger target selectivity again.The present invention is scientific and reasonable, and asymmetric substituted 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 that the anticancer compound for preparing respectively of embodiment 1,2,3,4,5 is on the figure that affects of normal mouse spleen lymphocyte.
Embodiment
Following examples are used for explanation 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), be heated to backflow.After will newly steaming the mixing of pyrroles (5.53mL, 80mmol) and 10mL propionic acid, in 30min, slowly be added drop-wise in the propionic acid solution.Then continue reaction 1h, be cooled to room temperature, separate out solid, filter, solid is used respectively methyl alcohol, hot wash, drying.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 the equation of reaction 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 obtains the purple solid except acetic acid.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.Take methylene chloride/methanol as eluent, the further refined product of neutral alumina or silica gel column chromatography.The first colour band is unreacted raw material, and saffron the 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, namely have the purple solid to occur, filter to get 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 the equation of reaction 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 bromo phenyl aldehyde (11.1g, 60mmol) and aubepine (2.7g, 20mmol), be heated to backflow.After will newly steaming the mixing of pyrroles (5.53mL, 80mmol) and 10mL propionic acid, in 30min, slowly be added drop-wise in the propionic acid solution.Then continue reaction 1.5h, be cooled to room temperature, separate out solid, filter, solid is used respectively methyl alcohol, hot wash, drying.The acquisition yield is 8.6% 5-(4-p-methoxy-phenyl)-10,2922,2853,1603,1506,1469,1345,1244,1172,1010,963,798,732,591cm 15,20-three (4-bromophenyl) porphyrin (1b) is (1.64g):
-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 the equation of reaction 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 the equation of reaction 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), be heated to backflow.After will newly steaming the mixing of pyrroles (5.53mL, 80mmol) and 10mL propionic acid, in 30min, slowly be added drop-wise in the propionic acid solution.Then continue reaction 2h, be cooled to room temperature, separate out solid, filter, solid is used respectively methyl alcohol, hot wash, drying.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 the equation of reaction 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 the equation of reaction 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 lower adding of frozen water cooling 30ml newly steams methylene dichloride, boron tribromide (0.2mmol, 50mg), stirring at room 2h, TLC follows the tracks of reaction.Add a small amount of shrend and go out after the reaction, produce black solid, filter, use respectively methylene dichloride, water, saturated aqueous common salt organic layer, anhydrous Na
2SO
4Dry.So that methylene dichloride/sherwood oil=silica gel column chromatography was collected the second colour band and got product as eluent in 1: 1, the acquisition yield is 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 the equation of reaction 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 obtains the purple solid except acetic acid.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.Take methylene chloride/methanol as eluent, the further refined product of neutral alumina or silica gel column chromatography.The first colour band is unreacted raw material, and saffron the 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, namely have the purple solid to occur, filter to get 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 the equation of reaction 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); add 5-bromine Valeric acid ethylester (62mg, 0.30mmol) behind the stirring at normal temperature 0.5h.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.Take methylene dichloride/sherwood oil=1: 1 as eluent, silica gel column chromatography, collecting the first colour band is product, the acquisition yield is 80% 5-(4-ethoxycarbonyl butoxy phenyl)-10,15,20-three (4-aminomethyl phenyl) porphyrin (3a) (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 the equation of reaction 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 7.5-15mL glacial acetic acid, backflow 12h.The TLC monitoring is to reacting completely.Steaming obtains the purple solid except acetic acid.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.Take methylene chloride/methanol as eluent, the further refined product of neutral alumina or silica gel column chromatography.The first colour band is unreacted raw material, and saffron the 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, namely have the purple solid to occur, filter to get product.Obtain yield and be 72.9% chlorination 5-(4-ethoxycarbonyl butoxy phenyl)-, 10,15,20-three (4-aminomethyl phenyl) porphyrin gold (6a) is (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 the equation of reaction 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. the inhibiting rate to tumour cell is high, and half-inhibition concentration is little
After SGC-7901 (people's cancer of the stomach 7901 cell strains) or the digestion of SMMC-7721 (strain of people's 7721 hepatocellular carcinoma) cell routine, take cell count as 2 * 10
5ML
-1Density be inoculated in 96 orifice plates, after 24h was adherent, the every hole of dosing group added 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.By formula " inhibiting rate=(1-medicine hole OD value/control wells OD value) * 100% " calculates the external inhibiting rate to SGC-7901 or SMMC-7721 tumor cell proliferation of test-compound, and calculation of half inhibitory concentration IC
50The results are shown in Table 1 and table 2.
The external restraining effect to the SGC-7901 tumor cell proliferation of table 1
The external restraining effect to the SMMC-7721 tumor cell proliferation of table 2
Table 1, table 2 result show, asymmetric substituted porphyrin gold (III) class anticancer compound and lead compound G0 are external all to have obvious restraining 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 according to a conventional method ICR mouse spleen lymphocyte suspension, 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 is blue) 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 larger, 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 (2)
1. asymmetric substituted porphyrin gold (III) class anticancer compound, its structural formula is:
In the formula, R
1Be methyl, R
2Be methoxyl group.
2. the preparation method of described asymmetric substituted porphyrin gold (III) class anticancer compound according to claim 1 is characterized in that described preparation method may further comprise the steps:
(1) with mol ratio is the 5-(4-p-methoxy-phenyl)-10 of 1:2.4-3.2:8-12,15,20-three (4-aminomethyl phenyl) porphyrin, potassium chloraurate, sodium acetate and corresponding every mmole 5-(4-p-methoxy-phenyl)-10,15, the glacial acetic acid of 20-three (4-aminomethyl phenyl) porphyrin 300-600 ml adds in the reaction vessel successively, at reaction vessel internal reflux 9-13 h, TLC monitors to reacting completely;
(2) steam the acetic acid that removes in step (1) reaction solution through rotatory evaporator and obtain the purple solid, the purple solid is dissolved in corresponding every mmole 5-(4-p-methoxy-phenyl)-10,15, the methylene dichloride of 20-three (4-aminomethyl phenyl) porphyrin 150-300 ml, and with corresponding every mmole 5-(4-p-methoxy-phenyl)-10, the distilled water wash of 15,20-three (4-aminomethyl phenyl) porphyrin 600-1200 ml 3-5 time;
(3) with the methylene dichloride in the solution behind distilled water wash in the step (2) with corresponding every mmole 5-(4-p-methoxy-phenyl)-10,15, the anhydrous sodium sulfate drying of 20-three (4-aminomethyl phenyl) porphyrin 32-40g filters, and removes methylene dichloride through the rotatory evaporator vacuum rotary steam;
(4) will remove the solution of methylene dichloride take methylene chloride/methanol as eluent through the rotatory evaporator vacuum rotary steam in the step (3), neutral alumina or silica gel column chromatography, the the second colour band product that forms is removed eluent methylene dichloride, methyl alcohol fully, use acetone afterwards until dissolved product removes by filter insolubles;
(5) filtrate in the step (4) being added concentration is 0.1-0.3 g/mL, corresponding every mmole 5-(4-p-methoxy-phenyl)-10,15, the lithium chloride solution of 20-three (4-aminomethyl phenyl) porphyrin 100-200 ml, slowly revolve steaming, treat that the purple solid occurs, obtain asymmetric substituted porphyrin gold (III) class anticancer compound after filtering.
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