Antitumor and DNA-binding properties of a group of oligomeric complexes of Pt(II) and Pt(IV)

The antitumor and DNA-binding properties of a group of oligomeric platinum(II) and platinum(IV) complexes are described. The compounds, having the stoichiometry [cis-PtII(X)2(mu-OH)]2(NO3)2, where X is NH3, NH2CH2CH3, and NH2CH(CH3)2, were found to be inactive or only weakly active against L-1210 leukemia. In vitro studies involving PM2-DNA show that these compounds bind to and unwind closed circular DNA in a manner similar to cis-PtII-(NH3)2Cl2. The Pt(IV) complexes produced by hydrogen peroxide oxidation of the Pt(II) dimers are inactive as antitumor agents and are incapable of unwinding PM2-DNA. The cyclotrimer [cis-PtII(RR-DACH)(mu-OH)]3(NO3)3, where RR-DACH is (R,R)-1,2 diaminocyclohexane, exhibits potent antitumor activity against L-1210 leukemia and modest activities with B-16 and M5076 tumor lines. This compound platinates DNA, causing DNA unwinding and mobility shifts.     

Chemical and biological studies on a series of lipid-soluble (trans-(R,R)- and -(S,S)-1,2-diaminocyclohexane)platinum(II) complexes incorporated in liposomes

cis-Bis(neodecanoato)(trans-(R,R)-1,2-diaminocyclohexane)platinum( II) [L-NDDP] is a liposome incorporated lipophilic cisplatin analogue that has shown promising antitumor activity against tumors resistant to cisplatin and liver metastases in mice. L-NDDP is currently under clinical evaluation. However, NDDP is an isomeric mixture of different species having various isomeric neodecanoic moities as liganded leaving groups. A series of new highly lipid-soluble cis-bis(neodecanoato)(trans-(R,R)- and -(S,S)-1,2-diaminocyclohexane)platinum(II) [Pt] complexes, using single isomers of neodecanoic acid, were synthesized and characterized by analytical and spectroscopic techniques (infrared and 195Pt NMR). Multilamellar vesicles (MLVs) composed of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) at a molar ratio of 7:3 were used as carriers of the Pt complexes. The efficiency of incorporation of the liposomal-platinum (L-Pt) preparations was greater than 95% and stability in normal saline at 4 degrees C was greater than 95% at day 14 in each case. The iv LD50 values of all L-Pt preparations tested were in the range of 62.3 to 104 mg/kg. The % T/C obtained after a single ip injection of the optimal dose of L-Pt preparations against L1210 leukemia was in the range of 150 to 253 (160 for cisplatin). When a multiple ip injection schedule was used (on days 1, 5, and 9) the L-Pt preparations of R,R complexes (1, 7, and 9) were more active than cisplatin at the optimal dose (% T/C = 257 for each vs 220 for cisplatin). The L-Pt preparations of R,R complexes were also markedly active against L1210 leukemia resistant to cisplatin (% T/C 355, 231, and 185 respectively vs 112 for cisplatin). These studies show that the single isomers of NDDP are comparable to the original isomeric mixture in terms of toxicity and biological activity.     

Anticancer activity in murine and human tumor cell lines of bis(platinum) complexes incorporating straight-chain aliphatic diamine linker groups.

The biological activity of a series of dinuclear bis(platinum) complexes of formula [(cis-PtX2-(NH3)]2(NH2(CH2)nNH2)] (X = Cl, n = 4-9, compounds 6-11; X2 = malonate, n = 5 or 6, compounds 12 and 13) is described in selected murine leukemia, murine solid tumor, and human tumor cell lines and in murine leukemia cell lines rendered resistant to cisplatin (cis-[Pt(NH3)2Cl2]). The bis(platinum) compounds showed greater activity in vitro against murine tumor cell lines resistant to either cisplatin or DACH ([Pt(DACH)Cl2]). The resistance factor is dependent on chain length of the diamine, and the structural feature of a dinuclear complex is of general use in reducing cross-resistance with cisplatin. In vivo [(cis-PtCl2(NH3)]2(NH2(CH2)5NH2)] (7) showed a % T/C of 204 against murine L1210 leukemia resistant to cisplatin compared to a % T/C of 104 for cisplatin itself at optimal doses. The complex [(Pt(mal)(NH3)]2(NH2(CH2)6NH2)] (13) was highly active in the colon 26 tumor line with 3/10 tumor-free survivors (dose of 186 mg/kg, ip D1,5,9); however, 13 was subject to substantial cross-resistance in the cisplatin resistant L1210 leukemia (% T/C 139 versus % T/C of 223 in the sensitive line). In four selected human tumor lines in vitro, compounds 6-11 were uniformly more potent than cisplatin. In the corresponding xenografts, compound 7 showed greater activity in the HCT-8 (coloadenocarcinoma) and H23 (nonsmall cell lung), but diminished potency in AH125 and H520 (both nonsmall cell lung) lines in comparison to cisplatin. Retention of activity against cisplatin-resistant cell lines and a different spectrum of activity compared to cisplatin in some human tumor cell lines suggest that this class of complexes is mechanistically different from mononuclear complexes and worthy of further development toward clinical trials.     

Activity of platinum(II) intercalating agents against murine leukemia L1210

Four series of intercalating, square-planar Pt(II) complexes derived from the ligands 2,2'-bipyridine, 2,2':6',2"-terpyridine, 1,10-phenanthroline, and 3,4,7,8-tetramethyl-1,10-phenanthroline were synthesized and aspects of their activity against murine leukemia L1210 cells investigated. The 2,2':6',2"-terpyridine-thiolato complexes are growth inhibitory in culture, with IC50 values in the range 6-32 microM, and cause cell lysis at high concentrations. Of the remaining three series, the 2,2'-bipyridine complexes are the least potent in their effects. There is a general enhancement in activity on moving from the 1,10-phenanthroline complexes to the 3,4,7,8-tetramethyl-1,10-phenanthroline analogues. Flow cytometric analysis on representative complexes shows that they are not cell cycle specific. Alkaline elution experiments indicate no damage to DNA of cells exposed to (thiophenolato)(2,2':6',2"-terpyridine)platinum(II) chloride monohydrate and (ethylenediamine)(1,10-phenanthroline)platinum(II) dichloride dihydrate although (ethylenediamine)(3,4,7,8-tetramethyl-1,10-phenanthroline)platinum(II) dichloride dihydrate causes both single-strand breaks and DNA cross-links. Compounds 2a, 5a, and 6a showed no antitumor activity against L1210 in mice.     

Tumor inhibiting [1,2-bis(fluorophenyl)ethylenediamine]platinum(II) complexes. Part II: Biological evaluation-in vitro studies on the P 388 D1 leukemia cell line

Experiments on the P 388 D1 cell line (48 h exposure) demonstrate that [1,2-bis-(fluorophenyl)ethylenediamine]platinum(II) complexes are comparably active on the cell number and 3H-thymidine incorporation, irrespective of the position of the fluorine atom (ortho, meta, or para) and the nature of the "leaving group" (Cl- or H2O). However, the compounds of the R,R/S,S series are more active than those of the R,S series and comparable to cisplatin. In the "tumor colony forming assay" the R,R/S,S configurated compounds are about ten times as active as cisplatin. The R,R/S,S configurated diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) salts reach their half maximum effect more readily (t1/2 approximately equal to 1.6 h) than their R,S configurated analogues (t1/2 approximately equal to 20 h). A time limited contact of the cells with R,R/S,S configurated diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) salts (-1h) leads to a similar inhibition like a permanent drug exposure indicating a fast uptake of the complex by the tumor cell. In experiments on the Ehrlich ascites tumor of the mouse and on the L 1210 leukemia cell line R,R/S,S-[1,2-bis(4-fluorophenyl)ethylenediamine]dichloroplatinum(II) turns out to be equipotent with cisplatin.     

Synthesis, DNA binding and cytotoxicity of isohelical DNA groove binding platinum complexes

The two platinum complexes [[Pt(dien)]2mu-dpzm]4+ and trans-[Pt(NH3)2(mu-dpzm)2]2+(dpzm = 4,4'-dipyrazolylmethane) have been synthesized and their DNA binding and cytotoxicity studied in order to evaluate the potential of square-planar platinum complexes as DNA groove binding anti-cancer agents. 1H-NMR spectroscopy was used to study the binding of both metal complexes to the dodecanucleotide d(CGCGAATTCGCG)2. For both platinum complexes, a considerable number of intermolecular NOE contacts were observed in NOESY spectra of the platinum complex bound dodecanucleotide. The NOE data demonstrated that each platinum complex bound in the minor groove at the central AATT region. Neither platinum complex appeared to induce any major DNA conformation change. In vitro cytotoxicity studies in the murine leukaemia cell lines L1210 and L1210/cisR showed that trans-[Pt(NH3)2(mu-dpzm)2]2+ had some activity (IC50: 64 and 32 microM respectively) while the [[Pt(dien)]2mu-dpzm]4+ complex showed no activity at all (>200 microM). The results indicate that it may be possible to synthesize platinum complexes that are useful as groove binding agents in the treatment of cancer.     

Chemical and biological properties of a new series of cis-diammineplatinum(II) antitumor agents containing three nitrogen donors: cis-[Pt(NH3)2(N-donor)Cl]+

A series of 32 cationic platinum(II) complexes of the form cis-[PtA2(Am)Cl]+, where A is a monodentate (NH3 or i-PrNH2) or A2 is a bidentate (ethylenediamine or 1,2-diaminocyclohexane) amine and Am is either a heterocyclic amine based on a pyridine, pyrimidine, purine, piperidine, or a saturated amine (RNH2) ligand, was prepared and screened against in vivo murine tumor models. Each compound was tested against Sarcoma 180 ascites (S180a) in mice, with 20 members of the series showing activity (ILS greater than 50%). Antitumor activity also was demonstrated in 4 of 16 compounds tested in the L1210 murine leukemia model (ILS greater than 25%) and in 3 of 3 tested in the P388 murine leukemia model (ILS greater than 30%). The most active and potent analogues of the series were obtained when A was NH3 and Am was N1-pyridine, N1-4-methylpyridine, N1-4-bromopyridine, N1-4-chloropyridine, N3-cytosine, or N7-2'-deoxyguanosine. Complexes containing chelating and saturated amine ligands (A), as well as two trans isomers of active cis analogues (trans-[Pt(NH3)2(Am)Cl]+, where Am = N1-pyridine or N1-4-methylpyridine), were inactive in the S180a screen. All complexes were characterized by means of elemental analysis, HPLC, and 195Pt NMR spectroscopy, and the structure of one analogue, cis-[Pt(NH3)2(N3-cytosine)Cl](NO3), was determined by using single-crystal X-ray diffraction methods. While members of this series of compounds demonstrate antitumor activity in vivo, these new agents are not classical analogues of cisplatin (i.e. cis-[PtA2X2] complexes), as they contain three nitrogen donors and only one leaving group. The results of these studies suggest that further work should be conducted to better define the limits of the structure-activity relationships among platinum(II) complexes.     

Cytotoxicity and antitumor activity of bis(platinum) complexes. A novel class of platinum complexes active in cell lines resistant to both cisplatin and 1,2-diaminocyclohexane complexes

The in vitro cytotoxicity and in vivo antitumor activity of bis(platinum) complexes of general formula [(PtX2-(L))2H2N(CH2)nNH2] (L = NH3, X = Cl or X2 = malonato or where L = py, X = Cl) is reported. Chloride complexes [(PtCl2(NH3]2H2N(CH2)nNH2] may exist as three possible isomers: those containing both coordination units in the cis configuration (2,2/c,c), both coordination units in the trans configuration (2,2/t,t), and the mixed cis,trans species (2,2/c,t), whose synthesis is reported here. The preparation of further complexes with sterically hindered diamine backbones, such as 2,5-dimethyl-2,5-hexanediamine, is exemplified. The biological activity of all complexes were compared. The 2,2/c,c complexes are particularly active in tissue culture in cells resistant both to cisplatin and its 1,2-diaminocyclohexane (dach) analogue. The inhibition of DNA synthesis in L1210/0 cells by the 2,2/c,c complexes is equivalent to that of cisplatin. The presence of at least one cis-[Pt(amine)2] unit appears necessary for activity in cell lines sensitive to cisplatin.     

Platinum complexes with 5-methyl-5(4-pyridyl)hydantoin and its 3-methyl derivatives: synthesis and cytotoxic activity - quantitative structure-activity relationships

3,5‐Dimethyl‐5‐(4‐pyridyl)hydantoin (L) and its platinum(II) and platinum(IV) complexes with the general formula cis‐[PtL₂X₂] · n H₂O and [PtL₂Cl₄], where X?Cl, I and n = 2‐4 were synthesized. A new Pt(IV) complex with 5‐methyl‐5‐(4‐pyridyl)hydantoin (L′) with the formula cis‐[Pt(L′)₂Cl₂(OH)₂] · 5 H₂O was also synthesized. The novel compounds were characterized by elemental analysis, IR, ¹H‐, ¹³C‐, ¹⁹⁵Pt‐NMR spectra and molar conductivity. The cytotoxic effects of these complexes were examined on three human tumor cell lines by MTT‐dye reduction assay. These four new Pt(II) and Pt(IV) complexes and a set of another twelve Pt(II), Pt(IV), and Pd(II) complexes previously synthesized and tested were compiled and a QSAR model was derived in order to direct the further rational synthesis.     

Platinum(II) and palladium(II) complexes with 2-acetylpyridine thiosemicarbazone: cytogenetic and antineoplastic effects

The effect of three novel complexes of Pt(II) and three complexes of Pd(II) with 2-acetylpyridine thiosemicarbazone (HAcTsc) on sister chromatid exchange (SCE) rates and human lymphocyte proliferation kinetics on a molar basis was studied. Also, the effect of Pt(II) and Pd(II) complexes against leukemia P388 was investigated. Among these compounds, the most effective in inducing antitumor and cytogenetic effects were the complexes [Pt(AcTsc)2] x H2O and [Pd(AcTsc)2] while the rest, i.e. (HAcTsc), [Pt(AcTsc)Cl], [Pt(HAcTsc)2]Cl2 x 2H2O, [Pd(AcTsc)Cl] and [Pd(HAcTsc)2]Cl2, displayed marginal cytogenetic and antitumor effects.     

Synthesis, base-catalyzed hydrolytic reactivity, and anticancer evaluation of O-aryl phosphorodiamidates as a novel class of pro(phosphorodiamidic acid mustards).

Bis(2-chloroethyl)phosphoramidic dichloride [MP(O)Cl2, M = N(CH2CH2Cl)2] has been used as the starting material for the synthesis of O-aryl phosphorodiamidates having the general structure MP(O)(NHR)OAr: 9, R = H, Ar = 4-NO2C6H4; 10, R = H, Ar = C6F5; 11, R = C6H5, Ar = C6F5; 12, R = 4-MeC6H4, Ar = C6F5; and 13, R = 4-EtOC6H4, Ar = C6F5. The phosphorodiamidic chloride precursor to 13 (14) was also isolated. Kinetics for the base-catalyzed hydrolysis of compounds 9--13 were investigated by UV and NMR methods and are considered in connection with service of these compounds as pro(phosphorodiamidic acid mustards) [MP(O)(NHR)OAr leads to MP(O)(NHR)OH] via an E1cB mechanism involving the intermediacy of a mustard-bearing metaphosphorodiimide [MP(O)=NR]. Anticancer screening tests against L1210 lymphoid leukemia in mice indicated that 9--14 are inactive; similar negative results were obtained with the KB cell culture, except in the case of 14 which was marginally active.     

Synthesis, cytotoxicity, cell uptake and DNA interstrand cross-linking of 4,4'-dipyrazolylmethane-linked multinuclear platinum anti-cancer complexes

Two cationic multinuclear platinum complexes linked with the 4,4'-dipyrazolylmethane (dpzm) ligand, trans-[[Pt(NH3)2Cl]2-mu-dpzm]Cl2 (di-Pt) and trans-[trans-[Pt(NH3)2Cl]2[trans-[Pt(NH3)2(mu-dpzm)2]]]Cl4 (tri-Pt), have been synthesized. Both complexes show activity in the murine leukaemia cell line L1210 (IC50 = 3.8 and 2.5 microm, respectively) and the cisplatin-resistant subline L1210/DDP (8.8 and 3.6 microM), and in the human ovarian carcinoma 2008 (2.5 and 17.8 microM) and its cisplatin-resistant subline C13*5 (20.9 and 37.7 microM). Both complexes show high levels of uptake into 2008 cells, when administered at 100 microM, but significantly reduced uptake in the cisplatin-resistant cell line C13*5 (di-Pt, 66% decrease; tri-Pt, 42%; cisplatin, 86%). Both complexes form very high levels of DNA interstrand cross-links in vitro, with 50% interstrand cross-linking observed at far lower concentrations (di-Pt, 12 nM; tri-Pt, 22 nM) than cisplatin (450 nM). It is proposed that the higher extent of interstrand cross-linking may be due to the rigid nature of the dpzm linking ligand, which prevents the complexes from forming short-range intrastrand adducts, like the GpG adduct formed by cisplatin. The results of this study indicate the importance of the flexibility of the linking ligand for the cytotoxicity of di- and trinuclear platinum anti-cancer complexes.     

Murine anti-tumor activity of new water soluble platinum(II) complexes with reduced toxicity

A series of new water soluble sugar and non-sugar containing platinum(II) complexes was synthesized and evaluated for effects of the sugar moiety on water solubility, anti-tumor activity, and acute leukopenia. When tested in vivo against the murine P388 and L1210 leukemias at LD10/maximally effective doses, the compound cis-[(gluconylamino)malonato-O,O'](1R,2R-cyclohexanediami ne-N,N')platinum (II), R,RG-AMP produced comparable or superior anti-tumor activity to cisplatin, carboplatin, and tetraplatin. Efficacy was also demonstrated for the L1210/DDP (cisplatin-resistant) leukemia. Further, R,R-G-AMP is non-nephrotoxic and produces less leukopenia than cisplatin, carboplatin, and tetraplatin.     

Synthesis and antitumor activity of cyclotriphosphazene-(diamine)platinum(II) conjugates

A new class of water-soluble cyclotriphosphazene-(diamine)platinum(II) conjugate drugs [NP(Am-Li2)(Am.PtA2)]3 (Am: dicarboxylic amino acid; A2: diamine) has been synthesized and characterized by means of elemental analysis, multinuclear (1H, 31P, 13C, 195Pt) NMR and IR spectroscopies. All the title compounds were subjected to both in vitro and in vivo assays against the murine leukemia L1210 cell line and selected human tumor cells. Most of the title compounds have shown higher in vivo antitumor activity than cisplatin and carboplatin, and, in particular, [NP(L-Glu-Li2)(L-Glu.Pt(-dach)]3 (Glu=glutamate, dach=trans(+/-)-1,2-diaminocyclohexane) showed extraordinary high activity (ILS>500%) equally against both parent and cisplatin-resistant leukemia L1210 cell lines. Furthermore, this candidate compound (KI 60606) exhibited a wider spectrum of in vitro activity by showing higher cytotoxicity against all the selected human tumor cells than cisplatin and, therefore, was subjected to preclinical studies which are now near completion.     

Synthesis,characterization and mutagenicity of new cis-[Pt(2-substituted-benzimidazole)2Cl2] complexes

In this study, four new platinum(II) complexes with the structures cis-[Pt(Ligand)2Cl2] (ligand = 2-(p-methoxy-/or-p-chlorobenzyl or p-methoxyphenyl)benzimidazol (1, 2, 4 respectively) and 5(6)-methyl-2-phenoxymethylbenzimidazole (3) were synthesized and characterized by their elemental analysis, and IR and 1H NMR spectra. The potentials of the Pt(II) complexes for short-term bacterial mutagenicity were tested in reverse-mutation assays using Salmonella typhimurium frame-shift strain T 98 and S. typhimurium TA 100 and TA 102 strains, which carry mutations particularly sensitive to reversion by DNA base-pair substitution. The tests were performed in the absence of S9 rat liver fraction. Among the complexes tested 1 had no mutagenic activity. Complex 4 was found to be weakly mutagenic in TA 98 only. The Pt(II) complexes 2 and 3 were found to be mutagenic in TA 98, TA 100 and TA 102.     

Synthesis and oral antitumor activity of tetrakis(carboxylato)platinum(IV) complexes

A novel class of tetrakis(carboxylato)platinum(IV) complexes, [Pt(O(2)CR)(4)(dach)] (dach = trans-(+/-)-1,2-diaminocyclohexane; R = C(n)H(2n+1), n = 1 approximately 5), was synthesized and studied for physicochemical properties and oral antitumor activity. Lipophilicity and aqueous solubility of the title complexes were greatly dependent on the alkyl chain length of the carboxylate ligand, and their partition coefficient and solubility changed by 4 or 5 orders of magnitude from acetate to hexanoate complexes. On the other hand, the range of their cathodic reduction potential (-546 approximately -403 mV) depending on the chain length of the carboxylate ligand was relatively small. Among the title complexes, the tetrakis(propionato)platinum(IV) complex, [Pt(O(2)CC(2)H(5))(4)(dach)], with appropriate lipophilicity (log P = 0.18) and aqueous solubility (14.6 mg/mL) was found to exhibit better oral antitumor activity than JM216 against the human ovarian tumor xenograft SKOV3 in nude mice.     

Tumor inhibiting [1,2-bis(fluorophenyl)ethylenediamine]platinum(II) complexes, III: Evaluation of the mammary tumor inhibiting properties

Diastereomeric diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) sulfates and nitrates produce a strong inhibition of the hormone-dependent MXT-M 3.2 mammary carcinoma of the B6D2F1 mouse. Besides an interference in the DNA synthesis in analogy to cisplatin a lowering of the estrogen level due to an interference in steroid biosynthesis is suggested as the mode of action. In contrast to the R,R/S,S configurated diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) salts the corresponding R,S configurated compounds are also markedly active on the hormone-independent MXT-Ovex mammary carcinoma of the B6D2F1 mouse.     

In vitro action of platinum (II) and platinum (IV) complexes on Trypanosoma cruzi and Leishmania donovani

The in vitro activities of 22 neutral Pt(II) complexes, 4 Pt(IV) complex salts, and one Pt(II) complex salt on epimastigote forms of Trypanosoma cruzi and promastigote forms of Leishmania donovani were studied. Only 2 out of the 18 complexes with cis-Pt(DDH)Xn structure completely inhibited the growth of the epimastigote forms of T. cruzi and the promastigote of L. donovani. Against T. cruzi the cis-Pt(L)n(Cl)2 complexes showed no activities, but the complex in which the (L) ligand was stilbamidine did show a limited activity against L. donovani. Of the Pt(IV)complex salts, [Pt X6]H2(L) were very active against the epimastigote forms of T. cruzi. However, the Pt(II) complex salt [cis-Pt Cl4]H2 (pentamidine) showed no activity. The actions of the Pt(IV) complex salts on the promastigote forms of L. donovani were different and only those salts in which the (L) ligand was pentamidine or stilbamidine induced parasite growth inhibition. The one Pt(II) salt tested showed no antiparasitic activity. At the same time, the known antiparasitic activities of the nifurtimox and pentamidine molecules were confirmed.     

Synthesis and cytotoxicity of platinum(II) complexes of a physiologically active carrier histamine

A series of novel platinum(II) complexes involving a physiologically active carrier histamine as the carrier, cis-[Pt(histamine)X2] (X2=2Cl-, oxalate, malonate, 1,1-cyclobutanedicarboxylate (CBDCA), 3-hydroxy-1,1-cyclobutanedicarboxylate (HO-CBDCA)), have been synthesized and characterized by elemental analysis and spectroscopic data along with X-ray crystal structure for a representative complex cis-[Pt(histamine)Cl2]. The cytotoxicity of the complexes has also been assessed in the human cancer cell lines A549/ATCC, HT-29, and LNcap. One complex, cis-[Pt(histamine)Cl2], is more active than carboplatin against both the sensitive and resistant cells.     

Antitumor effect of Pt(II) amine phosphonate complexes on sarcoma sa-180 in mice. Crystal structure of cis-dichlorobis(diethyl-4-pyridylmethylphosphonate-kappaN)platinum(II) hydrate, cis-[PtCl2(4-pmpe)2].H20

The cisplatin analogoues platinum (II) complexes of the general formula cis-[PtL2Cl2], where L is monodentate diethyl 2-, 3- or 4-pyridylmethylphosphonate (2-, 3- or 4-pmpe) ligand, have been synthesized and characterized by means of IR and NMR (1H, 31P, 195Pt) spectroscopy. The crystal and molecular structure of cis-[Pt(4-pmpe)2 Cl2].H2O (A3) shows a square planar geometry of PtL2Cl2, with two organic molecules and two chloride leaving ligands in a cis configuration. The antitumor activity of the platinum (II) complexes was examined against Sarcoma Sa-180 in mice. The obtained results indicate a marked anticancer effect of platinum phosphonate complexes, and moderate nephrotoxicity evaluated in the BUN and creatinine levels in comparison with cisplatin (CDDP).