The cyclopalladate complexes of imidazoline (Imd) derivatives [PdCl2 (C6H5CH2C3H5N2)2] and [PdCl(SEt2)(C6H4-C3H5-N2)2] exhibited important cytotoxic activity against HL-60, with IC50 values, lower than 10 mg/ml, close to those of cis-DDP and considerably higher than the free ligand. Thus, the cytotoxic activity of free Imd increased upon coordination with Pd(II).41
Two diastereomeric cyclopalladated complexes arising from [Pd2(mpba)2(m-OAc)2] (mpba is 4-methoxy-benzoylbenzylideneimine, Figure 21.8b) were isolated, characterized, and tested against colon CX-1 and lung LX-1 human tumor cells, with compound II more active than I. The two complexes differ in the orientation of their benzoyl groups and this may also explain the higher activity of II over I.42
The orthopalladated complexes [Pd(C2-dmba)(N3)(dppe)] and [Pd(C2-N-dmba)(cis-dppet)](N3) (dmba is N,N'-dimethylbenzylamine) were found to be the most active against a panel of three human cancer cell lines (Hela, Hep-2 and C6) among a series of synthesized complexes containing the azido group (N3) and diphosphines. The IC50 values were 1.0, 1.8 and <0.5 mM and 1.75, 2.20 and 0.85 mM, respectively.43 Also, the complexes [Pd(S(-)(C2,N-dmba)(dppe)]-Cl2, [Pd(S(-)(C2,N-dmba)2(m-dppe)]Cl2 and [Pd2(R(-)(C2,N-dmba)2 (m-dppe)]Cl2 showed activity against B16-Nex2 cells in a dose, for 100% cell death in vitro with IC50 <1.25 mM44 (Figure 21.8d).
The dimers [Pd(cpba)X]245 and [Pd(bpba)X]246) (cpba is N-(4-chlorophenyl)-a-benzoylbenzylideneamine, bpba is N-(4-methoxyphenyl)-a-benzoylbenzyl-ideneamine and X is Cl or OAc) were tested against the MDA-MB 468 (breast carcinoma) and HL-60 cell lines. The m-Cl bridged complex with cpba was active with IC50 values close to that of cis-DDP.
Pd P Ph
Pd P Ph
[Pd(C2,N-dmba)(c/s-dpet)](N3) Pd(C2-dmba)(N3)(dppp) (d)
NHCH Ph NHCH Ph
Palladium(II) halide complexes containing the diethyl and di-n-butyl esters of (a-anilino-N-benzyl)phosphonic acid and [a-(4-benzeneazoanilino)-N-benzyl] phosphonic acid of formula trans-PdL2X2 (L is these ligands and X is Cl, Br) are mononuclear (Figure 21.8g). By contrast, ligands containing azobenzene form binuclear organopalladium complexes with chloro-bridges, [Pd(L-H+)Cl]2. All complexes were found to be active against KB and L1210 cell lines. The most active was Pd(diethyl-a-benzeneazoaniline-N-benzyl-phosphonate)2Cl2 with IC50 values near 0.70 mM, comparable to those of cs-DDP.47
The dimeric complexes of Pd(II) with putrescine (put), [Pd2(put)2Cl4] and [putH2][PdCl4], and spermine (sperm), [Pd2(sperm)Cl4] and [PdCl2 (spermH)2][PdCl4] (Figure 21.9e) were assayed for in vitro anti-proliferative activity against MDA-MB468 and HL-60 human cancer cells. The putrescine complexes had IC50 values twofold lower than that of cis-DDP, but not those containing spermine.48 However, the spermidine compounds of formulae [Pd(sperH)2][PdCl4] and [(PdCl2)3(sper)2] were very active against MDA-
MB468 (human breast) cancer cell line with ID50 values, similar or even lower to those of cis-DDP (0.76 mg/ml, 0.56 mg/ml, and 0.80 mg/ml respectively49).
The anti-tumor properties against L929 (murine fibroblastoma), K562 (human myelogenous leukemia) and Hela cell lines of the enantiomerically pure trans-PdCl2[(R)(—)bornylamino]2 complex showed that its activity against Hela was comparable to those of cisplatin, carboplatin and oxalilplatin.50
Complexes of general formula [Pd(NnN)(XO3)] (NnN is 1,10-phenanthro-line, 2,2'-dipyridylamine, ethylenediamine or (+/—)-trans-1,2-diaminocyclo-hexane and XO3 is [SeO3]2— or [TeO3]2—) were tested against P388 cells. While the selenides showed ID50 values lower than cisplatin, the tellurides usually had higher values.51
The mixed ligand complexes of formulae [Pd(dach)(3-methylorot)] and [Pd(dach)(5-fluoro-orot)] (dach is 1,2-diaminocyclohexane and orot is orotic acid) were found to be active against sarcoma 180 cell lines with T/C = 270% and 267%, respectively, compared with 277% for cisplatin (T is the median survival time of treated mice, C is the median survival time of the control). It is worthwhile mentioning that the corresponding Pt(II) complexes were inactive and this result was attributed to the slow hydrolysis of the Pd(II) and the non-hydrolysis of the Pt(II) complexes.3
The 2-quinolylmethylphosphonate (2-dqmp) complexes of Pd(II) of formulae [(2-Hdqmp)][PdCl4] and [Pd(2-dqmp)X2] (X is Cl, Br) were found to be active against KB and L1210 cell lines, with the dimeric [Pd(2-dqmp)Br2]2 complex being the most active.52
The dipalladium complex [Pd2(m-meso-N3, N4)2(phen)2](NO3)2 (phen is 1,10-phenanthroline, Hmptpo is 5,7-dihydro-7-oxo-5-methyl[1,2,4]triazolopyrimi-dine) showed high activity against TG ovarian carcinoma and notable activity against BT-20 breast carcinoma.53 It was more active than cisplatin and carboplatin.
Complexes of formula [Pd(L)]Cl2 [L is N,N'-dimethyl-1,10-phenanthroline-2,9-dimethanamine (L1) , N,N'-diethyl-1,10-phenanthroline-2,9-dimethanamine (L2), N,N'-dipropyl-1,10-phenanthroline-2,9-dimethanamine (L3), N,N-di-tert-butyl-1,10-phenanthroline-2,9-dimethanamine (L4), or N,N'-dicyclohexyl-1, 10-phenanthroline-2,9-dimethanamine (L5)] were tested against mouse L1210 and Bel-7402 (liver carcinoma) tumor cells and were found active, with their activity dependent on the nature of L. The ID50 values of the complexes with ligands L3, L4 and L5 against L1210 were 11.59, 10.26 and 8.20 mM, respectively (cisplatin, 15.33 mM) and against Bel-7402 were 10.62 mM, 9.53 mM and 8.20 mM, respectively (cisplatin, 23 mM).54
Only one of the four complexes of formulae [Pd(ethylenediamine)LCl](NO3) (L is pyridine (py), 4-methylpyridine, 4-hydroxypyridine or 4-aminopyridine), namely [Pd(en)(py)Cl](NO3), was found active against HL-60 cell lines with an ID50 value of 1.17 mM comparable to that exhibited by cisplatin (1.07 mM).55
The amino acid derivatives of formula [Pd(L)(amac)]Cl (L is 2,2-dipyridy-lamine or 1,10-phenanthroline, amac is the anion of the amino acids Gly,
L-Ala, L-Leu, L-Phenala, L-Tyr, L-Trp, L-Val, L-Pro, and L-Ser) were screened for cytotoxicity against P388 cells. The complex [Pd(dipy)(L-Ala)]Cl was found more active than cis-DDP, while [Pd(phen)(Gly)]Cl and [Pd(phen)(L-Val)]Cl showed comparable activity.56,57 However, the complexes [Pd(phen) (L-Trp)]Cl-5H2O and [Pd(5-NO2-phen)(L-Trp)]Cl-5H2O showed anti-cancer activity against the lung cancer cell AZGY-83a with IC50 values of 0.25 and 0.44mM, respectively.58
The synthesis, characterization and cytotoxic properties of complex trans-[Pd(harmine)(DMSO)Cl2] (harmine is an alkaloid) were tested against the P388, L1210 and K562 cell lines. The IC50 values for the complex, cis-DDP, carboplatin and 5-FU in mM were (a) against P388: 0.385, 0.500, >27, 1.15; (b) against L1210: 0.385, 0.833, >27, 1.15; and (c) against K562: 0.364, 20.0, 27.0, not tested.59
The cytokinin-derived compounds bohemine (Boh) (6-(benzylamino)-2-[(3-(hydroxypropyl)amino]-9-isopropylpurine) and olomoucine (Olo) (6-(benzy-lamino)-2-[(2-(hydroxyethyl)amino]-9-methylpurine) were used as ligands in Pd(II) complexes to screen against G3G1 (human malignant melanoma), HOS (human astrogenic sarcoma), K562 and MCF-7 (human breast adeno-carcinoma). (Figure 21.9k). The complexes [Pd(BohH(+))Cl3]H2O, [Pd(Boh) Cl2(H2O)], [Pd(Boh-H+)Cl(H2O)2] EtOH were found active.60 For the G3G1 cell line, the most active complex was [Pd(Boh-H+)Cl(H2O)2]EtOH but the IC50 value was high at 26 mM compared with 3 mM for cis-DDP. For MCF-7, the IC50 value of the same complex was close to that exhibited by cis-DDP.
The complexes of Pd(II) with mitomycine (MMC, an anti-tumor agent) with formula [Pd(MMC)Cl2] maintained an anti-tumor activity against K562 leukemia cells as compared to the free ligand (IC50 = 15.8 ± 5.3 mM for the complex and 1.0 ± 0.3 mM for the free ligand).61 Similarly, the complex of Pd(II) with the anti-tumor antibiotic Altromycin B was the most active against K562 leukemia and GLC4 lung tumor cell lines (resistant to deoxorubicin-RRD).62 The IC50 value for the Pd(II) complex was 6.9 ± 1.5 nm and of the free ligand 3.8 ± 0.3 nm in K562 leukemia-resistant cell lines. For GLC4 lung tumor resistance lines, the values were 1.4 ± 0.1 nm for the complex and 1.1 ± 0.2 nm for the free ligand.
The complexes [Pd2(bipy)2(dsa)]Cl2 and [Pd2(bipy)2(daa)]Cl2 (dsa is the dianion of meso-a-a'-diaminosuberic acid and daa is the dianion of meso-a-a'-diaminoadipic acid) were tested against P388 cells. They showed ID50 values comparable or lower than cis-DDP.63
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