Cyclobutane Dicarboxylate Research Articles

Biological activity of PtIV prodrugs triggered by riboflavin-mediated bioorthogonal photocatalysis

We have recently demonstrated that riboflavin (Rf) functions as unconventional bioorthogonal photocatalyst for the activation of PtIV prodrugs. In this study, we show how the combination of light and Rf with two PtIV prodrugs is a feasible strategy for light-mediated pancreatic cancer cell death induction. In Capan-1 cells, which have high tolerance against photodynamic therapy, Rf-mediated activation of the cisplatin and carboplatin prodrugs cis,cis,trans-[Pt(NH3)2(Cl)2(O2CCH2CH2CO2H)2] (1) and cis,cis,trans-[Pt(NH3)2(CBDCA)(O2CCH2CH2CO2H)2] (2, where CBDCA = cyclobutane dicarboxylate) resulted in pronounced reduction of the cell viability, including under hypoxia conditions. Such photoactivation mode occurs to a considerable extent intracellularly, as demonstrated for 1 by uptake and cell viability experiments. 195Pt NMR, DNA binding studies using circular dichroism, mass spectrometry and immunofluorescence microscopy were performed using the Rf-1 catalyst-substrate pair and indicated that cell death is associated with the efficient light-induced formation of cisplatin. Accordingly, Western blot analysis revealed signs of DNA damage and activation of cell death pathways through Rf-mediated photochemical activation. Phosphorylation of H2AX as indicator for DNA damage, was detected for Rf-1 in a strictly light-dependent fashion while in case of free cisplatin also in the dark. Photochemical induction of nuclear pH2AX foci by Rf-1 was confirmed in fluorescence microscopy again proving efficient light-induced cisplatin release from the prodrug system.

Synthesis of Cis-Diammine (1,1-cyclobutane dicarboxylate) Platinum(II)

Platinum-based anticancer drugs are chemotherapeutic agents to treat cancer. Carboplatin (cis diammine cyclobutane dicarboxylate platinum (II)) is a second generation drug that has less toxic than cisplatin, allowing for high dosages. In the first stage, 1,3-Cyclobutane dicarboxylic acid, a key intermediate for the preparation of carboplatin, have been synthesized in good yields using different methodology to achieve high purity then carboplatin was synthesized from the reaction of the prepared ligand with cisplatin. Purity of prepared carboplatin was confirmed by High-Performance Liquid Chro­matography (HPLC). Platinum(II) complex carboplatin,have been characterized with 1H and 13C nuclear magnetic resonance spectra and infrared spectroscopy.

Potentiometric and Speciation Studies on the Complex Formation Reactions of [Pd(2-methylaminomethyl)-pyridine)(H2O)2]2+ with Some Bio-active Ligands and Displacement Reaction of Coordinated Inosine

The stoichiometry and stability constants of the complexes formed between [Pd(MAMP)(H2O)2]2+ and various biologically relevant ligands containing different functional groups were investigated. The ligands used are amino acids, peptides and DNA constituents. The results show the formation of 1:1 complexes with amino acids and peptides and the corresponding deprotonated amide species. Structural effects of peptides on amide deprotonation were investigated. The purine and pyrimidine bases uracil, uridine, cytosine, inosine, inosine 5′-monophosphate (5′-IMP) and thymine form 1:1 and 1:2 complexes. The concentration distribution of the various complex species was calculated as a function of pH. The effect of chloride ion concentration on the formation constant of CBDCA with Pd(MAMP)2+ was also reported. The results show ring opening of CBDCA and monodentate complexation of the DNA constituent with the formation of [Pd(MAMP)(CBDCA-O)DNA], where (CBDCA-O) represents cyclobutane dicarboxylate coordinated by one carboxylate oxygen. The equilibrium constant of the displacement reaction of coordinated inosine, as a typical DNA constituent, by SMC and/or methionine was calculated. The results are expected to contribute to the chemistry of antitumor agents. The calculated parameters of the optimized complexes support the measured formation constants.

Determination methods for the anticancer drug dicycloplatin, a supramolecule assembled through hydrogen bonding.

Dicycloplatin is a new generation supramolecular platinum-containing anti-cancer drug. Due to its structure, it is difficult to differentiate dicycloplatin from physical mixtures of carboplatin and cyclobutane dicarboxylate, and confounding results may arise during drug characterization. To solve this problem, this study aims to provide a reliable and reproducible standard for the determination of dicycloplatin. A simple method for dicycloplatin quality control has been developed using X-ray powder diffraction (XRPD) and high performance liquid chromatography (HPLC). XRPD allowed the control of impurities and dissociation of the dicycloplatin active ingredient to less than 1%, and HPLC allowed the monitoring and control of the relative molar ratio of carboplatin and cyclobutane dicarboxylate within the purity range. The study proved for the first time that the dicycloplatin supramolecule is substantially different from a physical mixture of carboplatin and cyclobutane dicarboxylate.

Chemical conversion of cisplatin and carboplatin with histidine in a model protein crystallized under sodium iodide conditions.

Cisplatin and carboplatin are platinum anticancer agents that are used to treat a variety of cancers. Previous X-ray crystallographic studies of carboplatin binding to histidine in hen egg-white lysozyme (HEWL) showed a partial chemical conversion of carboplatin to cisplatin owing to the high sodium chloride concentration used in the crystallization conditions. Also, the co-crystallization of HEWL with carboplatin in sodium bromide conditions resulted in the partial conversion of carboplatin to the transbromoplatin form, with a portion of the cyclobutanedicarboxylate (CBDC) moiety still present. The results of the co-crystallization of HEWL with cisplatin or carboplatin in sodium iodide conditions are now reported in order to determine whether the cisplatin and carboplatin converted to the iodo form, and whether this took place in a similar way to the partial conversion of carboplatin to cisplatin in NaCl conditions or to transbromoplatin in NaBr conditions as seen previously. It is reported here that a partial chemical transformation has taken place to a transplatin form for both ligands. The NaI-grown crystals belonged to the monoclinic space group P21 with two molecules in the asymmetric unit. The chemically transformed cisplatin and carboplatin bind to both His15 residues, i.e. in each asymmetric unit. The binding is only at the N(δ) atom of His15. A third platinum species is also seen in both conditions bound in a crevice between symmetry-related molecules. Here, the platinum is bound to three I atoms identified based on their anomalous difference electron densities and their refined occupancies, with the fourth bound atom being a Cl atom (in the cisplatin case) or a portion of the CBDC moiety (in the carboplatin case).

Room-temperature X-ray diffraction studies of cisplatin and carboplatin binding to His15 of HEWL after prolonged chemical exposure

The anticancer complexes cisplatin and carboplatin are known to bind to both the Nδ and the Nℇ atoms of His15 of hen egg-white lysozyme (HEWL) in the presence of dimethyl sulfoxide (DMSO). However, neither binds in aqueous media after 4 d of crystallization and crystal growth, suggesting that DMSO facilitates cisplatin/carboplatin binding to the N atoms of His15 by an unknown mechanism. Crystals of HEWL cocrystallized with cisplatin in both aqueous and DMSO media, of HEWL cocrystallized with carboplatin in DMSO medium and of HEWL cocrystallized with cisplatin and N-acetylglucosamine (NAG) in DMSO medium were stored for between seven and 15 months. X-ray diffraction studies of these crystals were carried out on a Bruker APEX II home-source diffractometer at room temperature. Room-temperature X-ray diffraction data collection removed the need for cryoprotectants to be used, ruling out any effect that the cryoprotectants might have had on binding to the protein. Both cisplatin and carboplatin still bind to both the Nδ and Nℇ atoms of His15 in DMSO media as expected, but more detail for the cyclobutanedicarboxylate (CBDC) moiety of carboplatin was observed at the Nℇ binding site. However, two molecules of cisplatin were now observed to be bound to His15 in aqueous conditions. The platinum peak positions were identified using anomalous difference electron-density maps as a cross-check with Fo-Fc OMIT electron-density maps. The occupancies of each binding site were calculated using SHELXTL. These results show that over time cisplatin binds to both N atoms of His15 of HEWL in aqueous media, whereas this binding is speeded up in the presence of DMSO. The implication of cisplatin binding to proteins after a prolonged period of time is an important consideration for the length of treatment in patients who are given cisplatin.

Sequential CH Arylation and Olefination: Total Synthesis of the Proposed Structure of Pipercyclobutanamide A

Sequential CH Arylation and Olefination: Total Synthesis of the Proposed Structure of Pipercyclobutanamide A

Synthesis and characterization of some potential antitumor palladium(II) complexes of 2-aminomethylbenzimidazole and amino acids

The stoichiometry and stability constants of complexes formed between [Pd(AMBI)(H2O)2]2+ (AMBI = 2-(aminomethyl)-benzimidazole) with some selected bio-relevant ligands containing different functional groups were investigated at 25°C and 0.1 mol L−1 ionic strength. The ligands used are imidazole, cysteine, glutathione (GSH), threonine, aspartic acid, 1,1-cyclobutane dicarboxylic acid (CBDCA) and lysine. The stoichiometry and stability constants of the formed complexes were reported and the concentration distribution of the various complex species was evaluated as a function of pH. The results show ring opening of CBDCA and monodentate complexation of the DNA constituent with the formation of [Pd(AMBI)(CBDCA–O)DNA], where (CBDCA–O) represents cyclobutane dicarboxylate coordinated by one carboxylate oxygen. The equilibrium constant of the displacement reaction of coordinated inosine, as a typical DNA constituent, by glutathione, as a typical thiol ligand, was investigated. The effect of dioxane on the formation constant of CBDCA with Pd(AMBI)2+ is reported. Five new palladium(II) complexes of the formula [Pd(AMBI)(AA)] n + (where AMBI = 2-aminomethyl benzimidazole, AA is an anion of glycine, alanine, cysteine, methionine, and serine) have been synthesized. These palladium(II) complexes have been ascertained by elemental, molar conductance, infrared and 1H-NMR spectroscopy. The isolated Pd(II) complexes were screened for their antibacterial and cytotoxic activities and the results are discussed.

Unprecedented Water Addition to the α,β‐Unsaturated Enone Bond, Mediated by the Combination of Carbonate and Platinum(II)

The cytostatic compounds cis-[Pt(A9pyp)(dmso)Cl(2)] (1) and [Pt(A9pyp)(dmso)(cbdca)] (2) (A9pyp=(E)-[1-(9-anthryl)-3-(2-pyridyl)-2-propenone) as carrier ligand; cbdca=cyclobutane dicarboxylate) have been found to add water across the enone C==C bond of the ligand A9pyp. The water addition occurs in the presence of carbonate buffer, and has been followed in detail using NMR and ESI-MS spectroscopy. The spectroscopic data clearly indicate that the platinum(II) ion, the carbonate species, and the proximity of the enone C==C bond to the metal ion, are all required for this unusual hydration. A difference in kinetics is observed between chloride and cbdca, showing that the Pt-ligand dissociation plays an important role in the hydration kinetics.

Complex-formation reactions and stability constants for mixed-ligand complexes of diaqua(2-picolylamine)palladium(ii) with some bio-relevant ligands

The complex-formation reactions of [Pd(Pic)(H2O)2]2+ (pic = 2-Picolylamine) with selected bio-relevant ligands, containing different functional groups, were investigated. Stoichiometry and stability constants for the complexes formed are reported. The results show the formation of 1 : 1 complexes with amino acids and dicarboxylic acids. The effect of chelate ring size of the dicarboxylic acid complexes on their stability constants was examined. Peptides form both 1 : 1 complexes and the corresponding deprotonated amide species. Structural effects of the peptide on the amide deprotonation were investigated. DNA pyrimidinic constituents, such as uracil, uridine, thymidine and thymine, form 1 : 1 and 1 : 2 complexes, whereas purinic constituents, such as inosine 5′-monophosphate (5′-IMP) and guanosine 5′-monophosphate (5′-GMP), form only 1 : 1 complexes. Both DNA constituents and cyclobutane dicarboxylate (CBDCA) react with [Pd(Pic)(H2O)2]2+ forming [Pd(Pic)(CBDCA-O)DNA], where (CBDCA-O) represents cyclobutane dicarboxylate coordinated by one carboxylate oxygen atom. The concentration distribution of the complexes in solution was evaluated. The effect of dioxane on the acid dissociation constants of CBDCA and the formation constant of its complex with Pd(Pic)2+ is reported. The effect of increasing chloride concentration on the formation of the CBDCA complex was investigated.

Chemical properties and cytotoxic activity of complexes of platinum(II) and palladium(II) containing dmso and various anions; synthesis and structural characterization of [Pt(dmso)2{O2(CO)2CCH2CH2CH2}

Treatment of cis-[Pt(dmso)2Cl2] with 2 mol of KBr or KI leads to the formation of the analogous dibromide or diiodide complexes. Treatment of [M(dmso)2Cl2] [M = Pt (cis-) or Pd (trans-)] with AgNO3 (2 mol) in H2O followed by 1mol of potassium oxalate, maleate, cyclobutane dicarboxylate (CBDC), malonate or 2mol of potassium cyclohexane carboxylate or pivalate leads to the formation of the corresponding PtII and PdII carboxylate complexes. The single crystal X-ray structure determination of [Pt(dmso)2(CBDC)] has been discussed and compared with data on other related complexes. The in vitro cytotoxic activity of some of these complexes against eight tumour cell lines has been examined using the MTT-colorimetric assay.

Novel carboplatin analogs containing flexible and potentially intercalating ligands: preparation and X-ray crystal structures of di-2-pyridyl ketone cyclobutanedicarboxylate platinum(II) and of 2,3-bis(2-pyridyl)pyrazine cyclobutane dicarboxylate platinum(II)

The crystal structures of the cyclobutanedicarboxylate (ebde) platinum(II) complexes of di-2-pyridyl ketone (dpk) 1, [Pt(dpk)(ebde)] and of 2,3-bis(2-pyridyl)pyrazine (bpp) 2, [Pt(bpp)(cbdc)] · 2CH2Cl2 have been determined by X-ray crystallography. Crystal data are: 1, orthorhombic space group Pbcn, a = 16.164(3), b = 10.749(2), c = 18.601(3) Å, V = 3232(1) Å3 and Z = 8; 2, triclinic space group P̄1, a = 9.437(2), b = 15.424(3), c = 9.342(2) Å, α = 107.45(2), β = 91.92(1), γ = 82.68(1), V = 1287(1) Å3 and Z = 2. In the former structure, the dpk ligand did not undergo the metal promoted hydration reaction to yield a facial tridentate ligand. It binds the platinum in a bidentate fashion retaining the sp2 hybridization around the carbonyl carbon. The conformational strain is relieved by distortion of the planar ligand through rotation of the pyridyl rings around the bonds connecting them to the carbonyl group to yield a non-planar ligand. In the second structure (bpp complex), the ehelating pyrazine and pyridyl rings are coplanar and the non-ligating pyridyl ring is nearly perpendicular to them.

Ｃｉｓ−ｄｉａｍｍｉｎｅ−１， １−ｃｙｃｌｏｂｕｔａｎｅ ｄｉｃａｒｂｏｘｙｌａｔｅ ｐｌａｔｉｎｕｍ （ＩＩ） を用いた温熱化学療法に関する基礎的研究

We studied the optimal timing for the enhancement of the antitumor effects of the CDDP analogue cis-diammine-1, 1-cyclobutane dicarboxylate platinum (II)(CBDCA) combined with hyperthermia against CD-1 mice bearing Ehrlich ascites tumor (EAT) cells in vivo and the effect of hyperthermia on drug influx and efflux in vitro. The tumor doubling time was prolonged when two modalities were combined. The longest tumor doubling time was obtained by the simultaneous use of CBDCA and hyperthermia. The findings indicated that the most effective treatment was the simultaneous use of CBDCA and hyperthermia. An increase in the intratumoral platinum concentration was obtained by simultaneous treatment with CBDCA and hyperthermia.Ehrlich ascites tumor cells were used in cellular accumulation studies with a flameless atomic absorption spectrophotometer. The cells were incubated in the serum-free RD medium. After 1 hour of exposure to 40μg/ml CBDCA (final concentration), the influx at 42.5°C was approximately 2 -fold higher than control (37.0°C incubation). After 1 hour of exposure to CBDCA at 37.0°C or 42.5°C, the rate of efflux in the 5 % calf serum RD medium at 37.0°C or 42.5°C was measured after drug removal. There was a significant difference between the control group (uptake and efflux at 37.0°C) and the heated group (uptake and efflux at 42.5°C), but no significant difference between the control group and the treatment group (uptake at 42.5°C and efflux at 37.0°C). We concluded that hyperthermia increases the intracellular accumulation of CBDCA.

(Malonato)bis[sulfinylbis[methane]-S]platinum(II) compounds: versatile synthons for a new general synthesis of antitumor symmetrical and dissymmetrical (malonato)platinum(II) complexes

New (malonato)platinum(II) compounds, cis-[Pt(OOCACOO)(Me 2 SO) 2 ] (A=CH 2 , cycloalkyl), have been prepared, and their reactions with various amines have led to a new general synthesis of antitumor symmetrical and dissymmetrical (malonato)platinum(II) complexes. Reaction of trans-(―)-1,2-cyclohexanediamine (CHDA) with the cyclobutanedicarboxylate (CBDC) complex cis-[Pt(CBDC)(Me 2 SO) 2 ] has been studied in detail, and crystallographic molecular structure determinations have been carried out on the Pt(CHDA)(Me 2 SO)(CBDC) intermediate and the Pt(CHDA)(CBDC) product

Photoreactive polyamides having m‐ or 1‐type dimer moiety derived from 4‐(3‐oxo‐3‐phenyl‐1‐propenyl)benzoic acid derivatives

AbstractPhotoreactive polyamides having m‐ or 1‐type cyclobutane moiety were prepared via a topochemical photodimerization of 4‐(3‐oxo‐3‐phenyl‐1‐propenyl)benzoic derivatives,4 followed by polycondensation of cyclobutane dicarboxylate derivatives with diamines. From the spectral studies of resulted polyamides compared with the corresponding reference diamides, it was concluded that both types of polyamides were depolymerized photochemically to give the same type of amide derivative having chalcone moiety with a small amount of undefined side reaction. The cyclobutane ring of the m‐dimer from 4‐(3‐oxo‐3‐phenyl‐1‐propenyl)benzoic acid in crystal is severely twisted presumably because of the enhanced steric repulsions between two pairs of adjacent substituents. The higher quantum yield of the m‐dimer for the photocleavege, compared with that of the 1‐dimer, has been interpreted in terms of such steric repulsions by the strained structure of the m‐dimer.