The Reaction of Pt-Antitumor Drugs with Selected Nucleophiles.: II. Preparation and Characterization of Coordination Compounds of Pt(II) andl-Histidine

Various His-Pt(II) coordination compounds were prepared by reaction of K₂PtCl₄ or cis-[Pt(NH₃)₂Cl₂](cis-DDP) with His and analyzed by ¹H and ¹³C NMR spectroscopy, electrophoresis, and ion-exchange chromatography. His may be coordinated to Pt by the imidazol iminogroup and/or the α-aminogroup; the carboxy group remains always free. Both bidentate as well as monodentate ligands were identified. Cis-DDP reacts with His to give a mixture of compounds where all these possibilities are present: cis-diamine-(histidine-N,N-)Pt(II) and three different types of cis-diammine-bis(histidine). HCl trans cleavage of compounds with bidentate His ligands leads to a mixture of two compounds having His ligated to Pt by an amino or imin group. The methods applied are suitable for analyzing reactions of His with cis-DDP under model conditions similar to physiological conditions.     

Heteropolymetallic complexes of 1,1′-bis(diphenylphosphino)ferrocene (dppf). IV. Solvolytic behavior and cytostatic properties towards the KB cell-line of dppf and 1,2-bis(diphenylphosphino)ethane cis-complexes of Pt(II) and Pd(II)

The novel cis-platinum(II) complexes [(dppe)Pt(μ-OH)]₂(BF₄)₂ and [(dppe)Pt(DMF)₂](BF₄)₂ have been prepared and characterized by ³¹P NMR, together with cis-[(dppe)Pt(μ-Cl)]₂(BF₄)₂, both in poorly and strongly coordinating solvents (dppe = 1,2-bis(diphenylphosphino)ethane). All these complexes and their dppf analogs (dppf = 1,1′-bis(diphenylphosphino)ferrocene) as well as (dppf)PtCl₂, (dppe)PtCl₂, (dppf)PdCl₂, [(dppf)Pd(μ-Cl)]₂(BF₄)₂ and [(dppf)Pd(μ-OH)]₂(BF₄)₂ have been tested as antiproliferating agents towards Eagle's KB cell-line. Their activity is compared with that of free diphosphine ligands. For Pt(II) complexes, the ID₅₀ figures are found to be higher than those observed for free dppf and dppe. On the contrary, the activity of the palladium dppf complexes is substantially identical to that of free diphosphine.     

Modulation of oxidative DNA damage and DNA-crosslink formation induced by cis-diammine-tetrachloro-platinum(IV) in the presence of endogenous reductants

Platinum(IV) [Pt(IV)] complex, satraplatin, is currently in clinical trials for the treatment of various cancers. As a key step of the anti-cancer effect exertion, satraplatin is supposed to be reduced by endogenous reductants to platinum(II) [Pt(II)] complex. In this study, we investigated the interaction of DNA, Pt(IV), and the endogenous reductants such as ascorbic acid (AsA) and glutathione (GSH). As a model Pt(IV) compound, cis-diammine-tetrachloro-Pt(IV) [cis-Pt(IV)], which is a prodrug of cisplatin [cis-diammine-dichloro-Pt(II), cis-Pt(II)], was incubated with calf thymus DNA in the presence of AsA or GSH. In the presence of AsA, cis-Pt(IV) induced oxidative DNA damage. Hydroxyl radical scavengers suppressed the AsA-associated oxidative damage, thereby suggesting that hydroxyl radicals are involved in the DNA oxidation. cis-Pt(II)-like CD spectral change and crosslink formation in calf thymus DNA were also observed during this DNA oxidation, suggesting cis-Pt(IV) reduction by AsA and DNA conformational change induced by the newly formed cis-Pt(II) binding to DNA. GSH did not induce oxidative DNA damage likely due to its own hydroxyl radical scavenging ability. Further, GSH suppressed the Pt(II)-mediated DNA conformational change and crosslink formation, suggesting that GSH sequesters the cis-Pt(II) away from DNA by GSH-cis-Pt(II) complex formation.     

Adducts formed between deoxyguanosine and cis-Dichlorodiammineplatinum(II): Separation by means of cation-exchange chromatography

The interaction between deoxyguanosine (dG) and cis-dichlorodiammineplatinum(II) (cis-Pt) leads to the 2:1 and the 1:1 dG-Pt adducts. These adducts were separated on an Aminex A6 cationexchange column by use ot 0.01 M K₂CO₃ (pH 11) as an eluent. The stoichiometry of the adducts was determined from the ^195mPt radioactivity and from the absorbance of the guanine chromophore at 280 nm. Time-course studies show that dG reacts initially with cis-Pt to form the 1:1 adduct, which then interacts with a second molecule of dG to form the 2:1 adduct. Acid hydrolysis (100°C in 88% formic acid for 5–15 min) of the 1:1 and 2:1 adducts results in their conversion to two new products, which elute differently from the column but which still contain Pt bound in the same stoichiometric ratio to dG as in the nonhydrolyzed adducts. The hydrolyzed adducts show a negative diphenylamine reaction indicative ot cleavage of the glycosidic bond. It is concluded that mild acid hydrolysis converts the 1:1 and 2:1 dG-Pt adducts into the corresponding guanine-Pt adducts, which are chromatographically distinguishable. This acid hydrolysis-high pressure liquid chromatography (HPLC) procedure has application to the identification of the Pt adducts formed in DNA.     

Synthesis and structure of platinum(II) complexes containing an asymmetric chelating diamine 2-morpholinoethylamine as the carrier

A series of novel platinum(II) complexes involving an asymmetric chelating diamine 2-morpholinoethylamine (MPEA) as the carrier, cis-[Pt(MPEA)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(MPEA) (CBDCA)]. The Pt(II) is in a square planar environment and is coordinated by a chelating CBDCA and MPEA in cis position. The complexes with dicarboxylate are quite soluble (>25 mg/ml) and stable in water. The cytotoxicity of the complexes has been assessed in the human lung cancer cell lines A549 and A549/ATCC. One complex, cis-[Pt(MPEA)Cl₂], is more active than carboplatin against both the sensitive and resistant cells, and has less cross-resistance with cisplatin.     

Synthesis,characterization, and biological activity of platinum II,III, and IV pivaloamidine complexes

Imino ligands have proven to be able to activate the trans geometry of platinum(II) complexes towards antitumor activity. These ligands, like aromatic N-donor heterocycles, have a planar shape but, different from the latter, have still an H atom on the coordinating nitrogen which can be involved in H-bond formation. Three classes of imino ligands have been extensively investigated: iminoethers (HN=C(R)OR′), ketimines (HN=CRR′), and amidines (HN=C(R)NR′R″). The promising efficacy of the platinum compounds with amidines (activity comparable to that of cisplatin for cis complexes and much greater than that of transplatin for trans complexes) prompted us to extend the investigation to amidine complexes with a bulkier organic residue (R = t-Bu). The tert-butyl group can confer greater affinity for lipophilic environments, thus potentiating the cellular uptake of the compound. In the present study we describe the synthesis and characterization of pivaloamidine complexes of platinum(II), (cis and trans-[PtCl₂(NH₃){Z-HN=C(t-Bu)NH₂}] and cis and trans-[PtCl₂{Z-HN=C(t-Bu)NH₂}₂]), platinum(III) ([Pt₂Cl₄{HN=C(t-Bu)NH}₂(NH₃)₂]), and platinum(IV) (trans-[PtCl₄(NH₃){Z-HN=C(t-Bu)NH₂}] and trans-[PtCl₄{Z-HN=C(t-Bu)NH₂}₂]). The cytotoxicity of all new Pt complexes was tested toward a panel of cultured cancer cell lines, including cisplatin and multidrug resistant variants. In addition, cellular uptake and DNA binding, perturbations of cell cycle progression, induction of apoptosis, and p53 activation were investigated for the most promising compound trans-[PtCl₂(NH₃){Z-HN=C(t-Bu)NH₂}]. Remarkably, the latter complex was able to overcome both acquired and intrinsic cisplatin resistance.     

cis-Dichloroplatinum (II) complexes with aminomethylnicotinate and -isonicotinate ligands

6-Aminomethylnicotinic acid (1a) and 2-aminomethylisonicotinic acid (1b) were each reacted with K₂PtCl₄ in aqueous 1 M HCl to give the corresponding N,N-chelated cis-dichloroplatinum(II) complexes 2. These were converted into amides 3 via their mixed anhydrides by treating them first with ethyl chloroformate and then with the respective 1° or 2° amine. The analogous 6-aminomethylnicotinic acid ester complexes 7 were obtained by reaction of the preformed ligands with K₂PtCl₄.     

Pt(IV) complexes as prodrugs for cisplatin

The antitumor effects of platinum(IV) complexes, considered prodrugs for cisplatin, are believed to be due to biological reduction of Pt(IV) to Pt(II), with the reduction products binding to DNA and other cellular targets. In this work we used pBR322 DNA to capture the products of reduction of oxoplatin, c,t,c-[PtCl₂(OH)₂(NH₃)₂], 3, and a carboxylate-modified analog, c,t,c-[PtCl₂(OH)(O₂CCH₂CH₂CO₂H)(NH₃)₂], 4, by ascorbic acid (AsA) or glutathione (GSH). Since carbonate plays a significant role in the speciation of platinum complexes in solution, we also investigated the effects of carbonate on the reduction/DNA-binding process. In pH 7.4 buffer in the absence of carbonate, both 3 and 4 are reduced by AsA to cisplatin (confirmed using ¹⁹⁵Pt NMR), which binds to and unwinds closed circular DNA in a manner consistent with the formation of the well-known 1, 2 intrastrand DNA crosslink. However, when GSH is used as the reducing agent for 3 and 4, ¹⁹⁵Pt NMR shows that cisplatin is not produced in the reaction medium. Although the Pt(II) products bind to closed circular DNA, their effect on the mobility of Form I DNA is different from that produced by cisplatin. When physiological carbonate is present in the reduction medium, ¹³C NMR shows that Pt(II) carbonato complexes form which block or impede platinum binding to DNA. The results of the study vis-à-vis the ability of the Pt(IV) complexes to act as prodrugs for cisplatin are discussed.     

Synthesis and characterization of the novel Pt(II) complexes of the types cis- and trans-Pt(Ypy)(pyrazine)Cl2, K2[Cl3Pt(μ-pyrazine)PtCl3] and trans, trans-(Ypy)Cl2Pt(μ-pyrazine)Pt(Ypy)Cl2 (Ypy = pyridine derivative)

New types of Pt(II) mixed-ligand complexes containing a pyridine derivative (Ypy) and pyrazine (pz) were synthesized. The compounds were characterized by infrared spectroscopy and by multinuclear (¹H, ¹³C and ¹⁹⁵Pt) magnetic resonance. The complexes cis-Pt(Ypy)(pz)Cl₂ were synthesized from the reaction of K[Pt(Ypy)Cl₃] with pyrazine (1:1 proportion) in water. When the reaction was carried on in a 2:1 ratio, a mixture of compounds was obtained, which was refluxed in CH₂Cl₂ for several days. The final product was found to be pure and it was identified as trans,trans-Cl₂(Ypy)Pt(μ-pyrazine)Pt(Ypy)Cl₂. The cis monomers isomerize to the trans isomers in organic solvents. Different methyl derivatives of pyridine were studied in order to determine the influence of substitution in ortho position on the pyridine ligand in the complexes. In IR spectroscopy, the cis monomers showed two ν(Pt-Cl) bands, while the trans monomers and dinuclear species showed only one ν(Pt-Cl) band. The NMR results were interpreted in relation to the solvent effect, which seems important in these complexes. The ¹⁹⁵Pt NMR signals of the cis monomers were found at slightly higher fields than those of the corresponding trans isomers. The coupling constants J(¹⁹⁵Pt-¹H) and J(¹⁹⁵Pt-¹³C) are larger in the cis geometry. The δ(¹⁹⁵Pt) of the dinuclear species were found close to those of the trans monomers and the coupling constants are similar to those of the trans monomers, strongly suggesting a trans-trans configuration for the dinuclear compounds. The pyrazine-bridged complex K₂[Cl₃Pt(μ-pz)PtCl₃] was also synthesized and spectroscopically studied. The crystal structures of the compounds cis-Pt(3,5-lut)(pz)Cl₂ and trans-Pt(2,4,6-col)(pz)Cl₂ were determined by X-ray diffraction methods.     

Synthesis and characterization of functionalized thymidine as a potential carrier for cisplatin-like drugs

Pursuing the idea of using a biological nanovector to drive the non-specific cytotoxic activity of Pt(II) complexes toward biological targets, we have singled out thymidine (T) as a potential biological carrier for delivery of cisplatin-like drugs to DNA. Thymidine was functionalized by first reacting it with solid sodium hydride and 1,3-diiodopropane, producing high yields of N3-iodopropylthymidine. Further reaction with ethylenediamine gave the bio-ligand N3-(3-ethylenediamine)propylthymidine which reacts in turn with K₂PtCl₄, resulting in a cisplatin-like nucleoside.This derivative (or more soluble analogues) can be phosphorylated by the cellular enzyme pool and incorporated into the growing DNA chain, thus making them suitable candidates as potential antiproliferative agents, exploiting both alkylating and antimetabolite mechanisms.     

Specificity of the interaction of DNA-platinum, amount of platinum, and pH measurement]

Interaction between the sodium salt of a DNA extracted from salmon sperm (41% GC) with [Pt(NH₃)₄]Cl₂, [Pt(NH₂? (CH₂)₂? NH? (CH₂)₂? NH₂Cl]Cl, cis-Pt(NH₂? (CH₂)₂? NH₂)Cl₂, cis-Pt(NH₃)₂Cl₂, trans-Pt(NH₃)₂Cl₂, K[Pt(C₂H₄)Cl₃], and K₂[PtCl₄) indicates at least three types of complexation. A correlation is found between the change of pH and the number of platinum atoms fixed per (AT + GC) unit. The first binding site is located on the G-C pairs (guanine–cytosine), most likely the N-7(G) site, as it was shown in a previous study of the guanosine-platinum salts. The fixation of the second platinum atom by the pair (AT + GC) takes place with liberation of protons. In the case of the complexes cis-Pt(NH₂? (CH₂)₂? NH₂)Cl₂, cis-Pt(NH₃)₂Cl₂, and trans-Pt(NH₃)₂Cl₂ the second interaction seems to involve simultaneously the N-7(A) and the N-1(G) and N-3(C) sites. This latter intercrosslink between guanine and cytosine obviously liberates protons and the decrease of pH is related in this case to the trans effect of the platinum compounds. The first two platinum atoms in the reaction of K₂PtCl₄] or the Zeise salt, K[Pt(C₂H₄)Cl₃] with DNA are fixed on the G-C pairs. A maximum of six platinum atoms per (AT + GC) unit were fixed in this case. Preliminary experiments with a DNA extracted from bacteria Micrococcus lysodeikticus (72% GC) give similar results.     

A new route to N(1)-5R-tetrazole complexes via azidation to nitriles coordinated to Pt(II) and Pt(IV)

New tetrazolate complexes trans-[PtCl₂(RCN₄)₂]²⁻, trans-[PtCl₄(RCN₄)₂]²⁻ with Ph₃PCH₂Ph⁺ and (CH₃)₂NH₂⁺ counterions have been obtained by azidation of nitriles coordinated to Pt(II) and Pt(IV) {trans-[PtCl₂(RCN)₂] and trans-[PtCl₄(RCN)₂] (R = Et, Ph)} and characterized. The composition and the molecular structure of the complexes obtained were established by the СHN elemental analyses, ¹Н and ¹³С NMR spectroscopy, IR spectroscopy, mass spectrometry, and X-ray diffraction. The coordination of nitriles to Pt(II) and Pt(IV) is shown significantly activate the azidation: the reaction proceeds with a higher rate and at relatively low temperature compared with the classical 1,3-dipolar addition of azides to nitriles.     

Synthesis and structures of platinum(II) complexes with 5-ferrocenylpyrimidine

Reaction of platinum(II) salts with 5-ferrocenylpyrimidine (FcPM) afforded cis-[Pt(NH₃)₂(FcPM)₂](PF₆)₂ (1), trans-[Pt(NH₃)₂(FcPM)₂](PF₆)₂ (2), cis-[PtCl₂(FcPM)₂] (3), and cis-[PtCl₂(DMSO)(FcPM)] (4): their spectroscopic and electrochemical properties were investigated. Complexes 1 and 2 were structurally characterized by X-ray crystallography.     

Synthesis,characterization and study of the PtPt interaction in cis-[(aa)(bb)FCrNCPt(CN)3] (aa,bb=bidentate amine)

Two new dinuclear μ-cyano complexes, cis-[(en)(tn)FCrNCPt(CN)₃] and cis-[(chxn)(tn)FCrNCPt(CN)₃] en=ethylenediamine, tn=1,3-diaminepropane and chxn=1,2-cyclohexanediamine) have been obtained by solid state heating of the trans[Cr(aa)(bb)F(H₂O)][Pt(CN)₄] salts. These complexes have been characterized by chemical analysis, electronic and IR spectra. The dinuclear complexes show strong PtPt interaction both in the solid state and in solution. The association constant of the oligomers formed has been calculated and correlated with the size of the amine ligands. An orbital explanation is proposed to account for the enhancement of the PtPt interaction in the dinuclear complexes relative to the complex salts.     

Novel trans-platinum complexes of the histone deacetylase inhibitor valproic acid; synthesis, in vitro cytotoxicity and mutagenicity

The first examples of Pt complexes of the well known anti-epilepsy drug and histone deacetylase inhibitor, valproic acid (VPA), are reported. Reaction of the Pt(II) am(m)ine precursors trans-[PtCl₂(NH₃)(py)] and trans-[PtCl₂(py)₂] with silver nitrate and subsequently sodium valproate gave trans-[Pt(VPA_−1H)₂(NH₃)(py)] and trans-[Pt(VPA_−1H)₂(py)₂], respectively. The valproato ligands in both complexes are bound to the Pt(II) centres via the carboxylato functionality and in a monodentate manner. The X-ray crystal structure of trans-[Pt(VPA_−1H)₂(NH₃)(py)] is described. Replacement of the dichlorido ligands in trans-[PtCl₂(py)₂] and trans-[PtCl₂(NH₃)(py)] by valproato ligands (VPA_−1H) to yield trans-[Pt(VPA_−1H)₂(py)₂] and trans-[Pt(VPA_−1H)₂(NH₃)(py)] respectively, significantly enhanced cytotoxicity against A2780 (parental) and A2780 cisR (cisplatin resistant) ovarian cancer cells. The mutagenicity of trans-[Pt(VPA_−1H)₂(NH₃)(py)] and trans-[Pt(VPA_−1H)₂(py)₂] was determined using the Ames test and is also reported.     

Trend in cytotoxic activity of a series of cis-[APtCl2] (A = ethylenediamine methylated at different positions) complexes

The study of a series of cis-[APtCl₂] complexes (A = ethylenediamine, en, methylated at different positions) was carried out to evaluate the effect of different methyl substitutions on the cytotoxic properties of the resulting derivatives. As expected, differentially methylated complexes were found to differ widely in their cytotoxic effects on human cultured ovarian carcinoma cells (A2780). Molecular mechanics (MM) calculations have been performed to assess the relationship between differential diamine methylation and the repulsive energy of the corresponding complexes when interacting with DNA. Compounds that bind DNA at high energetic cost relative to cisplatin, due to the steric hindrance of additional methyl groups, have shown high values for IC₅₀ (concentration inhibiting tumour cell growth by 50%). Semi-quantitative analyses with a DNA electrochemical biosensor confirm that the interaction between cis-[APtCl₂] complexes and ds-DNA deposed onto the electrode is stronger for the non-methylated derivative with respect to the fully methylated congener. In addition, MM calculations were used to investigate the interactions between DNA and cis-[(P-L-A)PtCl₂] complexes [A = en group linked to an antiestrogen-like pharmacophore, P, via a –(CH₂)n– spacer (n = 2, 4, 6, 8 and 10), L].     

Synthesis, structures and in vitro cytotoxicity of some cationic cis-platinum(II) complexes containing chelating thiocarbamates

The thiocarbamates 4-RC₆H₄NHC(S)NR₂′ (R = H, Cl; R′ = Me, Et), 4-ClC₆H₄NHC(S)NR (NR = 2-pyridylpiperazine) react with cis-[PtCl₂(PTA)₂] (PTA = 1,3,5-triaza-7-phosphaadamantane) in the presence of base to afford the monocationic platinum(II) complexes cis-[Pt{SC(NR₂′) = NC₆H₄R}(PTA)₂]⁺ (R = H, Cl; R′ = Me, Et), cis-[Pt{SC(NR) = NC₆H₄Cl}(PTA)₂]⁺ (NR = 2-pyridylpiperazine), which were isolated as their PF₆ salts in high yields. The complexes were fully characterised spectroscopically and also by X-ray crystallography. Cytotoxicity of these complexes was studied in vitro in three human cancer cell lines (CH1, A549 and SW480) using the MTT assay.     

Synthesis of new platinum(II) compounds with several bidentate and tridentate nitrogen-donor ligands. Structural analyses by H, C{H} and Pt{H} NMR spectroscopy and X-ray crystal structure

The reaction of the N-alkylaminopyrazole (NN′) ligands 1-[2-(ethylamino)ethyl]-3,5-dimethylpyrazole (deae), 1-[2-(tert-butylamino)ethyl]-3,5-dimethylpyrazole (deat), or (NN′N) ligands bis[(3,5-dimethylpyrazolyl)methyl]ethylamine (bdmae) and bis[(3,5-dimethylpyrazolyl)ethyl]ethylamine (ddae) with [PtCl₂(CH₃CN)₂] affords a series of square-planar Pt(II) complexes with formula [PtCl₂(NN′)] (NN′ = deae (1); deat (2)), [PtCl₂(bdmae)] (3), or [PtCl(ddae)]Cl (4). Treatment of complex 4 in the presence of AgBF₄ in CH₂Cl₂/methanol (3:1) gives [PtCl(ddae)](BF₄) (5). These Pt(II) complexes have been characterised by elemental analyses, conductivity measurements and IR, ¹H, ¹³C{¹H}, and ¹⁹⁵Pt{¹H} NMR spectroscopies. The ¹H NMR spectroscopic studies of the complexes prove the rigid conformation of the ligands when they are complexed. The solid-state structure of complex 1 was determined by single crystal X-ray diffraction methods. The deae ligand is coordinated through the N_pz and N_amino atoms to the metallic centre, which completes its coordination with two chlorine atoms in cis disposition.     

Platinum(II) complexes with aryl tellurols and diaryl ditellurides: Syntheses and spectral investigations

Arytellurol complexes [PtCl(TeAr)(PPh₃)₂] (I) and [Pt(TeAr)₂(PPh₃)₂] (II) are readily obtained from cis-[PtCl₂(PPh)₃)₂] and NaTeAr (Ar = C₆H₅, 4-CH₃OC₆H₄ and 4-CH₃CH₂OC₆H₄) in ethanolbenzene at room temperature. ³¹P NMR spectra of (I) and (II) indicate their trans configuration in solution. Metathetical reactions between I (Ar = 4-CH₃OC₆H₄) and NaX (X = I, Br, SCN) occur in methanol to give [Pt(X)(TeC₆H₄OCH₃-4)(PPh₃)₂]. ¹H NMR shows that equimolar proportions of NaTeC₆H₅, NaTeC₆H₄OCH₂CH₃-4 and cis-[PtCl₂(PPh₃)₂] give a mixture of three complexes: II, Ar = C₆H₅; II, Ar = 4-CH₃CH₂OC₆H₄; and [Pt(TeC₆H₅)(TeC₆H₄OCH₂CH₃-4)(PPh₃)₂]. Polymeric complexes [PtCl(TeAr)]_n (III) and [Pt(TeAr)₂]_n (IV) result from reaction between K₂[PtCl₄] and NaTeAr in aqueaous ethanol. They react with excess of PPh₃ in CDCl₃ to yield monomeric complexes I and II respectively which were characterized in situ by ¹H and ³¹P NMR of the reaction mixtures. IR spectra indicate the presence of bridging chloride ligands in III. An alternating chloride and tellurol bridged chain structure for III and a tellurol bridged for IV have been proposed. Reaction between equimolar amounts of III and PPh₃ in dichloromethane yielded a tellurol bridged dimeric complex [PtCl(μ-TeAr)(PPh₃)]₂ (V) with terminal chloride ligand as suggested by IR study. Ethanolic solutions of diarylditellurides also react readily with an aqueous solution of K₂[PtCl₄] at 10 °C to give complexes for which the structure trans-[PtCl₂(ArTeTeAr)₂] (VI) is suggested from their elemental analyses, IR, Raman (in one case only), ¹H, ¹²⁵Te (in one case only), and ¹⁹⁵Pt NMR spectra and reactions with triphenylphosphine which liberated free ditellurides. At 40 °C or above the same ditellurides form polymeric complexes III with K₂[PtCl₄] in aquaeous ethanol.     

A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor

A strategy is described for the re-design of DNA damaging platinum(II) complexes to afford elevated toxicity towards cancer cells expressing the estrogen receptor (ER). Two platinum-based toxicants are described in which a DNA damaging warhead, [Pt(en)Cl₂] (en, ethylenediamine), is tethered to either of two functional groups. The first agent, [6-(2-amino-ethylamino)-hexyl]-carbamic acid 2-[6-(7α-estra-1,3,5,(10)-triene)-hexylamino]-ethyl ester platinum(II) dichloride ((Est-en)PtCl₂), terminates in a ligand for the ER. The second agent is a control compound lacking the steroid; this compound, N-[6-(2-amino-ethylamino)-hexyl]-benzamide platinum(II) dichloride ((Bz-en)PtCl₂)), terminates in a benzamide moiety, which lacks affinity for the ER. Using a competitive binding assay, Est-en had 28% relative binding affinity (RBA) for the ER as compared to 17β-estradiol. After covalent binding to a synthetic DNA duplex 16-mer, the compound retained its affinity for the ER; specificity of the binding event was demonstrated by the ability of free 17β-estradiol as a competitor to disrupt the DNA adduct-ER complex. The (Est-en)PtCl₂ compound showed higher toxicity against the ER positive ovarian cancer cell line CAOV3 than did the control compound. (Est-en)PtCl₂ was also more toxic to the ER positive breast cancer line, MCF-7, than to an ER negative line, MDA-MB231.