Copper Purine Derivatives Complexes

The synthesis, characterization and biological (anti-tumour and anti-proliferative) activity of new mononuclear or binuclear copper(II) complexes with 6-(2-chlorobenzyl-amino)purine (HL1) (A) and 6-(3-chlorobenzylamino)purine (HL2) (B) (Scheme 12.1) have been reported by Travnycek etal.,22 the composition of the complexes depending on the molar ratio of the reactants and the pH of the medium. The mononuclear complex [Cu(H+L2)2Cl3]Cl • H2O (1) was isolated and green-blue crystals suitable for single-crystal X-ray analysis were obtained. On the other hand, binuclear complexes of composition [Cu2(m-Cl)2(m-L1)2(H2O)2] (2) and [Cu2(m-HL02(m-Cl)2(HL1)2Cy (3) were characterized and studied. From all the obtained data and comparison with crystallographic parameters observed for similar complexes,23 their structures were proposed.

Biological activity testing against mouse melanoma cell line B16-F0, human malignant melanoma cell line G361, human osteogenic sarcoma cell line HOS and human breast adenocarcinoma cell line MCF7 were performed for the three complexes, using a calcein AM assay, in which the incubation of cells with

Scheme 12.1

the tested complexes lasted for 72 h at 37 °C in 5% CO2 atmosphere. At the end of this period, the cells were incubated for 1 h with calcein AM and the fluorescence of the live cells was measured. Inhibition of p34cdc2 kinase by the complexes was assayed as described previously.24 The stability of the tested complexes in the media used was monitored by measurement of UV-V spectra. No significant changes in the maxima of the absorption peaks were observed after 24 h.

Both the anti-tumour and p34cdc2 inhibitory activities of the complexes and the starting compounds, i.e. CuCl22H2O, HL1 and HL2, were assayed in in vitro kinase and cytotoxicity assays, respectively. The data obtained from a cyto-toxicity assay are presented in Table 12.1. All the tested complexes are shown to be potent growth inhibitors of the different cancer cell lines used. The IC50

Table 12.1 IC50 values (mM) for selected complexes assessed by a calcein AM assay of surviving tumour cells compared with the values found for CuCl2-2H2O, HL^ HL2 and Bohemin, respectively

Cell line

Table 12.1 IC50 values (mM) for selected complexes assessed by a calcein AM assay of surviving tumour cells compared with the values found for CuCl2-2H2O, HL^ HL2 and Bohemin, respectively

Cell line

Compound

B16-F0

G361

HOS

MCF 7

1a

17

59

69

54

2a

8.5

31

29

30

3a

8.2

20

23

24

CuCl2-2H2O

100

>100

>100

>100

HL1

85

95

>100

>100

hl2

>100

>100

>100

>100

Boheminb

c

c

46

53

aThe studied complexes were sufficiently soluble in the solvent mixture (DMSO/water) needed for testing.

b6-(Benzylamino)-2-[(3-hydroxypropyl)amino]-9-isopropylpurine. cNot tested.

aThe studied complexes were sufficiently soluble in the solvent mixture (DMSO/water) needed for testing.

b6-(Benzylamino)-2-[(3-hydroxypropyl)amino]-9-isopropylpurine. cNot tested.

values for CuCl2 • 2H2O, HL1 and HL2 obtained on all used cell lines were found to be remarkably higher than those for the appropriate Cu(II) complexes. This indicates that the cytotoxic activity of the ligands strongly increases after the formation of the Cu(II) complexes. The most sensitive to the assayed compounds were B16-F0 mouse melanoma cells, displaying cytotoxicities with IC50 in the range from 8.2 to 19 mM. G361, HOS and MCF7 cell lines were usually less sensitive, with IC50 values ranging from 20 to 88 mM. Surprisingly, the values obtained for HOS and MCF7 cell lines were in many cases lower than those found for the best-known cytokine-derived cdk inhibitor, Bohemin (Table 12.1). Moreover, for the G361 and HOS cell lines, the mononuclear complex 1 was found to be several times less potent than tested binuclear Cu(II) species 2 and 3.

The inhibition of crude p34cdc2 kinase by complexes 2 and 3 was also estimated. The data obtained are shown in Table 12.2. The IC50 values are significantly lower than those previously reported for the two structurally similar Ni(II) complexes, for which larger inhibitory values (80 and 110 mM, respectively) were found.24 In conclusion, the prepared complexes exhibit considerable anti-cancer activity, and studies are continuing to explore their possible clinical use.22

Travnycek etal.25 prepared also a new dimeric Cu(II) complex with the ligand HL2 (B) (see Scheme 12.1), of composition [Cu2(m-Cl)2(m-HL2)2Cl2] (4) and with a structure similar to that of complex 2; two chloride ions replacing two water molecules, and two ligands HL2 connecting the central atoms through N(3) and N(9) atoms of HL2.

Anti-tumour activity of complex 4 was determined using the cytotoxicity assay mentioned above. Obtained data (Table 12.3) show that this complex is a potent growth inhibitor of the same cancer cell lines tested for previous copper complexes and the human chronic myelogenous leukaemia K562. Surprisingly, formation of Cu(II) complexes had even stronger impact on anti-tumour activity than the non-toxic compound HL2: the IC50 values found for complex 4 were in the range from 32 to 39 mM, whereas the lowest IC50 value determined for the starting compounds HL2 and CuCl2 • 2H2O was 100 mM.

Table 12.2

IC50 values for tested compounds added to crude p34cdc2 kinasea

Compound

IC50 (mM)

Boheminb

1.2

2

15

3

10

BAPc

200

aIC50 values were subtracted from the dose-response curves. b6-(Benzylamino)-2-[(3-hydroxypropyl)amino]-9-isopropylpurine. c 6-Benzylaminopurine.

aIC50 values were subtracted from the dose-response curves. b6-(Benzylamino)-2-[(3-hydroxypropyl)amino]-9-isopropylpurine. c 6-Benzylaminopurine.

Table 12.3 IC50 values (mM) assessed by a calcein AM assay of surviving tumour cells (complex 4) compared with the values found for CuCl2 ■ 2H2O and HL2

Compound

Cell line

K562

G361

HOS

MCF7

4

32

36

38

39

CuCl2 ■ 2H2O

100

>100

>100

>100

hl2

>100

>100

>100

>100

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