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Thiosemicarbazones

Thiosemicarbazones and other sulfur-containing ligands have been used to prepare Pd(II) complexes with possible anti-tumor properties. Such ligands are included in Figure 21.7a-h.

Thiosemicarbazones have anti-tumor properties in their own right, and this activity was found to increase in their complexes with Pd(II).

Thus, the reaction of p-isopropylbenzaldehyde thiosemicarbazone (p-isoTSCN) with Pd(II) acetate yielded two tetrameric orthopalladate isomeric complexes of formula [Pd(p-isoTSCN)4] with a CNS2 donor environment around the metal.6 The complexes were found active in several types of tumor cell lines (for the most active isomer values of IC50 ± SD in mM/vs cis-DDP: Jurkat (human T-cell leukemic cell line) 7 ± 0.3/22 ± 3, Hela 4 ± 0.1/7 ± 0.5, 3T3 3 ± 0.2/35 ± 2 and PAM (normal murine Keratinocytes cell line) 8 ± 0.3/ 164 ± 8). With the Pam-Ras (normal murine Keratinocytes cell line transformed with the H-ras ongogen) tumor cells resistant to cis-DDP, this Pd(II) isomer was 33 times more active than cis-DDP (the IC50 ± SD in mM/vs cis-DDP: Pam-Ras 5 ± 0.3/165 ± 5).6 All three complexes exhibited higher cyto-toxic activity than the drugs etoposide and adriamycin in the cis-DDP resistant cell lines.6

The binuclear complex [Pd(p-isoTSCN)(m-Cl)]2 shows IC50 values of the same range as cis-DDP, and it also displays cytotoxic activity against tumor cell lines resistant to this drug.28

Cyclometallated Pd(II) complexes of substituted thiosemicarbazones such as [Pd(p-isoTSCN-NHMe)] and [Pd(p-isoTSCN-NHex)]4 show specific cytotoxic properties (apoptosis induction) in tumor cells transformed by cis oncogenes (Pam-212-ras) resistant to cis-DDP.29 Similarly, the complexes Pd(phenylacet-aldehyde thiosemicarbazone)Cl2 and its Pt(II) analogue exhibit IC50 values higher than cis-DDP, etoposide and adriamycin against several tumor lines sensitive to cis-DDP [(HL-60 (human myeloid leukemia cell line), U-937 (human monoblastic cell line), Jurkat, Hela)] and resistant to cis-DDP (Pam-Ras).30

The polymeric complex [Pd(ESDT)Cl]n, where ESDT is ethyl ethylamino-acetate dithiocarboxylate, with the ligand bound to Pd(II) using two sulfur atoms, one of which coordinates to Pd(II) of a neighboring complex, in a ClS3 donor environment, demonstrated markedly greater cytotoxicity than cis-DDP in resistant tumor cell lines, such as human ovarian carcinoma cells and C13 adenocarcinoma cells. However, this cytotoxicity is not useful owing to the high nephrotoxicity induced by the complex.31,32 In addition, the mixed ligand complex [Pd(ESDT)(PrNH2)Cl], with ClNS2 donor atoms, showed a similar

Me Me

R = NHCH3 = p-iso-TSCN-NHMe R = N(CH3)2 = p-iso-TSCN-NMe2

p-iso-TSCN-Hex

on2 s Cl

Me s Py

ESDT

TSTDM

S^NHR

Me N

H2N SH HS NH2 H2N SH

HS NH2 H2N SH

Ph Ph N

HS NH2

H2L2

H2L4

H2L3

Figure 21.7

activity to that of [Pd(ESDT)Cl]n32, while the complex [Pd(ESDT)(py)Cl] was characterized by IC50 values of 3.11 ± 0.13 for HL-60 and 5.61 ± 1.01 for Hela cell lines, lower than those of cis-DDP of 3.40 ± 0.11 and 6.33 ± 0.11, respectively.32

Of the two complexes of formulae [Pd(TSDTM)X2] (X is Cl or Br) and [Pd(TSDT)X]4 (TSDTM is tert-butylsarcosine (S-methyl)dithiocarbamate and

TSDT is tert-butylsarcosinedithiocarbamate) tested against HL-60 and adeno-carcinoma Hela cells, the former were completely inactive and only the complex [Pd(TSDT)Br]n showed an IC50 value comparable to that of cis-DDP (IC50 (mM) ± SD 5.20 ± 0.99 for HL-60 and 11.01 ± 0.43 for Hela cells).33

The Pd(II) complexes of formulae [Pd(AcN(4)alkyl)X2] and [Pd(AcN(4)-alkyl)2]X2 (AcN(4)alkyl is 2-acetylpyridine N(4) alkyl thiosemicarbazone and X is Cl or Br) inhibited DNA synthesis in P388 lymphoblastic leukemia and L1210 lymphocytic leukemia cell cultures. More particularly (i) the two complexes differ in their activity from the free ligands, (ii) the chlorides were more cytotoxic than the bromides, and (iii) the less toxic and most effective against P388-bearing BDF1 mice was the complex [Pd(AcN(4)Et)2].34

The two complexes [Pd(pyTSC)Cl] and [Pd(pyTSC)2] (pyTSC is pyridine-2-carbaldehyde thiosemicarbazone) with an N2S2 environment around Pd(II) were tested in vivo for anti-tumor activity. [Pd(pyTSC)2] showed eight times higher activity than the free ligand.

Thiosemicarbazone derivatives (Figure 21.7h) of H2L2, H2L3 and H2L4 of formulae [PdCl2(H2L2)], [PdCl2(H2L3)] and [Pd(L4)] were screened against several human, monkey and marine cell lines (Hela, Vero (cells derived from the kidney of Cercopithicus aethiops), and Pam 212) and resistant (Pam-ras) to cis-DDP. The [Pd(L4)] complex showed IC50 values similar to those of cis-DDP and exhibited notable cytotoxic activity in Pam-ras cells resistant to the drug.35

Other sulfur-containing ligands

Of the first Pd(II) complexes found to be active against 9KB, a human epiderm-oid carcinoma of the nasopharynx, was the one with the anionic form of the acetone Schiff base of S-methyldithiocarbazate (asme) of formula [Pd(asme)2].4 Both complexes [Pd(asme)2] and [Pd(asbz)2] (asbz is the anionic form of the acetone Schiff base of S-benzyldithiocarbazate) were active against T-lympho-plastic leukemia cells, with IC50 values of 2.5 and 2.9 mg/cm3, respectively. It should be mentioned, however, that the corresponding [Pt(asme)2] and [Pt(asbz)2] complexes exhibited only a very weak activity against the same leukemic cells.4

The mixed ligand complex of Pd(II) with diethyldithiocarbamate (ddtc) and bidendate aromatic donors of formulae [Pd(ddtc)L] (L is 1,10-phenanthroline or 2,2'-bipyridine) were active against leukemia cells.36 Similarly, Pd(II) complexes of dithiocarbamate, thiomorpholine, piperidine and morpholine, their methyl esters and the corresponding thiuramdisulfides showed noticeable cyto-static activity against KB, L1210 and P388 cells.37,38

Carrara etal.39 tested the complex [Pd(MPH)3X]X (X is Cl or Br and MPH is 6-mercaptopyridine), isostructural to the corresponding Pt(II) complexes, against the tumor cell lines F10 (hybridoma), Fohn (renal cell carcinoma), LoVo (human colonic carcinoma), Hela and 3T3 (aneuploid murine cell line). The most active was [Pd(MPH)3Br]Br especially against LoVo cells.

The mixed ligand complexes of Pd(II) with cis-dichloromethionine, 2-mer-captopyrimidine and 2-aminopyrimidine were characterized and screened in vitro for anti-tumor activity against Hela and CHO cell lines, and were found active.17 A correlation between the anti-tumor activity of Pd(II) complexes and their ability to cure plasmids exists.17

Finally, the complexes Pd(L-L)(SR)Cl: (L-L = Ph2PCH2CH2PPh2 (dppe) or Ph2AsCH2CH2PPh2 (dadpe); RSH glutathione, L-cysteine or N-acetyl-L-cysteine) have been prepared and the glutathione complexes were tested against the cell lines L1210, ADJ/PC6 (murine plasmocytoma) and CH1 (human ovarian carcinoma). The cytotoxicities toward L1210 cells were comparable to those of the parent dichlorocomplexes.40 They could be useful in combination therapy with established drugs, such as cis-DDP.

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