The metal complexes of carboranylporphyrins with antitumor activity

 

The invention relates to new compounds, metalcomplexes of carboranylporphyrins General formula I,

with antitumor activity and low toxicity, which can be used in boron neutron capture therapy had cancer. 3 Il.

The invention relates to new compounds of General formula I; which can be used in boron neutron capture therapy had cancer (BNCT),

It is known for a similar structure connection (S. C. Kahl and M. S. Koo./ Synthesis of Tetrakis-carborane-carboxylate Esters of 2,4-Bis-(,-dihydroxyethy1)-deuteroporphyrin IX.//J. Chem. Soc., Chem. Commun., 1990, p. 1769-1771) of formula II.

The compound was obtained by the reaction of the acid chloride of 1-o-carboran-carboxylic acid with dimethyl ether bis(,-dihydroxyethyl) datareporting IX in the presence of 4-dimethylaminopyridine. It showed high antitumor activity in vitro and in vivo.

Carboranylporphyrins General formula III is also obtained by the condensation of porphyrins with carborane (Zakharkin L. I., Olshevsky C. A., Panfilov, S. Yu, Peter P. C., Lasheka, 1999, No. 12, S. 2337-2339) when exposed to a mixture of porphyrin and carboran-directbuylighting.com or when activated carboxyl groups propionic acid residues by revalorisation.

The compounds obtained can be used for BNCT. We propose the synthesis of metal complexes of carboranylporphyrins expanding range of products, the potential applied to the method of BNCT. Used derivatives of 5,10,15,20-tetraphenylporphyrin and natural gemin - iron complex of protoporphyrin IX, which was introduced into the condensation with various carborane.

Due to the complexity of the molecules of porphyrins and carboranes structure of target compounds can vary both the nature of the relationships and types of ionic structures, which of course can affect the activity of the compounds as antitumor agents. To improve this ability derivatives of porphyrins have been modified with the introduction of the coordination sphere of the metal atom. Previous studies have confirmed the effectiveness of metal complexes of carboranylporphyrins for certain types of tumors (Miura M., Joel D. D, Nawrocky, M. M, Micca R. L., Fisher, C. D., Heinrichs J. C., Rising C. E., Walker, W., Slatkin, D. N. Carborane-containing metalloporphyrins for BNCT // Advances in Nove natural or synthetic porphyrins. In the description of the invention provides several types of data connections.

Example No. 1 1,3,5,8-Tetramethyl-2,4-divinyl-6,7-di[2'-(m-carboran-9-yl)methoxycarbonylethyl]porfiriato iron (III) (1a).

To a solution of 100 mg (0.15 mmole) protohemin in 8 ml of methylene chloride and 8 ml of pyridine, cooled to 0C, add 100 mg (0.46 mmole) of ditretbutilfenol and stirred for 10 minutes Then add 9-hydroxymethyl-m-carboran and after five minutes, 10 mg of 4-dimethylaminopyridine. The reaction mass is stirred for 4 hours After removal of the solvents in vacuo the product produce by using column chromatography on silica gel. Output: 102,7 mg (71%).

Electronic spectrum (l3),maxnm (10-3): 643 (5.22); 542 (10.78); 511.4 (11.19); 389.2 (99.00). IR-spectrum (KBr),cm-1: 2590 (EXT), 1713 (CO), 1602 (-CH=CH2). Mass spectrum, m/z: 964 [M+].

According to this method, the obtained compounds 1B,1D, 1D, 1E.

1,3,5,8-Tetramethyl-2,4-divinyl-6,7-di[2'-N-(o-carboran-3-yl)CT-Samolety]porfiriato iron (III) (1B). Output: to 86.7 mg (62%).

Electronic spectrum (l3),maxnm (10-3): 642.2 Mass spectrum, m/z: 933 [M+].

Example No. 2 1,3,5,8-Tetramethyl-2,4-divinyl-6,7-di[2'-(Nido-7,8-di-carboran-3-yl)carbamoylethyl]porfiriato iron (III) tetrabutylammonium (1B). To a solution of 50 mg (0.05 mmole) of (1B) in 15 ml of tetrahydrofuran was added 39.2 mg (0.15 mmole) and tetrabutylammonium boil for 4 hours. Autogreet tetrahydrofuran, washed with excess of 15 ml of water, filtered, the precipitate is dried. Output 47.5 mg (85%).

Electronic spectrum (l3),maxnm (10-3): 588.0 (0.38); 512.4 (1.18); 415.4 (17.07). IR-spectrum (KBr),cm-1: 2522 (EXT), 1725 (CO), 1656 (-CH=CH2). Mass spectrum, m/z: 1118 [M+].

A similar technique has also been obtained compound 1G, 1l, 1m, 1N.

1,3,5,8-Tetramethyl-2,4-divinyl-6(7)-[2'-(closo-monocarbon-1-yl)-methoxycarbonylethyl]-7(6)-(2'-carboxyethyl)porfiriato iron (III) (1G). Output 65.8 mg (57%).

Electronic spectrum (l3),maxnm (10-3): 642.8 (3.82); 539.6 (7.05); 510.6 (7.37); 389.4 (85.79). IR-spectrum (KBr),cm-1: 2560 (EXT), 1737 (CO), 1649 (-CH=CH2). Mass spectrum, m/z: 770 [M+].

1,3,5,8-Tetramethyl-2,4-divinyl-6(7)-[2'-phenyl,2'-(closo-monocarbon-1-yl)methoxycarbonylethyl]-7(6)-(2'-carbox the max nm (10-3): 642.2 (1.81); 543.6 (3.86); 511.2 (4.19); 387.4 (37.70). IR-spectrum (KBr),cm-1: 2531 (EXT), 1726 (CO), 1624 (-CH=CH2, Ph). Mass spectrum, m/z: 846 [M+].

1,3,5,8-Tetramethyl-2,4-divinyl-6(7)-[2'-(closo-monocarbon-1-yl)-methoxycarbonylethyl]-7(6)-[2'-N-(o-carboran-3-yl)carbamoylethyl]porfiriato iron (III) (1E). Output 37.4 mg (63%).

Electronic spectrum (l3),maxnm (10-3): 592 (0.91); 553 (0.87); 492 (4.45); 411 (2.45); 361.8 (3.89). IR-spectrum (KBr),cm-1: 2587 (EXT), 1682 (CO). Mass spectrum, m/z: 911 [M+].

Example 3 [2-(1'-closo-o-methylcarbamoyl)hydroxymethyl-5,10,15, 20-tetraphenylporphyrinate] copper(II) (1G).

To a solution of 70 mg (0.1 mmol) of copper complex of 2-formyl-5,10,15,20-tetraphenylporphyrin in 10 ml of tetrahydrofuran is added at 20With the suspension nitipaisalkul (obtained by addition of the benzene solution of utility 0.3 ml (0.4 mmol, 1.3 M) to a solution of 63 mg (0.4 mmol) of close metalcarbon 0.4 mmol close-carboran in 5 ml of tetrahydrofuran in a stream of argon), stirred for 1 hour in a stream of argon.

The reaction was poured into 15 ml of water, extracted with methylene chloride (3*5) ml.

Dissolve>),maxnm, (10-3): 419.0(158.5), 544.4(9.3), 583.4(3.8). IR spectrum (film),cm-1: 3615(HE), 2983 (CH porphyrin), 2576 (NR). Mass spectrum, m/z: 861,5 [M-1]+

A similar technique was also derived compounds 1H, 1i, 1K. [2-(1'-closo-m-isopropylcarbonate) hydroxymethyl-5,10,15,20-tetraphenylporphyrinate] copper(II) (1Z). Yield 51 mg (57%).

Electronic spectrum (l3),maxnm, (10-3): 421.2(145.6), 547.0(8.9), 584.3(3.6). IR spectrum (film),cm-1: 3605(OH), 2960 (CH porphyrin), 2590 (NR). Mass spectrum, m/z: 890.5 [M]+

[2-(1'-closo-o-methylcarbamoyl)hydroxymethyl-5,10,15,20-tetraphenylporphyrinate] cobalt(II) (1i). Yield 40 mg (46%).

Electronic spectrum (l3),maxnm, (10-3): 415.1(127.0), 545.6(22.4), 587.3(12.7). IR spectrum (film),cm-1: 3610(OH), 2975 (SN porphyrin), 2580 (NR). Mass spectrum, m/z: 858 [M-1]+.

[2-(1'-closo-m-isopropylcarbonate) hydroxymethyl-5,10,15,20-tetraphenylporphyrinate] cobalt(II) (1K). Yield 48 mg (54%).

Electronic spectrum (l3),cm-1: 3630 (HE), 2840 (SN porphyrin), 2610 (NR). Mass spectrum, m/z: 886 [M-1]+

[2-(1'-Nido-o-methylcarbamoylmethyl) hydroxymethyl-5,10,15, 20-tetraphenylporphyrinate] copper(II) (1l). Yield 36 mg (65%).

Electronic spectrum (l3),maxnm, (10-3): 418.6 (120.4), 542.8 (6.8). IR-spectrum (KBr),cm-1: 2966, 2874 (SN porphyrin), 2519 (NR). Mass spectrum, m/z: 1096 [M+1]+

[2-(1'-Nido-m-isopropylcyclopentadienyl) hydroxymethyl-5,10,15,20-tetraphenylporphyrinate] cobalt(II) (1m). Yield 38 mg (67%).

Electronic spectrum (l3),maxnm, (10-3): 414.8 (111.5), 535.6 (19.5). IR-spectrum (KBr),cm-1: 2967, 2926 (CH porphyrin), 2531 (NR). Mass spectrum, m/z: 1126 [M+]

All the metal complexes of carboranylporphyrins were isolated using column chromatography as microcrystallin dark red color, soluble in chloroform, methylene chloride, acetone, dimethyl sulfoxide, methanol and slightly soluble in water. Below are the results of testing the anticancer activity of the main representatives of the new metallotorgkomplekt of carboranylporphyrins for cultivated lines of human tumor cells A (adenocarcinoma of the lung) and C (leukemia). In parallel experiments tested the toxicity of these compounds to non - neoplastic cells of the primary culture of fibroblasts of human skin (FCC). The substance was dissolved in dimethyl sulfoxide to a concentration of 10 mm. Further cultivation was carried out in aqueous media; the final concentration of DMSO in the cell culture did not exceed 0.1% and had no effect on cell viability. Cell death, determined to restore the cells 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenyltriazene (MTT-test) [Mossman, 1983], was detected after 72 h incubation of cells with complexes of carboranylporphyrins.

At the first stage of testing was necessary to confirm that the metal complexes of porphyrins possess no less cytotoxicity than the original tetraphenylporphyrin. Indeed, the introduction of the si in the coordination sphere of tetraphenylporphyrin allowed to get a few more active compound (Fig. 1). This experiment established the possibility of using metal complexes of porphyrins for the induction of tumor cell death.

Next, the tested compounds are representatives of the main groups of the claimed substances. In Fig.2 presents a comparison of antitumor activity 1,3,5,8 for (1G), and-o-methyl- (1l), m-isopropyl-closo- (1G) and Nido- (1Z) carboranylmethyl copper complex of tetraphenylporphyrin. Such a selection of compounds for biological testing due to the fact that 1G is a derivative of natural compounds - protohemin and 1G-l are derived synthetic tetraphenylporphyrin. Was that the greatest activity had a connection 1Z (concentration that causes death of 50% of the cells (LD50) amounted to about 13 μm) (Fig. 2). Substances 1G and 1l also caused cell death A in low micromolar concentrations(Fig. 2).

Finally, we studied the toxicity of the most active derivative - 1H - tumor (C) and nonneoplastic (FCC) cells. It is important that this copper carboranylporphyrins was nontoxic to FCC at concentrations up to 100 μm for 72 h of incubation, whereas the same substance caused cell death C lower dose: LD50about 10 μm (Fig. 3). Only in high concentrations (about 100 μm), in which carboranylporphyrins formed precipitates in the aquatic environment, magisteriate connection 1Z caused a slight decrease in survival of non-neoplastic fibroblasts.

Thus, the predominant activity of new carboranylporphyrins promising for further research as antitumor agents.

Captions to drawings

Cytotoxicity of new metal complexes of carboranylporphyrins for cell lines A (Fig.1-2), C and PKC (Fig.3).

Fig.1: increase in toxicity when the metallation of DFT; Fig. 2: comparative activity of the metal complex of carboranylporphyrins on the basis of hemin (1G) and a copper-containing carboranylporphyrins (1G-l); Fig.3: - toxicity 1Z for tumor (C), but not to non-neoplastic (FCC) cells. Cytotoxic activity of compounds was determined in the MTT-test (96-well format).

Claims

The metal complexes of carboranylporphyrins General formula

where Ia: R=H; R1=R3=R5=R8= -CH3; R2=R4= -CH=CH2; R6=R7=m-C2B10H11-CH2-COO-(CH2)2-; M=Fe+

IB: R=H; R1=R3=R5=R8= -CH3; R2=R4= -CH=CH2; R6=R7= o-C2B10H11-NH-CO-(CH2)2-; M=Fe+

IB: R=H; R1=R3=R5=R8= -CH3; R2=R4= -CH=CH2;

; M=Fe+

Iك: R=H; R1=R3=R5=R8= -CH3; R2=R4= -CH=CH2; R6(R7)= -(CH2)23=R5=R8= -CH3; R2=R4= -CH=CH2;

R6(R7)= -CH2CH2COOH; M=Fe+

S: R=H; R1=R3=R5=R8= -CH3; R2=R4= -CH=CH2; R6(R7)= o-C2B10H11-NH-CO-(CH2)2-

R6(R7)= -(CH2)2-COO-CH2-CB11H-11; M=Fe+

If: R=C6H5;;

R2=R3=R4=R5=R6=R7=R8=H; M=Cu

Z: R=C6H5;;

R2=R3=R4=R5=R6=R7=R8=H; M=Cu

AI: R=C6H5;;

R2=R3=R4=R5=R6=R7=R8=H; M=Co

IK: R=C6H5;;

R2=R3=R4=R5=R6=R7=R8=H; M=Co

Il: R=C6H5;;

R2=R3=R4=R5=R6=R7=R8=H; M=Cu

Ei: R=C6H5;;

R2=R3=R4=R5=R6=R7=R8=H; M=Co,

with antitumor activity.

 

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