Its Platinum Research Articles

Potent Platinum(IV) Prodrugs That Incorporate a Biotin Moiety to Selectively Target Cancer Cells

Four platinum(IV) prodrugs incorporating a biotin moiety to selectively target cancer cells were synthesised, characterised, and their biological activity assessed. All complexes exhibited exceptional in vitro cytotoxicity against a panel of cancer cell lines, with [Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO3)2, (2) exhibiting the lowest GI50 of 4 nM in the prostate Du145 cancer cell line. Each complex displayed significantly enhanced activity compared to cisplatin, with 2 being 1000-fold more active in the HT29 colon cancer cell line. Against the MCF-7 breast cancer cell line, in which high levels of biotin receptors are expressed, 2, [Pt(4,7-dimethoxy-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO3)2, (3), and [Pt(5-methyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO3)2, (4) exhibited enhanced activity compared to their platinum(II) cores, with 4 being 6-fold more active than its platinum(II) precursor. Furthermore, 3 exhibited 3-fold greater selectivity towards MCF-7 breast cancer cells compared to MCF10A breast healthy cells, and this was further confirmed by platinum uptake studies, which showed 3 to have almost 3-fold greater uptake in MCF-7 cells, compared to MCF10A cells. The results show that lipophilicity and selectivity both contributed to the cellular uptake of 1-4; however, this was not always translated to the observed cytotoxicity.

Theoretical investigation and antineoplastic potential of Zn (II) and Pd (II) complexes of 6-methylpyridine-2-carbaldehyde-N (4)-ethylthiosemicarbazone

Density Functional Theoretical (DFT) and molecular docking studies have been used to elucidate the antineoplastic potential of the ligand 6-Methylpyridine-2-carbaldehyde-N (4)-ethylthiosemicarbazone (MET) and its platinum(II) and zinc(II) complexes. The frontier molecular orbital and the global quantum reactivity parameters were used to study the reactivity and stability of the modeled complexes. The energy gap showed that the complexes have their reactivity in the order Pd[MET] < [MET] < Zn[MET] suggesting a higher reactivity of the Pd complex compared to its Zn(II) congener. NBO indicated Pd(MET)Cl complex to have the highest E(2) energies and exhibiting highest interaction arising from strong coordination of the thiolato sulfur and chloride atoms around the Pd2+ as seen in the σ*S21 -Pd13→ σ*Pd31 – Cl32 transition. QTAIM revealed that highest density of electrons follows the order [Pd(MET)Cl] >[Zn(MET)Cl] > [MET], while computational drug design protocols carried out provided the order of binding affinity as Pd(MET)Cl > Zn(MET)Cl and MET which again presents Pd complex as having greater antineoplastic activity. Our DFT findings are in excellent agreement with previous experimental reports thereby affirming the potential of these complexes as possible candidates for antineoplastic chemotherapeutic treatment against the human colon tumor cell lines (HCT 116) .

Synthesis, characterization, electrochemistry and in vitro cytotoxicity of a new “Triazole-Maltol” ligand and its platinum(II) complex

The 3-methoxy-2-methyl-4H-pyran-4-one (MeO-Malt) was incorporated into the structure of 1H-1,2,3-triazole-4-carboxylate via click chemistry. The new ligand methyl-1-((3-methoxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (3) was reacted with platinum to give mononuclear complex 4. Investigation of the crystal structure of the free ligand 3 highlighted a chain structure established by hydrogen bonding between triazole units and carboxylic groups. The platinum complex was characterized by ATR-IR, NMR and UV–vis spectroscopies. Cyclic voltammograms of 3 and 4 were also discussed. Furthermore, they were tested for cytotoxic activity against squamous cell carcinoma (A431), lung cancer (A549), human melanoma (A375 and HT144) and human colorectal cancer (HT29 and HCT116) cells.

The comparative study of the DNA binding and biological activities of the quaternized dicnq as a dicationic form and its platinum(II) heteroleptic cationic complex

The square-planar heteroleptic Pt(II) coordination compound [Pt(bpy)(dicnq)](NO3)2 (1) and the quaternized dicnq ligand, namely 12,13-dicyano-5,6-dihydrodipyrazino[2,3-f:1′,2′,3′,4′-lmn][1,10]phenanthroline-4,7-diium dibromide (2) (Fig. 1) were synthesized and fully characterized by means of FTIR, NMR, MALDI-TOF MS and the purity was confirmed by CHN analyses. The DNA binding profiles of 1 and 2 were identified in an identical condition. The biological activities of these compounds were investigated by the assays of transcription and replication inhibition, cytotoxic and antimicrobial activity.The result of this study indicates that, both compounds strongly bind to DNA via intercalation but only 1 has a strong nuclease activity. The coordination compound of dicnq (1) binds to the DNA only slightly stronger than the quaternized form of dicnq (2), and is more potent as an inhibitor of transcription and replication and therefore, 1 has more potential as an anticancer agent but the compounds did not show cytotoxic activity against MCF-7 and MDA-MB-231 breast cancer, and DLD-1 colon cancer cell lines it was found that they only had activities against HepG2 liver cancer cell line with following IC50 values; 94.75 and 159.60 µM for 1 and 2, respectively. In addition, tested bacteria are more susceptible to compound 1. These biological activities of 1 may strongly be due to its ability to digest DNA as a chemical nuclease. According to this study, the quaternization of the ligand does not make biologically more active than the coordination compound of the same ligand in this case. The compound (1) is worth further investigation for its antitumor activities.

Synthesis, characterization, cytotoxic activity, and 19F NMR spectroscopic investigations of (OC-6-33)-diacetato(ethane-1,2-diamine)bis(3,3,3-trifluoropropanoato)platinum(IV) and its platinum(II) counterpart

Tetracarboxylatoplatinum(IV) complexes are interesting representatives of potential anticancer active platinum(IV) drugs. Revealing higher kinetic inertness in comparison to their cytotoxic platinum(II) counterparts, they offer an opportunity to reduce toxic and deactivating side reactions. Platinum(IV) complexes are generally considered as prodrugs, which have to be reduced in order to exert their anticancer activity. Two model complexes, a platinum(II) and platinum(IV) complex featuring two equatorial 3,3,3-trifluoropropanoato (tfpa) and in the case of the latter two axial acetato ligands, were synthesized and characterized in detail by multinuclear (1H, 13C, 15N, 19F, 195Pt) one- and two-dimensional NMR spectroscopy, high-resolution electrospray ionization mass spectrometry, elemental analysis and X-ray diffraction analysis. Cytotoxicity was evaluated in three human cancer cell lines (A549, SW480 and CH1/PA-1) by the MTT colorimetric assay, exhibiting IC50 values down to the low micromolar range. The fluorinated ligands in equatorial positions allowed detailed and highly sensitive 19F NMR spectroscopic investigations. Besides reaction studies in the presence of small molecules, e.g. ascorbic acid and 5′-GMP, the reduction of the platinum(IV) complex was additionally investigated in two cancer cell extracts deriving from the cell lines SW480 and CH1/PA-1 in order to estimate the intracellular reduction behavior. A significant increase in the rate of reduction in cell extracts (depending on the chosen cell line) compared to the reduction with ascorbic acid could be demonstrated.

Effective platinum(IV) prodrugs conjugated with lonidamine as a functional group working on the mitochondria

Platinum-based anticancer drugs are one of the most widely used anticancer chemotherapeutics in oncology. Lonidamine (LND) could increase the response of human tumor cells to platinum(II) drugs in preclinical studies by working on the mitochondria. Herein, five platinum(IV) prodrugs conjugated with their potentiator LND are prepared, and most of the target complexes achieve improved anticancer activities compared with their platinum(II) precursors. Notably, Pt(NH3)2(LND)Cl3 (complex 1) derived from cisplatin achieve significantly improved anticancer activities against LNCaP cells and could trigger cancer cell death via an apoptotic pathway and the cell cycle arrest mainly at S phases. And the induction of apoptosis by complex 1 in LNCaP cells is closely associated with mitochondrial function disruption and reactive oxygen species (ROS) accumulation. Moreover, it is possessed of the ability to overcome cisplatin-resistance. Further research revealed that complex 1 could be easily reduced to release its platinum(II) precursor and axial ligand by ascorbic acid. All the results provid evidence to support the design strategy of conjugating platinum complexes with its potentiator to improve their anticancer effect.

Synthesis and structural characterization of a sterically encumbered ferrocenecarboxamido diphosphine and its platinum(II) complex

{[Bis(2-(diphenylphosphino)ethyl)amino]carbonyl}ferrocene (3), a bulky ferrocenecarboxamido-diphosphine, was prepared in a good yield by the reaction of pentafluorophenyl ferrocenecarboxylate (2) with bis[2-(diphenylphosphino)ethyl]amine. The NMR data (1H VT NMR study in particular) indicated a limited molecular mobility of amide 3 that presumably results from a hindered rotation around the amide C–N bond leading to a non-equivalency of the substituents attached to the amide nitrogen. Compound 3 was further converted to the corresponding diphosphine disulfide 4 and reacted with [PtCl2(cod)] (cod = η2:η2-cycloocta-1,5-diene) to give the symmetric, ligand-bridged diplatinum complex [(μ-3)PtCl2]2 (5) having cis square-planar geometry around the Pt(II) centers. The molecular structures of 4 and 5 were determined by single-crystal X-ray diffraction analysis.

4-aminoquinoline analogues and its platinum (II) complexes as antimalarial agents

The high incidence of malaria and drug-resistant strains of Plasmodium have turned this disease into a problem of major health importance. One of the approaches used to control it is to search for new antimalarial agents, such as quinoline derivates. This class of compounds composes a broad group of antimalarial agents, which are largely employed, and inhibits the formation of β-haematin (malaria pigment), which is lethal to the parasite. More specifically, 4-aminoquinoline derivates represent potential sources of antimalarials, as the example of chloroquine, the most used antimalarial worldwide. In order to assess antimalarial activity, 12 4-aminoquinoline derived drugs were obtained and some of these derivatives were used to obtain platinum complexes platinum (II). These compounds were tested in vivo in a murine model and revealed remarkable inhibition of parasite multiplication values, whose majority ranged from 50 to 80%. In addition they were not cytotoxic. Thus, they may be object of further research for new antimalarial agents.

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-[PtL(2) X(2) ] · n H(2) O and [PtL(2) Cl(4) ], 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')(2) Cl(2) (OH)(2) ] · 5 H(2) O was also synthesized. The novel compounds were characterized by elemental analysis, IR, (1) H-, (13) C-, (195) Pt-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.

Cytotoxic effect, differentiation, inhibition of growth and theoretical calculations of an N, N-donor ligands and its platinum(II), palladium(II) and copper(II) complexes

The new pyrazole ligand 5-(2-hydroxyphenyl)-3-methyl-1-(2-pyridylo)-1 H-pyrazole-4-carboxylic acid methyl ester ( 2) and the corresponding Pt(II), Pd(II) and Cu(II) complexes 3– 5 have been synthesized as potential anticancer compounds, and characterized using IR, and 1H NMR as well as mass spectrometry. The 3-D structures of the Cu(II) complexes were determined by quantum mechanic calculation DFT methodology (density functional theory). The cytotoxicity assay of the ligand and complexes has been performed on leukemia cell lines. In general, the complexes showed lower cytotoxicity than cisplatin, and the Pt(II) and Cu(II) complexes were found to be more efficient in the induction of leukemia cell death than the Pd(II) complex. Our investigations indicate that the antiproliferating activity of the Pt(II) and Cu(II) complexes was partly due to the modulation of cellular differentiation.

Studies on the interaction of altromycin B and its platinum(II) and palladium(II) metal complexes with calf thymus DNA and nucleotides

The interaction of the anticancer antibiotic altromycin B and its isostructrural Pt(II) and Pd(II) metal complexes with native calf thymus (CT) DNA was studied using UV–thermal denaturation experiments, circular dichroism spectroscopy and temperature controlled spectrophotometric titrations. Altromycin B stabilizes the double helix by raising the T m, mainly by intercalation of its chromophore between the base pairs and interacting electrostatically via its sugar moieties with the edges of the DNA helix. Moreover, altromycin B induces a B→A structural transition of CT DNA. The effect on DNA stability and conformation depends on the metal ion. Pt(II) and Pd(II) complexes induce the B→A structural transition and stabilize the double helix similarly but they present lower final hyperchromicity due to premelting effects which were caused by intra- and interstrand crosslinking. Thus, a synergic effect of the metal ions to altromycin B–CT DNA interaction is observed in both cases. Altromycin B interacts with 5′-GMP, 5′-AMP and 5′-CMP by electrophilic attack of the opened epoxide ring to the N(7)G, N(1)/N(7)A and N(3)C. Thus, covalent binding between these nucleotides and altromycin B takes place and explain the multiple binding mode suggested by the studies of the interaction of altromycin B and its complexes with DNA. The [Pd(II)–altroB] complex dissociates in the presence of the nucleotides, and various species of Pd(II)–nucleotide complexes, especially with 5′-GMP, are formed. The [Pt(II)–altroB] complex dissociates too, but only one or two species of Pt(II)–nucleotide complexes are formed, and in the case of 5′-AMP interaction the formation of a tertiary altroB–Pt(II)–5′AMP complex is proposed. 5′-TMP reacts very weakly in comparison with the other three nucleotides. These interactions were followed by 1H-NMR.

Spectral-luminescent study of the porphyrin-diketones and their complexes

Syntheses of octaethylporphine-diketone (OEPDK) and its platinum(II) and palladium(II) complexes (PtOEPDK, PdOEPDK) were optimized, and the dyes were isolated in a pure form in preparative quantities. They were characterized by the NMR, UV–VIS absorption and emission spectroscopy. Electronic spectra of these dyes (absorption and luminescence) were investigated in detail, and compared to corresponding porphyrins and porphyrin-monoketones. OEPDK showed a strong fluorescence at about 700 nm, while PtOEPDK and PdOEPDK showed very weak room-temperature phosphorescence in the region of 850–1100 nm and practically no fluorescence. Protonation mechanisms were studied for these dyes. Protonation at sites other than pyrrole nitrogen atoms was shown to occur, corresponding protomeric spectral forms are presented. The possibilities of the use of porphyrin-diketones as longwave fluorescent and phosphorescent probes are discussed.

The Synthesis of Ethane-1,2-diamine-N,N'-bis(methylenephosphonic) Acid and its Platinum(II) Complex, Bis{(ethane-1,2-diamine-N,N'-bis(methylenephosphonato)}platinum(II)

An improved synthesis of the ligand ethane-1,2-diamine-N,N′-bis(methylenephosphonic) acid (H4edbmp) is described along with its crystal structure. H4edbmp crystallizes in the monoclinic, space group P21/c, with a 7.705(2), b 10.284(2), c 7.999(2) A, β 110.42(2)˚, and its crystal structure was refined to an R value of 0.039 (on 980F). The bis(ligand) platinum(II) complex, [Pt(H3edbmp)2]·2H2O, was prepared and its crystal structure determined. [Pt(H3edbmp)2]·2H2O crystallizes in the triclinic, space group P1–, with a 8.4499(3), b 8.7886(3), c 9.6736(4) A, α 89.885(1), β 65.243(1), γ 61.866(1)˚, and the structure was refined to an R value of 0.018 (on 2569F). Manuscript received: 14 March 2001.

N-{2-(4-methoxyphenyltelluro)ethyl}morpholine ( L1) and its platinum(II) and ruthenium(II) complexes. Synthesis and crystal structure of L1 and trans-[PtCl 2( L1) 2

The first tellurated derivative of morpholine, N-{2-(4-methoxyphenyltelluro)ethyl}morpholine ( L 1 ) has been synthesized by reacting in situ generated ArTe − with 4-(2-chloroethyl)morpholine hydrochloride under N 2 atmosphere. The compound L 1 gives molecular ion peak at m/ z 351 and is characterized structurally. The donor atoms N and Te in compound L 1 are rightly oriented for its ligation in bidentate mode. The TeC(alkyl) is 0.02 Å longer than TeC(aryl). The complexes of ligand L 1 having composition [PtCl 2( L 1 ) 2] ( 1) and [RuCl 2( p-cymene) L 1 ] ( 2) have been synthesized. The compound 1 has been characterized structurally. The Pt has a square planar geometry in complex 1 and two molecules of ligand L 1 bonded through Te alone are trans to each other (PtTe=2.583(2) Å). The 13C{ 1H} NMR spectrum of complex 1 is as expected. The 1H NMR spectrum of single crystals of complex 1 shows multiplication of signals, which is supported by HETCOR experiments. The complex 2 also has ligand L 1 in a monodentate coordination mode, bonded through Te alone. This is supported by deshielded CH 2Te and ArCTe signals in 1H and 13C{ 1H} NMR spectra of complex 2 with respect to those of free ligand L 1 . The HETCOR spectrum of complex 2 has been used to authenticate the assignments of CH 2Te group, as its two protons appear to be magnetically non-equivalent.

The First Metal Complexes of 1,4-Oxatellurane: Synthesis and Crystal Structure of its Platinum(II) complex

The palladium(II) and platinum(II) complexes of 1,4-oxatellurane (L), having the composition [MCl2L2], are synthesized and characterized spectroscopically and structurally (Pt complex only; Pt–Cl 2.3169(9) Å; Pt–Te 2.5945(3) Å) for the first time.

Cellular pharmacology of cis and trans pairs of platinum complexes in cisplatin-sensitive and -resistant human ovarian carcinoma cells

The cellular pharmacology of two pairs of cis and trans platinum complexes has been studied in three human ovarian carcinoma cell lines, a parental relatively cisplatin-sensitive line (CH1), a subline possessing acquired cisplatin resistance (3-fold; CH1cisR) and an intrinsically cisplatin resistant line (13-fold; SKOV-3). Growth inhibition studies showed that both JM335 [ trans ammine (cyclohexylaminedichloro dihydroxo) platinum(IV)] and its platinum(II) dichloro homolog JM334 were relatively less cross-resistant against both acquired and intrinsic cisplatin resistant cells. In contrast, resistance circumvention was not apparent in these cell lines with their cis isomeric counterparts (JM149 for JM335 and JM118 for JM334). The trans compound JM335 was more potent than its cis isomer against all three cell lines. There was no clear correlation between intracellular accumulation following 2 h exposure to each compound and resulting DNA platination or growth inhibition. The selective activity of the trans platinum complexes against the SKOV-3 cell line correlated with a deficiency in the repair of adducts within a fragment of the N- ras gene induced by trans compounds whereas adducts induced by the cis counterparts, and cisplatin, were repaired. The CH1 parental line appeared repair deficient at the gene-specific level to adducts induced by both cis ( including cisplatin) and trans compounds. Resistance in CH1cisR was associated with a lack of gene-specific repair of lesions formed by JM118 and JM149. All four compounds induced apoptosis in all three cell lines, as measured by fluorescent microscopy and field inverted gel electrophoresis, although the kinetics of apoptosis was markedly faster for the trans versus cis compounds. In summary, the trans platinum complexes JM335 and JM334 possess unique cellular properties compared to their cis counterparts particularly with respect to gene specific repair of DNA adducts and the rate of induction of apoptosis.

New bis(phosphines) derived from N,N '-substituted ethylenediamine derivatives. Synthesis and transition metal chemistry of X2PN(R)CH2CH2(R)NPX2 (R = CH2Ph or Ph, X = Ph; R = CH2Ph, X2 = O2C6H4). The crystal and molecular structure of Ph2PN(CH2Ph)CH2CH2(CH2Ph)NPPh2 and cis-[{PtCl2Ph2PN(CH2Ph)CH2CH2(CH2Ph)NPPh2}

The bis(phosphines) of the type X2PN(R)CH2CH2(R)NPX2 (R = Ph or CH2Ph, X = Ph; R = CH2Ph, X2 = O2C6H4) with the ethylenediamine framework were prepared by reaction of X2PCl with the corresponding N,N '-substituted ethylenediamine derivatives. These ligands readily formed complexes with Group 6 metals and RuII, NiII, PdII and PtII. All complexes were characterised by elemental analysis, IR and NMR spectroscopic methods of which 31P-{1H} is most valuable. The structures of the bis(phosphine) ligand Ph2PN(CH2Ph)CH2CH2(CH2Ph)NPPh2 and its platinum(II) complex cis-[PtCl2{PPh2N(CH2Ph)CH2CH2(CH2Ph)NPPh2}] were determined by X-ray crystallography. The ligand crystallises in the extended conformation with both the nitrogen atoms nearly planar and the bond angles around them close to 120°. The P-N distances are shorter than normally accepted P-N single bond lengths (ca. 1.77 A) suggesting some degree of P-N bonding. The seven-membered chelate ring in the platinum complex is non-planar but the metal atom is in a typical square planar environment with two phosphorus atoms and two chlorine atoms in a mutually cis disposition and the ethylenediamine bridge is folded with respect to the plane in an 'open envelope' fashion.

Phosphaalkyne cyclodimerization at a rhodium(I) centre. Syntheses of a cationic η4-1,3-diphosphacyclobutadiene rhodium complex and of its platinum(II) or tungsten(0) adducts

Treatment of [RhCl(triphos)] [triphos = PPh(CH2CH2PPh2)2] in thf with PCBut, in the presence of TlBF4, gave the η4-1,3-diphosphacyclobutadiene complex [Rh(triphos){η4-(PCBut)2}][BF4] 1a which formed the diadducts [Rh(triphos){η4∶η1∶η1-[W(CO)5]2(PCBut)2}][BF4] 2 or [Rh(triphos){η4∶η1∶η1-[PtCl2(PEt3)]2(PCBut)2}][BF4] 3 on reaction with [W(CO)5(thf)] or [Pt2Cl4(PEt3)2], respectively. These adducts dissociated in solution, the former in the presence of Na[BPh4] to give [Rh(triphos){η4-(PCBut)2}][BPh4] 1b, and the latter to the mono-η1-adduct [Rh(triphos){η4∶η1-[PtCl2(PEt3)](PCBut)2}][BF4] 4. Reactions of [RhCl(triphos)] in thf with the 1-alkynes HCCR (R = CO2Me or CO2Et) in the presence of Tl[BF4] afforded the corresponding benzene derivative complexes [Rh(triphos){η4-(HCCR)3}][BF4] 5a or 5b.

Studies on a selena-aza-crown ether: Synthesis and catalytic behavior in hydrosilylation

The synthesis of a new type of selena-aza crown ether-6-(4-nitrobenzyl)-1,4,7,10-selenatriazacyclododecane (L) derivated from phenylalamine, and its platinum (II) complex was described. The catalytic activity of this complex for the hydrosilylation of olefins by triethoxysilane was investigated.

Palladium(II) and platinum(II) complexes containing dimesyloxy-substituted chiral diamines

The physically stable but chemically reactive square-planar complex (+)-[(dichloro){(S,S)-1,4-dimesyloxy-2,3-butanediamine} palladium(II)] and its platinum(II) analogue have been prepared from the reactions between the dihydrochloride salt of the diamine and K 2MCl 4 (where M=Pd, Pt) in water. The palladium complex has been analysed by X-ray crystallography. In contrast to their metal complexes, the free diamine ligand and its dihydrochloride salt are unstable and cannot be isolated.